Methods for preventing or slowing progression of cognitive decline or impairment in subjects exhibiting normal cognitive performance

Abstract

The present invention relates to methods of preventing or slowing the progression of cognitive impairment or preventing the development of cognitive decline or reducing the rate of cognitive decline in a subject exhibiting or exhibiting cognitive performance within a normal range of age of the subject. The method comprises administering to the subject one or more levetiracetam, briracetam, or cetriracetam, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising levetiracetam, briracetam, or cetriracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, the invention relates to a GABAA alpha 5 receptor agonist or a pharmaceutically acceptable salt, a hydrate, a solvate, an isomer or a polymorph of the GABAA alpha 5 receptor agonist, and a pharmaceutical composition containing the GABAA alpha 5 receptor agonist or the pharmaceutically acceptable salt, the hydrate, the solvate, the isomer or the polymorph of the GABAA alpha 5 receptor agonist and a pharmaceutically acceptable carrier. Or a combination or composition comprising levetiracetam, briracetam or setriracetam, or a pharmaceutically acceptable salt thereof, and a GABAA alpha5 receptor agonist, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorphic substance thereof. In some embodiments, the subject has one or more risk factors that are predicted or related to the onset or progression of cognitive impairment or decline.

Description

Government Support Statement

[0001] The subject matter of this disclosure was made with government support under Grant No. 1R21AG056882-01 awarded by the National Institutes of Health (NIH), and specifically its National Institute on Aging (NIA), an agency of the U.S. Government. The U.S. Government has certain rights in the subject matter of this disclosure. Related Applications

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 326,773, filed on April 1, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to a method for preventing or slowing the progression of cognitive impairment or preventing the development of cognitive decline or reducing the rate of cognitive decline in a subject who exhibits or presents cognitive performance within the normal range for the subject's age. The method comprises administering to the subject one or more of levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, GABA A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, comprising GABA A A pharmaceutical composition comprising an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharmaceutically acceptable carrier, or a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutically salt thereof and GABA A A combination or pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof.

[0004] In some aspects of the present disclosure, the subject has one or more risks predicted to develop cognitive decline or cognitive impairment or progression of decline or impairment or associated with the development or progression of cognitive decline or cognitive impairment. Such risks are associated with aging, with the presence of one or more genetic risks of genomic variation, mutation or polymorphism in the subject's genome associated with changes in gene expression selected from the group consisting of ATP-binding cassette subfamily A member 7 (ABCA7), clusterin (CLU), complement receptor type 1 (CR1), phosphatidylinositol-binding clathrin assembly protein (PICALM), phospholipase D3 (PLD3), triggering receptor expressed on myeloid cells 2 (TREM2) and sortilin-related receptor 1 (SORL1); with the presence of at least one allele of the APOE4 gene in the subject's genome, with the presence of one of a plurality of biofluid biomarkers selected from the group consisting of p-tau, t-tau and amyloid beta 42 in the subject, or with the presence of altered hippocampal functional connectivity in the subject. Background Art

[0005] Cognitive abilities may decline as a normal consequence of aging or may be associated with changes in hippocampal functional connectivity, with genomic variations, mutations or polymorphisms, or with various biofluid biomarkers associated with the development of cognitive impairment or decline in the context of CNS diseases and disorders such as Alzheimer's disease. Although a subject may present or demonstrate cognitive performance within the normal range for their age, they may still be at risk for developing cognitive impairment or decline.

[0006] In addition to aging, other such risk factors include genetic risk factors, characterized by genomic variation, polymorphism and mutation related to the development of CNS diseases or illnesses related to cognitive impairment or decline. For example, genome-wide association studies (GWAS) have been used to associate variants of the ABCA7 gene with the development of Alzheimer's disease. In fact, it is reported that these variants are enriched in Alzheimer's patients (De Roeck A, Van Broeckhoven C, Sleegers K. The role of ABCA7 in Alzheimer's disease: evidence from genomics, transcriptomics and methylomics. Acta Neuropathol., August 2019; 138 (2): 201-220). Similarly, it is reported that CR1 polymorphism and CLU variants are associated with AD pathogenesis. It is reported that polymorphisms within and around the PICALM gene (rare missense variants in the PLD3 gene) and some variants of SORL1 are also associated with the development of late-onset AD. Similarly, variants in the TREM2 gene are associated with AD and induce partial loss of TREM2 protein function and alter the behavior of microglia, including their response to amyloid plaques.

[0007] Neuropathological, structural and functional changes, including increased hippocampal functional connectivity, the presence of at least one allele of the APOE4 gene in the subject's genome, or the presence of one or more biofluid biomarkers selected from the group consisting of p-tau, t-tau, and amyloid beta 42 in the subject, may also be predictive and / or associated with CNS diseases and disorders, including AD associated with cognitive impairment or cognitive decline. These changes and genetic risks may potentially begin 20 to 30 years before cognitive symptoms and cognitive performance are below the normal age range.

[0008] Currently, there are no FDA-approved preventive therapies for subjects who exhibit or present cognitive performance within the normal range for the subject's age, but who may be at risk of developing or progressing to cognitive impairment or cognitive decline.

[0009] There is therefore a need for effective clinical and therapeutic measures to prevent or slow the progression of cognitive impairment, or to prevent the development of cognitive decline or reduce the rate of cognitive decline, in subjects who exhibit or present cognitive performance within the normal range for the subject's age, but who may be at risk of developing or progressing to cognitive impairment or cognitive decline. Summary of the invention

[0010] The present disclosure relates to a method for preventing or slowing the progression of cognitive impairment or preventing the development of cognitive decline or reducing the rate of cognitive decline in a subject who exhibits or presents cognitive performance within the normal range for the subject's age. The method comprises administering to the subject one or more of levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, GABA A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, comprising GABA A A pharmaceutical composition comprising an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharmaceutically acceptable carrier, or a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutically salt thereof and GABA A A combination or composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph.

[0011] In some aspects of the present disclosure, the subject presents one or more risk factors that predict or are associated with the development of cognitive decline or cognitive impairment or the progression of decline or impairment. In some aspects of the present disclosure, these risk factors can be associated with aging, with the presence of one or more variations, mutations or polymorphisms in the subject's genome associated with changes in gene expression selected from the group consisting of ATP-binding cassette subfamily A member 7 (ABCA7), clusterin (CLU), complement receptor type 1 (CR1), phosphatidylinositol-binding clathrin assembly protein (PICALM), phospholipase D3 (PLD3), triggering receptor expressed on myeloid cells 2 (TREM2) and sortilin-related receptor 1 (SORL1); with the presence of at least one allele of the APOE4 gene in the subject's genome, with the presence of one or more biofluid biomarkers selected from the group consisting of p-tau, t-tau and amyloid beta 42 in the subject, or with the presence of altered hippocampal functional connectivity in the subject.

[0012] In some embodiments, the methods of the present disclosure comprise administering to a subject a daily dose of 0.7-350 mg of levetiracetam, brivaracetam, or seltripracetam, or a pharmaceutically acceptable salt thereof, or comprises administering to a subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam, or seltripracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] In some embodiments, the daily dose of levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof is 7-350 mg. In some embodiments, the daily dose of brivaracetam or a pharmaceutically acceptable salt thereof is 0.7-180 mg. In other embodiments, the daily dose of levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof is 125-250 mg. In some embodiments, the daily dose of levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof is 220 mg. In some embodiments, the daily dose of levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof is 190 mg.

[0014] In some embodiments, levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof is formulated as an oral form, an extended release form or a single unit dosage form or for one or more of once daily administration. In some embodiments, the extended release form is a controlled release form, a delayed release form, a sustained release form, a delayed release form or a slow release form.

[0015] In some embodiments of the present disclosure, the method comprises administering to the subject a daily dose of a pharmaceutical composition comprising 220 mg of levetiracetam or a pharmaceutically acceptable salt thereof, 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg-1.4 mg of colloidal silicon dioxide, 92.8 mg-119.2 mg of silicified microcrystalline cellulose, and 6.0 mg-6.7 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 220 mg and the pharmaceutical composition additionally comprises 280 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 92.8 mg of silicified microcrystalline cellulose, and 6.0 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 220 mg and the pharmaceutical composition further comprises 347.5 mg of hydroxypropyl methylcellulose, 1.4 mg of colloidal silicon dioxide, 119.2 mg of silicified microcrystalline cellulose and 6.7 mg of magnesium stearate. In other embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In other embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

[0016] In some embodiments of the present disclosure, the method comprises administering to the subject a daily dose of a pharmaceutical composition comprising 190 mg of levetiracetam or a pharmaceutically acceptable salt thereof, 300 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 102.8 mg of silicified microcrystalline cellulose or amorphous dibasic calcium phosphate, and 6 mg of magnesium stearate. In other embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In other embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

[0017] In some embodiments of the present disclosure, the method includes administering a pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in an extended release form, wherein the method provides a steady-state plasma concentration of levetiracetam in a subject between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and for at least 8 hours in a 24-hour period after the administration. In some embodiments, the extended-release pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof provides a steady-state plasma concentration of levetiracetam within 2 hours after the administration and for at least 13 hours in a 24-hour period after the administration. In some embodiments, the extended-release pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof provides a steady-state plasma concentration of levetiracetam within 1 hour after the administration and for at least 13 hours in a 24-hour period after the administration. In other embodiments, an extended release pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof provides a steady-state plasma concentration of levetiracetam within 1 hour after administration and extending for at least 13 to 16 hours over a 24 hour period after said administration. (See Figure 2 and WO2016191288, which are incorporated herein by reference in their entirety).

[0018] In some embodiments, the pharmaceutical composition of levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof is formulated as an oral form, an extended release form or a single unit dosage form or for one or more of once daily administration. In other embodiments, the extended release form is a controlled release form, a delayed release form, a sustained release form, a delayed release form or a slow release form.

[0019] In some embodiments, the GABA of the present disclosure A GABA of α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) Compounds of formula II: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; R 1 , R 2 , R 4 and R 5 Each occurrence of is independently selected from: 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 and -P(O)(H)(OR); R 3 Selected from the group consisting of: 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 and -P(O)(H)(OR); -C≡CH, -C≡CR 9 、-(C1-C6)alkyl-C≡CR 10 、-CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Where R 3 independently substituted with 0-5 R'; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; wherein R7 is selected from the group consisting of: -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5 to 10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; wherein each R7 is independently substituted by 0-5 R'; Each R 8independently 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 membered heteroaryl, and -(C1-C6)alkyl-5-10 membered heteroaryl; Where each R except -H and -(C1-C6)alkyl 8 independently substituted by 0-5 -halogen, -(C1-C6)alkyl, -CF3, -OCF3 or O-(C1-C6)alkyl; Where R 9 Selected from the group consisting of: -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl, 5-10 membered heterocyclic, Each R 9 Independently by 0-5 R 11 replace; Where R 10 is selected from the group consisting of -H, halogen, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5-10 membered heteroaryl, Each R 10 replaced by 0-5 R's; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CN, SCH3, -CF3, -OH, -OCF3, OCHF2, -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5- to 10-membered heteroaryl; Each R is independently selected from the group consisting of: 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)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-, (C6-C10)-aryl-N(R")-(C1-C12)aliphatic-, 3- to 10-membered heterocyclic group-, (3- to 10-membered heterocyclic)-(C1-C12)aliphatic-, (3- to 10-membered heterocyclic group)-O-(C1-C12)aliphatic group-, (3- to 10-membered heterocyclic)-N(R")-(C1-C12)aliphatic-, 5- to 10-membered heteroaryl-, (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-; and (5- to 10-membered heteroaryl)-N(R")-(C1-C12)-aliphatic-; wherein the heterocyclyl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O, S, SO and SO2, and the heteroaryl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O and S; wherein each occurrence of R is independently replaced by 0-5 R'; or when two R groups are attached to the same atom, the two R groups may be taken together with the atoms to which they are attached to form a 3- to 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', and wherein the ring is optionally fused to a (C6-C10)aryl, a 5- to 10-membered heteroaryl, a (C3-C10)cycloalkyl, or a 3- to 10-membered heterocyclyl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-, wherein each occurrence of R" is independently substituted with 0-5 substituents 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 )2, where R o Each occurrence of is independently selected from the group consisting of: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl; and ii) Compounds of formula IV: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; Each R 1 , R 4 and R 5 Independently selected from: R 1 , R 4 and R 5 Each occurrence of is independently selected from: 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) 0-3 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 8 , CH2CF3 or CHF2; R 2 Select from -OR 8 、-SR 8 、-(CH2) n OR 8 、-(CH2) n O(CH2) n R 8 、-(CH2) p R 8 or -(CH2) n N(R”)R 10 , wherein n is an integer selected from 0-4; p is an integer selected from 2-4; Where R 2 independently substituted with 0-5 R'; Each R 3 Independently selected from: -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- or 6-membered heterocyclic group, 5- or 6-membered heteroaryl, -(C1-C6) alkyl-C≡CR10 、-CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-10 membered heterocyclic or heteroaryl group is substituted by 0-3 R7; Where R 3 independently substituted with 0-5 R'; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; R7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl; wherein each R7 is independently substituted with 0-5 R'; R 8 independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, 5-10-membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl, and -(C1-C6)alkyl-(C3-C6)cycloalkyl; Where R 8 Each occurrence of is independently replaced by 0-5 R'; Where R 9 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 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, Each of which each of R 9 Independently by 0-5 R 11 replace; R 10is selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, 5- to 10-membered heteroaryl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5- to 10-membered heteroaryl, Where R 10 Each occurrence of is independently replaced by 0-5 R'; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CF3, -OCF3, -OH, OCF2H, -O-(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, -O-CH2-(C3-C6)cycloalkyl, -CN, and -5- to 10-membered heteroaryl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-aliphatic, -(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-; wherein each occurrence of R' is independently replaced by 0-5 R independently selected from the group consisting of t Substitution: 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl-.

[0020] In some embodiments, the GABA of the present disclosure Aα5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or, or GABA of the pharmaceutical composition of the present disclosure A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) Compounds of formula II: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; Each R 1 independently selected from the group consisting of halogen, -H, -(C1-C6)alkyl, -OH, -O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3, -OCHF2, -OMe, -C≡CR 8 , -CHF2, -CH2CF3, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; wherein R 1 independently substituted with 0-5 R'; R 2 Selected from the group consisting of: -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)-aryl-、 (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-, (C6-C10)-aryl-N(R")-(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-N(R")-(C1-C12)aliphatic-, (3- to 10-membered heterocyclic)-(C1-C12)aliphatic-, (3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-, and (3- to 10-membered heterocyclyl)-N(R")-(C1-C12)aliphatic-, Where R 2 independently substituted with 0-5 R'; R 3 Selected from the group consisting of: -(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- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, -(C1-C6) alkyl-C≡CR 10 、-CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Where R 3 independently substituted with 0-5 R'; R 4 and R 5 Each is independently selected from the group consisting of: -H, halogen, -(C1-C6)alkyl, or -(C1-C6)alkyl-(C6-C10)aryl; the (C6-C10)aryl is independently substituted by 0-5 halogens; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; wherein R7 is selected from the group consisting of: -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5 to 10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; wherein each R7 is independently substituted by 0-5 R'; Each R 8independently 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 membered heteroaryl, and -(C1-C6)alkyl-5-10 membered heteroaryl; Where each R except -H and -(C1-C6)alkyl 8 independently substituted by 0-5 -halogen, -(C1-C6)alkyl, -CF3, -OCF3, or O-(C1-C6)alkyl; Where R 9 Selected from the group consisting of: -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl, 5-10 membered heterocyclic, Each of which each of R 9 Independently by 0-5 R 11 replace; Where R 10 is selected from the group consisting of -H, halogen, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5-10 membered heteroaryl, Each R 10 replaced by 0-5 R's; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CN, SCH3, -CF3, -OH, -OCF3, OCHF2, -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5- to 10-membered heteroaryl; Each R is independently selected from the group consisting of: 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)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-, (C6-C10)-aryl-N(R")-(C1-C12)aliphatic-, 3- to 10-membered heterocyclic group-, (3- to 10-membered heterocyclic)-(C1-C12)aliphatic-, (3- to 10-membered heterocyclic group)-O-(C1-C12)aliphatic group-, (3- to 10-membered heterocyclic)-N(R")-(C1-C12)aliphatic-, 5- to 10-membered heteroaryl-, (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-; and (5- to 10-membered heteroaryl)-N(R")-(C1-C12)-aliphatic-; wherein the heterocyclyl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O, S, SO and SO2, and the heteroaryl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O and S; wherein each occurrence of R is independently replaced by 0-5 R'; or when two R groups are attached to the same atom, the two R groups can be taken together with the atoms to which they are attached to form a 3- to 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', and wherein the ring is optionally fused to a (C6-C10)aryl, a 5- to 10-membered heteroaryl, a (C3-C10)cycloalkyl, or a 3- to 10-membered heterocyclyl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-, wherein each occurrence of R" is independently substituted with 0-5 substituents 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 )2, where R o Each occurrence of is independently selected from the group consisting of: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl; and ii) Compounds of formula IV: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; Each R 1 independently selected from the group consisting of: halogen, -H, -(C1-C6)alkyl, -C≡CR 9 , -OH, -O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3, -CHF2, -CH2CF3, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Where R 1 independently substituted with 0-5 R'; R 2 Selected from the group consisting of: -OR 8 、-SR 8 、-(CH2) n OR 8 、-(CH2)n O(CH2) n R 8 、-(CH2) p R 8 and -(CH2) n N(R”)R 10 , wherein n is an integer selected from 0-4; p is an integer selected from 2-4; Where R 2 independently substituted with 0-5 R'; Each R 3 Independently selected from the group consisting of: -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- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-10 membered heterocyclic or heteroaryl group is substituted by 0-3 R7; Where R 3 independently substituted with 0-5 R'; R 4 and R 5 each independently selected from the group consisting of: -H, halogen, and -(C1-C6)alkyl; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; R7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl; wherein each R7 is independently substituted with 0-5 R'; R 8independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, 5-10-membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl, and -(C1-C6)alkyl-(C3-C6)cycloalkyl; Where R 8 Each occurrence of is independently replaced by 0-5 R'; Where R 9 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 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, Each of which each of R 9 Independently by 0-5 R 11 replace; R 10 is selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, 5- to 10-membered heteroaryl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5- to 10-membered heteroaryl, Where R 10 Each occurrence of is independently replaced by 0-5 R'; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CF3, -OCF3, OCF2H, -O-(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, -O-CH2-(C3-C6)cycloalkyl, and -5- to 10-membered heteroaryl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-aliphatic, -(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-; wherein each occurrence of R' is independently replaced by 0-5 R independently selected from the group consisting of t Substitution: 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl-.

