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

Abstract

A method for preventing or slowing the progression of cognitive impairment or preventing the onset or slowing the rate of cognitive decline in a subject exhibiting or displaying 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 pharma- ceutical acceptable salt thereof, a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutical salt thereof and a pharma- ceutical acceptable carrier, GABA. A α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, GABA A A pharmaceutical composition comprising an alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharma- ceutically acceptable carrier, or a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutical salt thereof and a GABA receptor antagonist. A The method includes administering a combination or composition comprising an alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof.

Description

[Technical field]

[0001] Statement of Government Support The subject matter of this disclosure was made with Government support under Grant No. 1R21AG056882-01 awarded by the National Institutes of Health (NIH), an agency of the United States Government, specifically the National Institute on Aging (NIA). The United States Government has certain rights in the subject matter of this disclosure.

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

[0003] Field of the Disclosure The present disclosure relates to a method for preventing or slowing the progression of cognitive impairment or preventing the onset or slowing the rate of cognitive decline in a subject exhibiting or exhibiting 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 pharma- ceutical acceptable salt thereof, a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutical salt thereof and a pharma- ceutical acceptable carrier, GABA. A α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, GABA A A pharmaceutical composition comprising an alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharma- ceutically acceptable carrier, or a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutical salt thereof and a GABA receptor antagonist. A The method includes administering a combination or composition comprising an alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof.

[0004] In some embodiments of the present disclosure, the subject has one or more risks that predict or are related to the onset of cognitive decline or cognitive impairment or the progression of cognitive decline or cognitive impairment.Such risks are related to aging, one or more genetic risks selected from the group of genomic variants, mutations or polymorphisms related to the change in expression of genes selected from the group consisting of ATP-binding cassette subfamily A member 7 (ABCA7), clusterin (CLU), complement receptor type 1 (CR1), phosphatidylinositol-linked clathrin assembly protein (PICALM), phospholipase D3 (PLD3), triggering receptor 2 expressed on myeloid cells (TREM2) and sortilin-related receptor 1 (SORL1) in the genome of the subject, the presence of at least one allele of APOE4 gene in the genome of the subject, the presence of one of the further biofluid biomarkers selected from the group consisting of p-tau, t-tau and amyloid beta 42 in the subject, or the presence of altered functional connectivity in the hippocampus in the subject. [Background technology]

[0005] Background of the Disclosure Cognitive ability may decline as a normal result of aging, or may be associated with changes in hippocampal functional connectivity, genomic variation, mutation or polymorphism, or various biofluid biomarkers associated with the development of cognitive impairment or cognitive decline in the context of CNS disease and disorders, such as Alzheimer's disease.Subjects may exhibit or show normal range cognitive ability for their age, but these subjects may still be at risk of developing cognitive impairment or cognitive decline.

[0006] In addition to aging, other such risk factors include genetic risk factors that may feature genomic variants, polymorphisms and mutations associated with the onset of CNS diseases or disorders associated with the onset of cognitive impairment or cognitive decline. For example, using genome-wide association studies (GWAS), variants of the ABCA7 gene have been associated with the onset of Alzheimer's disease. In fact, it has been reported that these variants are enriched in Alzheimer's disease 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. 2019 Aug;138(2):201-220). Similarly, CR1 polymorphisms and CLU variants have been reported to link with AD pathogenesis. Multiple polymorphisms in and around the PICALM gene, a rare missense variant in the PLD3 gene, and some variations in SORL1 have also been reported to be associated with the onset of late-onset AD. Similarly, variants in the TREM2 gene are associated with AD and induce partial loss of function of the TREM2 protein, altering the behavior of microglial cells, including their response to amyloid plaques.

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

[0008] Currently, there is no FDA-approved prophylactic treatment for subjects who exhibit or display cognitive abilities within the normal range for their age, but who may be at risk of developing or progressing to cognitive impairment or decline. Thus, there is a need for effective clinical and therapeutic measures to prevent or slow the progression of cognitive impairment, or to prevent the onset of cognitive decline, or to slow the rate of cognitive decline, in subjects who exhibit or exhibit cognitive abilities within the normal range for their age, but who may be at risk of developing or progressing to cognitive impairment or decline. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] De Roeck A, Van Broeckhoven C, Sleegers K. The role of ABCA7 in Alzheimer's disease: evidence from genomics, transcriptomics and methylomics. Acta Neuropathol. 2019 Aug;138(2):201-220 Summary of the Invention [Means for solving the problem]

[0010] BRIEF SUMMARY OF THE DISCLOSURE The present disclosure relates to a method for preventing or slowing the progression of cognitive impairment or preventing the onset or slowing the rate of cognitive decline in a subject exhibiting or exhibiting 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 pharma- ceutical acceptable salt thereof, a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutical salt thereof and a pharma- ceutical acceptable carrier, GABA. Aα5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, GABA A A pharmaceutical composition comprising an alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharma- ceutically acceptable carrier, or a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam or a pharmaceutical salt thereof and a GABA receptor antagonist. A The method includes administering a combination or composition comprising an alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof.

[0011] In some embodiments of the present disclosure, the subject exhibits one or more risk factors that predict or are related to the onset of cognitive decline or cognitive impairment or the progression of cognitive decline or cognitive impairment.In some embodiments of the present disclosure, these risk factors can be related to aging, the presence of one or more variants, mutations or polymorphisms in the genome of the subject that are related to the change in the expression of the gene selected from the group consisting of ATP-binding cassette subfamily A member 7 (ABCA7), clusterin (CLU), complement receptor type 1 (CR1), phosphatidylinositol-linked clathrin assembly protein (PICALM), phospholipase D3 (PLD3), triggering receptor 2 expressed on myeloid cells (TREM2) and sortilin-related receptor 1 (SORL1), the presence of at least one allele of the APOE4 gene in the genome of the subject, the presence of one of the further biofluid biomarkers selected from the group consisting of p-tau, t-tau and amyloid beta 42 in the subject, or the presence of altered functional connectivity in the hippocampus in the subject.

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

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

[0014] In some embodiments, levetiracetam, brivaracetam or seletracetam of its pharmaceutically acceptable salt is formulated to be administered in one or more of oral form, sustained release form or single unit dosage form, or once a day.In some embodiments, the sustained release form is a controlled release form, an extended 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 includes administering to the subject a daily dose of a pharmaceutical composition comprising 220 mg of levetiracetam or a pharma- ceutically acceptable salt thereof, 280 mg to 350 mg of hydroxypropyl methylcellulose, 1.2 mg to 1.4 mg of colloidal silicon dioxide, 92.8 mg to 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg to 6.7 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam or a pharma-ceutically 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 another embodiment, the daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 347.5 mg hydroxypropyl methylcellulose, 1.4 mg colloidal silicon dioxide, 119.2 mg silicified microcrystalline cellulose, and 6.7 mg magnesium stearate. In another embodiment, the hydroxypropyl methylcellulose is hypromellose 2208. In another embodiment, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC90.

[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 pharma- ceutically acceptable salt thereof, 300 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 102.8 mg of silicified microcrystalline cellulose or anhydrous dicalcium phosphate, and 6 mg of magnesium stearate. In other embodiments, the hydroxypropyl methylcellulose is hypromellose 2208. In other embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC90.

[0017] In some embodiments of the present disclosure, the method includes administering a pharmaceutical composition comprising a daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof in a sustained release form, wherein the method results in a steady state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL in the subject within 3 hours of administration, lasting for at least 8 hours of a 24-hour period after said administration. In some embodiments, a sustained release pharmaceutical composition comprising a daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof results in a steady state plasma concentration of levetiracetam within 2 hours of administration, lasting for at least 13 hours of a 24-hour period after said administration. In some embodiments, a sustained release pharmaceutical composition comprising a daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof results in a steady state plasma concentration of levetiracetam within 1 hour of administration, lasting for at least 13 hours of a 24-hour period after said administration. In other embodiments, a sustained release pharmaceutical composition comprising a daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof provides said steady state plasma concentration of levetiracetam within 1 hour after administration, said steady state plasma concentration of levetiracetam lasting for at least 13-16 hours out of a 24 hour period after said administration (see FIG. 2 and WO2016191288, which is incorporated herein by reference in its entirety).

[0018] In some embodiments, the pharmaceutical composition of levetiracetam, brivaracetam or seletracetam or its pharmaceutically acceptable salt is formulated to be administered in one or more of oral form, sustained release form or single unit dosage form, or once a day.In other embodiments, the sustained release form is a controlled release form, an extended release form, a sustained release form, a delayed release form or a slow release form.