[0021] In some embodiments, the GABA of the present disclosure A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer or GABA of the pharmaceutical composition of the present disclosure A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound of formula II as described in paragraph 19, or a compound of formula II as described in paragraph 20, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In other embodiments, the GABA of the present disclosure A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer or GABA of the pharmaceutical composition of the present disclosure A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound of formula IV as described in paragraph 19, or a compound of formula IV as described in paragraph 20, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

[0022] In some embodiments, the GABA of the present disclosure AGABA α5 receptor agonist or pharmaceutical composition A The α5 receptor agonist is selected from the group consisting of compounds 1-12, 44-56, 101-268, 270-644, 646-687, 689-698, 700-703, 705, 707-721 and 723-740, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. See, for example, WO2018130868, WO2018130869, WO2019246300, WO2021127543 and WO2022011318. Each of these publications is incorporated herein by reference in its entirety, particularly with respect to the compounds described, their synthesis and properties.

[0023] In some embodiments, the GABA of the present disclosure A GABA α5 receptor agonist or pharmaceutical composition A The α5 receptor agonist is selected from the group consisting of: and pharmaceutically suitable salts, hydrates, solvates, polymorphs, isomers or combinations thereof.

[0024] In some embodiments, the GABA of the present disclosure A GABA of α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or pharmaceutical composition AThe α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound having the following structure: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

[0025] In other embodiments, the GABA of the present disclosure A GABA of α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a polymorphic crystalline form of a compound having the following structure: Wherein the polymorphic crystalline form is Form A and exhibits an XRPD comprising: a. at least one peak selected from 3.0 and 21.0° 2θ ± 0.2° 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 ° 2θ ± 0.2 ° 2θ. See pages 292-295 of WO2022011318, which is incorporated herein by reference in its entirety, particularly with respect to the compounds described, their syntheses and properties.

[0026] In some embodiments, the GABA of the present disclosure A GABA of α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a polymorphic crystalline form of a compound having the following structure: Wherein the polymorphic crystalline form is Form B and exhibits an XRPD comprising: a. at least one peak selected from 13.0 and 15.3° 2θ ± 0.2° 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° 2θ±0.2° 2θ. See pages 295-297 of WO2022011318, which is incorporated herein by reference in its entirety, particularly with respect to the compounds described, their syntheses and properties.

[0027] In some embodiments, the GABA of the present disclosure AGABA of α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a solvate crystalline form of a compound having the following structure: Wherein the solvate crystalline form is Form C and exhibits an XRPD comprising: a. at least one peak selected from 8.5 and 18.9° 2θ ± 0.2° 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° 2θ ± 0.2° 2θ. See pages 302-305 of WO2022011318, which is incorporated herein by reference in its entirety, particularly with respect to the compounds described, their syntheses and properties.

[0028] In some embodiments, the GABA of the present disclosure A GABA of α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a polymorphic crystalline form of a compound having the following structure: Wherein the polymorphic crystalline form is Form E and exhibits an XRPD comprising: a. at least one peak selected from the group consisting of 11.4, 18.1 and 21.6° 2θ ± 0.2° 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° 2θ±0.2° 2θ. See pages 297-300 of WO2022011318, which is incorporated herein by reference in its entirety, particularly with respect to the described compounds, their syntheses and properties.

[0029] In some embodiments, the GABA of the present disclosure A GABA of α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a hydrate crystalline form of a compound having the following structure: Wherein the hydrate crystalline form is Form F and exhibits an XRPD comprising: a. at least one peak selected from the group consisting of 9.9, 11.9, 17.3, 19.4 and 25.7° 2θ ± 0.2° 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° 2θ ± 0.2° 2θ. See pages 300-302 of WO2022011318, which is incorporated herein by reference in its entirety, particularly with respect to the described compounds, their syntheses and properties.

[0030] In some embodiments, the GABA of the present disclosure A GABA of α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) Compounds of formula Ia: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, in: m is an integer selected from 0-4; Each R 1 Independently selected from: halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl) Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclic group, (C3-C10)-cycloalkenyl wherein each 5-6 membered heteroaryl and 3-10 membered heterocyclic ring is substituted by 0-4 R7; Each R 9Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3-10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace; Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; R 3 independently selected from: -H, -(C1-C6)alkyl, -5 to 10 membered heteroaryl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl and -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R o , oxo, -CH2OR o 、-CH2N(R o )2、-C(O)N(R o )2. -C(O)OR o , -CF3, -OCF3 and -N(R o )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, -(3-10 membered)heterocyclyl, and (C6-C10)-aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C1-C6)alkyloxy, (C1-C6)alkylamino, -(C3-C6)cycloalkyl, -5 to 10-membered heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -5 to 10-membered heteroaryl-(C1-C6)alkyl, and -3-10-membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; or when two R7 groups are attached to the same atom, the two R7 groups may be taken together with the atoms to which they are attached to 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'; each occurrence of R' is wherein each occurrence of each R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2, wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, and -(C6-C10)aryl; R" is independently substituted by 1-3 substituents, wherein the substituents are selected from: halogen, -CF3, -OCF3, -O-(C1-C6)-aliphatic or -(C1-C6)-aliphatic; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 Selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; ii) Compounds of formula Ib: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -Ome, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-6 membered heteroaryl or 3-10 membered heterocycle is substituted by 0-4 R7; Each R 9Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3-10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace; Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; R 3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 、-(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -3 to 10 membered heterocyclyl and -5-10 membered heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C1-C6)alkyloxy, (C1-C6)alkylamino, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5 to 10 membered heteroaryl and -3-10 membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; or when two R7 groups are attached to the same atom, the two R7 groups may be taken together with the atoms to which they are attached to 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'; each occurrence of R' wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R")2; wherein R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-5- to 10-membered heteroaryl, —5- to 10-membered heteroaryl, —3- to 10-membered heterocyclyl, —(C3-C6)cycloalkyl, and —(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from: halogen, -CF3, -OCF3, -O(C1-C6)-aliphatic, -(C1-C6)-aliphatic and -5 to 10 membered heteroaryl; Each R 4 and R 6 Independently selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; iii) Compounds of formula Ic: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl R 9 Each occurrence of is independently represented by 0-5 R 11 replace; R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; Each occurrence of R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5- to 10-membered heteroaryl, and -3-10-membered heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R")2, wherein each occurrence of R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-5 to 10 membered heteroaryl, -5 to 10 membered heteroaryl, -3 to 10 membered heterocyclyl, -(C3-C6)cycloalkyl, and -(C6-C10)aryl, and R" is independently substituted with 1 to 3 substituents selected from: halogen, -CF3, -OCF3, -(C1-C6)-aliphatic, and -5 to 10 membered heteroaryl; Each R 4 and R 6 Independently selected from -H or (C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; iv) Compounds of formula Id: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3-10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; R 3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 、-(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12Independently selected from: -H, -halogen, -OR o , R 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl; wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5 to 10 membered heteroaryl and -3-10 membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2; wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe and -(C6-C10)aryl; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 Selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; v) Compounds of formula le: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl R 9 Each occurrence of is independently represented by 0-5 R 11 Substitution, where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -3-10-membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2, wherein each R' is independently substituted with 0-5 R"; wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe and -(C6-C10)aryl; Each R 4 are independently -H or (C1-C6)alkyl; Each R 6 are independently -H or -(C1-C6)alkyl; Each R 13 and R 14are independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; and vi) Compounds of formula If: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl R 9 Each occurrence of is independently represented by 0-5 R 11 Substitution, where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -3-10-membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2; wherein each R' is independently substituted by 0-5 R", wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe and -(C6-C10)aryl; R 4 is -H or (C1-C6) alkyl; R 6 is -H or -(C1-C6)alkyl; Each R 13 and R 14 Independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0031] In some embodiments, the GABA of the present disclosure A GABA α5 receptor agonist or pharmaceutical composition A The α5 receptor agonist is selected from the group consisting of: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0032] Also provided in various aspects of the present disclosure are pharmaceutical compositions comprising a compound of Formula Ia, Ib, Ic, Id, Ie and If, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0033] In some embodiments, the compound of Formula Ia is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula Ib is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula Ic is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula Id is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula Ie is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula If is GABA A α5 Receptor Positive Allosteric Modulators. In some aspects of the present disclosure, one or more of the compounds of Formula Ia, Ib, Ic, Id, Ie, or If can be used to treat the conditions described herein.

[0034] In some embodiments, the GABA described in this disclosure is A α5 receptor positive allosteric modulators and GABA disclosed in PCT applications WO2015 / 095783A1, WO2016 / 205739A1, WO2018 / 130869A1, WO2019 / 246300A1, WO2021 / 127543 and WO2022 / 011314 A One or more of the α5 receptor positive allosteric modulators, including in particular one or more of Compounds 1-740 (as described above individually). In some embodiments, the GABA described in the present disclosure AThe α5 receptor positive allosteric modulators or the combinations described above can be used in combination with one or more SV2a inhibitors, including in some embodiments one or more of levetiracetam, brivaracetam, and seletracetam, as disclosed in PCT application WO2022 / 011318, for the treatment of such cognitive impairment and other conditions described herein.

[0035] In some embodiments, the method comprises administering to the subject: A) levetiracetam, brivaracetam or seltestam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam, brivaracetam or seltestam or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and B) GABA of the present disclosure A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA containing the content of the present disclosure A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharmaceutically acceptable carrier, or C) a pharmaceutical composition comprising A and B and a pharmaceutically acceptable carrier.

[0036] In some embodiments, A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof, and B's GABA are orally administered. A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or a pharmaceutical composition of C. In some embodiments, A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof, and B's GABA are administered once daily. A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or a pharmaceutical composition of C. In other embodiments, A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof, and B's GABA are administered twice daily. Aα5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or a pharmaceutical composition of C.

[0037] In some embodiments, A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof, and B's GABA are administered simultaneously. A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof. In some embodiments, sequential administration of A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof and B's GABA A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof.

[0038] In some embodiments, the levetiracetam, brivaracetam, or seletracetam of A or C, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of 0.7-350 mg. In some embodiments, the levetiracetam or seletracetam of A or C, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of 125-250 mg. In other embodiments, the levetiracetam or seletracetam of A or C, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of 220 mg. In some embodiments, the levetiracetam or seletracetam of A or C, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of 190 mg. In some embodiments, the brivaracetam of A or C, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of 0.7-180 mg. In some embodiments, the levetiracetam or seletracetam of A or C, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of 7-350 mg. In some embodiments, the pharmaceutical composition of A and the pharmaceutical composition of B are packaged together. In some embodiments, the pharmaceutical composition of A and the pharmaceutical composition of B are packaged separately.

[0039] In some embodiments, one or more of the pharmaceutical compositions of A and B, or the pharmaceutical compositions of C are formulated for oral administration, extended release, or a single unit dosage form or for once-daily administration. In some embodiments, the extended release form is a controlled release form, a delayed release form, a sustained release form, a delayed release form, or a slow release form.

[0040] In some embodiments of the methods of the present disclosure, the pharmaceutical composition of A comprises levetiracetam or a pharmaceutically acceptable salt in an amount of 220 mg and additionally comprises 280-350 mg of hydroxypropyl methylcellulose, 1.2-1.4 mg of colloidal silicon dioxide, 92.8-119.2 mg of silicified microcrystalline cellulose, and 6.0-6.7 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises levetiracetam or a pharmaceutically acceptable salt in an amount of 220 mg and additionally comprises 280 or 347.5 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 92.8 or 119.2 mg of silicified microcrystalline cellulose, and 6.0 or 6.7 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises levetiracetam or a pharmaceutically acceptable salt in an amount of 190 mg and additionally comprises 300 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 102.8 mg of silicified microcrystalline cellulose or amorphous calcium hydrogen phosphate, and 6 mg of magnesium stearate. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In some embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

[0041] In some embodiments of the methods of the present disclosure, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof of A or C is in an extended release form, and provides a steady-state plasma concentration of levetiracetam in a subject between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and extending for at least 8 hours in a 24-hour period after said administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof of A or C is in an extended release form, and provides a steady-state plasma concentration of levetiracetam in a subject between 1.9 μg / mL and 4.4 μg / mL within 2 hours after administration and extending for at least 13 hours in a 24-hour period after said administration. In some embodiments, the pharmaceutical composition of A or C comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in an extended release form, and provides a steady-state plasma concentration of levetiracetam in a subject between 1.9 μg / mL and 4.4 μg / mL within 1 hour after administration and for at least 13 hours in a 24-hour period after said administration. In other embodiments, the pharmaceutical composition of A or C comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in an extended release form, and provides a steady-state plasma concentration of levetiracetam in a subject between 1.9 μg / mL and 4.4 μg / mL within 1 hour after administration and for at least 13 to 16 hours in a 24-hour period after said administration. (See, e.g., Figure 2 and WO2016191288, which are incorporated herein by reference in their entirety).

[0042] In some embodiments of the methods of the present disclosure, one or more of the pharmaceutical compositions of A or C comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof are formulated in an oral form, an extended release form, or a single unit dosage form or for once daily administration. In other embodiments, the extended release form is a controlled release form, a delayed release form, a sustained release form, a delayed release form, or a slow release form.

[0043] In some embodiments of the methods of the present disclosure, the subject to be treated is at risk for developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of altered hippocampal functional connectivity in the subject.

[0044] In some embodiments of the methods of the present disclosure, the subject to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with aging.

[0045] In some embodiments of the methods of the present disclosure, the subject to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is a genetic risk associated with the presence of one or more genomic variations, mutations or polymorphisms in the subject's genome associated with changes in gene expression from the group consisting of ABCA7, CLU, CR1, PICALM, PLD3, TREM2 and SORL1. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of at least one allele of the APOE4 gene in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more biofluid biomarkers selected from the group consisting of p-tau, t-tau and amyloid beta 42 in the subject. In some embodiments, the subject is human.

[0046] In some embodiments of the methods of the present disclosure, the GABA of the pharmaceutical composition in B or C A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is a compound of formula II as described in paragraph 19, or a compound of formula II as described in paragraph 20, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments, the GABA in the pharmaceutical composition of B or C A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is a compound of formula IV as described in paragraph 19, or a compound of formula IV as described in paragraph 20, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the methods of the present disclosure, the GABA in the pharmaceutical composition of B or C is A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is selected from the group consisting of compounds 1-12, 44-56, 101-268, 270-644, 646-687, 689-698, 700-703, 705, 707-721 and 723-740, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

[0047] In some embodiments of the methods of the present disclosure, the GABA of the pharmaceutical composition in B or C AThe α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is a compound of Formula Ia to If as described in paragraph 30, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the methods of the present disclosure, the GABA in the pharmaceutical composition of B or C A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is a compound of formula Ia as described in paragraph 30, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments, the GABA in the pharmaceutical composition of B or C A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is a compound of formula Ib as described in paragraph 30, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the methods of the present disclosure, the GABA in the pharmaceutical composition of B or C A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is a compound of formula Ic as described in paragraph 30, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments, the GABA in the pharmaceutical composition of B or C A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is a compound of formula Id as described in paragraph 30, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the methods of the present disclosure, the GABA in the pharmaceutical composition of B or C A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is a compound of formula Ie as described in paragraph 30, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments, the GABA in the pharmaceutical composition of B or C A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is a compound of formula If as described in paragraph 30, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the methods of the present disclosure, the GABA in the pharmaceutical composition of B or C AThe α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is selected from the group consisting of compounds 742-755, 758-763, 765-779, 781-795, 797-810, 813-828, 830, 831, 833-846, 848-891, 893-903, 905, 907-977, 979-1012 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

[0048] In some embodiments of the methods of the present disclosure, the compound of formula IV as described in paragraph 19 or the compound of formula IV as described in paragraph 20 in composition B or C, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, is a crystalline form of compound 606, wherein the polymorphic crystalline form is type A, type B, type C, type E or type F. In some embodiments, the pharmaceutical composition of B or C comprises one or more crystalline forms of compound 606, wherein the one or more crystalline forms are selected from the group consisting of type A, type B, type C, type E or type F, see WO2022011318, which is incorporated herein by reference in its entirety and in particular with respect to the compounds described, their synthesis and properties.

[0049] In some embodiments of the pharmaceutical composition of B or C, GABA A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is present in an amount between 5 mg and 1000 mg. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated as a tablet, capsule, pill, lozenge, powder, granule, solution or suspension.

[0050] In some embodiments, the GABA in Composition B or C A One or more of the α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph is in an extended release form, a non-extended release form or an immediate release form. In some embodiments, the GABA in composition B or C A The α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph is in an extended release form. In some embodiments, the extended release form is a controlled release form, a delayed release form, a sustained release form, a delayed release form or a slow release form. In some embodiments, the GABA in composition B or C A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is in a non-extended release form.

[0051] One aspect of the disclosure relates to one or more of the pharmaceutical compositions or combinations of the disclosure for the preparation of a drug for preventing or slowing the progression of cognitive impairment or preventing the development of cognitive decline or reducing the rate of cognitive decline in a subject showing or presenting cognitive performance within the normal range of the subject's age. In some embodiments, as described above, the subject has the risk of developing cognitive impairment or decline or the progress of damage or decline. In other embodiments, the disclosure relates to one or more of the compounds, pharmaceutical compositions or combinations of the disclosure for preventing or slowing the progression of cognitive impairment or preventing the development of cognitive decline or reducing the rate of cognitive decline in a subject showing or presenting cognitive performance within the normal range of the subject's age. In some embodiments, as described above, the subject has the risk of developing cognitive impairment or decline or the progress of damage or decline.