[0019] In some embodiments, GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or the GABA A The alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) A compound of formula II: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, m is 0 to 3; R 1 , R 2 , R 4 and R 5 For each occurrence, the following: halogen, -R, -OR, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 , -SiR 3 , -N(R) 2 , -SR, -SOR, -SO 2 R, -SO 2 N(R) 2 , -SO 3 R, -(CR 2 ) 1~3 R, -(CR 2 ) 1~3 -OR, -(CR 2 ) 0~3 -C(O)NR(CR 2 ) 0~3 R, -(CR 2 ) 0~3 -C(O)NR(CR 2 ) 0~3 OR, -C(O)R, -C(O)C(O)R, -C(O)CH 2 C(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 , -(CR 2 ) 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)SO 2 R, -N(R)SO 2 N(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), each independently selected from R 3 is halogen, -R, -OR, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 , -SiR 3 , -N(R) 2 , -SR, -SOR, -SO 2 R, -SO 2 N(R) 2 , -SO 3 , -SO 2 ) 1~3 , - (CR 2 ) 1~3 , -OR, - (CR 2 ) 0~3 , -C(O)NR(CR 2 ) 0~3 , - (CR 2 ) 0~3 , -C(O)NR(CR 2 ) 0~3 , -C(O)R, -C(O)C(O)R, -C(O)CH 2 C(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 , - (CR 2 ) 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)SO 2 , -N(R)SO 2N(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 , -CH 2 -OR 10 , -CH 2 -O-CH 2 -R 10 [ka] is selected from the group consisting of Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 3 is independently substituted with 0 to 5 R'; R 6 is selected from the group consisting of -H and -(C1-C6)alkyl; R 7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl; R 7 each is independently substituted with 0 to 5 R'; R 8are each 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; R 8 are -halogen, -(C1-C6)alkyl, -CF, excluding -H and -(C1-C6)alkyl. 3 , -OCF 3 or O-(C1-C6)alkyl; R 9 is -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 heterocycle, [ka] is selected from the group consisting of R 9 Each has an R of 0 to 5. 11 and R 10 is -H, halogen, -(C1-C6) alkyl, -(C6-C10) aryl, -5-10 membered heteroaryl, -(C3-C6) cycloalkyl, -CH 2 -(C3-C6)cycloalkyl, -CH 2 -(C6-C10)aryl and -CH 2 - 5 to 10 membered heteroaryl R 10 is each substituted with 0 to 5 R'; R 11 For each occurrence, -halogen, -CN, SCH 3 , -CF 3 , -OH, -OCF3 , O.C.H.F. 2 , -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5-10 membered heteroaryl; R is: 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-, 3-10 membered heterocyclyl-, (3-10 membered heterocyclyl)-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-O-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-N(R")-(C1-C12)aliphatic-, 5-10 membered heteroaryl-, (5-10 membered heteroaryl)-(C1-C12)-aliphatic-, (5-10 membered heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 membered heteroaryl)-N(R")-(C1-C12)-aliphatic- are independently selected from the group consisting of The heterocyclyl is selected from N, NH, O, S, SO and SO 2wherein the heteroaryl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, and S; R is independently substituted at each occurrence by 0 to 5 R'; or when two R groups are attached to the same atom, the two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO 2 wherein the ring is optionally substituted with 0-5 R', and the ring is optionally fused to a (C6-C10)aryl, a 5-10 membered heteroaryl, a (C3-C10)cycloalkyl, or a 3-10 membered heterocyclyl; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from the group consisting of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl-, (C6-C10)-aryl-, (5-10 membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5-10 membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-; R" at each occurrence is halogen, -R o , -OR o , oxo, -CH 2 OR o , -CH 2N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 and R is independently substituted with 0 to 5 substituents selected from the group consisting of o is independently selected from the group consisting of -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl- and (C6-C10)-aryl at each occurrence; and ii) A compound of formula IV: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, m is 0 to 3; R 1 , R 4 and R 5 are each independently selected from: R 1 , R 4 and R 5 For each occurrence, -R, -OR, -NO 2 , -NCS, -CN, -CF 3 , -OCF 2 H-OCF 3 , -SiR 3 , -N(R) 2 , -SR, -SOR, -SO 2 R, -SO 2 N(R) 2 , -SO 3 R, -(CR 2 ) 1~3 R, -(CR 2 ) 1~3 -OR, -(CR 2 ) 1~3 -O(CR 2 ) 1~3 -R, -(CR 2 ) 0~3 -C(O)NR(CR2 ) 0~3 R, -(CR 2 ) 0~3 -C(O)NR(CR 2 ) 0~3 OR, -C(O)R, -C(O)C(O)R, -C(O)CH 2 C(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 , -(CR 2 ) 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)SO 2 R, -N(R)SO 2 N(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 , CH 2 CF 3 or CHF 2 each independently selected from R 2 is -OR 8 , -SR 8 , -(CH 2 ) n OR 8 , -(CH 2 ) n O(CH 2 ) n R 8 , -(CH 2 ) p R 8or -(CH 2 ) n N(R”)R 10 wherein n is an integer selected from 0 to 4, and p is an integer selected from 2 to 4; R 2 is independently substituted with 0 to 5 R'; R 3 are -H, -CN, halogen, -(C1-C6) aliphatic, -CH=CR 9 , -C≡CR 9 , -SO 2 ((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 , -CH 2 -OR 10 , -CH 2 -O-CH 2 -R 10 [ka] are independently selected from Each 5-10 membered heterocycle or heteroaryl is selected from 0-3 R 7 is replaced by R 3 is independently substituted with 0 to 5 R'; R 6 is selected from the group consisting of -H and -(C1-C6)alkyl; R 7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, -5-10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; R 7each is independently substituted with 0 to 5 R'; R 8 is independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl or 5-10 membered heteroaryl, 5-10 membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl and -(C1-C6)alkyl-(C3-C6)cycloalkyl; R 8 is independently substituted at each occurrence by 0 to 5 R'; R 9 is -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, [ka] is selected from the group consisting of R 9 Each has an R of 0 to 5. 11 and R 10 is -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3-10 membered heterocyclyl, (C6-C10)-aryl, 5-10 membered heteroaryl, -CH 2 -(C3-C6)cycloalkyl, -CH 2 -(C6-C10)aryl and -CH 2 - selected from the group consisting of 5 to 10 membered heteroaryl; R 10 is independently substituted at each occurrence by 0 to 5 R'; R 11 For each occurrence, -halogen, -CF 3 , -OCF 3 , -OH, OCF 2H, -O-(C1-C6) alkyl, -(C6-C10) aryl, -(C1-C6) alkyl, -O-CH 2 independently selected from the group consisting of -(C3-C6)cycloalkyl, -CN, and -5-10 membered heteroaryl; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from the group consisting of R" at each occurrence 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-; R" at each occurrence is halogen, -R o , -OR o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 0 to 5 R independently selected from the group consisting of t and R ois independently selected at each occurrence 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, GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA A The alpha5 receptor agonist, or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof of the pharmaceutical composition of the present disclosure, is selected from the group consisting of: i) A compound of formula II: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, m is 0 to 3; R 1 are halogen, -H, -(C1-C6) alkyl, -OH, -O((C1-C6) alkyl), and -NO 2 , -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OMe, -C≡CR 8 , -CHF 2 , -CH 2 CF 3 , -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; R 1 is independently substituted with 0 to 5 R'; R 2 teeth, -H, halogen, -OH, -(C1~C6) aliphatic, -O((C1~C6) alkyl), -C(O)O((C1~C6) alkyl), -C(O)NR 2 , -(CR 2 ) 1~3 -OR, -(CR2 ) 1~3 -O(CR 2 ) 1~3 -R, -OR 9 , -C(O)R 8 , -CH 2 R 8 , -CH 3 , -CH 2 -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-, (5-10 membered heteroaryl)-(C1-C12)aliphatic-, (5-10 membered heteroaryl)-O-(C1-C12)aliphatic-, (5-10 membered heteroaryl)-N(R")-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-O-(C1-C12)aliphatic-, and (3-10 membered heterocyclyl)-N(R")-(C1-C12) aliphatic- is selected from the group consisting of R 2 is independently substituted with 0 to 5 R'; R 3 is -(C1-C6) alkyl, -(C2-C6) alkenyl, -C≡CH, -C≡CR 9 , -CN, halogen, -SO 2 ((C6-C10)-aryl), -SO 2 ((C1-C6) alkyl), -C(O)N((C1-C6) alkyl) 2 , -C(O)NH 2 , -C(O)O((C1-C6)alkyl), -C(O)((C1-C6)alkyl), -(C6-C10)aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, -(C1-C6)alkyl-C≡CR 10, -CH 2 -OR 10 , -CH 2 -O-CH 2 -R 10 [ka] is selected from the group consisting of Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 3 is independently substituted with 0 to 5 R'; R 4 and R 5 are each independently selected from the group consisting of -H, halogen, -(C1-C6)alkyl, or -(C1-C6)alkyl-(C6-C10)aryl, wherein (C6-C10)aryl is independently substituted with 0-5 halogens; R 6 is selected from the group consisting of -H and -(C1-C6)alkyl; R 7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl; R 7 each is independently substituted with 0 to 5 R'; R 8 are each 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; R 8 are -halogen, -(C1-C6)alkyl, -CF, excluding -H and -(C1-C6)alkyl. 3 , -OCF 3or O-(C1-C6)alkyl; R 9 is -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 heterocycle, [ka] is selected from the group consisting of R 9 Each has an R of 0 to 5. 11 and R 10 is -H, halogen, -(C1-C6) alkyl, -(C6-C10) aryl, -5-10 membered heteroaryl, -(C3-C6) cycloalkyl, -CH 2 -(C3-C6)cycloalkyl, -CH 2 -(C6-C10)aryl and -CH 2 - 5 to 10 membered heteroaryl R 10 is each substituted with 0 to 5 R'; R 11 For each occurrence, -halogen, -CN, SCH 3 , -CF 3 , -OH, -OCF 3 , O.C.H.F. 2 , -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5-10 membered heteroaryl; R is: 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-, 3-10 membered heterocyclyl-, (3-10 membered heterocyclyl)-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-O-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-N(R")-(C1-C12)aliphatic-, 5-10 membered heteroaryl-, (5-10 membered heteroaryl)-(C1-C12)-aliphatic-, (5-10 membered heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 membered heteroaryl)-N(R")-(C1-C12)-aliphatic- are independently selected from the group consisting of The heterocyclyl is selected from N, NH, O, S, SO and SO 2 wherein the heteroaryl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, and S; R is independently substituted at each occurrence by 0 to 5 R'; or when two R groups are attached to the same atom, the two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO 2wherein the ring is optionally substituted with 0-5 R', and the ring is optionally fused to a (C6-C10)aryl, a 5-10 membered heteroaryl, a (C3-C10)cycloalkyl, or a 3-10 membered heterocyclyl; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from the group consisting of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl-, (C6-C10)-aryl-, (5-10 membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5-10 membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-; R" at each occurrence is halogen, -R o , -OR o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 and R is independently substituted with 0 to 5 substituents selected from the group consisting ofo is independently selected from the group consisting of -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl- and (C6-C10)-aryl at each occurrence; and ii) A compound of formula IV: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, m is 0 to 3; R 1 are halogen, -H, -(C1-C6) alkyl, and -C≡CR. 9 , -OH, -O((C1-C6) alkyl), -NO 2 , -CN, -CF 3 , -OCF 3 , -CHF 2 , -CH 2 CF 3 independently selected from the group consisting of -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 1 is independently substituted with 0 to 5 R'; R 2 -OR 8 , -SR 8 , -(CH 2 ) n OR 8 , -(CH 2 ) n O(CH 2 ) n R 8 , -(CH 2 ) p R 8 and -(CH 2 ) n N(R”)R 10 wherein n is an integer selected from 0 to 4, and p is an integer selected from 2 to 4; R 2is independently substituted with 0 to 5 R'; R 3 are -H, -CN, halogen, -(C1-C6) aliphatic, -CH=CR 9 , -C≡CR 9 , -SO 2 ((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, -CH 2 -OR 10 , -CH 2 -O-CH 2 -R 10 [ka] are independently selected from the group consisting of Each 5-10 membered heterocycle or heteroaryl is selected from 0-3 R 7 is replaced by R 3 is independently substituted with 0 to 5 R'; R 4 and R 5 are each independently selected from the group consisting of -H, halogen, and -(C1-C6)alkyl; R 6 is selected from the group consisting of -H and -(C1-C6)alkyl; R 7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, -5-10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; R 7 each is independently substituted with 0 to 5 R'; R 8is independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl or 5-10 membered heteroaryl, 5-10 membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl and -(C1-C6)alkyl-(C3-C6)cycloalkyl; R 8 is independently substituted at each occurrence by 0 to 5 R'; R 9 is -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, [ka] is selected from the group consisting of R 9 Each has an R of 0 to 5. 11 and R 10 is -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3-10 membered heterocyclyl, (C6-C10)-aryl, 5-10 membered heteroaryl, -CH 2 -(C3-C6)cycloalkyl, -CH 2 -(C6-C10)aryl and -CH 2 - selected from the group consisting of 5 to 10 membered heteroaryl; R 10 is independently substituted at each occurrence by 0 to 5 R'; R 11 For each occurrence, -halogen, -CF 3 , -OCF 3 , OCF 2 H, -O-(C1-C6) alkyl, -(C6-C10) aryl, -(C1-C6) alkyl, -O-CH 2independently selected from the group consisting of -(C3-C6)cycloalkyl and -5-10 membered heteroaryl; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from the group consisting of R" at each occurrence 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-; R" at each occurrence is halogen, -R o , -OR o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 0 to 5 R independently selected from the group consisting of t and R o is independently selected at each occurrence 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, GABA A α5 receptor agonists, or pharma- ceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof, or the GABA A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof of the pharmaceutical composition of the present disclosure is a compound of formula II as described in paragraph 19, or a compound of formula II as described in paragraph 20, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In other embodiments, GABA A α5 receptor agonists, or pharma- ceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof, or the GABA A The alpha5 receptor agonist, or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, of the pharmaceutical composition of the present disclosure is a compound of formula IV as set forth in paragraph 19, or a compound of formula IV as set forth in paragraph 20, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

[0022] In some embodiments, GABA A α5 receptor agonist or GABA 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 pharma- ceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof.See, for example, WO2018130868, WO2018130869, WO2019246300, WO2021127543 and WO2022011318.Each of these published documents is incorporated herein by reference in its entirety, particularly in the context of the compounds described, their synthesis and properties.

[0023] In some embodiments, GABA A α5 receptor agonist or GABA A Alpha 5 receptor agonists are

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[0024] In some embodiments, GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or the GABA A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof has the structure: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

[0025] In another embodiment, GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or the GABA A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof has the structure: [ka] wherein the polymorphic crystalline form is Form A, and a. at least one peak selected from 3.0 and 21.0 degrees 2θ ± 0.2 degrees 2θ; and b. at least one additional peak selected from the group consisting of 9.1, 10.7, 13.8, 22.0, 23.1, 23.9, 24.4, and 27.1 degrees 2θ ± 0.2 degrees 2θ Figure 1 shows an XRPD including: See pages 292-295 of WO2022011318, which is incorporated herein by reference in its entirety, particularly in the context of the compounds described, their synthesis and properties.

[0026] In some embodiments, GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or the GABA A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof has the structure: [ka] The polymorphic crystalline form of the compound having the following crystalline form: a. at least one peak selected from 13.0 and 15.3 degrees 2θ ± 0.2 degrees 2θ; and b. at least one additional peak selected from the group consisting of 7.0, 9.3, 10.2, 10.4, 12.5, 13.6, 14.0, 22.0, 23.0, 23.6, and 27.3 degrees 2θ ± 0.2 degrees 2θ Figure 1 shows an XRPD including: See pages 295-297 of WO2022011318, which is incorporated herein by reference in its entirety, particularly in the context of the compounds described, their synthesis and properties.

[0027] In some embodiments, GABA Aα5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or the GABA A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof has the structure: [ka] wherein the solvate crystalline form is Form C, and a. at least one peak selected from 8.5 and 18.9 degrees 2θ ± 0.2 degrees 2θ; and b. at least one additional peak selected from the group consisting of 7.1, 9.4, 10.3, 12.3, 12.5, 14.2, 20.7, 22.1, 23.2, 23.7, 24.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ See pages 302-305 of WO2022011318, which is incorporated herein by reference in its entirety, particularly in the context of the compounds described, their synthesis and properties.

[0028] In some embodiments, GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or the GABA A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof has the structure: [ka] The polymorphic crystalline form of the compound having the following formula: a. at least one peak selected from the group consisting of 11.4, 18.1, and 21.6 degrees 2θ ± 0.2 degrees 2θ; and b. at least one additional peak selected from the group consisting of 7.2, 22.0, 23.0, 24.2, 25.0, and 26.6 degrees 2θ ± 0.2 degrees 2θ; Figure 1 shows an XRPD including: See pages 297-300 of WO2022011318, which is incorporated herein by reference in its entirety, particularly in the context of the compounds described, their synthesis and properties.

[0029] In some embodiments, GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or the GABA A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof has the structure: [ka] wherein the hydrate crystalline form is Form F, and a. at least one peak selected from the group consisting of 9.9, 11.9, 17.3, 19.4, and 25.7 degrees 2θ ± 0.2 degrees 2θ, and b. at least one additional peak selected from the group consisting of 9.7, 12.1, 20.8, 23.2, 23.7, 24.2, 25.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ See pages 300-302 of WO2022011318, which is incorporated herein by reference in its entirety, particularly in the context of the compounds described, their synthesis and properties.