[0052] In some embodiments of the methods and uses of the present disclosure, the compound, pharmaceutical composition, combination, or drug is administered subcutaneously, intravenously, orally, sublingually, buccally, transdermally, intraarterially, intradermally, intramuscularly, intraperitoneally, ocularly, intranasally, intraspinally, or intracerebrally. In some embodiments, the compound, pharmaceutical composition, combination, or drug is administered orally. In some embodiments, the subject is a human. In some embodiments, the compound, pharmaceutical composition, combination, or drug is administered once daily. In some embodiments, the compound, pharmaceutical composition, combination, or drug is administered twice daily. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 Depicted are plasma concentrations of levetiracetam that are effective in treating cognitive impairment based on aged-impaired rat studies and Phase II studies in aMCI patients. In one aspect of the disclosure, the effective plasma concentration is between 1.9 and 4.4 μg / mL. In another aspect, the effective plasma concentration is between 2.9 and 4.4 μg / mL. In another aspect, the effective plasma concentration is between 1.9 and 3.9 μg / mL.

[0054] Figure 2 The steady-state model for the PK profile of 190 mg Tablet A of Table 1 is shown, indicating that the tablet provides plasma concentrations of levetiracetam between 1.9 and 4.4 μg / mL.

[0055] Figure 3 The steady-state model for the PK profile of the 220 mg Tablet D of Table 2 is shown, indicating that the tablet provides plasma concentrations of levetiracetam between 2.9 and 4.4 μg / mL.

[0056] Figure 4 Flow chart of one embodiment of a process for preparing an extended release composition of levetiracetam (eg, the 190 mg and 220 mg tablets listed in Tables 1 and 2).

[0057] Figure 5 A flow chart showing a Phase II, randomized, double-blind, placebo-controlled, crossover clinical trial testing the effects of levetiracetam in cognitively normal (CN) subjects with abnormal hippocampal functional connectivity.

[0058] Figure 6 Shown are the changes in hippocampal functional connectivity between placebo-treated and levetiracetam-treated subjects. *Symbols indicate significant differences between groups. DETAILED DESCRIPTION

[0059] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the techniques of cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein and the nomenclature used in connection therewith are those well known and commonly used in the art. See, e.g., “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 Edition,” WH Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th Edition,” WH Freeman & Co., NY (1999); Gilbert et al., “Developmental Biology, 6th Edition,” Sinauer Associates, Inc., Sunderland, MA (2000).

[0060] Chemical terms used herein are used according to conventional usage in the art as exemplified by "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., ed., McGraw-Hill, San Francisco, CA (1985).

[0061] All publications, patents, and published patent applications mentioned in this application are expressly incorporated herein by reference. In case of conflict, the present specification, including specific definitions, will control.

[0062] Throughout the present specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated 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).

[0063] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0064] “Including” is used to mean “including, but not limited to.” “Including” and “including, but not limited to” are used interchangeably.

[0065] "Patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. Patients, subjects, or individuals may include mammals, such as humans, primates, livestock animals (including cattle, pigs, etc.), companion animals (e.g., canines, felines, etc.), and rodents (e.g., mice and rats). In some embodiments, the patient, subject, or individual is a human.

[0066] "Preventing" the development or progression of cognitive decline or impairment means affecting normal or unimpaired cognitive performance so that it does not decline or does not fall below the cognitive performance observed in the subject at first presentation or diagnosis or delaying such decline.

[0067] "Slowing" the development or progression of cognitive decline refers to delaying the progression of cognitive decline in a subject. This can be determined by a physician or by comparison with a normal population.

[0068] "Cognitive impairment" or "cognitive decline" refers to cognitive performance in a subject that is not as robust as the normal range expected in subjects of similar age. In some cases, cognitive performance is reduced by about 5%, about 10%, about 30% or more compared to the normal range of cognitive performance expected in subjects of similar age. In some cases, "cognitive impairment" in a subject affected by age-related cognitive impairment can mean that the subject's cognitive performance is not as robust as expected in age-matched subjects, or is not as robust as the performance of a young adult subject (e.g., a subject with an average score for a given age on a cognitive performance test).

[0069] As used herein, "genetic risk" or "genetic susceptibility" refers to a "genomic polymorphism", "genomic variant" or "genomic mutation" associated with the development of a disease or condition associated with cognitive impairment or cognitive decline. GWAS or preclinical models can be used to identify genetic risk. Genetic risk may also be associated with expression changes, including increases, decreases or abnormalities in protein expression. Genetic risk factors can be used as predictors, but do not absolutely indicate the progression or development of the disease or disorder.

[0070] "Cognitive performance" refers to measurable cognitive behavior or cognitive ability in a subject. There are various art-recognized tests for assessing human cognitive performance, such as, but not limited to, the Clinical Global Impression of Change Scale (CIBIC-+ scale); Mini-Mental State Examination (MMSE); Neuropsychiatric Questionnaire (NPI); Clinical Dementia Rating Scale (CDR); Cambridge Neuropsychological Test Automated Battery (CANTAB); Sando Clinical Assessment of Geriatrics (SCAG), Buschke Selected Association Test (Buschke and Fuld, 1974); Verbal Paired Related Subtest; Logical Memory Subtest; Visual Repetition Subtest of the Revised Wechsler Memory Scale (WMS-R) (Wechsler, 1997); Benton Visual Retention Test, or MATRICS Consistency Neuropsychological Test Battery, which includes tests of working memory, speed of processing, attention, verbal learning, visual learning, reasoning and problem solving, and social cognition. See Folstein et al., J Psychiatric Res 12:189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994. See also Buchanan, RW, Keefe, RSE, Umbricht, D., Green, MF, Laughren, T. and Marder, SR (2011), The FDA-NIMH-MATRICS guidelines for clinicaltrial design of cognitive-enhancing drugs: what do we know 5years later? Schizophr. Bull. 37, 1209-1217. Another example of cognitive experiment in humans is a clear 3-option forced choice task. In this experiment, color photos of common objects are presented to the subject, and the photos are composed of a mixture of 3 types of image pairs: similar pairs, identical pairs, and irrelevant foils. The second one in the similar object pair is called "bait". These image pairs are completely random and presented separately as a series of images. The subject is instructed to make a judgment about whether the object seen is new, old or similar. The "similar" reaction to the presentation of the bait stimulus indicates that the subject's memory retrieval is successful. In contrast, calling the bait stimulus "old" or "new" indicates that correct memory retrieval does not occur.

[0071] In addition to assessing cognitive performance, cognitive impairment and dementia progression can be monitored by assessing substitution changes in the subject's brain. Substitution changes include, but are not limited to local brain volume changes, anterior perforated pathway degeneration and changes in brain function seen by resting fMRI (R-fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), fluorodeoxyglucose positron emission tomography (FDG-PET) or any other imaging techniques that allow measurement of brain function. Examples of local brain volumes that can be used to monitor age-related cognitive impairment and dementia progression include a reduction in hippocampal volume and a reduction in the volume or thickness of the entorhinal cortex. These volumes can be measured in a subject by, for example, MRI. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010). It has been confirmed that anterior perforated pathway degeneration is associated with age and reduced cognitive performance. For example, elderly adults with more anterior perforated pathway degeneration tend to perform worse in hippocampal-dependent memory tests. The degeneration of the anterior perforated pathway can be monitored in subjects by ultra-high resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107: 12687-12691 (2010). Resting state fMRI (R-fMRI) involves imaging the brain during rest, and records the large amplitude spontaneous low frequency (<0.1Hz) fluctuations in the fMRI signal, which are temporally related to functionally related areas. The functional connectivity between brain regions (particularly those regions whose connectivity increases or decreases with age and the degree of cognitive impairment and / or dementia) is revealed using seed-based functional connectivity, independent component analysis and / or frequency domain analysis of the signal. FDG-PET uses the uptake of FDG as a measure of regional metabolic activity in the brain. It has been confirmed that the decline in FDG uptake in regions such as the posterior cingulate cortex, temporoparietal cortex and prefrontal association cortex is related to the degree of cognitive decline and dementia. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002).

[0072] "Pharmaceutically acceptable salts" include, but are not limited to, for example, water-soluble and water-insoluble salts such as acetate, ansorlate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, etopoate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolyl p-aminophenylarsonic acid salt, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, Iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthenate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-di-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, branyl salt, tannate, tartrate, 8-chlorotheophylline salt, toluenesulfonate, triethyl iodide and valerate.

[0073] "Pharmaceutically acceptable salts" include both acid and base addition salts. "Pharmaceutically acceptable acid addition salts" may refer to salts that retain the biological effectiveness and properties of the free bases that are biologically or otherwise undesirable, and that are formed with inorganic acids such as, but not limited to, hydrohalic acids, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as, but 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, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethyl Sulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, glycolic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic 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.

[0074] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts can be prepared by adding inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, alkali metal and alkaline earth metal salts, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of 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; dimethylethanolamine; 2-dimethylaminoethanol; 2-diethylaminoethanol; dicyclohexylamine; amino acids; lysine; arginine; histidine; caffeine; procaine; halamine; choline; betaine; phenethylbenzylamine; dibenzylethylenediamine; ethylenediamine; glucosamine; methylglucamine; theobromine; triethanolamine; tromethamine; purines; piperazine; piperidine; N-ethylpiperidine; polyamine resins; and the like.

[0075] Conversely, said salt forms can be converted into the free forms by treatment with an appropriate base or acid.

[0076] "Hydrate" refers to a combination of water and a compound wherein the water maintains its molecular state as water and is absorbed, adsorbed, or contained within the crystal lattice of the compound.

[0077] "Polymorph" refers to different crystalline forms and other solid molecular forms of the same compound, including pseudopolymorphs, such as hydrates (e.g., bound water present in the crystal structure) and solvates (e.g., bound solvents other than water) of the same compound. Due to the different packing of molecules in the crystal lattice, different crystalline polymorphs have different crystal structures. This leads to different crystal symmetries and / or unit cell parameters, which directly affect their physical properties, such as the X-ray diffraction characteristics of crystals or powders. For example, different polymorphs will usually diffract at different angle groups and will give different intensity values. Therefore, X-ray powder diffraction can be used to identify different polymorphs in a reproducible and reliable manner, or a solid form containing more than one polymorph. Some polymorphic forms may exhibit enhanced thermodynamic stability, or may be easier to prepare in large quantities with high purity, and are therefore more suitable for inclusion in pharmaceutical formulations. Due to different lattice energies, some polymorphs may show other favorable physical properties, such as lack of hygroscopic tendency, increased solubility and enhanced dissolution rate.

[0078] The present application considers all isomers of the compounds of the present disclosure. "Isomer" as used herein includes optical isomers (such as stereoisomers, for example, enantiomers and diastereomers), Z (zusammen) or E (entgegen) isomers and tautomers. Many compounds that can be used for the methods, uses, combinations, pharmaceutical compositions, drugs, combinations for the purposes or pharmaceutical compositions for the purposes of the present disclosure have at least one stereocenter in their structure. The stereocenter can exist in R or S configuration, and the R and S symbols are used according to the rules described in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure also relates to all stereoisomeric forms of the compounds such as enantiomeric forms and diastereomeric forms or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO 01 / 062726. In addition, some compounds containing alkenyl groups can exist as Z (zusammen) or E (entgegen) isomers. In each case, the present disclosure includes mixtures and individual single isomers. Multiple substituents on the piperidinyl or azepanyl rings can also be in cis or trans relationships relative to the plane of the piperidinyl or azepanyl rings. Some compounds can also exist in tautomeric forms. Although such forms are not explicitly stated, they are intended to be included in the scope of the present disclosure. With regard to the method, use, combination, pharmaceutical composition, combination for the use or pharmaceutical composition for the use of the present disclosure, reference to one or more compounds is intended to include each possible isomeric form and mixtures thereof of the compound, unless specific isomeric forms are specifically mentioned. See, for example, WO 01 / 062726.

[0079] As used herein, "aliphatic" refers to a straight or branched chain alkyl, alkenyl or alkynyl. It should be understood that alkenyl or alkynyl embodiments require at least 2 carbon atoms in the aliphatic chain. Aliphatic groups typically contain 1 (or 2) to 12 carbons, such as 1 (or 2) to 4 carbons.

[0080] As used herein, "aryl" refers to a monocyclic or bicyclic carbocyclic aromatic ring system. As used herein, aryl includes (C6-C12)-aryl-. For example, the aryl used herein can be a C6-C10 monocyclic or C8-C12 bicyclic carbocyclic aromatic ring system. In some embodiments, the aryl used herein can be (C6-C10)-aryl-. Phenyl (or Ph) is an example of a monocyclic aromatic ring system. Bicyclic aromatic ring systems include systems in which two rings are aromatic, for example, naphthyl; and systems in which only one of the two rings is aromatic, for example, tetralin.

[0081] As used herein, "heterocycle" refers to a chemically stable monocyclic or bicyclic non-aromatic ring system having 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH, S, SO or SO2. The heterocycle used herein includes a 3 to 12-membered heterocyclyl- having 1-4 heteroatoms independently selected from O, N, NH, S, SO or SO2. For example, the heterocycle used herein can be a chemically stable 3 to 10-membered monocyclic or 8 to 12-membered bicyclic non-aromatic ring system having 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH, S, SO or SO2. In some embodiments, the heterocycle used herein can be a 3 to 10-membered heterocyclyl- having 1-4 heteroatoms independently selected from O, N, NH, S, SO or SO2. In the bicyclic non-aromatic ring system embodiment of the "heterocyclic group", one or both rings can contain the heteroatoms or heteroatom groups. In another bicyclic "heterocyclic group" embodiment, one of the two rings can be aromatic. In yet another heterocyclic ring system embodiment, a non-aromatic heterocyclic ring may be optionally fused to an aromatic carbocyclic ring.

[0082] Examples of heterocyclic rings include 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane and 1,3-dihydro-imidazol-2-one.

[0083] As used herein, "heteroaryl" refers to a chemically stable monocyclic or bicyclic aromatic ring system having 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH or S. As used herein, heteroaryl includes 5 to 12-membered heteroaryl groups having 1-4 heteroatoms independently selected from O, N, NH or S. In some embodiments, the heteroaryl used herein may be a 5 to 10-membered heteroaryl group having 1-4 heteroatoms independently selected from O, N, NH or S. For example, the heteroaryl used herein may be a chemically stable monocyclic or 8 to 12-membered bicyclic aromatic ring system having 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH or S in one or both rings. In such a bicyclic aromatic ring system embodiment of "heteroaryl": - Both rings are aromatic; and - One or both rings may contain said heteroatom or heteroatom group.

[0084] Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), ), 2-thienyl, 3-thienyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl).

[0085] "Cycloalkyl or cycloalkenyl" refers to a non-aromatic monocyclic or fused or bridged bicyclic carbocyclic ring system. For example, the cycloalkyl or cycloalkenyl used herein can be a non-aromatic C3-C10 monocyclic or fused or bridged C8-C12 bicyclic carbocyclic ring system. The cycloalkenyl ring has one or more unsaturated units. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl and decahydronaphthyl.

[0086] "Heteroaralkyl" refers to an alkyl group in which an alkyl H atom is replaced with a heteroaryl group. For example, the alkyl group can be any straight chain hydrocarbon and can include 1 to 12 carbon atoms (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl), wherein the alkyl group can be substituted with any heteroaryl group, including, but not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2- Thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl , 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl) and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).

[0087] When a substituted moiety is described without specifying the atom to which such moiety is bonded, the substituent may be bonded via any suitable atom in such moiety. For example, for a substituted 5- to 10-membered heteroaryl, a substituent on the heteroaryl may be bonded to any ring-forming atom of the heteroaryl ring that is substitutable (i.e., an atom that is bonded to one or more hydrogen atoms).

[0088] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring-forming atom in the ring that is substitutable (i.e., an atom that is bound to one or more hydrogen atoms), unless otherwise indicated or implied from the context. For example, when the R group is defined as pyridine and the pyridine is depicted as follows: The pyridine ring can be bonded to the benzodiazepine derivative through any one of the ring carbon atoms in the pyridine ring. As another example, when the R group is defined as pyrazole and the pyrazole is depicted as follows: The pyrazole ring can be bonded to the benzodiazepine derivative through any one of the ring carbon atoms in the pyrazole ring, or bonded to sp 3 N-atom.

[0089] The carbon atom names used herein may have the indicated integer and any intervening integers. For example, the number of carbon atoms in a (C1-C4)-alkyl group is 1, 2, 3 or 4. It should be understood that these names refer to the total number of atoms in the appropriate group. For example, in a (C3-C10)-heterocyclyl, the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9 or 10. Compounds, compositions, combinations and medicaments useful in the methods of the present disclosure

[0090] The compounds, compositions, combinations and medicaments useful in the methods and uses of the present disclosure are characterized by one or more of levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, and GABA A An α5 receptor agonist, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. Levetiracetam, brivaracetam, and seletracetam

[0091] Levetiracetam refers to the compound (2S)-2-(2-oxopyrrolidin-1-yl)butanamide (International Union of Pure and Applied Chemistry (IUPAC) name). Levetiracetam is a widely used anti-epileptic drug. Levetiracetam binds to a specific site in the CNS: synaptic vesicle protein 2A (SV2A) (see, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006), and has been further shown to directly inhibit synaptic activity and neurotransmission by inhibiting presynaptic neurotransmitter release (Yang et al., 2007). Levetiracetam is an FDA-approved anti-epileptic drug (Kepran) for sale. Typically, levetiracetam The therapeutically effective dose is in the range of 1000-3000 mg / day.

[0092] Levetiracetam is rapidly and almost completely absorbed after oral administration, and its bioavailability is not affected by food. The plasma half-life of levetiracetam is about 7 ± 1 hours (due to decreased renal function, it is expected to be 9-10 hours in the elderly). It is absorbed rapidly, and the peak plasma concentration occurs about 1 hour after oral administration. Steady state can be reached after 2 days of multiple twice-daily administration.

[0093] The typical starting dose of levetiracetam for the treatment of epilepsy in humans is 500 mg twice daily, and the dose is then increased until optimal efficacy is achieved, up to a maximum of 3000 mg per day.

[0094] Brivaracetam refers to the compound (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide (IUPAC name). It has anticonvulsant activity and binds to SV2A in the brain. It is known by the name The typical starting dose is 50 mg orally twice a day, and the maintenance dose is 25-100 mg orally twice a day.

[0095] Seletracetam refers to the compound (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]butanamide (IUPAC name). It is an antiepileptic drug and binds to SV2A in the brain.

[0096] In the methods and uses of the present disclosure, levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt thereof, can be administered at a dose disclosed, for example, in U.S. Patent Application 12 / 580,464 (Publication No. US-2010-0099735), U.S. Patent Application 13 / 287,531 (Publication No. US-2012-0046336), U.S. Patent Application 13 / 370,253 (Publication No. US-2012-0214859), WO2010044878, WO2012109491, WO2014144663, and WO2022011318. Each of these disclosed documents is incorporated herein by reference in its entirety.

[0097] In some embodiments, the administration interval of levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing, is once every 12 hours (twice a day) or once every 24 hours. A lower frequency interval administration may also be used, for example, once every 6 hours.

[0098] In some embodiments, levetiracetam or its pharmaceutically acceptable salt is administered at a daily dose of 70mg to 140mg, or 7mg to 180mg, or 25mg to 180mg, or 40mg to 130mg, or 140 to 300mg, or 200 to 300mg, or 140 to 200mg, or 7mg to 350mg, 70mg to 350mg, 100mg to 300mg, or 125mg to 250mg. In some embodiments, levetiracetam or its pharmaceutically acceptable salt is administered at a daily dose of 190mg to 220mg. In some embodiments, levetiracetam or its pharmaceutically acceptable salt is administered at a daily dose of 190mg to 240mg. In some embodiments, levetiracetam or its pharmaceutically acceptable salt is administered at a daily dose of 220mg. In some embodiments, levetiracetam or its pharmaceutically acceptable salt is administered at a daily dose of 190mg.

[0099] In some embodiments of the methods of the present disclosure, levetiracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, is in oral form, extended release form (e.g., controlled release form, delayed release form, sustained release form, delayed release form, or slow release form), or a single unit dosage form or for once daily administration. In some embodiments, levetiracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam or a pharmaceutically acceptable salt thereof, is administered once or twice daily.

[0100] In certain embodiments of the present disclosure, brivaracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of 7 to 15 mg, or 0.7 to 180 mg, or 2.5 to 180 mg, or 4.0 to 130 mg, or 14 to 30 mg. In other embodiments. 0.7-50mg, 0.7-75mg, 0.7-100mg, 0.7-150mg, 0.7-180mg, 1.8-50mg, 1.8-75mg, 1.8-100mg, 1.8-150mg, 1.8-180mg, 3.5-50 mg, 3.5-75mg, 3.5-100mg, 3.5-150mg, 3.5-180mg, 5-50mg, 5-75mg, 5-100mg, 5-150mg, 5-180mg, 7-50mg, 7-75mg, 7-100mg, 7 -150 mg, 7-180 mg, 15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150 mg, 35-180 mg of brivaracetam or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising brivaracetam or a pharmaceutically acceptable salt thereof, is in oral form, extended release form (e.g., controlled release form, delayed release form, sustained release form, delayed release form, or slow release form), or a single unit dosage form or for once daily administration. In some embodiments, brivaracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising brivaracetam or a pharmaceutically acceptable salt thereof, is administered once or twice daily.

[0102] In some embodiments, Seletracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of 70 mg to 140 mg, or 7 mg to 180 mg, or 25 mg to 180 mg, or 40 mg to 130 mg, or 140 to 300 mg, or 200 to 300 mg, or 140 to 200 mg, or 7 mg to 350 mg, 70 mg to 350 mg, 100 mg to 300 mg, or 125 mg to 250 mg. In some embodiments, Seletracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of 190 mg to 220 mg. In some embodiments, Seletracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of 190 mg to 240 mg. In some embodiments, Seletracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of 220 mg. In some embodiments, Seletracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of 190 mg.

[0103] In some embodiments of the methods of the present disclosure, Seletracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Seletracetam or a pharmaceutically acceptable salt thereof, is in an oral form, an extended release form (e.g., a controlled release form, a delayed release form, a sustained release form, a delayed release form, or a slow release form), or a single unit dosage form or for once-daily administration. In some embodiments, Seletracetam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Seletracetam or a pharmaceutically acceptable salt thereof, is administered once or twice daily.

[0104] In certain embodiments of the methods and uses of the present disclosure, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 220 mg and the pharmaceutical composition further comprises 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg-1.4 mg of colloidal silicon dioxide, 92.8 mg-119.2 mg of silicified microcrystalline cellulose, and 6.0 mg-6.7 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 220 mg and the pharmaceutical composition further comprises 280 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 92.8 mg of silicified microcrystalline cellulose, and 6.0 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 220 mg and the pharmaceutical composition further comprises 347.5 mg of hydroxypropyl methylcellulose, 1.4 mg of colloidal silicon dioxide, 119.2 mg of silicified microcrystalline cellulose and 6.7 mg of magnesium stearate. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In some embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

[0105] In some embodiments of the methods and uses of the present disclosure, the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 190 mg and the pharmaceutical composition further comprises 300 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 102.8 mg of silicified microcrystalline cellulose or amorphous calcium hydrogen phosphate and 6 mg of magnesium stearate. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208. In some embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90. In some embodiments, the extended release pharmaceutical composition of levetiracetam or a pharmaceutically acceptable salt thereof is in solid form. In some embodiments, the extended release pharmaceutical composition is in the form of tablets or capsules.

[0106] In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in an extended release form and provides a steady-state plasma concentration of levetiracetam in a subject between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and in a 24-hour time period after the administration for at least 8 hours. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in an extended release form and provides a steady-state plasma concentration of levetiracetam in a subject within 3 hours after administration and in a 24-hour time period after the administration for at least 8 hours. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in an extended release form and provides a steady-state plasma concentration of levetiracetam in a subject within 1 hour after administration and in a 24-hour time period after the administration for at least 13 hours. In other embodiments, the pharmaceutical composition provides the steady-state plasma concentration of levetiracetam in a subject within 1 hour after administration and in a 24-hour time period after the administration for at least 13 to 16 hours. See, for example, WO2016191288.

[0107] In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is formulated into an oral form, an extended release form, or a single unit dosage form or for one or more of once daily administration. In other embodiments, the extended release form is a controlled release form, a time-delayed release form, a sustained release form, a delayed release form, or a slow release form. In some embodiments, the extended release pharmaceutical composition of levetiracetam or a pharmaceutically acceptable salt thereof is in solid form. In some embodiments, the extended release pharmaceutical composition of levetiracetam or a pharmaceutically acceptable salt thereof is in tablet or capsule form.

[0108] Table 1 provides a description of three formulations of levetiracetam (190 mg tablets A, B, and C). In some embodiments, the pharmaceutical composition useful in the methods and uses of the present disclosure is a formulation in Table 1. In one embodiment of the methods and uses of the present disclosure, the pharmaceutical composition is a 190 mg tablet A formulation. Table 1 - Process for preparing an extended release composition comprising 190 mg of levetiracetam

[0109] Table 2 provides a description of two formulations of levetiracetam (220 mg tablets D and E). In some embodiments of the methods and uses of the present disclosure, the pharmaceutical composition is a formulation in Table 2. In one embodiment, the pharmaceutical composition is a 220 mg tablet D formulation. Table 2 - Process for preparing an extended release composition comprising 220 mg of levetiracetam GABA A α5 receptor agonists

[0110] GABAA receptors (GABAARs) are pentameric assemblies from a pool of different subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ) that form a Cl-permeable channel gated by the neurotransmitter γ-aminobutyric acid (GABA). Different pharmacological effects (including anxiety, epilepsy, insomnia, pre-anesthetic sedation and muscle relaxation) are mediated by different GABA A Isotype mediated.

[0111] Various studies have demonstrated that reduced GABA signaling is associated with different CNS disorders with cognitive impairment. For example, some studies have demonstrated that in rats with age-related cognitive decline, GABA A The hippocampal expression of the α5 subunit of the receptor is reduced (see, e.g., WO 2007 / 019312). And other studies have shown that α5-containing GABA A GABA is a positive allosteric modulator of R A α5 receptor agonists can be used to treat cognitive impairment associated with the CNS disorders, cognitive impairment associated with brain cancer, brain cancer or Parkinson's disease psychosis. See, for example, WO 2015 / 095783, WO 2018 / 130868, WO 2016 / 205739, WO 2018 / 130869, WO 2019 / 246300 and US62 / 950,886, all of which are specifically incorporated herein by reference.

[0112] In some embodiments of the methods and uses of the present disclosure, GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA included as part of a pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) Compounds of formula II: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; R 1 , R 2 , R 4 and R 5 Each occurrence of is independently selected from: 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 and -P(O)(H)(OR); R 3Selected from the group consisting of: 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 and -P(O)(H)(OR); -C≡CH, -C≡CR 9 、-(C1-C6)alkyl-C≡CR 10 、-CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Where R 3 independently substituted with 0-5 R'; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; wherein R7 is selected from the group consisting of: -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5 to 10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; wherein each R7 is independently substituted by 0-5 R'; Each R 8 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 membered heteroaryl, and -(C1-C6)alkyl-5-10 membered heteroaryl; Where each R except -H and -(C1-C6)alkyl 8 independently substituted by 0-5 -halogen, -(C1-C6)alkyl, -CF3, -OCF3, or O-(C1-C6)alkyl; Where R 9 Selected from the group consisting of: -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl, 5-10 membered heterocyclic, Each R 9 Independently by 0-5 R 11 replace; Where R 10 is selected from the group consisting of: -H, halogen, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl, and -CH2-5-10 membered heteroaryl, Each R 10 replaced by 0-5 R's; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CN, SCH3, -CF3, -OH, -OCF3, OCHF2, -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5- to 10-membered heteroaryl; Each R is independently selected from the group consisting of: 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)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-, (C6-C10)-aryl-N(R")-(C1-C12)aliphatic-, 3- to 10-membered heterocyclic group-, (3- to 10-membered heterocyclic)-(C1-C12)aliphatic-, (3- to 10-membered heterocyclic group)-O-(C1-C12)aliphatic group-, (3- to 10-membered heterocyclic)-N(R")-(C1-C12)aliphatic-, 5- to 10-membered heteroaryl-, (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-; and (5- to 10-membered heteroaryl)-N(R")-(C1-C12)-aliphatic-; wherein the heterocyclyl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O, S, SO and SO2, and the heteroaryl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O and S; wherein each occurrence of R is independently replaced by 0-5 R'; or when two R groups are attached to the same atom, the two R groups can be taken together with the atoms to which they are attached to form a 3- to 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', and wherein the ring is optionally fused to a (C6-C10)aryl, a 5- to 10-membered heteroaryl, a (C3-C10)cycloalkyl, or a 3- to 10-membered heterocyclyl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-, wherein each occurrence of R" is independently substituted with 0-5 substituents 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 )2, where R o Each occurrence of is independently selected from the group consisting of: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl; and ii) Compounds of formula IV: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; Each R 1 , R 4 and R 5 Independently selected from: R1 , R 4 and R 5 Each occurrence of is independently selected from: 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) 0-3 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 8 , CH2CF3 or CHF2; R 2 Select from -OR 8 、-SR 8 、-(CH2) n OR 8 、-(CH2) n O(CH2) n R 8 、-(CH2) p R 8 or -(CH2) n N(R”)R 10 , wherein n is an integer selected from 0-4; p is an integer selected from 2-4; Where R 2 independently substituted with 0-5 R'; Each R 3 Independently selected from: -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- or 6-membered heterocyclic group, 5- or 6-membered heteroaryl, -(C1-C6) alkyl-C≡CR 10 、-CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-10 membered heterocyclic or heteroaryl group is substituted by 0-3 R7; Where R 3 independently substituted with 0-5 R'; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; R7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl; wherein each R7 is independently substituted with 0-5 R'; R 8 independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, 5-10-membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl, and -(C1-C6)alkyl-(C3-C6)cycloalkyl; Where R 8 Each occurrence of is independently replaced by 0-5 R'; Where R 9Selected 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 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, Each R 9 Independently by 0-5 R 11 replace; R 10 is selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, 5- to 10-membered heteroaryl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5- to 10-membered heteroaryl, Where R 10 Each occurrence of is independently replaced by 0-5 R'; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CF3, -OCF3, -OH, OCF2H, -O-(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, -O-CH2-(C3-C6)cycloalkyl, -CN, and -5- to 10-membered heteroaryl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-aliphatic, -(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-; wherein each occurrence of R' is independently replaced by 0-5 R independently selected from the group consisting of t Substitution: 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl-.

[0113] In some embodiments, GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA included as part of a pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) Compounds of formula II: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; Each R 1 independently selected from the group consisting of halogen, -H, -(C1-C6)alkyl, -OH, -O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3, -OCHF2, -OMe, -C≡CR 8 , -CHF2, -CH2CF3, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; wherein R 1 independently substituted with 0-5 R'; R 2 Selected from the group consisting of: -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)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-, (C6-C10)-aryl-N(R")-(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-N(R")-(C1-C12)aliphatic-, (3- to 10-membered heterocyclic)-(C1-C12)aliphatic-, (3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-, and (3- to 10-membered heterocyclic)-N(R")-(C1-C12)aliphatic-, Where R 2 independently substituted with 0-5 R'; R 3 Selected from the group consisting of: -(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- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, -(C1-C6) alkyl-C≡CR 10 、-CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Where R 3 independently substituted with 0-5 R'; R 4 and R 5 Each is independently selected from the group consisting of: -H, halogen, -(C1-C6)alkyl, or -(C1-C6)alkyl-(C6-C10)aryl; the (C6-C10)aryl is independently substituted by 0-5 halogens; R 6selected from the group consisting of: -H and -(C1-C6)alkyl; wherein R7 is selected from the group consisting of: -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5 to 10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; wherein each R7 is independently substituted by 0-5 R'; Each R 8 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 membered heteroaryl, and -(C1-C6)alkyl-5-10 membered heteroaryl; Where each R except -H and -(C1-C6)alkyl 8 independently substituted by 0-5 -halogen, -(C1-C6)alkyl, -CF3, -OCF3, or O-(C1-C6)alkyl; Where R 9 Selected from the group consisting of: -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl, 5-10 membered heterocyclic, Each R 9 Independently by 0-5 R 11 replace; Where R 10 is selected from the group consisting of: -H, halogen, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl, and -CH2-5-10 membered heteroaryl, Each R 10 replaced by 0-5 R's; Where R 11Each occurrence of is independently selected from the group consisting of -halogen, -CN, SCH3, -CF3, -OH, -OCF3, OCHF2, -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5- to 10-membered heteroaryl; Each R is independently selected from the group consisting of: 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)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-, (C6-C10)-aryl-N(R")-(C1-C12)aliphatic-, 3- to 10-membered heterocyclic group-, (3- to 10-membered heterocyclic)-(C1-C12)aliphatic-, (3- to 10-membered heterocyclic group)-O-(C1-C12)aliphatic group-, (3- to 10-membered heterocyclic)-N(R")-(C1-C12)aliphatic-, 5- to 10-membered heteroaryl-, (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-; and (5- to 10-membered heteroaryl)-N(R")-(C1-C12)-aliphatic-; wherein the heterocyclyl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O, S, SO and SO2, and the heteroaryl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O and S; wherein each occurrence of R is independently replaced by 0-5 R'; or when two R groups are attached to the same atom, the two R groups can be taken together with the atoms to which they are attached to form a 3- to 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', and wherein the ring is optionally fused to a (C6-C10)aryl, a 5- to 10-membered heteroaryl, a (C3-C10)cycloalkyl, or a 3- to 10-membered heterocyclyl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-, wherein each occurrence of R" is independently substituted with 0-5 substituents 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 )2, where R o Each occurrence of is independently selected from the group consisting of: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl; and ii) Compounds of formula IV: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; Each R 1 independently selected from the group consisting of: halogen, -H, -(C1-C6)alkyl, -C≡CR9 , -OH, -O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3, -CHF2, -CH2CF3, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and --(C3-C6)cycloalkyl; Where R 1 independently substituted with 0-5 R'; R 2 Selected from the group consisting of: -OR 8 、-SR 8 、-(CH2) n OR 8 、-(CH2) n O(CH2) n R 8 、-(CH2) p R 8 and -(CH2) n N(R”)R 10 , wherein n is an integer selected from 0-4; p is an integer selected from 2-4; Where R 2 independently substituted with 0-5 R'; Each R 3 Independently selected from the group consisting of: -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- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-10 membered heterocyclic or heteroaryl group is substituted by 0-3 R7; Where R 3 independently substituted with 0-5 R'; R 4 and R 5 each independently selected from the group consisting of: -H, halogen, and -(C1-C6)alkyl; R 6selected from the group consisting of: -H and -(C1-C6)alkyl; R7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl; wherein each R7 is independently substituted with 0-5 R'; R 8 independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, 5-10-membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl, and -(C1-C6)alkyl-(C3-C6)cycloalkyl; Where R 8 Each occurrence of is independently replaced by 0-5 R'; Where R 9 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 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, Each of which each of R 9 Independently by 0-5 R 11 replace; R 10 is selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, 5- to 10-membered heteroaryl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5- to 10-membered heteroaryl, Where R 10 Each occurrence of is independently replaced by 0-5 R'; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CF3, -OCF3, OCF2H, -O-(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, -O-CH2-(C3-C6)cycloalkyl, and -5- to 10-membered heteroaryl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-aliphatic, -(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-; wherein each occurrence of R' is independently replaced by 0-5 R independently selected from the group consisting of t Substitution: 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl-.