[0030] In some embodiments, GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or the GABA A The alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) A compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. (In the formula, m is an integer selected from 0 to 4; R 1 are halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, (C3-C10)-cycloalkenyl [ka] is selected from The 5- to 6-membered heteroaryl and the 3- to 10-membered heterocycle each have 0 to 4 R 7 is replaced by R 9 are respectively -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl [ka] is selected from R 9 Each occurrence is 0 to 5 R 11and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -(C6-C10)aryl, and -5-10 membered heteroaryl; R 3 is independently selected from -H, -(C1-C6)alkyl, -5-10 membered heteroaryl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, and -(C1-C6)alkyl-(C6-C10)aryl; R 3 is 0 to 5 R 12 and R 12 are -H, -halogen, and -OR, respectively. o , R o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -CF 3 , -OCF 3 and -N(R o ) 2 are independently selected from R o is independently selected at each occurrence from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, -(3-10 membered)heterocyclyl and (C6-C10)-aryl; R 7 are -H and -CF 3 , -(C1-C6) alkyl, -(C1-C6) alkyloxy, (C1-C6) alkylamino, -(C3-C6) cycloalkyl, -5-10 membered heteroaryl, -(C6-C10) aryl, -CH 2 -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl, and -3-10 membered heterocyclyl; R 7 are each independently substituted with 0 to 5 R'; or two R's 7 If the groups are attached to the same atom, two R 7 The groups, together with the atoms to which they are attached, are N, NH, O, S, SO, and SO 2 and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, and —(C6-C10)aryl; R" is independently substituted with 1 to 3 substituents, the substituents being halogen, -CF 3 , -OCF 3 , -O-(C1-C6)-aliphatic or -(C1-C6)-aliphatic; R 4 are each selected from -H or -(C1-C6)alkyl; R 6 are each selected from -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl. ii) A compound of formula Ib: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. (m is an integer selected from 0 to 4, During the ceremony, R 1 are -halogen, -(C6-C10)aryl, -Ome, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each of the 5- to 6-membered heteroaryl and the 3- to 10-membered heterocycle is selected from 0 to 4 R 7 is replaced by R 9 are respectively -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3, -OMe, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 3 is -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 and -5-10 membered heteroaryl; R 3 is 0 to 5 R 12 and R 12 are -H, -halogen, and -OR, respectively. o , R o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 are independently selected from R o is independently selected at each occurrence from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl; R 7 are -H and -CF 3 , -(C1-C6)alkyl, -(C1-C6)alkyloxy, (C1-C6)alkylamino, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5-10 membered heteroaryl and -3-10 membered heterocyclyl; R 7are each independently substituted with 0 to 5 R'; or two R's 7 If the groups are attached to the same atom, two R 7 The groups, together with the atoms to which they are attached, are N, NH, O, S, SO, and SO 2 and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-5-10 membered heteroaryl, -5-10 membered heteroaryl, -3-10 membered heterocyclyl, -(C3-C6)cycloalkyl, and -(C6-C10)aryl; R" is independently substituted with 1 to 3 substituents, the substituents being halogen, -CF 3 , -OCF 3 , -O(C1-C6)aliphatic, -(C1-C6)-aliphatic and -5-10 membered heteroaryl; R 4 and R 6 are each independently selected from -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl. iii) A compound of formula Ic: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. (m is an integer selected from 0 to 4, R 1 are -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), or -(3-10 membered)heterocyclyl. [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3, -OCF 3 , -OMe, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 7 For each occurrence, -CF 3 , -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5-10 membered heteroaryl and -3-10 membered heterocyclyl; R 7 each is independently substituted with 0 to 5 R'; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from R″ at each occurrence is selected from: -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-5-10 membered heteroaryl, -5-10 membered heteroaryl, -3-10 membered heterocyclyl, -(C3-C6)cycloalkyl, and -(C6-C10)aryl; R″ is independently substituted with 1 to 3 substituents, the substituents being halogen, -CF 3 , -OCF 3 , -(C1-C6)-aliphatic and -5-10 membered heteroaryl; R 4 and R 6 are each independently selected from -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl. iv) Compounds of formula Id: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. (m is an integer selected from 0 to 4, During the ceremony, R 1 are -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are respectively -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl [ka] is selected from R 9 Each occurrence is 0 to 5 R 11and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -OMe, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 3 is -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; R 3 is 0 to 5 R 12 and R 12 are -H, -halogen, and -OR, respectively. o , R o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 are independently selected from R o is independently selected at each occurrence from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl; R 7 -CF 3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5-10 membered heteroaryl and -3-10 membered heterocyclyl; R 7 each is independently substituted with 0 to 5 R'; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, and —(C6-C10)aryl; R 4 are each selected from -H or -(C1-C6)alkyl; R 6 are each selected from -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl. v) A compound of formula Ie: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. (m is an integer selected from 0 to 4, R 1 are -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7, C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), or -(3-10 membered)heterocyclyl. [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -OMe, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, -5-10 membered heteroaryl-(C1-C6)alkyl, and -3-10 membered heterocyclyl; R7 each is independently substituted with 0 to 5 R'; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 wherein each R' is independently substituted with 0 to 5 R"; R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, and —(C6-C10)aryl; R 4 are each independently -H or (C1-C6) alkyl; R 6 are each independently -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl, and vi) A compound of formula If: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. (m is an integer selected from 0 to 4, R 1 are -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), or -(3-10 membered)heterocyclyl. [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -OMe, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, -5-10 membered heteroaryl-(C1-C6)alkyl, and -3-10 membered heterocyclyl; R 7 each is independently substituted with 0 to 5 R'; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from each R' is independently substituted with 0-5 R" where 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; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0031] In some embodiments, GABA A α5 receptor agonist or GABA A Alpha 5 receptor agonists are [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

Table 5-14

Table 5-15

Table 5-16

Table 5-17

Table 5-18

Table 5-19

Table 5-20

Table 5-21

Table 5-22

Table 5-23

[0032] In various aspects, the present disclosure also provides pharmaceutical compositions comprising compounds of formula Ia, Ib, Ic, Id, Ie, and If, or pharma- ceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof.

[0033] In some embodiments, the compound of formula Ia is GABA A In some embodiments, the compound of formula Ib is a GABA receptor positive allosteric modulator. AIn some embodiments, the compound of formula Ic is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of formula Id is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of formula Ie is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of formula If is a GABA receptor positive allosteric modulator. A In some embodiments of the present disclosure, one or more of the compounds of formula Ia, Ib, Ic, Id, Ie, or If are useful for treating the conditions described herein.

[0034] In some embodiments, the GABA A The α5 receptor positive allosteric modulators include, in particular, the GABA receptor positive allosteric modulators disclosed in PCT applications WO2015 / 095783A1, WO2016 / 205739A1, WO2018 / 130869A1, WO2019 / 246300A1, WO2021 / 127543, and WO2022 / 011314, including any one of the further compounds 1-740 individually described above. A In some embodiments, the GABA receptor positive allosteric modulators described in the present disclosure are used in combination with one or more of the α5 receptor positive allosteric modulators. A In some embodiments, an alpha5 receptor positive allosteric modulator or the above combination may be used in combination with one or more SV2a inhibitors, including one or more of levetiracetam, brivaracetam and seletracetam, as disclosed in PCT application WO2022 / 011318, in the treatment of such cognitive disorders and other conditions described herein.

[0035] In some embodiments, the method comprises administering to a subject: A) levetiracetam, brivaracetam or seletracetam, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam, or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier; and B) GABA of the present disclosure A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA A a pharmaceutical composition comprising an α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharma- ceutically acceptable carrier; or C) A pharmaceutical composition comprising A and B and a pharma- ceutically acceptable carrier. The method includes administering

[0036] In some embodiments, a pharmaceutical composition comprising A. levetiracetam, seletracetam or brivaracetam or a pharma- ceutical acceptable salt thereof, or B. GABA A α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or GABA A The pharmaceutical composition comprising an α5 receptor agonist or a pharma- ceutical acceptable salt, hydrate, solvate, isomer or polymorph thereof, or the pharmaceutical composition C is orally administered. In some embodiments, the pharmaceutical composition comprising A levetiracetam, seletracetam or brivaracetam or a pharma- ceutical acceptable salt thereof, or levetiracetam, brivaracetam or seletracetam or a pharma- ceutical acceptable salt thereof, and B GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA AIn another embodiment, the pharmaceutical composition comprising alpha5 receptor agonist or a pharma- ceutical acceptable salt, hydrate, solvate, isomer or polymorph thereof, or the pharmaceutical composition C is administered once a day. In another embodiment, the pharmaceutical composition comprising levetiracetam, seletracetam or brivaracetam or a pharma- ceutical acceptable salt thereof, or levetiracetam, brivaracetam or seletracetam or a pharma- ceutical acceptable salt thereof, and GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA A The pharmaceutical composition comprising an α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or the pharmaceutical composition of C, is administered twice daily.

[0037] In some embodiments, a pharmaceutical composition comprising A. levetiracetam, seletracetam or brivaracetam or a pharma- ceutical acceptable salt thereof, or B. GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA A The pharmaceutical composition comprising the α5 receptor agonist or its pharma- ceutical acceptable salt, hydrate, solvate, isomer or polymorph is administered simultaneously. In some embodiments, A is levetiracetam, seletracetam or brivaracetam or its pharma- ceutical acceptable salt, or B is GABA. A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA A The pharmaceutical compositions comprising an α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof are administered sequentially.