[0114] In some embodiments, the compound has the structure of Formula Ia: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m is an integer selected from 0-4; Each R 1 independently selected from halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -NCS, -NO2, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 2Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl and (C3-C10)-cycloalkenyl; wherein each 5-6 membered heteroaryl and 3-10 membered heterocyclic ring is substituted by 0-4 R7; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5 to 10-membered heteroaryl-(C1-C6)alkyl and -3-10-membered heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, the two R7 groups may be taken together with the atoms to which they are attached to 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'; Each R 8 is selected from -H, -(C1-C6 alkyl), -(5-10 membered heteroaryl), -(3-10 membered) heterocyclyl, (C3-C10)-cycloalkenyl, -(C6-C10) aryl, -(C3-C6) cycloalkyl, -CH2-(C3-C6) cycloalkyl, -CH2-(C6-C10) aryl and -CH2-5-10 membered heteroaryl, wherein R 8 Each occurrence of is independently replaced by 0-5 R', Each R 9 is selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl, (C3-C10)-cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5- to 10-membered heteroaryl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl, wherein R 9 Each occurrence of is independently represented by 0-5 R 11 replace; Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -Ome, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, and SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, and S, R3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 、-(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(3-10 membered)heterocyclyl, -5-10 membered heteroaryl, -C(O)-(C6-C10)aryl, -C(O)-(C1-C6)alkyl, -C(O)-(C3-C6), wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl, wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO and SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O and S; R 4 Selected from -H or -(C1-C6)alkyl; R 6 Selected from -H or -(C1-C6)alkyl Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R")2; wherein each occurrence of R" is independently selected from -H, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-, wherein each occurrence of R" is independently substituted with 0-3 substituents, and particularly in some aspects of the disclosure, R" is independently substituted with 1-3 substituents, wherein the substituents are selected from: 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, -O(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl-, wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO and SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O and S.

[0115] In some embodiments, the compound has the structure of Formula Ib: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 As defined in Formula Ia.

[0116] In some embodiments, the compound has the structure of Formula Ic: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 3 , R 4 , R6 , R 13 and R 14 As defined in Formula Ia.

[0117] In some embodiments, the compound has the structure of Formula Id: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 As defined in Formula Ia.

[0118] In some embodiments, the compound has the structure of Formula Ie: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 As defined in Formula Ia.

[0119] In some embodiments, the compound has the structure of Formula If: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 As defined in Formula Ia.

[0120] In some embodiments, the present disclosure provides compounds of Formula Ia: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, in: m is an integer selected from 0-4; Each R 1 Independently selected from: halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl) Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclic group, (C3-C10)-cycloalkenyl Each 5-6 membered heteroaryl and 3-10 membered heterocyclic ring is substituted by 0-4 R7, each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3-10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace; Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; R 3 independently selected from: -H, -(C1-C6)alkyl, -5 to 10 membered heteroaryl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl and -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R o , oxo, -CH2OR o 、-CH2N(R o )2、-C(O)N(R o )2. -C(O)OR o , -CF3, -OCF3 and -N(R o )2, where R oEach occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, -(3-10 membered)heterocyclyl, and (C6-C10)-aryl; wherein each R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10-membered heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -5 to 10-membered heteroaryl-(C1-C6)alkyl, and -3-10-membered heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, the two R7 groups may be taken together with the atoms to which they are attached to 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'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2, wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, and -(C6-C10)aryl; R" is independently substituted by 1-3 substituents, wherein the substituents are selected from: halogen, -CF3, -OCF3, -O(C1-C6)-aliphatic or -(C1-C6)-aliphatic; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 Selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl;

[0121] In some embodiments of the compound of Formula Ia, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, Where: m is 0, 1 or 2; When m is 1 or 2, R 1 at least one occurrence of is halogen or -O((C1-C6)alkyl); Each R 1 Independently selected from: -halogen and -O(C1-C6)alkyl; R 2 Selected from: C≡CR 9 、(C3-C10)-cycloalkenyl wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl and -O-(C1-C6)alkyl; R 3 independently selected from: -H, -(C1-C6)alkyl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl and -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C6-C10)aryl or -CH2-(C6-C10)aryl, wherein each R7 is independently substituted by 0-5 R'; R 4 and R 6 Each occurrence of is -H.

[0122] In some embodiments, the present disclosure provides compounds of Formula Ib: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -Ome, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-6 membered heteroaryl or 3-10 membered heterocycle is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3-10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -Ome, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; R 3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 、-(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -3 to 10 membered heterocyclyl and -5-10 membered heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl. wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10-membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5 to 10-membered heteroaryl and -3-10-membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; or when two R7 groups are attached to the same atom, the two R7 groups may be taken together with the atoms to which they are attached to 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'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2; wherein R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-5- to 10-membered heteroaryl, —5- to 10-membered heteroaryl, —3- to 10-membered heterocyclyl, —(C3-C6)cycloalkyl, and —(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from: halogen, -CF3, -OCF3, -O-(C1-C6)aliphatic, -(C1-C6)-aliphatic and -5 to 10 membered heteroaryl; Each R 4 and R 6 Independently selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl;

[0123] In some embodiments of the compound of Formula Ib, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, Where: m is 0, 1 or 2; When m is 1 or 2, R 1 at least one occurrence of is halogen or -O((C1-C6)alkyl); Each R 1 Independently selected from: -halogen and -O(C1-C6)alkyl; R 2 Selected from: C≡CR 9 , wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, wherein R 9 Each occurrence of is independently represented by 0-5 R 11 replace Where R 11 Each occurrence of is selected from -(C1-C6)alkyl; R 3 are independently selected from: -H, -(C1-C6)alkyl or -CH2-(C6-C10)aryl and -3 to 10 membered heterocyclic group, wherein R 3 Independently by 0-5 R 12 replace; wherein R7 is selected from -(C1-C6)alkyl, -CH2-(C6-C10)aryl, -(C3-C6)cycloalkyl and -(3-10) membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; R 4 and R 6 Each occurrence of is -H.

[0124] In some embodiments, the present disclosure provides compounds of Formula Ic: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl R 9 Each occurrence of is independently represented by 0-5 R 11 replace; R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; Each occurrence of R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5- to 10-membered heteroaryl, and -3-10-membered heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R")2, wherein each occurrence of R" is selected from -Cl, -F, -(C1-C6)alkyl, -Ome, -(C1-C6)alkyl-5 to 10 membered heteroaryl, -5 to 10 membered heteroaryl, -3 to 10 membered heterocyclyl, -(C3-C6)cycloalkyl, and -(C6-C10)aryl, and R" is independently substituted 1-3 with 1-3 substituents selected from: halogen, -CF3, -OCF3, -(C1-C6)-aliphatic, and -5 to 10 membered heteroaryl; Each R 4 and R 6 Independently selected from -H or (C1-C6)alkyl; Each R 13 and R 14 Independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0125] In some embodiments of the compound of Formula Ic, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, Where: m is 0, 1 or 2; When m is 1 or 2, R 1 at least one occurrence of is halogen or -O((C1-C6)alkyl); Each R 1Independently selected from: -halogen and -O(C1-C6)alkyl; R 2 Selected from: CO(O)R7, C≡CR 9 , wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: H or -(C1-C6)alkyl, where R 9 Each occurrence of is independently represented by 0-5 R 11 replace R 11 Each occurrence of is selected from -(C1-C6)alkyl; R 4 and R 6 Each occurrence of is -H.

[0126] In some embodiments, the present disclosure provides compounds of Formula Id: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -Ome, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3-10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -Ome, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; R 3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 、-(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl. wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5 to 10 membered heteroaryl and -3-10 membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2; wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe and -(C6-C10)aryl; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 Selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 Independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0127] In some embodiments of the compound of Formula Id, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, Where: m is 0, 1 or 2; When m is 1 or 2, R 1 at least one occurrence of is halogen or -O((C1-C6)alkyl); Each R 1 Independently selected from: -halogen and -O(C1-C6)alkyl; R 2 Selected from: C≡CR 9 , wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, wherein R 9 Each occurrence of is independently represented by 0-5 R 11 Substitution, where R 11 Each occurrence of is selected from -(C1-C6)alkyl; R 3 are independently selected from: -H, -(C1-C6)alkyl or -CH2-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 Substitute, where each R 12 Independently selected from: -H or -F, wherein R7 is selected from -(C1-C6)alkyl, -CH2-(C6-C10)aryl, -(C3-C6)cycloalkyl and -(3-10) membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; R 4 and R 6 Each occurrence of is -H.

[0128] In some embodiments, the present disclosure provides compounds of Formula Ie: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl R 9 Each occurrence of is independently represented by 0-5 R 11 Substitution, where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -3-10-membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2, wherein each R' is independently substituted with 0-5 R"; wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe and -(C6-C10)aryl; Each R 4 are independently -H or (C1-C6)alkyl; Each R 6 are independently -H or -(C1-C6)alkyl. Each R 13 and R 14 Independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0129] In some embodiments of the compound of Formula le, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, Where: m is 0, 1 or 2; When m is 1 or 2, R 1 at least one occurrence of is halogen or -O((C1-C6)alkyl); Each R 1 Independently selected from: -halogen and -O(C1-C6)alkyl; R 2 Selected from: CO(O)R7, C≡CR 9 , wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: H or -(C1-C6)alkyl, where R 9 Each occurrence of is independently represented by 0-5 R 11 replace Where R 11 Each occurrence of is selected from -(C1-C6)alkyl; R 4 and R 6 All are -H.

[0130] In some embodiments, the present disclosure provides compounds of Formula If: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl R 9 Each occurrence of is independently represented by 0-5 R 11 Substitution, where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -3-10-membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2; wherein each R' is independently substituted by 0-5 R", wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe and -(C6-C10)aryl; R 4 is -H or (C1-C6) alkyl; R 6 is -H or -(C1-C6)alkyl; Each R 13 and R 14 Independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0131] In some embodiments of the compound of Formula If, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein: m is 0, 1, or 2; When m is 1 or 2, R 1 at least one occurrence of is halogen or -O((C1-C6)alkyl); Each R 1 Independently selected from: -halogen and -O(C1-C6)alkyl; R 2 Selected from: CO(O)R7, C≡CR 9 , wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: H or -(C1-C6)alkyl, where R 9 Each occurrence of is independently represented by 0-5 R 11 Replace, and R 11 Each occurrence of is selected from -(C1-C6)alkyl; R 4 and R 6 All are -H.

[0132] In some embodiments, GABA AThe α5 receptor agonist is a compound of formula II as described in paragraph 19, or a compound of formula II as described in paragraph 20, or a compound of formula IV as described in paragraph 19, or a compound of formula IV as described in paragraph 20, or a compound of formula Ia as described in paragraph 30; or a compound of formula Ib as described in paragraph 30, or a compound of formula Ic as described in paragraph 30; or a compound of formula Id as described in paragraph 30; or a compound of formula Ie as described in paragraph 30; or a compound of formula If as described in paragraph 30; or a compound 1-12, 44-56, 101-268, 270- 644, 646-687, 689-698, 700-703, 705, 707-721, 723-740, 742-755, 758-763, 765-779, 781-795, 797-810, 813-828, 830, 831, 833-846, 848-891, 893-903, 905, 907-977, 979-1012, or Compound 606, Form A, Compound 606, Form B, Compound 606, Form C, Compound 606, Form E, or Compound 606, Form F, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. See pages 284-305 of WO2022011318, which is incorporated herein by reference in its entirety, particularly with respect to the compounds described, their syntheses and properties.

[0133] In some embodiments, the GABA of the present disclosure A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof or GABA included as part of the pharmaceutical composition of the present disclosure A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound of formula II as described in paragraph 19 or a compound of formula II as described in paragraph 20, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In other embodiments, the GABA of the present disclosure A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof or GABA included as part of the pharmaceutical composition of the present disclosure A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound of formula IV as described in paragraph 19 or a compound of formula IV as described in paragraph 20, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments, the GABA of the present disclosure Aα5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof or GABA included as part of the pharmaceutical composition of the present disclosure A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound of formula Ia, Ib, Ic, Id, Ie and If as described in paragraph 30.

[0134] In other aspects of the methods and uses of the present disclosure, the compound is GABA A A crystalline form of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof. Such a crystalline form can be, for example, selected from the group consisting of: compound 606, type A (polymorphic crystalline form), compound 606, type B (polymorphic crystalline form), compound 606, type C (solvate crystalline form), compound 606, type E (polymorphic crystalline form) and compound 606, type F (hydrate crystalline form). In other aspects of the methods and uses of the present disclosure, the pharmaceutical composition comprises GABA A One or more crystalline forms of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof, including, for example, those selected from the group consisting of: Compound 606, Type A (polymorphic crystalline form), Compound 606, Type B (polymorphic crystalline form), Compound 606, Type C (solvate crystalline form), Compound 606, Type E (polymorphic crystalline form) and Compound 606, Type F (hydrate crystalline form). In some embodiments, the crystalline form is Compound 606, Type A. In some embodiments, the crystalline form is Compound 606, Type B. In some embodiments, the crystalline form is Compound 606, Type C. In some embodiments, the crystalline form is Compound 606, Type E. In some embodiments, the crystalline form is Compound 606, Type F. See WO2022011318, which is incorporated herein by reference in its entirety, particularly with respect to the compounds described, their synthesis and properties.

[0135] In some embodiments, the crystalline form is an anhydrous crystalline form of compound 606, wherein the crystalline form corresponds to Form A, Form B, or Form E. In some embodiments, the crystalline form is a solvated crystalline form of compound 606, wherein the crystalline form corresponds to Form C or Form F. In certain such embodiments, the solvated crystalline form of compound 606 is a methanolate or a hydrate.

[0136] In some embodiments of the methods and uses of the present disclosure, the crystalline form is compound 606, Form A, characterized by an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 29 of WO2022011318, the pattern having at least one of 3.0 and / or 21.0°2θ±0.2°2θ and further comprising one or more of additional peaks selected from 9.1, 10.7, 13.8, 22.0, 23.1, 23.9, 24.4, and 27.1°2θ±0.2°2θ. In some embodiments, the crystalline form is compound 606, Form A, characterized by a C2 / c single crystal x-ray diffraction space group. In some embodiments, the crystalline form is compound 606, Form A, characterized by a single crystal x-ray diffraction unit cell having the following parameters: α=90°, β=90.261(2)°, γ=90°, In some embodiments, the crystalline form is compound 606, Type A, characterized by a differential scanning calorimetry (DSC) curve substantially as shown in Figure 27B of WO2022011318. In some embodiments, the crystalline form is compound 606, Type A, characterized by a differential scanning calorimetry (DSC) curve having an exothermic starting point at about 207°C. In some embodiments, the crystalline form is compound 606, Type A, characterized by two or more of the following: (a) an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 29 of WO2022011318; (b) a C2 / c single crystal x-ray diffraction space group; (c) a single crystal x-ray diffraction unit cell having the following parameters: α=90°, β=90.261(2)°, γ=90°, (d) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 27B of WO2022011318; and (e) a differential scanning calorimetry (DSC) curve having an exotherm with an onset of about 207°C.

[0137] In some embodiments of the methods and uses of the present disclosure, the crystalline form is compound 606, Type B, characterized by an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 34 of WO2022011318, the pattern having at least one peak selected from 13.0 and / or 15.3°2θ±0.2°2θ and further comprising one or more of additional 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°2θ±0.2°2θ. In some embodiments, the crystalline form is compound 606, Type B, characterized by a monoclinic single crystal x-ray diffraction unit cell. In some embodiments, the crystalline form is compound 606, Type B, characterized by about Single crystal x-ray diffraction chemical formula unit volume. In some embodiments, the crystalline form is compound 606, Type B, characterized by a differential scanning calorimetry (DSC) curve having an exotherm starting at about 190°C. In some embodiments, the crystalline form is compound 606, Type B, characterized by two or more of the following: (a) an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 34 of WO2022011318; (b) about and (c) a differential scanning calorimetry (DSC) curve having an exotherm with an onset of about 190° C.

[0138] In some embodiments of the methods and uses of the present disclosure, the crystalline form is compound 606, Type C, characterized by an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 41 of WO2022011318, the pattern having at least one peak selected from 8.5 and / or 18.9°2θ±0.2°2θ and further comprising one or more of additional 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°2θ±0.2°2θ. In some embodiments, the crystalline form is compound 606, Type C, characterized by a monoclinic single crystal x-ray diffraction unit cell. In some embodiments, the crystalline form is compound 606, Type C, characterized by about Single crystal x-ray diffraction chemical formula unit volume. In some embodiments, the crystalline form is compound 606, Type C, characterized by a differential scanning calorimetry (DSC) curve substantially as shown in Figure 42B of WO2022011318. In some embodiments, the crystalline form is compound 606, Type C, characterized by a differential scanning calorimetry (DSC) curve having an exothermic starting point at about 190°C. In some embodiments, the crystalline form is compound 606, Type C, characterized by two or more of the following: (a) an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 41 of WO2022011318; (b) a monoclinic single crystal x-ray diffraction unit cell; (c) about (d) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 42B of WO2022011318; and (e) a differential scanning calorimetry (DSC) curve having an exotherm with a starting point of about 190°C.

[0139] In some embodiments of the methods and uses of the present disclosure, the crystalline form is compound 606, Form E, characterized by an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 45 of WO2022011318, the pattern having at least one peak selected from 11.4, 18.1 and / or 21.6°2θ±0.2°2θ and further comprising one or more of additional 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 form is compound 606, Form E, characterized by a P21 / n single crystal x-ray diffraction space group. In some embodiments, the crystalline form is compound 606, Form E, characterized by a single crystal x-ray diffraction unit cell having the following parameters: α=90°, β=101.5333(11)°, γ=90°, In some embodiments, the crystalline form is compound 606, Type E, characterized by a differential scanning calorimetry (DSC) curve substantially as shown in Figure 36B of WO2022011318. In some embodiments, the crystalline form is compound 606, Type E, characterized by a differential scanning calorimetry (DSC) curve having an exothermic starting point at about 201°C. In some embodiments, the crystalline form is compound 606, Type E, characterized by two or more of the following: In some embodiments, (a) an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 35 of WO2022011318; (b) a P21 / n single crystal x-ray diffraction space group; (c) a single crystal x-ray diffraction unit cell having the following parameters: α=90°, β=101.5333(11)°, γ=90°, (d) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 36B of WO2022011318; and (e) a differential scanning calorimetry (DSC) curve having an exotherm with an onset of about 201°C.