[0038] In some embodiments, levetiracetam, brivaracetam or seletracetam of A or C, or a pharma- ceutically acceptable salt thereof, is administered in a daily dose of 0.7-350 mg. In some embodiments, levetiracetam or seletracetam of A or C, or a pharma- ceutically acceptable salt thereof, is administered in a daily dose of 125-250 mg. In other embodiments, levetiracetam or seletracetam of A or C, or a pharma- ceutically acceptable salt thereof, is administered in a daily dose of 220 mg. In some embodiments, levetiracetam or seletracetam of A or C, or a pharma- ceutically acceptable salt thereof, is administered in a daily dose of 190 mg. In some embodiments, brivaracetam of A or C, or a pharma- ceutically acceptable salt thereof, is administered in a daily dose of 0.7-180 mg. In some embodiments, A or C of levetiracetam or seletracetam or a pharma- ceutical 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, sustained release, or single unit dosage form, or for once daily administration. In some embodiments, the sustained release form is a controlled release, extended release, sustained release, delayed release, or slow release form.

[0040] In some embodiments of the method of the present disclosure, the pharmaceutical composition of A comprises levetiracetam or a pharma- ceutically acceptable salt in an amount of 220 mg, and further comprises 280 mg to 350 mg of hydroxypropyl methylcellulose, 1.2 mg to 1.4 mg of colloidal silicon dioxide, 92.8 mg to 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg to 6.7 mg of magnesium stearate. In some embodiments, the pharmaceutical composition comprises levetiracetam or a pharma-ceutically acceptable salt in an amount of 220 mg, and further 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. In some embodiments, the pharmaceutical composition comprises levetiracetam or a pharma- ceutically acceptable salt in an amount of 190 mg, and further comprises 300 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silicon dioxide, 102.8 mg silicified microcrystalline cellulose or anhydrous dicalcium phosphate, and 6 mg magnesium stearate. In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2208. In some embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC90.

[0041] In some embodiments of the method of the present disclosure, the pharmaceutical composition comprising a daily dose of levetiracetam A or C or a pharma- ceutically acceptable salt thereof is in sustained release form and provides in a subject a steady state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL within 3 hours of administration, lasting for at least 8 hours of a 24 hour period after said administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam A or C or a pharma- ceutically acceptable salt thereof is in sustained release form and provides in a subject a steady state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL within 2 hours of administration, lasting for at least 13 hours of a 24 hour period after said administration. In some embodiments, a pharmaceutical composition comprising a daily dose of levetiracetam A or C or a pharma- ceutically acceptable salt thereof is in sustained release form and provides a steady state plasma concentration of levetiracetam between 1.9μg / mL and 4.4μg / mL in a subject within 1 hour of said administration, lasting for at least 13 hours of a 24 hour period after said administration. In other embodiments, a pharmaceutical composition comprising a daily dose of levetiracetam A or C or a pharma- ceutically acceptable salt thereof provides a steady state plasma concentration of levetiracetam between 1.9μg / mL and 4.4μg / mL in a subject within 1 hour of said administration, lasting for at least 13 hours of a 24 hour period after said administration (see, e.g., FIG. 2 and WO2016191288, the entirety of which is incorporated herein by reference).

[0042] In some embodiments of the method of the present disclosure, one of the plurality of pharmaceutical compositions comprising the daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof of A or C is formulated for administration in oral form, sustained release form or single unit dosage form, or once a day. In other embodiments, the sustained release form is a controlled release form, an extended 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 being treated is at risk of developing cognitive decline or impairment, which risk is associated with the presence of altered functional connectivity of the hippocampus in the subject.

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

[0045] In some embodiments of the method of the present disclosure, the subject to be treated is at risk of developing cognitive decline or cognitive impairment, and this risk is a genetic risk associated with the presence of one or more genomic variants, mutations or polymorphisms in the genome of the subject, which are associated with the change 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, and this risk is associated with the presence of at least one allele of the APOE4 gene in the genome of the subject.In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, and this risk is associated with the presence of one of the further biofluid biomarkers in the subject, which are selected from the group consisting of p-tau, t-tau and amyloid beta 42.In some embodiments, the subject is a human being.

[0046] In some embodiments of the methods of the present disclosure, the GABA A The α5 receptor agonist, or a pharma- ceutically 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 pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments, the GABA A The α5 receptor agonist, or a pharma- ceutically 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 pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the method of the present disclosure, the GABA AThe α5 receptor agonist, or a pharma- ceutically 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 pharma-ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

[0047] In some embodiments of the methods of the present disclosure, the GABA A The α5 receptor agonist, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, is a compound of formula Ia-If described in paragraph 30, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the method of the present disclosure, the GABA A The α5 receptor agonist, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, is a compound of formula Ia, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, as described in paragraph 30. In some embodiments, the GABA A The α5 receptor agonist, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, is a compound of formula Ib described in paragraph 30, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the method of the present disclosure, the GABA A The α5 receptor agonist, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, is a compound of formula Ic, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, as set forth in paragraph 30. In some embodiments, the GABA AThe α5 receptor agonist, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, is a compound of formula Id, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, as set forth in paragraph 30. In some embodiments of the method of the present disclosure, the GABA A The α5 receptor agonist, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, is a compound of formula Ie described in paragraph 30, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments, the GABA A The α5 receptor agonist, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, is a compound of formula If set forth in paragraph 30, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the method of the present disclosure, the GABA A The alpha5 receptor agonist, or a pharma- ceutically 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 pharma-ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

[0048] In some embodiments of the disclosed method, the compound of formula IV described in paragraph 19 or the compound of formula IV described in paragraph 20, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, in the composition of B or C is a crystalline form of compound 606, and the polymorphic crystalline form is Form A, Form B, Form C, Form E or Form 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 Form A, Form B, Form C, Form E and Form F. See WO2022011318, the entirety of which is incorporated herein by reference, particularly in the context of the compounds described therein, their synthesis and properties.

[0049] In some embodiments of the pharmaceutical composition of B or C, GABA A The alpha5 receptor agonist or its pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph is present in an amount between 5mg and 1000mg. In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically 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 one or more GABA in the composition of B or C. A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is present in a sustained release form, a non-sustained release form or an immediate release form. In some embodiments, the GABA A The α5 receptor agonist or its pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph is present in sustained release form. In some embodiments, the sustained release form is a controlled release form, a long-term release form, a sustained release form, a delayed release form or a slow release form. In some embodiments, the GABA in the composition of B or C is A The alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is present in a non-sustained release form.

[0051] One aspect of the present disclosure relates to the use of one or more of the pharmaceutical compositions or combinations of the present disclosure in the manufacture of medicaments for preventing or slowing the progression of cognitive impairment, or for preventing the onset of cognitive decline, or for slowing the rate of cognitive decline, in subjects who exhibit or exhibit cognitive abilities within the normal range for the age of the subject.In some embodiments, as described above, the subject is at risk of developing cognitive impairment or cognitive decline, or at risk of developing cognitive impairment or cognitive decline.In other embodiments, the present disclosure relates to the use of one or more of the compounds, pharmaceutical compositions, or combinations of the present disclosure for preventing or slowing the progression of cognitive impairment, or for preventing the onset of cognitive decline, or for slowing the rate of cognitive decline, in subjects who exhibit or exhibit cognitive abilities within the normal range for the age of the subject.In some embodiments, as described above, the subject is at risk of developing cognitive impairment or cognitive decline, or at risk of developing cognitive impairment or cognitive decline.

[0052] In some embodiments of the disclosed method and use, the compound, pharmaceutical composition, combination or medicament is administered subcutaneously, intravenously, orally, sublingually, bucally, transdermally, intraarterially, intradermally, intramuscularly, intraperitoneally, intraocularly, intranasally, intrathecally or intracerebrally.In some embodiments, the compound, pharmaceutical composition, combination or medicament is administered orally.In some embodiments, the subject is a human.In some embodiments, the compound, pharmaceutical composition, combination or medicament is administered once a day.In some embodiments, the compound, pharmaceutical composition, combination or medicament is administered twice a day. [Brief description of the drawings]

[0053] [Figure 1]FIG. 1 illustrates the effective plasma concentration of levetiracetam for treating cognitive impairment based on an aged impaired rat study and a Phase II study in aMCI patients. In one embodiment of the present disclosure, the effective plasma concentration is between 1.9-4.4 μg / mL. In another embodiment, the effective plasma concentration is between 2.9-4.4 μg / mL. In another embodiment, the effective plasma concentration is between 1.9-3.9 μg / mL.

[0054] [Diagram 2] Figure 2 shows steady-state modeling of the PK profile of the 190 mg tablet A from Table 1, which shows that this tablet produces plasma concentrations of levetiracetam between 1.9 and 4.4 μg / mL.

[0055] [Diagram 3] Figure 3 shows steady-state modeling of the PK profile of the 220 mg tablet D from Table 2, which demonstrates that this tablet produces plasma concentrations of levetiracetam between 2.9 and 4.4 μg / mL.

[0056] [Figure 4] FIG. 4 is a flow diagram of one embodiment of a process for producing sustained release compositions of levetiracetam (eg, the 190 mg and 220 mg tablets listed in Tables 1 and 2).

[0057] [Diagram 5] FIG. 5 demonstrates a flow diagram of a Phase II, randomized, double-blind, placebo-controlled, crossover clinical trial to test the efficacy of levetiracetam in cognitively normal (CN) subjects with hippocampal functional connectivity abnormalities.

[0058] [Figure 6] Figure 6 demonstrates changes in hippocampal functional connectivity between placebo and levetiracetam treated subjects. The symbol * indicates a significant difference between the groups. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0059] Detailed Description of the Disclosure Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. In general, the nomenclature and techniques used in connection with 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 are well known and commonly used in the art. See, for example, "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4 th ed.," WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7 th ed.," WH Freeman & Co., NY (1999); Gilbert et al., "Developmental Biology, 6 th ed.," 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, Calif. (1985).

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

[0062] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a specified integer (or component) or group of integers (or components) but not the exclusion of any other integer (or component) or group of integers (or components).

[0063] The singular forms "a," "an," and "the" include plurals 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 either a human or a non-human animal. Patients, subjects, or individuals can include mammals such as humans, primates, livestock animals (including cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats). In some embodiments, the patient, subject, or individual is a human.

[0066] "Preventing" the onset or progression of cognitive decline or cognitive impairment refers to affecting normal or unimpaired cognitive capacity so that it does not decline or does not decline below the cognitive capacity observed in the subject at the time of initial presentation or diagnosis, or such decline is delayed.

[0067] "Slowing" the onset or progression of cognitive decline refers to slowing the progression of cognitive decline in a subject, which can be determined by a physician or by comparison to a normal population.

[0068] "Cognitive impairment" or "cognitive decline" refers to a subject's cognitive ability not being as robust as the normal range expected in a subject of similar age.In some cases, cognitive ability is reduced by about 5%, about 10%, about 30% or more compared to the normal range of cognitive ability expected in a subject of similar age.In some cases, "cognitive impairment" in a subject suffering from age-related cognitive impairment can refer to a subject's cognitive ability not being as robust as the normal range expected in a subject of the same age, or as the ability of a young adult subject (e.g., a subject who has the average score for a given age in a cognitive ability test).

[0069] As used herein, "genetic risk" or "genetic predisposition" refers to "genomic polymorphisms", "genomic variants" or "genomic mutations" associated with the onset of disease or disorder associated with cognitive impairment of cognitive decline. Genetic risk can be identified using GWAS or preclinical models. Genetic risk can also be related to changes in expression, including increased, decreased or abnormal protein expression. Genetic risk factors may be used as predictive indicators, but do not absolutely indicate the progression or onset of said disease or disorder.

[0070] "Cognitive ability" refers to measurable cognitive behavior or cognitive ability in a subject.There are various art-recognized tests for evaluating cognitive ability in humans, such as and without limitation: Clinical Global Impression of Change (CIBIC-Plus Scale); Mini-Mental State Examination (MMSE); Neuropsychopathological Inventory (NPI); Clinical Dementia Scale (CDR); Cambridge Neuropsychological Test Automated Battery (CANTAB); Sandoz Clinical Assessment of the Aged (SCAG); Buschke Multiple Choice Recall Test (Buschke and Fuld, 1974); Verbal Paired Associations Subtest; Logical Memory Subtest; Visual Reproduction Subtest of Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); Benton Visual Retention Test or MATRICS Consensus Neuropsychological Test Battery (which includes tests of working memory, processing speed, attention, verbal learning, visual learning, reasoning and problem solving and social cognition). 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); See 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 clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209-1217. Another example of a cognitive test in humans is the explicit three-alternative forced choice task.In this test, subjects are presented with color photographs of common objects consisting of three types of image pairs: similar pairs, identical pairs, and an intermix of unrelated controls (foils). The second of the similar object pair is termed the "decoy." These image pairs are fully randomized and presented individually as a sequence of images. Subjects are instructed to judge whether the object viewed is new, old, or similar. A "similar" response to the presentation of the decoy stimuli indicates successful memory retrieval by the subject. In contrast, evoking the decoy stimuli as "old" or "new" indicates that correct memory retrieval did not occur.

[0071] In addition to evaluating cognitive ability, cognitive impairment and dementia progression can be monitored by evaluating surrogate changes in the brain of a subject.Surrogate changes include, but are not limited to, regional brain volume changes, perforant path degradation, and changes observed in brain function by resting-state fMRI (R-fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), fluorodeoxyglucose positron emission tomography (FDG-PET), or any other imaging technique that can measure brain function.Examples of regional brain volumes useful for monitoring the progression of age-related cognitive impairment and dementia include hippocampal volume loss and entorhinal cortex volume or thickness loss.These volumes can be measured in a subject, for example, by MRI.Aisen et al., Alzheimer's & Dementia 6:239-246 (2010).Perforant path degradation has been shown to be linked to age and cognitive decline. For example, older adults with more perforant path degradation tend to perform worse on hippocampus-dependent memory tests. Perforant path degradation 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 at rest and recording large amplitude spontaneous low frequency (<0.1 Hz) fluctuations of the fMRI signal that are temporally correlated across functionally related regions. Seed-based functional connectivity, independent component analysis of signals and / or frequency domain analysis are used to reveal functional connectivity between brain regions, particularly those regions whose connectivity increases or decreases with age, as well as the degree of cognitive impairment and / or dementia. FDG-PET uses FDG uptake as a measure of regional metabolic activity in the brain. Decreased FDG uptake in areas such as the posterior cingulate cortex, temporoparietal cortex, and frontal association cortex has been shown to be associated with cognitive decline and the degree of dementia.Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002).

[0072] Examples of "pharmacologically acceptable salts" include, but are not limited to, acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamic acid, glycolyl arsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, Water soluble and insoluble salts include lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate salts.

[0073] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" are salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, including, but not limited to, inorganic acids such as hydrohalides, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and, 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-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, glyceric ... It may refer to salts formed with organic acids such as heptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydroxyacetic 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, and undecylenic acid.

[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 from the addition of inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, alkali metal salts and alkaline earth metal salts, i.e., sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, 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; naturally occurring substituted amines, substituted amines including cyclic amines; basic ion exchange resins; isopropylamine; trimethylamine; diethylamine; triethylamine; tripropylamine; diethanolamine; ethanolamine; deanol; 2-dimethylaminoethanol; 2-diethylaminoethanol; dicyclohexylamine; amino acids; lysine; arginine; histidine; caffeine; procaine; hydrabamine; choline; betaine; benethamine; benzathine; ethylenediamine; glucosamine; methylglucamine; theobromine; triethanolamine; tromethamine; purine; 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 where the water retains its molecular state as water and is either absorbed, adsorbed, or contained within the crystal lattice of the compound.

[0077] "Polymorphism" refers to different crystalline forms and other solid state molecular forms (including pseudopolymorphisms) of the same compound, such as hydrates (e.g., bound water present in the crystal structure) and solvates (e.g., bound solvent other than water) of the same compound. Different crystalline polymorphs have different crystal structures due to different packing of molecules in their lattices. This results in different crystal symmetries and / or unit cell parameters, which directly affect physical properties such as X-ray diffraction characteristics of crystals or powders. For example, different polymorphs generally diffract at a different set of angles, resulting in different values ​​for their intensities. Thus, powder X-ray diffraction can be used to identify different polymorphs, or solid forms that contain more than one polymorph, in a reproducible and reliable manner. Certain polymorphic forms may exhibit improved thermodynamic stability or may be more easily manufactured in large quantities with high purity, and therefore more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may exhibit other advantageous physical properties, such as lack of hygroscopic tendency, improved solubility due to different lattice energies, and enhanced dissolution rates.

[0078] This application contemplates all isomers of the compounds of this disclosure. "Isomers" as used herein includes optical isomers (stereoisomers, such as enantiomers and diastereoisomers), Z (zusammen) or E (entgegen) isomers, and tautomers. Many of the compounds useful in the methods, uses, combinations, pharmaceutical compositions, and medicaments of this disclosure. The combinations used in this disclosure, or the pharmaceutical compositions used in this disclosure, have at least one stereogenic center in their structure. This stereogenic center can be in the R or S configuration, and the R and S designations are used according to the rules set forth in Pure Appl. Chem. (1976), 45, 11-30. This disclosure also relates to all stereoisomers, such as enantiomers and diastereoisomers of this compound, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO01 / 062726. Furthermore, certain compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each case, the present disclosure includes both mixtures and separate individual isomers. Substituents on the piperidinyl or azepanyl ring may also be in either cis or trans relationship with respect to the plane of the piperidinyl or azepanyl ring. Some of the present compounds may also exist in tautomeric forms. Such forms are intended to be included within the scope of the present disclosure even if not explicitly indicated. With respect to the method, use, combination, pharmaceutical composition, combination for use, or pharmaceutical composition for use of the present disclosure, when referring to a compound or compounds, it is intended to include the compound in each of its possible isomers and mixtures thereof, unless a specific isomer is specifically mentioned. See, for example, WO01 / 062726.