[0140] In some embodiments of the methods and uses of the present disclosure, the crystalline form is compound 606, Form F, characterized by an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 37 of WO2022011318, the pattern having at least one peak selected from 9.9, 11.9, 17.3, 19.4 and / or 25.7°2θ±0.2°2θ and further comprising one or more of additional peaks selected from 9.7, 12.1, 20.8, 23.2, 23.7, 24.2, 25.0 and 26.4°2θ±0.2°2θ. In some embodiments, the crystalline form is compound 606, Form F, characterized by a triclinic single crystal x-ray diffraction unit cell. In some embodiments, the crystalline form is compound 606, Form F, characterized by about In some embodiments, the crystalline form is Compound 606, Form F, characterized by a differential scanning calorimetry (DSC) curve having an exotherm above about 120°C. In some embodiments, the crystalline form is Compound 606, Form F, characterized by two or more of the following: (a) an x-ray powder diffraction (XRPD) pattern substantially as shown in Figure 37 of WO2022011318; (b) a triclinic single crystal x-ray diffraction unit cell; (c) about and (d) a differential scanning calorimetry (DSC) curve having an exotherm above about 120° C.

[0141] The pharmaceutical compositions or combinations (or components thereof) of the methods and uses of the present disclosure can be administered by intraoral and oral delivery (including sublingual and buccal administration, e.g. Danckwerts (2003). Intraoral Drug Delivery: A Comparative Review. American Journal of Drug Delivery. 1. 171-186). Such delivery can be in the form of bioadhesive polymers, tablets, patches, films, liquids and semisolids (see, e.g. Smart JD. Buccaldrug delivery. Expert Opin Drug Deliv. 2005 May; 2(3): 507-17).

[0142] A person of ordinary skill in the art, such as a physician, can readily determine the amount of GABA required to treat a subject using the compositions and methods of the present disclosure. A It will be appreciated that the dosage regimen will be determined on an individual basis, taking into account, for example, changes in the selected GABA A The effect of the α5 receptor agonist depends on various factors, the severity or stage of the disease, the route of administration, and individual characteristics such as age, weight, size, and degree of cognitive impairment.

[0143] In certain embodiments of the present disclosure, GABA A The daily dose of the α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is in an amount of 0.0015 mg to 5000 mg or 5 mg to 1000 mg. In some embodiments of the present disclosure, GABA A The dosage of the α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is about 0.1-500 mg / day. In some embodiments of the present disclosure, GABA A The dosage of the α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is about 1-250 mg / day. In some embodiments of the present disclosure, GABA A The dosage of the α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is about 10-100 mg / day. In some embodiments of the present disclosure, GABA AThe dosage of the α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is about 1-10 mg / day. Daily dosages that can be used include, but are not limited to, 0.0015 mg / kg, 0.002 mg / kg, 0.0025 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg. g / kg, 0.7mg / kg, 0.8mg / kg, 0.9mg / kg, 1mg / kg, 1.2mg / kg, 1.4mg / kg, 1.5mg / kg, 1.6mg / kg, 1.8mg / kg, 2.0mg / kg, 2.2mg / k g, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.8mg / kg, 3.0mg / kg, 3.5mg / kg, 4.0mg / kg, 4.5mg / kg, 5.0mg / kg, 6.0mg / kg, 7.0mg / kg, 10mg / kg, 14mg / kg, 18mg / kg, 36mg / kg, 50mg / kg, 70mg / kg; or 0.1mg, 0.15mg, 0.18mg, 0.35mg, 0.7mg, 1.5mg, 2.0mg, 2.5mg, 2.8mg, 3.0mg, 3.5mg, 4.2mg, 5mg, 5.5mg, 6.0mg, 7mg, 8mg, 9mg, 10mg, 12mg, 15mg, 20mg, 25mg, 28mg, 30mg, 35mg, 40mg, 45mg In some embodiments, GABA is preferably a 100 mg, 200 mg, 300 mg, 350 mg, 400 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 2500 mg, 3500 mg, or 5000 mg. In some embodiments, GABA is preferably a 100 mg, 200 mg, 300 mg, 350 mg, 400 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 2500 mg, 3500 mg, or 5000 mg. AThe dosage of the α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is 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 Amount of α5 receptor agonist. Other dosages above, in between, or below these dosages may also be used and can be determined by one skilled in the art following the methods of the present disclosure.

[0144] In certain embodiments, GABA A Doses of alpha5 receptor agonists are between 0.0001 and 100 mg / kg / day in rodents (given a typical human subject of 70 kg, this is between 0.007 and 7000 mg / day).

[0145] In certain embodiments of the present disclosure, the frequency of administration of the above daily dose is 12 or 24 hours. In some embodiments, once daily administration is used. In some embodiments, more frequent interval administration, such as once every 6 hours, may also be used. For repeated administration over several days or weeks or longer, depending on the condition, treatment is continued until a sufficient level of cognitive function is achieved.

[0146] Less frequent dosing may also be used. For example, if administered by implant, device, or slow or extended release formulation, GABA A The α5 receptor agonist can be administered once, once or more times periodically as needed throughout the patient's life. Other administration intervals between or shorter than these dosage intervals can also be used and can be determined by those skilled in the art according to the methods of the present invention.

[0147] The desired administration time can be determined by those skilled in the art through routine experimentation. A The alpha 5 receptor agonist can be administered for 1-4 weeks, 1-3 months, 3-6 months, 6-12 months, 1-2 years, or longer, up to the lifetime of the patient.

[0148] In some embodiments of the methods and uses of the present disclosure, the compounds, pharmaceutical compositions, combinations and medicaments comprise levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof and / or GABA Aα5 receptor agonists (e.g., compounds of formula II as described in paragraphs 19 or 20 or compounds of formula IV as described in paragraphs 19 or 20; compounds of formula Ia, Ib, Ic, Id, Ie and If as described in paragraph 30; compounds 1-12, 44-56, 101-268, 270-644, 646-687, 689-698, 700-703, 705, 707-721, 723-740, 742-755, 758-763, 765-779, 781-795, 797-806, 810-811, 811-813, 813-814, 814-815, 815-816, 816-817, 817-818, 818-819, 819-820, 821-821, 822-823, 824-825, 826-827, 828-829, 830-831, 831-832, 832-833, 833-834, 834-835, 835-836, 836-837, 837-838, 838-839, 839-840, 839-841, 839-843, 839-844, 839-845, 839-846, 839-847, 839-848, 839-849, 840-841 97-810, 813-828, 830, 831, 833-846, 848-891, 893-903, 905, 907-977, 979-1012; or compound 606, Form A; compound 606, Form B; compound 606, Form C; compound 606, Form E; or compound 606, Form F) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof) can be in a solid dosage form such as a capsule, tablet, medicinal lozenge, pill, lozenge, cachet, powder, lozenge, wafer or granule. In such a dosage form, one or more compounds, pharmaceutical compositions, combined drugs (e.g., containing levetiracetam, brivaracetam or seletracetam), or a pharmaceutically acceptable salt thereof, and / or GABA Aα5 receptor agonists (e.g., compounds of formula II as described in paragraphs 19 or 20 or compounds of formula IV as described in paragraphs 19 or 20; compounds of formula Ia, Ib, Ic, Id, Ie and If as described in paragraph 30; compounds 1-12, 44-56, 101-268, 270-644, 646-687, 689-698, 700-703, 705, 707-721, 723 as described above) -740, 742-755, 758-763, 765-779, 781-795, 797-810, 813-828, 830, 831, 833-846, 848-891, 893-903, 905, 907-977, 979-1012, or compound 606, type A; compound 606, type B; compound 606, type C; compound 606, type E; or compound 606, type F) or Pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers) can be mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or calcium hydrogen phosphate) and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, for example, carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) humectants, such as glycerol; 4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite clays; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition or combination (or its components) may also include a buffer. Similar types of solid pharmaceutical compositions or combinations (or their components) may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugars and high molecular weight polyethylene glycols and the like.

[0149] Pharmaceutical compositions or combinations (or components thereof) that can be used in the methods and uses of the present disclosure (e.g., comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof, and / or GABA Aα5 receptor agonists (e.g., compounds of formula II as described in paragraphs 19 or 20 or compounds of formula IV as described in paragraphs 19 or 20; compounds of formula Ia, Ib, Ic, Id, Ie and If as described in paragraph 30; compounds 1-12, 44-56, 101-268, 270-644, 646-687, 689-698, 700-703, 705, 707-721, 723-740, 742-755, 758-763, 765-779, 781-795, 797-8 10, 813-828, 830, 831, 833-846, 848-891, 893-903, 905, 907-977, 979-1012, or compound 606, type A; compound 606, type B; compound 606, type C; compound 606, type E; or compound 606, type F) or its pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer) of the pharmaceutical composition or combination (or its components) can be in aqueous or non-aqueous liquid dosage form, including solution, emulsion, microemulsion, suspension, syrup, pastille or elixir. In some embodiments, the pharmaceutical composition or combination (or its components) is an aqueous solution. In some embodiments, the pharmaceutical composition or combination (or its components) is in the form of a suspension.

[0150] Where appropriate, the pharmaceutical compositions or combinations (or components thereof) may be prepared with a coating such as an enteric coating or may be formulated according to methods well known in the art to provide one or more compounds (e.g., levetiracetam, brivaracetam or seletracetam), or pharmaceutically acceptable salts thereof and / or GABA useful in the methods and uses of the present disclosure. Aα5 receptor agonists (e.g., compounds of formula II as described in paragraphs 19 or 20 or compounds of formula IV as described in paragraphs 19 or 20; compounds of formula Ia, Ib, Ic, Id, Ie and If as described in paragraph 30; compounds 1-12, 44-56, 101-268, 270-644, 646-687, 689-698, 700-703, 705, 707-721, 723-740, 742-755, 758-763, 765-779, 78 1-795, 797-810, 813-828, 830, 831, 833-846, 848-891, 893-903, 905, 907-977, 979-1012, or Compound 606, Form A; Compound 606, Form B; Compound 606, Form C; Compound 606, Form E; or Compound 606, Form F) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof) of an extended release (e.g., controlled release, extended release, sustained release, delayed release or slow release). Liquid dosage forms may also contain inert diluents commonly used in the art such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol (ethanol), isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral pharmaceutical compositions or combinations (or components thereof) useful in the methods and uses of the present disclosure may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances and preservatives. In addition to compounds (e.g., levetiracetam, brivaracetam or seletracetam) or pharmaceutically acceptable salts thereof, and / or GABA Aα5 receptor agonists (e.g., compounds of formula II as described in paragraphs 19 or 20 or compounds of formula IV as described in paragraphs 19 or 20; compounds of formula Ia, Ib, Ic, Id, Ie and If as described in paragraph 30; compounds 1-12, 44-56, 101-268, 270-644, 646-687, 689-698, 700-703, 705, 707-721, 723-740, 742-755, 758-763, 765-779, 781-795, 797-810, 813- 828, 830, 831, 833-846, 848-891, 893-903, 905, 907-977, 979-1012, or Compound 606, Form A; Compound 606, Form B; Compound 606, Form C; Compound 606, Form E; or Compound 606, Form F) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof, the suspension may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar and tragacanth, and mixtures thereof.

[0151] The pharmaceutical compositions or combinations (or their components) useful in the methods and uses of the present disclosure may be formulated for respiratory delivery (lung and nasal delivery). In such a form, they may be delivered by devices and in forms including, but not limited to, a variety of pressurized metered dose inhalers, dry powder inhalers, nebulizers, mist inhalers, drops, solutions, suspensions, sprays, powders, gels, ointments, and specialized systems such as liposomes and microspheres (see, e.g., Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabet Med. November 2003; 20(11): 886-98 and Martini G, Ciani L. Electron spin resonance spectroscopy indrug delivery. Phys Chem Phys. 2009).

[0152] The pharmaceutical compositions or combinations useful in the methods and uses of the present disclosure (or components thereof) may also be formulated for transdermal delivery using forms including, but not limited to, colloids, patches, and microemulsions.

[0153] In some embodiments of the methods and uses of the present disclosure, one or more of the compounds, pharmaceutical compositions or drugs may be packaged together. In other embodiments, one or more of the compounds, pharmaceutical compositions or drugs may be packaged separately. Combinations useful in the methods and uses of the present disclosure also include the following formulations: levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof, and GABA A α5 receptor agonists (e.g., compounds of formula II as described in paragraphs 19 or 20 or compounds of formula IV as described in paragraphs 19 or 20; compounds of formula Ia, Ib, Ic, Id, Ie and If as described in paragraph 30; compounds 1-12, 44-56, 101-268, 270-644, 646-687, 689-698, 700-703, 705, 707-721, 723-740, 742-755, 758-763, 765-779, 770-771, 771-772, 773-773, 774-774, 775-776, 777-777, 778-779, 779-780, 781-781, 782-783, 784-784, 785-786, 787-787, 788-789, 781-783, 789-784, 781-785, 786-787, 788-789, 781-783, 788-789, 781-781, 782-783, 783-784, 785-789, 781-781, 782-783, 783-784, 785-789, 789-781, 789-783, 789-784, 789-785, 789-786, 789-787, 789-788, 789 81-795, 797-810, 813-828, 830, 831, 833-846, 848-891, 893-903, 905, 907-977, 979-1012; or compound 606, Form A; compound 606, Form B; compound 606, Form C; compound 606, Form E; or compound 606, Form F) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, or a pharmaceutical composition containing each of them together in one preparation or in separate preparations.

[0154] Other suitable administration forms of the pharmaceutical compositions or combinations (or components thereof) that can be used in the methods and uses of the present disclosure include depot injectable formulations, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, devices, and formulations for ocular administration.

[0155] The pharmaceutical composition or combination (or its component) that can be used in the method and purposes of the present disclosure can also include adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. By including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc., the effect of preventing microorganisms can be provided. It may also be necessary to include isotonic agents, such as sugar, sodium chloride, etc. in the pharmaceutical composition or combination (or its component). In addition, by including agents such as aluminum monostearate and gelatin that delay absorption, the extended absorption of injectable drug forms can be achieved.

[0156] Pharmaceutical compositions, medicaments or combinations (or components thereof) useful in the methods and uses of the present disclosure may be prepared by methods well known in the pharmaceutical art, see, e.g., Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed., edited by JG Hardman, LELimbird and AG Gilman., McGraw Hill, New York. 2001; Ansel et al., Pharmaceutical Calculations, The Pharmacist's Handbook 2004, Lippincott Williams & Wilkins; Stoklosa et al., 2001 Pharmaceutical Calculations, 11th ed. (9780781731720) - Textbooks.com; and Bustamante et al., "A Modification of the Extended Hildebrand Approach to Predict the Solubility of Structurally Related Drugs in Solvent Mixtures," Journal of Pharmacy and Pharmacology, 45:253-257 (1993).

[0157] In some embodiments, the methods of the present disclosure include administering levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically acceptable salt, to a subject. In some embodiments, the method includes administering to a subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the method includes administering to a subject levetiracetam or a pharmaceutically acceptable salt. In some embodiments, the method includes administering to a subject brivaracetam or a pharmaceutically acceptable salt. In some embodiments, the method includes administering to a subject seletracetam or a pharmaceutically acceptable salt. In some embodiments, the method includes administering to a subject a pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the method includes administering to a subject a pharmaceutical composition comprising a daily dose of brivaracetam or a pharmaceutically salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the method includes administering to a subject a pharmaceutical composition comprising a daily dose of seletracetam or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. General synthetic methodology

[0158] The compounds of the present disclosure can be prepared generally by methods known to those skilled in the art. The following schemes 1-4 provide general synthetic routes for preparing compounds of formulas Ia to If. Other equivalent schemes that will be apparent to ordinary organic chemists may also be used alternatively for the various parts (or all) of the synthetic molecules, as shown in the following general schemes. Scheme 1. General synthesis of compounds of Formula Ia wherein X, W and V form a pyrazole ring. Scheme 2. General synthesis of compounds of formula Ib wherein X, W and V form a methylpyrazole ring. Scheme 3-A. General synthesis of compounds of Formula Ib wherein X, W and V form a pyrazole ring. Scheme 3-B. Alternative synthesis of compounds of formula Ib (main) starting from intermediate A, wherein X, W and V form a pyrazole ring Scheme 3-C. Alternative synthesis of compounds of Formula Ic starting from Intermediate A, wherein X, W and V form an isoxazole ring.

[0159] As one skilled in the art will recognize, compounds of Formula I, Ia, Ib, Ic, Id, Ie and If having variables other than those shown above may be prepared by varying the chemical reagents or synthetic routes. Predictive risk factors for cognitive decline or cognitive impairment in a subject who exhibits or presents with cognitive performance within the normal range for the subject's age.

[0160] In some embodiments, the subject to be treated in the methods and uses of the present disclosure (a subject who exhibits or presents cognitive performance within the normal range for the subject's age) is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with aging.

[0161] In some embodiments of the methods of the present disclosure, the subject to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of altered hippocampal functional connectivity in the subject. In some embodiments of the methods of the present disclosure, the subject to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of increased hippocampal functional connectivity in the subject.

[0162] In some embodiments, the subject to be treated in the methods and uses of the present disclosure (a subject who exhibits or presents cognitive performance within the normal range for the age of the subject) is at risk of developing cognitive decline or cognitive impairment, wherein the risk is a genetic risk associated with the presence of one or more genomic variations, mutations or polymorphisms in the subject's genome associated with changes in the expression of genes selected from the group consisting of ABCA7, CLU, CR1, PICALM, PLD3, TREM2 and SORL1. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variations, mutations or polymorphisms associated with ABCA7 in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variations, mutations or polymorphisms associated with CLU in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variations, mutations or polymorphisms associated with CR1 in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variations, mutations, or polymorphisms associated with PICALM in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variations, mutations, or polymorphisms associated with PLD3 in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variations, mutations, or polymorphisms associated with TREM2 in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variations, mutations, or polymorphisms associated with SORL1 in the subject's genome.

[0163] In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of at least one allele of the APOE4 gene in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one allele of the APOE4 gene in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of two (both) APOE4 alleles in the subject's genome.

[0164] In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more biofluid biomarkers selected from the group consisting of p-tau, t-tau, and amyloid beta 42 in the subject. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of the biofluid biomarker p-tau in the subject. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of the biofluid biomarker t-tau in the subject. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of the biofluid biomarker amyloid beta 42 in the subject. Example Example 1: Composition of Levetiracetam

[0165] The composition comprising levetiracetam may be administered by Figure 4 Briefly, silicified microcrystalline cellulose ProSolv TM SMCC HD90 (or Encompress, anhydrous calcium hydrogen phosphate) was sieved through a deagglomerated #30 US standard mesh sieve and then blended with colloidal silicon dioxide (16 quart V-shell mixer; 75 rev ± 5 rev). The blended sample was then passed through a Round 1601 impeller (2A024R sieve). 220 mg of levetiracetam and hypromellose 2208 (Methocel TM K15M Premium CR) (or Methocel TM K100M Premium CR) was sieved through a deagglomerated #30 US standard mesh sieve and then 3 The silicified microcrystalline cellulose ProSolv was ground in an oblique cone mixer (250 rev ± 5 rev). TM HD90 and colloidal silica were blended. The blended sample was then passed through a Round 1601 impeller (2A024R screen) and then 3 Sieve magnesium stearate in an oblique cone mixer (125 rev ± 5 rev) (through a deagglomerated #30 US standard mesh sieve) and blended. The blended sample is compressed into tablets. Optionally, the tablets are further coated with a hypromellose (HPMC-based) coating such as A similar process can be used for a composition comprising 190 mg of levetiracetam. Example 2: Evaluation of Levetiracetam Plasma Levels

[0166] AMCI clinical trial and aged rat study previously used WO2016191288 (incorporated herein by reference in its entirety.) to establish a steady-state levetiracetam plasma concentration range effective for treating cognitive impairment. In one embodiment, the concentration range of levetiracetam is between 2.9 and 4.4 μg / mL. In another embodiment, the concentration range of levetiracetam is between 1.9 and 4.4 μg / mL. On the other hand, the effective plasma concentration is between 1.9 and 3.9 μg / mL. See Figure 1 .

[0167] This example further describes a two-group, single-dose, two-period, two-way crossover, food-effect study of two extended-release levetiracetam tablets (i.e., 190 mg tablet A of Table 1 and 220 mg tablet D of Table 2). Study Design

[0168] This was an open label, randomized, two-group, single-dose, two-period crossover food effect study. Fifty six (56) healthy subjects were enrolled. Subjects who successfully completed the screening process were enrolled at the study center the evening before the first dose. Subjects who continued to meet the inclusion / exclusion criteria on the morning of dosing were assigned a subject number based on the order in which they successfully completed the required screening process and procedures. Dosing days were separated by a washout period of at least 7 days. Subjects were randomly assigned to one of two groups: Group 1: Subjects (n=28) received extended release tablet A of Table 1 (190 mg). Treatment A: Tablet A Dose = 1 x 190 mg tablet, orally, fasting Treatment B: Tablet A Dose = 1 x 190 mg tablet, orally with food Group 2: Subjects (n=28) received extended release tablet D of Table 2 (220 mg). Treatment A: Tablet D Dose = 1 x 220 mg tablet, orally, fasting Treatment B: Tablet D Dose = 1 x 220 mg tablet, orally with food Clinical Procedure Overview

[0169] During each study, 6 mL blood samples were obtained before each administration and after each dose at selected times until 24 hours after administration. A total of 34 pharmacokinetic blood samples were collected from each subject, with 17 samples during each study. In addition, blood was drawn and urine was collected for clinical laboratory tests at screening and exit from the study.

[0170] During each study period, subjects were allowed to enter the study unit the night before the scheduled dose. Subjects were confined to the study center during each study period until the 24-hour blood draw and other study procedures were completed. Procedure for collecting samples for pharmacokinetic analysis

[0171] Blood samples (1 x 6 mL) were collected in vacutainers containing K2-EDTA as a preservative before (0) and 1.0, 2.0, 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10, 12, 18 and 24 hours after dosing. Bioanalysis Overview

[0172] The plasma samples were analyzed for levetiracetam using a validated LC-MS-MS method. The method was validated for levetiracetam in the range of 0.0500 to 30.0 μg / mL based on the analysis of 0.200 mL human EDTA plasma. The data were stored in Watson Laboratory Information Management System (LIMS; Version 7.2.0.03, Thermo Fisher Scientific). Pharmacokinetic analysis

[0173] Data were analyzed by non-compartmental methods in WinNonlin. Concentration-time data below the limit of quantification (BLQ) were treated as zero in data summaries and descriptive statistics. In pharmacokinetic analyses, BLQ concentrations were treated as zero from time zero until the time when the first quantifiable concentration was observed; buried and / or terminal BLQ concentrations were treated as "missing". Actual sample times were used for all pharmacokinetic and statistical analyses.

[0174] The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to peak concentration (Tmax), elimination rate constant (λz), terminal half-life (T1 / 2), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUClast), and area under the plasma concentration-time curve extrapolated from time-zero to infinity (AUCinf). In addition, Cmax, AUClast, and AUCinf were dose normalized. Steady-state modeling

[0175] Based on steady-state modeling of the PK profile of 190 mg Tablet A, plasma concentrations of levetiracetam were between 1.9 and 4.4 μg / mL during most of the 24-hour period following dosing. Figure 2 .

[0176] Based on steady-state modeling of the PK profile of the 220 mg Tablet D, plasma concentrations of levetiracetam were between 2.9 and 4.4 μg / mL during most of the 24-hour period following dosing. Figure 3 . Example 3: Effect of levetiracetam on hippocampal functional connectivity: Alzheimer's disease-related LEV-HFC study Subjects

[0177] A phase 2, randomized, double-blind, placebo-controlled, crossover clinical trial was conducted in 26 CN subjects (age range 55 to 75 years) to evaluate the potential effects of levetiracetam on hippocampal functional connectivity (a marker of cognitive decline and cognitive impairment and risk of progression to AD). 35 patients were recruited and assessed for eligibility, and 26 eligible subjects were divided into either Group A or Group B treatment groups. Group A subjects received oral placebo tablets daily for two weeks, followed by a four-week washout period; then, subjects received oral levetiracetam tablets daily for two weeks (i.e., two weeks of placebo treatment, four weeks of washout period, and two weeks of levetiracetam treatment). Group B subjects received treatment in the opposite order (i.e., two weeks of levetiracetam treatment, four weeks of washout period, and two weeks of placebo treatment). The tablets are characterized by 220 mg of levetiracetam in an extended release form, i.e., Tablet D described above (Table 2). A flowchart of the study design is shown in Figure 5 middle. MRI Protocol

[0178] For each scanning session, imaging was performed on a 3T GE MR750 whole body scanner (GE Healthcare, Waukesha WI) with a body transmitter and a 32-channel head receiving coil (Nova Medical, Wilmington MA). Imaging acquisition included T1- and T2-weighted high-resolution anatomical images (TR = 2521.27 ms, TE = 3.596 ms, voxel resolution: 0.5x0.5x0.8 mm3, FOV: 25.6 cm, flip angle: 8°). Functional images included episodic memory (300 s duration), finger tapping (192 s duration), and two resting states (480 s duration, one AP axial scan and one PA axial scan). Functional imaging parameters included: TE: 33.5ms, TR: 800ms, 50° flip angle, 128×128 acquisition matrix, 20.8cm axial FOV, 2mm thick slices, 8-band simultaneous multi-slice acceleration, 1 / 3blipped-CAIPI field of view offset and 72 total slices, consistent with the Lifespan Human Connectome Project acquisition protocol. T2-discrimination (flair): voxel resolution: 0.5x0.5x 0.8mm3, FOV: 25.6cm, TR: 4002ms, TE: 161.893ms, 90° flip angle. Blood flow images (pcASL) included: 72 frames, voxel resolution: 1.875x1.875x4mm3, 24cm FOV, TR: 4667ms, TE: 56.32ms. Resting state image preprocessing

[0179] Image preprocessing was performed using Analysis of Functional NeuroImages (AFNI) software (http: / / afni.nimh.nih.gov / afni / ), SPM8 (Wellcome Trust, London, UK), and MATLAB (MathWorks, Natick, Massachusetts). Preprocessing allowed T1 balancing (removing the first 15 seconds of R-fMRI data); slice acquisition-related time shift correction (3dTshift); motion correction (3dvolreg); detrending (3dDetrend); despiking (3dDespike); spatial normalization (native to Montreal Neurological Institute [MNI] space, SPM8); retrieval of white matter and cerebrospinal fluid (CSF) signal averaged in MNI space using standard SPM white matter and CSF masks (3dROIstats); removal of white matter, CSF signal, and motion effects (3dDeconvolve); global signal removal necessity check (global signal is required) (see, e.g., Chen et al., 2012); and low-frequency bandpass filtering (3dFourier, 0.015-0.1 Hz). Total functional connectivity index

[0180] The total functional connectivity index (TFCI) was obtained based on the traditional region of interest (ROI)-based method (Chen et al., 2011), in which a single brain was automatically segmented into 90 regions according to the automatic anatomical labeling (AAL) toolbox (3), and the FCI was calculated as the sum of the Pearson cross-correlation coefficients between the seed region and all other regions in the brain. Specifically, first, the entire cerebral cortex was divided into 90 regions based on the AAL template, and the blood oxygen level-dependent (BOLD) time series of each region was extracted from the preprocessed resting-state dataset disclosed in Tzourio-Mazoyer et al. (2002) using the AAL template mask. Secondly, the functional connectivity between each ROI and other brain regions was calculated using Pearson cross-correlation analysis. Therefore, a vector consisting of 89 cross-correlation coefficient (CC) values ​​for each ROI was obtained. Finally, the FCI value of each ROI was calculated by summing the 89 CC values ​​within each ROI vector. In addition to eliminating outlier effects, the median functional connectivity index (MFCI) was calculated by the median of the 89 CC values ​​within each ROI vector. TFCI and MFCI were calculated for left, right, and bilateral regions. result

[0181] Of the 35 CN subjects assessed for eligibility, 9 did not meet the eligibility criteria and were not enrolled. One recruited subject had no detectable levetiracetam in the blood sample and was discarded from the analysis. A total of 25 participants (15 females, mean [SD] age of 65.9 [3.8] years, 10 males, mean [SD] age of 66.7 [5.5] years) were enrolled, randomly assigned (12 participants into Group A and 13 participants into Group B), and completed the study. See Table 3. Overall, levetiracetam treatment significantly reduced the functional connectivity of the hippocampal network compared with placebo (paired t-test, t=-2.8044, p<0.0098; Figure 6 ). Table 3 - Demographic characteristics and functional connectivity strength

[0182] In Table 3, in the Period I and II columns, numbers with * represent functional connectivity from subjects who received two weeks of placebo treatment, and all other numbers represent functional connectivity from subjects who received two weeks of levetiracetam treatment.

[0183] Table 3 shows the individual scores for each participant. Briefly, the columns from left to right indicate the subject's ID number, the subject's sex, the subject's age, the subject's education level in years, the subject's Montreal Cognitive Assessment (MoCA) test of dementia score, the subject's APOE genotype, the subject's baseline hippocampal functional connectivity, the hippocampal functional connectivity during the first two weeks of treatment (levetiracetam or placebo), the hippocampal functional connectivity during the second two weeks of treatment after washout (levetiracetam or placebo), and the levetiracetam level in the blood after treatment with levetiracetam.

[0184] Exemplary methods and materials are described, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of various aspects and embodiments. The materials, methods, and examples are illustrative only and not limiting.

Claims

1. A method for preventing or slowing the progression of cognitive impairment or preventing the development of cognitive decline or reducing the rate of cognitive decline in a subject who exhibits or presents cognitive performance within the normal range for the age of the subject, the method comprising administering to the subject levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof at a daily dose of 0.7-350 mg, or comprising administering to the subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam or seletracetam or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

2. The method according to claim 1, wherein the daily dose of levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof is 7-350 mg.

3. The method according to claim 1, wherein the daily dose of brivaracetam or a pharmaceutically acceptable salt thereof is 0.7-180 mg.

4. The method according to claim 1, wherein the daily dose of levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof is 125-250 mg.

5. The method according to claim 4, wherein the daily dose of levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof is 220 mg.

6. The method according to claim 4, wherein the daily dose of levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof is 190 mg.

7. The method of claim 1, wherein the pharmaceutical composition is formulated as one or more of an oral form, an extended release form, or a single unit dosage form or for once-daily administration.

8. The method according to claim 7, wherein the extended release form is a controlled release form, a delayed release form, a sustained release form, a delayed release form or a slow release form.

9. The method of claim 1, wherein the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 220 mg, and wherein the pharmaceutical composition further comprises 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg-1.4 mg of colloidal silicon dioxide, 92.8 mg-119.2 mg of silicified microcrystalline cellulose and 6.0 mg-6.7 mg of magnesium stearate.

10. The method of claim 9, wherein the pharmaceutical composition comprises 280 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 92.8 mg of silicified microcrystalline cellulose, and 6.0 mg of magnesium stearate.

11. The method of claim 9, wherein the pharmaceutical composition comprises 347.5 mg of hydroxypropyl methylcellulose, 1.4 mg of colloidal silicon dioxide, 119.2 mg of silicified microcrystalline cellulose, and 6.7 mg of magnesium stearate.

12. The method of claim 1, wherein the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 190 mg, and wherein the pharmaceutical composition additionally comprises 300 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 102.8 mg of silicified microcrystalline cellulose or amorphous calcium hydrogen phosphate and 6 mg of magnesium stearate.

13. The method according to any one of claims 9-12, wherein the hydroxypropyl methylcellulose is hypromellose 2208.

14. The method according to any one of claims 9 to 13, wherein the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

15. The method of claim 1, wherein the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is in extended release form and provides a steady-state plasma concentration of levetiracetam in a subject between 1.9 μg / mL and 4.4 μg / mL within 3 hours after administration and extending for at least 8 hours over a 24 hour period after said administration.

16. The method of claim 15, wherein the pharmaceutical composition provides a steady-state plasma concentration of levetiracetam within 2 hours after the administration and extending for at least 13 hours over a 24-hour period after the administration.

17. The method of claim 15, wherein the pharmaceutical composition provides a steady-state plasma concentration of the levetiracetam within 1 hour after the administration and extending for at least 13 hours over a 24-hour period after the administration.

18. The method of claim 1, wherein the pharmaceutical composition provides a steady-state plasma concentration of levetiracetam within 1 hour after the administration and extending for at least 13 to 16 hours over a 24 hour period after the administration.

19. The method of claims 15-18, wherein the pharmaceutical composition is formulated in one or more of an oral form, an extended release form, or a single unit dosage form or for once-daily administration.

20. The method of claim 19, wherein the extended release form is a controlled release form, a delayed release form, a sustained release form, a delayed release form or a slow release form.

21. A method for preventing or slowing the progression of cognitive impairment or preventing the development of cognitive decline or reducing the rate of cognitive decline in a subject who exhibits or presents cognitive performance within the normal range for the age of the subject, the method comprising administering GABA to the subject A An α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or administering to the subject a pharmaceutical composition comprising any of them and a pharmaceutically acceptable carrier.

22. The method of claim 21, wherein the GABA A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or GABA of the pharmaceutical composition A An α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, selected from the group consisting of: i) Compounds of formula II: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; R 1 , R 2 , R 4 and R 5 Each occurrence of is independently selected from: 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) 0-3 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) 0-3 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 and -P(O)(H)(OR); R 3 Selected from the group consisting of: 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) 0-3 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) 0-3 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 and -P(O)(H)(OR); -C≡CH, -C≡CR 9 , -(C1-C6)alkyl-C≡C-R 10 , -CH2-O-R 10 , -CH2-O-CH2-R 10 wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Where R 3 independently substituted with 0-5 R'; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; wherein R7 is selected from the group consisting of: -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5 to 10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; wherein each R7 is independently substituted by 0-5 R'; Each R 8 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 membered heteroaryl, and -(C1-C6)alkyl-5-10 membered heteroaryl; Where each R except -H and -(C1-C6)alkyl 8 independently substituted by 0-5 -halogen, -(C1-C6)alkyl, -CF3, -OCF3 or O-(C1-C6)alkyl; Where R 9 Selected from the group consisting of: -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl, 5-10 membered heterocyclic, Each R 9 Independently by 0-5 R 11 replace; Where R 10 is selected from the group consisting of -H, halogen, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5-10 membered heteroaryl, Each R 10 replaced by 0-5 R's; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CN, SCH3, -CF3, -OH, -OCF3, OCHF2, -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5- to 10-membered heteroaryl; Each R is independently selected from the group consisting of: 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)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-, (C6-C10)-aryl-N(R")-(C1-C12)aliphatic-, 3- to 10-membered heterocyclic group-, (3- to 10-membered heterocyclic)-(C1-C12)aliphatic-, (3- to 10-membered heterocyclic group)-O-(C1-C12)aliphatic group-, (3- to 10-membered heterocyclic group)-N(R")-(C1-C12)aliphatic group 5- to 10-membered heteroaryl-, (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-; and (5- to 10-membered heteroaryl)-N(R")-(C1-C12)-aliphatic-; wherein the heterocyclyl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O, S, SO and SO2, and the heteroaryl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O and S; where each occurrence of R is independently replaced by 0-5 R'; or when two R groups are attached to the same atom, the two R groups may be taken together with the atoms to which they are attached to form a 3- to 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', and wherein the ring is optionally fused to a (C6-C10)aryl, a 5- to 10-membered heteroaryl, a (C3-C10)cycloalkyl, or a 3- to 10-membered heterocyclyl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-, wherein each occurrence of R" is independently substituted with 0-5 substituents 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 )2, where R o Each occurrence of is independently selected from the group consisting of: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl; and ii) Compounds of formula IV: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; R 1 , R 4 and R 5 Each of which is independently selected from: R 1 , R 4 and R 5 Each occurrence of is independently selected from: 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) 0-3 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≡C-R 8 , CH2CF3 or CHF2; R 2 Select from -OR 8 、-SR 8 、-(CH2) n OR 8 、-(CH2) n O(CH2) n R 8 、-(CH2) p R 8 or -(CH2) n N(R”)R 10 , wherein n is an integer selected from 0-4; p is an integer selected from 2-4; Where R 2 independently substituted with 0-5 R'; Each R 3 Independently selected from: -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- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -(C1-C6)alkyl-C≡CR 10 、-CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-10 membered heterocyclic or heteroaryl group is substituted by 0-3 R7; Where R 3 independently substituted with 0-5 R'; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; R7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl; wherein each R7 is independently substituted with 0-5 R'; R 8 independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, 5-10-membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl, and -(C1-C6)alkyl-(C3-C6)cycloalkyl; Where R 8 Each occurrence of is independently replaced by 0-5 R'; Where R 9 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 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, Each of which each of R 9 Independently by 0-5 R 11 replace; R 10 is selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, 5- to 10-membered heteroaryl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5- to 10-membered heteroaryl, Where R 10 Each occurrence of is independently replaced by 0-5 R'; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CF3, -OCF3, -OH, OCF2H, -O-(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, -O-CH2-(C3-C6)cycloalkyl, -CN, and -5- to 10-membered heteroaryl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-aliphatic, -(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-; wherein each occurrence of R' is independently replaced by 0-5 R independently selected from the group consisting of t Substitution: 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl-.