[0079] "Aliphatic" as used herein refers to straight or branched alkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynyl embodiments require at least two 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] "Aryl" as used herein refers to a monocyclic or bicyclic carbocyclic aromatic ring system. Aryl as used herein includes (C6-C12)-aryl-. For example, aryl as used herein can be a C6-C10 monocyclic or a C8-C12 bicyclic carbocyclic aromatic ring system. In some embodiments, aryl as used herein can be (C6-C10)-aryl-. Phenyl (or Ph) is an example of a monocyclic aromatic ring system. Bicyclic aromatic ring systems include systems in which both rings are aromatic, e.g., naphthyl, and systems in which only one of the two rings is aromatic, e.g., tetralin.

[0081] "Heterocyclic" as used herein means any of O, N, NH, S, SO or SO 2 Heterocyclic refers to a monocyclic or bicyclic non-aromatic ring system having 1 to 4 heteroatoms or heteroatom groups in a chemically stable arrangement selected from the group consisting of O, N, NH, S, SO or SO 2 For example, heterocyclic, as used herein, includes O, N, NH, S, SO, or SO 2 In some embodiments, heterocyclic, as used herein, can be O, N, NH, S, SO, or SO. 2In a bicyclic non-aromatic ring system embodiment of "heterocyclyl", one or both rings may contain said heteroatom or heteroatom group. In another bicyclic "heterocyclyl" embodiment, one of the two rings may be aromatic. In yet another heterocyclic ring system embodiment, the 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, Examples of pyrazolinyl include 1,3-dihydro-imidazol-2-one, ...

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

[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), azolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

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

[0086] "Heteroaralkyl" refers to an alkyl in which a heteroaryl group is substituted with an alkyl H atom. For example, an alkyl group can be any straight chain hydrocarbon and can contain from 1 to 12 carbon atoms (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl), and the alkyl group can be, but is 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, aryl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2, It can be substituted by any heteroaryl group, including 3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

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

[0088] When a bond to a substituent is shown crossing a bond connecting two atoms in a ring, such substituent may be bonded to any of the substitutable ring-forming atoms in that ring (i.e., atoms bonded to one or more hydrogen atoms) unless otherwise specified or specifically implied by the context. For example, if the R group is defined as pyridine, said pyridine is: [ka] In the illustrated embodiment, the pyridine ring may be attached to the benzodiazepine derivative through any one of the ring carbon atoms in the pyridine ring. [ka] When the pyrazole ring is depicted as such, the pyrazole ring may be joined at any one or more of the ring carbon atoms of the pyrazole ring. 3 It may be attached to the benzodiazepine derivative via the N-atom.

[0089] The designations of carbon atoms, as used herein, can have the designated integer and any intervening integer. For example, the number of carbon atoms in a (C1-C4)-alkyl group can be 1, 2, 3, or 4. These designations should be understood to 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 and disclosed herein

[0090] The compounds, compositions, combinations and medicaments useful in the methods and uses of the present disclosure include one or more of levetiracetam, brivaracetam or seletracetam or pharma- ceutically acceptable salts thereof, and GABA. A The present invention features an alpha5 receptor agonist or a pharma- ceutically 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 antiepileptic drug. Levetiracetam has further been shown to directly inhibit synaptic activity and neurotransmission by binding 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 inhibiting presynaptic neurotransmitter release (Yang et al., 2007). Levetiracetam is marketed as the FDA-approved antiepileptic drug Keppra®. Typically, a therapeutically effective dose of levetiracetam (Keppra®) 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 approximately 7 ± 1 hour (expected to be 9-10 hours in elderly patients with reduced renal function). Absorption is rapid, with peak plasma concentrations occurring approximately 1 hour after oral administration. Steady state can be achieved after 2 days of multiple dosing twice daily.

[0093] A typical starting dose of levetiracetam in treating epilepsy in humans is 500 mg twice daily, which is then increased to optimal efficacy 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). Brivaracetam has anticonvulsant activity and binds to SV2A in the brain. Brivaracetam is approved under the name Briviact®. A typical starting dose is 50 mg orally twice daily, and a maintenance dose is 25-100 mg orally twice daily.

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

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

[0097] In some embodiments, the administration interval of levetiracetam, brivaracetam or seletracetam or pharma- ceutical acceptable salts thereof, or pharmaceutical compositions comprising any of the above, is once every 12 hours (twice a day) or once every 24 hours (once a day). Administration at less frequent intervals, such as once every 6 hours, may also be used.

[0098] In some embodiments, levetiracetam or a pharma- ceutically acceptable salt thereof is administered in 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, levetiracetam or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 190 mg to 220 mg. In some embodiments, levetiracetam or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 190 mg to 240 mg. In some embodiments, levetiracetam or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 220 mg. In some embodiments, levetiracetam or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 190 mg.

[0099] In some embodiments of the method of the present disclosure, levetiracetam or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam or a pharma- ceutically acceptable salt thereof, is administered in an oral form, a sustained release form (e.g., a controlled release form, an extended release form, a sustained release form, a delayed release form or a slow release form) or a single unit dosage form, or once a day. In some embodiments, levetiracetam or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising levetiracetam or a pharma- ceutically acceptable salt thereof, is administered once a day or twice a day.

[0100] In certain embodiments of the present disclosure, brivaracetam or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 7-15 mg, 0.7-180 mg, 2.5-180 mg, 4.0-130 mg, or 14-30 mg. In other embodiments, brivaracetam or a pharma-ceutically acceptable salt thereof is administered in a daily dose of 0.7-50 mg, 0.7-75 mg, 0.7-100 mg, 0.7-150 mg, 0.7-180 mg, 1.8-50 mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg, 1.8-180 mg, 3.5-50 mg, 3.5-75 mg, 3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 3.5-200 mg, 3.5-220 mg, 3.5-300 mg, 3.5-400 mg, 3.5-50 mg, 3.5-60 mg, 3.5-75 mg, 3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 3.5-220 mg, 3.5-300 mg, 3.5-400 mg, 3.5-50 mg, 3.5-60 mg, 3.5-70 mg, 3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 3.5-180 mg, 3.5-220 mg, 3.5-180 mg, 3.5-180 mg, 3.5-180 mg, 3.5-180 mg, 3.5-180 mg, 3.5-1 80mg, 5~50mg, 5~75mg, 5~100mg, 5~150mg, 5~180mg, 7~50mg, 7~75mg, 7~100mg, 7~150mg, 7~180mg, 15~50mg, 15~75mg, 15~100mg, 15~150mg, 15~180mg, 35~50mg, 35~75mg, 35~100mg, 35~150mg, 35~180mg.

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

[0102] In some embodiments, seletracetam or a pharma- ceutically acceptable salt thereof is administered in 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 mg to 300 mg, or 200 mg to 300 mg, or 140 mg to 200 mg, or 7 mg to 350 mg, or 70 mg to 350 mg, or 100 mg to 300 mg, or 125 mg to 250 mg. In some embodiments, seletracetam or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 190 mg to 220 mg. In some embodiments, seletracetam or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 190 mg to 240 mg. In some embodiments, seletracetam or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 220 mg. In some embodiments, seletracetam or a pharma- ceutically acceptable salt thereof is administered in a daily dose of 190 mg.

[0103] In some embodiments of the method of the present disclosure, seletracetam or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising seletracetam or its pharmaceutically acceptable salt, is administered in oral form, sustained release form (e.g., controlled release form, extended release form, sustained release form, delayed release form or slow release form) or single unit dosage form, or once a day.In some embodiments, seletracetam or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising seletracetam or its pharmaceutically acceptable salt, is administered once a day or twice a day.

[0104] In certain embodiments of the disclosed methods and uses, the daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 280 mg to 350 mg of hydroxypropyl methylcellulose, 1.2 mg to 1.4 mg of colloidal silicon dioxide, 92.8 mg to 119.2 mg of silicified microcrystalline cellulose, and 6.0 mg to 6.7 mg of magnesium stearate. In other embodiments, the daily dose of levetiracetam or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 220 mg, and the pharmaceutical composition further comprises 347.5 mg hydroxypropyl methylcellulose, 1.4 mg colloidal silicon dioxide, 119.2 mg silicified microcrystalline cellulose, and 6.7 mg magnesium stearate. In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2208. In some embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC90.