23. The method of claim 22, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) Compounds of formula II: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; Each R 1 independently selected from the group consisting of halogen, -H, -(C1-C6)alkyl, -OH, -O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3, -OCHF2, -OMe, -C≡CR 8 , -CHF2, -CH2CF3, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; wherein R 1 independently substituted with 0-5 R'; R 2 Selected from the group consisting of: -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)-aryl-、 (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-, (C6-C10)-aryl-N(R")-(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-N(R")-(C1-C12)aliphatic-, (3- to 10-membered heterocyclic)-(C1-C12)aliphatic-, (3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-, and (3- to 10-membered heterocyclic group)-N(R")-(C1-C12)aliphatic group Where R 2 independently substituted with 0-5 R'; R 3 Selected from the group consisting of: -(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- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, -(C1-C6) alkyl-C≡CR 10 、-CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Where R 3 independently substituted with 0-5 R'; R 4 and R 5 Each is independently selected from the group consisting of: -H, halogen, -(C1-C6)alkyl, or -(C1-C6)alkyl-(C6-C10)aryl; the (C6-C10)aryl is independently substituted by 0-5 halogens; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; wherein R7 is selected from the group consisting of: -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5 to 10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; wherein each R7 is independently substituted by 0-5 R'; Each R 8 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 membered heteroaryl, and -(C1-C6)alkyl-5-10 membered heteroaryl; Where each R except -H and -(C1-C6)alkyl 8 independently substituted by 0-5 -halogen, -(C1-C6)alkyl, -CF3, -OCF3 or O-(C1-C6)alkyl; Where R 9 Selected from the group consisting of: -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl, 5-10 membered heterocyclic, Each R 9 Independently by 0-5 R 11 replace; Where R 10 is selected from the group consisting of -H, halogen, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5-10 membered heteroaryl, Each R 10 replaced by 0-5 R's; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CN, SCH3, -CF3, -OH, -OCF3, OCHF2, -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5- to 10-membered heteroaryl; Each R is independently selected from the group consisting of: 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)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-, (C6-C10)-aryl-N(R")-(C1-C12)aliphatic-, 3- to 10-membered heterocyclic group-, (3- to 10-membered heterocyclic)-(C1-C12)aliphatic-, (3- to 10-membered heterocyclic group)-O-(C1-C12)aliphatic group-, (3- to 10-membered heterocyclic group)-N(R")-(C1-C12)aliphatic group 5- to 10-membered heteroaryl-, (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-; and (5- to 10-membered heteroaryl)-N(R")-(C1-C12)-aliphatic-; wherein the heterocyclyl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O, S, SO and SO2, and the heteroaryl has 1-4 heteroatoms independently selected from the group consisting of: N, NH, O and S; where each occurrence of R is independently replaced by 0-5 R'; or when two R groups are attached to the same atom, the two R groups may be taken together with the atoms to which they are attached to form a 3- to 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', and wherein the ring is optionally fused to a (C6-C10)aryl, a 5- to 10-membered heteroaryl, a (C3-C10)cycloalkyl, or a 3- to 10-membered heterocyclyl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-, wherein each occurrence of R" is independently substituted with 0-5 substituents 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 )2, where R o Each occurrence of is independently selected from the group consisting of: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl; and ii) Compounds of formula IV: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, wherein: m is 0-3; Each R 1 independently selected from the group consisting of: halogen, -H, -(C1-C6)alkyl, -C≡CR 9 , -OH, -O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3, -CHF2, -CH2CF3, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Where R 1 independently substituted with 0-5 R'; R 2 Selected from the group consisting of: -OR 8 、-SR 8 、-(CH2) n OR 8 、-(CH2) n O(CH2) n R 8 、-(CH2) p R 8 and -(CH2) n N(R”)R 10 , wherein n is an integer selected from 0-4; p is an integer selected from 2-4; Where R 2 independently substituted with 0-5 R'; Each R 3 Independently selected from the group consisting of: -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- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, -CH2-OR 10 、-CH2-O-CH2-R 10 wherein each 5-10 membered heterocyclic or heteroaryl group is substituted by 0-3 R7; Where R 3 independently substituted with 0-5 R'; R 4 and R 5 each independently selected from the group consisting of: -H, halogen, and -(C1-C6)alkyl; R 6 selected from the group consisting of: -H and -(C1-C6)alkyl; R7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl; wherein each R7 is independently substituted with 0-5 R'; R 8 independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, 5-10-membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl, and -(C1-C6)alkyl-(C3-C6)cycloalkyl; Where R 8 Each occurrence of is independently replaced by 0-5 R'; Where R 9 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 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, Each of which each of R 9 Independently by 0-5 R 11 replace; R 10 is selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, 5- to 10-membered heteroaryl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5- to 10-membered heteroaryl, Where R 10 Each occurrence of is independently replaced by 0-5 R'; Where R 11 Each occurrence of is independently selected from the group consisting of -halogen, -CF3, -OCF3, OCF2H, -O-(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, -O-CH2-(C3-C6)cycloalkyl, and -5- to 10-membered heteroaryl; wherein each occurrence 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; wherein each occurrence of R" is independently selected from the group consisting of H, -(C1-C6)-aliphatic, -(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-; wherein each occurrence of R' is independently replaced by 0-5 R independently selected from the group consisting of t Substitution: 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl-.

24. The method of claim 23, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound of formula II or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

25. The method of claim 23, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound of formula IV or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

26. The method of claim 21, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of Compounds 1-12, 44-56, 101-268, 270-644, 646-687, 689-698, 700-703, 705, 707-721 and 723-740 or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof.

27. The method of claim 26, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound having the following structure: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

28. The method of claim 27, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a polymorphic crystalline form of a compound having the following structure: wherein the polymorphic crystalline form is Form A and exhibits an XRPD comprising: a. at least one peak selected from 3.0 and 21.0° 2θ ± 0.2° 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 ° 2θ ± 0.2 ° 2θ.

29. The method of claim 27, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a polymorphic crystalline form of a compound having the following structure: wherein the polymorphic crystalline form is Form B and exhibits an XRPD comprising: a. at least one peak selected from 13.0 and 15.3° 2θ ± 0.2° 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° 2θ ± 0.2° 2θ.

30. The method of claim 27, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a solvate crystalline form of a compound having the following structure: wherein the solvate crystalline form is Form C and exhibits an XRPD comprising: a. at least one peak selected from 8.5 and 18.9° 2θ ± 0.2° 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° 2θ ± 0.2° 2θ.

31. The method of claim 27, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a polymorphic crystalline form of a compound having the following structure: wherein the polymorphic crystalline form is Form E and exhibits an XRPD comprising: a. at least one peak selected from the group consisting of 11.4, 18.1 and 21.6° 2θ ± 0.2° 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° 2θ ± 0.2° 2θ.

32. The method of claim 27, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a hydrate crystalline form of a compound having the following structure: Wherein the hydrate crystalline form is Form F and exhibits an XRPD comprising: a. at least one peak selected from the group consisting of 9.9, 11.9, 17.3, 19.4 and 25.7° 2θ ± 0.2° 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° 2θ ± 0.2° 2θ.

33. according to the method described in any one of claims 21-32, wherein said GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is present in an amount between 5 mg and 1000 mg.

34. The method of claim 21, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) Compounds of formula Ia: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, in: m is an integer selected from 0-4; Each R 1 Independently selected from: halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclic group, (C3-C10)-cycloalkenyl wherein each 5-6 membered heteroaryl and 3-10 membered heterocyclic ring is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3-10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace; Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; R 3 independently selected from: -H, -(C1-C6)alkyl, -5 to 10 membered heteroaryl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl and -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R o , oxo, -CH2OR o 、-CH2N(R o )2、-C(O)N(R o )2. -C(O)OR o , -CF3, -OCF3 and -N(R o )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, -(3-10 membered)heterocyclyl, and (C6-C10)-aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C1-C6)alkyloxy, (C1-C6)alkylamino, -(C3-C6)cycloalkyl, -5 to 10-membered heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -5 to 10-membered heteroaryl-(C1-C6)alkyl, and -3-10-membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; or when two R7 groups are attached to the same atom, the two R7 groups may be taken together with the atoms to which they are attached to 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'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2, wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, and -(C6-C10)aryl; R" is independently substituted by 1-3 substituents, wherein the substituents are selected from: halogen, -CF3, -OCF3, -O-(C1-C6)-aliphatic or -(C1-C6)-aliphatic; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 Selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; ii) Compounds of formula Ib: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -Ome, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-6 membered heteroaryl or 3-10 membered heterocycle is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3-10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace; Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; R 3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 、-(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -3 to 10 membered heterocyclyl and -5-10 membered heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C1-C6)alkyloxy, (C1-C6)alkylamino, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5 to 10 membered heteroaryl and -3-10 membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; or when two R7 groups are attached to the same atom, the two R7 groups may be taken together with the atoms to which they are attached to 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'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2; wherein R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-5- to 10-membered heteroaryl, —5- to 10-membered heteroaryl, —3- to 10-membered heterocyclyl, —(C3-C6)cycloalkyl, and —(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from: halogen, -CF3, -OCF3, -O(C1-C6)-aliphatic, -(C1-C6)-aliphatic and -5 to 10 membered heteroaryl; Each R 4 and R 6 Independently selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; iii) Compounds of formula Ic: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl R 9 Each occurrence of is independently represented by 0-5 R 11 replace; R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; Each occurrence of R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5- to 10-membered heteroaryl, and -3-10-membered heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R")2, wherein each occurrence of R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-5 to 10 membered heteroaryl, -5 to 10 membered heteroaryl, -3 to 10 membered heterocyclyl, -(C3-C6)cycloalkyl, and -(C6-C10)aryl, and R" is independently substituted with 1 to 3 substituents selected from: halogen, -CF3, -OCF3, -(C1-C6)-aliphatic, and -5 to 10 membered heteroaryl; Each R 4 and R 6 Independently selected from -H or (C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; iv) Compounds of formula Id: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3-10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl Where R 9 Each occurrence of is independently represented by 0-5 R 11 replace; Where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; R 3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 、-(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R 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 )2, where R o Each occurrence of is independently selected from: -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl; wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5 to 10 membered heteroaryl and -3-10 membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2; wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe and -(C6-C10)aryl; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 Selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; v) Compounds of formula le: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl R 9 Each occurrence of is independently represented by 0-5 R 11 Substitution, where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -3-10-membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2, wherein each R' is independently substituted with 0-5 R"; wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe and -(C6-C10)aryl; Each R 4 are independently -H or (C1-C6)alkyl; Each R 6 are independently -H or -(C1-C6)alkyl, R 13 and R 14 Each of is independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; and vi) Compounds of formula If: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 、-(C1-C6)alkyl-C≡CR 9 , -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered heteroaryl), -(3- to 10-membered)heterocyclyl R 9 Each occurrence of is independently represented by 0-5 R 11 Substitution, where R 11 Each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, and -5- to 10-membered heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5- to 10-membered heteroaryl-(C1-C6)alkyl and -3-10-membered heterocyclyl, wherein each R7 is independently substituted by 0-5 R'; each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3, and -N(R")2; wherein each R' is independently substituted by 0-5 R", wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe and -(C6-C10)aryl; R 4 is -H or (C1-C6) alkyl; R 6 is -H or -(C1-C6)alkyl; Each R 13 and R 14 Independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

35. The method of claim 34, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound selected from the group consisting of Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie and Formula If, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

36. The method of claim 21, wherein the GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of compounds 742-755, 758-763, 765-779, 781-795, 797-810, 813-828, 830, 831, 833-846, 848-891, 893-903, 905, 907-977, 979-1012, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof.

37. A method for preventing or slowing the progression of cognitive impairment or preventing the development of cognitive decline or reducing the rate of cognitive decline in a subject who exhibits or presents cognitive performance within the normal range for the age of the subject, the method comprising administering to the subject A) levetiracetam, brivaracetam or seltestam or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam, brivaracetam or seltestam or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and B) GABA A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or a compound containing GABA A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharmaceutically acceptable carrier, or C) a pharmaceutical composition comprising A and B and a pharmaceutically acceptable carrier.

38. The method according to claim 37, wherein A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof, and B's GABA are orally administered. A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or a pharmaceutical composition of C.

39. The method of claim 37, wherein A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof, and B's GABA are administered once daily. A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or a pharmaceutical composition of C.

40. The method of claim 37, wherein A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof, and B's GABA are administered twice daily. A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or a pharmaceutical composition of C.

41. The method according to claim 37, wherein A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof, and B's GABA are administered simultaneously. A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof.

42. The method according to claim 37, wherein A's levetiracetam, seleracetam or brivaracetam or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising levetiracetam, brivaracetam or seleracetam or a pharmaceutically acceptable salt thereof, and B's GABA are administered sequentially. A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof or a compound containing GABA A A pharmaceutical composition of an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof.

43. The method of claim 37, wherein the levetiracetam, brivaracetam or seletracetam of A or C or a pharmaceutically acceptable salt thereof is administered at a daily dose of 0.7-350 mg.

44. The method of claim 43, wherein the levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof of A or C is administered at a daily dose of 125-250 mg.

45. The method of claim 44, wherein the levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof of A or C is administered at a daily dose of 220 mg.

46. ​​The method of claim 44, wherein the levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof of A or C is administered at a daily dose of 190 mg.

47. The method of claim 43, wherein the brivaracetam or a pharmaceutically acceptable salt thereof of A or C is administered at a daily dose of 0.7-180 mg.

48. The method of claim 43, wherein A's levetiracetam or seletracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of 7-350 mg.

49. The method of claim 37, wherein the pharmaceutical composition of A, the pharmaceutical composition of B, or the pharmaceutical composition of C is formulated in one or more of an oral form, an extended release form, or a single unit dosage form, or for once-daily administration.

50. The method of claim 49, wherein the extended release form is a controlled release form, a delayed release form, a sustained release form, a delayed release form or a slow release form.

51. The method of claim 37, wherein the levetiracetam or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is present in an amount of 220 mg, and wherein the pharmaceutical composition further comprises 280 mg-350 mg of hydroxypropyl methylcellulose, 1.2 mg-1.4 mg of colloidal silicon dioxide, 92.8 mg-119.2 mg of silicified microcrystalline cellulose, and 6.0 mg-6.7 mg of magnesium stearate.

52. The method of claim 51, wherein the pharmaceutical composition comprises 280 mg or 347.5 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 92.8 mg or 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg or 6.7 mg of magnesium stearate.

53. The method of claim 37, wherein levetiracetam or a pharmaceutically acceptable salt in the pharmaceutical composition is present in an amount of 190 mg, and wherein the pharmaceutical composition further comprises 300 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 102.8 mg of silicified microcrystalline cellulose or amorphous dibasic calcium phosphate, and 6 mg of magnesium stearate.

54. The method of any one of claims 51-53, wherein the hydroxypropyl methylcellulose is hypromellose 2208.

55. The method according to any one of claims 51-54, wherein the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC 90.

56. The method of claim 37, wherein the pharmaceutical composition comprising levetiracetam or a pharmaceutically acceptable salt thereof of A or C is in an extended release form and provides a steady-state plasma concentration of levetiracetam in a subject within 3 hours after administration and extending for at least 8 hours in a 24-hour period after said administration, within 2 hours after administration and extending for at least 13 hours in a 24-hour period after said administration, within 1 hour after administration and extending for at least 13 hours in a 24-hour period after said administration, or within 3 hours after administration and extending for at least 13 to 16 hours in a 24-hour period after said administration.

57. according to the method described in any one of claims 37-56, wherein said GABA A α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph or GABA of the pharmaceutical composition A The α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is present in an amount between 5 mg and 1000 mg.

58. The method of any one of claims 1-57, wherein the subject is at risk for developing cognitive decline or impairment, wherein the risk is associated with the presence of altered hippocampal functional connectivity in the subject.

59. The method of any one of claims 1-57, wherein the subject is at risk for developing cognitive decline or impairment, wherein the risk is associated with the presence of one or more genomic variations, mutations, or polymorphisms in the subject's genome that are associated with changes in the expression of a gene selected from the group consisting of ABCA7, CLU, CR1, PICALM, PLD3, TREM2, and SORL1.

60. The method of any one of claims 1-57, wherein the subject is at risk for developing cognitive decline or impairment, wherein the risk is associated with the presence of one or more genomic variations, mutations, or polymorphisms in the subject's genome that are associated with changes in the expression of TREM2.

61. The method of any one of claims 1-57, wherein the subject is at risk for developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of at least one allele of the APOE4 gene in the subject's genome.

62. The method of any one of claims 1-57, wherein the subject is at risk for developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more biofluid biomarkers selected from the group consisting of p-tau, t-tau, and amyloid beta 42 in the subject.

63. The method of any one of claims 1-62, wherein the subject is a human.

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