[0105] In some embodiments of the disclosed method and use, the daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 190 mg, and the pharmaceutical composition further comprises 300 mg hydroxypropyl methylcellulose, 1.2 mg colloidal silicon dioxide, 102.8 mg silicified microcrystalline cellulose or anhydrous dicalcium phosphate and 6 mg magnesium stearate. In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2208. In some embodiments, the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC90. In some embodiments, the sustained release pharmaceutical composition of levetiracetam or a pharma- ceutically acceptable salt thereof is in solid form. In some embodiments, the sustained release pharmaceutical composition is in the form of a tablet or capsule.

[0106] In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof is in sustained release form and provides in a subject a steady state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL within 3 hours of administration, lasting for at least 8 hours of a 24 hour period after said administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof is in sustained release form and provides in a subject a steady state plasma concentration of levetiracetam within 2 hours of administration, lasting for at least 13 hours of a 24 hour period after said administration. In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharma- ceutically acceptable salt thereof is in sustained release form and provides in a subject a steady state plasma concentration of levetiracetam within 1 hour of administration, lasting for at least 13 hours of a 24 hour period after said administration. In other embodiments, the pharmaceutical composition provides said steady state plasma concentration of levetiracetam within 1 hour after administration, which lasts for at least 13-16 hours of a 24 hour period after said administration. See, e.g., WO2016191288.

[0107] In some embodiments, the pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutically acceptable salt thereof is formulated to be administered in one or more of oral form, sustained release form or single unit dosage form, or once a day.In other embodiments, the sustained release form is a controlled release form, a long-term release form, a sustained release form, a delayed release form or a slow release form.In some embodiments, the sustained release pharmaceutical composition of levetiracetam or a pharmaceutically acceptable salt thereof is in solid form.In some embodiments, the sustained release pharmaceutical composition of levetiracetam or a pharmaceutically acceptable salt thereof is in the form of a tablet or capsule.

[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 the formulation in Table 1. In one embodiment of the methods and uses of the present disclosure, the pharmaceutical composition is the 190 mg tablet A formulation. [Table 1]

[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 the formulation in Table 2. In one embodiment, the pharmaceutical composition is formulation D, which is a 220 mg tablet. [Table 2] GABA A Alpha 5 receptor agonists

[0110] GABA A Receptor (GABA A Neurotransmitters (R) are assemblies of pentamers derived from pools of distinct subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ) that form Cl-permeable channels gated by the neurotransmitter γ-aminobutyric acid (GABA). Various pharmacological effects, including anxiety disorders, epilepsy, insomnia, pre-anesthetic sedation and muscle relaxation, are attributed to various GABA receptors. AMediated by subtype.

[0111] Various studies have demonstrated that reduced GABA signaling is linked to various CNS disorders accompanied by cognitive impairment. For example, several studies have shown that in rats with age-related cognitive decline, GABA A It has been demonstrated that the expression of the α5 subunit of the receptor is decreased in the hippocampus (see, e.g., WO2007 / 019312). Other studies have demonstrated that the α5-containing GABA A R, GABA A The positive allosteric modulator of alpha5 receptor agonist is useful for treating the cognitive impairment associated with CNS disorder, the cognitive impairment associated with brain cancer, brain cancer or Parkinson's disease psychiatric disorders.See, for example, WO2015 / 095783, WO2018 / 130868, WO2016 / 205739, WO2018 / 130869, WO2019 / 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 a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or GABA as part of a pharmaceutical composition A The alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) A compound of formula II: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, m is 0 to 3; R 1 , R 2 , R 4 and R 5 For each occurrence, the following: halogen, -R, -OR, -NO 2 , -NCS, -CN, -CF 3, -OCF 3 , -SiR 3 , -N(R) 2 , -SR, -SOR, -SO 2 R, -SO 2 N(R) 2 , -SO 3 R, -(CR 2 ) 1~3 , -(CR 2 ) 1~3 -OR, -(CR 2 ) 0~3 -C(O)NR(CR 2 ) 0~3 , -(CR 2 ) 0~3 -C(O)NR(CR 2 ) 0~3 , -C(O)R, -C(O)C(O)R, -C(O)CH 2 C(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 , -(CR 2 ) 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)SO 2 , -N(R)SO 2 N(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) are each independently selected from R 3 is halogen, -R, -OR, -NO 2、-NCS、-CN、-CF 3 、-OCF 3 、-SiR 3 、-N(R) 2 、-SR、-SOR、-SO 2 R、-SO 2 N(R) 2 、-SO 3 R、-(CR 2 ) 1~3 R、-(CR 2 ) 1~3 -OR、-(CR 2 ) 0~3 -C(O)NR(CR 2 ) 0~3 R、-(CR 2 ) 0~3 -C(O)NR(CR 2 ) 0~3 OR、-C(O)R、-C(O)C(O)R、-C(O)CH 2 C(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 、-(CR 2 ) 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)SO 2 R、-N(R)SO 2 N(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 および-P(O)(H)(OR);-C≡CH、-C≡CR 9 、-(C1~C6)アルキル-C≡C-R10 , -CH 2 -OR 10 , -CH 2 -O-CH 2 -R 10 [ka] is selected from the group consisting of Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 3 is independently substituted with 0 to 5 R'; R 6 is selected from the group consisting of -H and -(C1-C6)alkyl; R 7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl; R 7 each is independently substituted with 0 to 5 R'; R 8 are each 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; R 8 are -halogen, -(C1-C6)alkyl, -CF, excluding -H and -(C1-C6)alkyl. 3 , -OCF 3 or O-(C1-C6)alkyl; R 9is -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 heterocycle, [ka] is selected from the group consisting of R 9 Each has an R of 0 to 5. 11 and R 10 is -H, halogen, -(C1-C6) alkyl, -(C6-C10) aryl, -5-10 membered heteroaryl, -(C3-C6) cycloalkyl, -CH 2 -(C3-C6)cycloalkyl, -CH 2 -(C6-C10)aryl and -CH 2 - 5 to 10 membered heteroaryl R 10 is each substituted with 0 to 5 R'; R 11 For each occurrence, -halogen, -CN, SCH 3 , -CF 3 , -OH, -OCF 3 , O.C.H.F. 2 , -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5-10 membered heteroaryl; R is: 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-, 3-10 membered heterocyclyl-, (3-10 membered heterocyclyl)-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-O-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-N(R")-(C1-C12)aliphatic-, 5-10 membered heteroaryl-, (5-10 membered heteroaryl)-(C1-C12)-aliphatic-, (5-10 membered heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 membered heteroaryl)-N(R")-(C1-C12)-aliphatic- are independently selected from the group consisting of The heterocyclyl is selected from N, NH, O, S, SO and SO 2 wherein the heteroaryl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, and S; R is independently substituted at each occurrence by 0 to 5 R'; or when two R groups are attached to the same atom, the two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO 2wherein the ring is optionally substituted with 0-5 R', and the ring is optionally fused to a (C6-C10)aryl, a 5-10 membered heteroaryl, a (C3-C10)cycloalkyl, or a 3-10 membered heterocyclyl; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from the group consisting of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl-, (C6-C10)-aryl-, (5-10 membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5-10 membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-; R" at each occurrence is halogen, -R o , -OR o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 and R is independently substituted with 0 to 5 substituents selected from the group consisting ofo is independently selected from the group consisting of -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl- and (C6-C10)-aryl at each occurrence; and ii) A compound of formula IV: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, m is 0 to 3; R 1 , R 4 and R 5 are each independently selected from: 1 , R 4 and R 5 For each occurrence, -R, -OR, -NO 2 , -NCS, -CN, -CF 3 , -OCF 2 H-OCF 3 , -SiR 3 , -N(R) 2 , -SR, -SOR, -SO 2 R, -SO 2 N(R) 2 , -SO 3 R, -(CR 2 ) 1~3 R, -(CR 2 ) 1~3 -OR, -(CR 2 ) 1~3 -O(CR 2 ) 1~3 -R, -(CR 2 ) 0~3 -C(O)NR(CR 2 ) 0~3 R, -(CR 2 ) 0~3 -C(O)NR(CR 2 ) 0~3 OR, -C(O)R, -C(O)C(O)R, -C(O)CH 2 C(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 , -(CR 2 ) 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)SO 2 R, -N(R)SO 2 N(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 , C.H. 2 CF 3 or CHF 2 are each independently selected from R 2 -OR 8 , -SR 8 , -(CH 2 ) n OR 8 , -(CH 2 ) n O(CH 2 ) n R 8 , -(CH 2 ) p R 8 or -(CH 2 ) n N(R”)R 10 wherein n is an integer selected from 0 to 4, and p is an integer selected from 2 to 4; R 2 is independently substituted with 0 to 5 R'; R 3 are -H, -CN, halogen, -(C1-C6) aliphatic, -CH=CR 9 , -C≡CR9 , -SO 2 ((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 , -CH 2 -OR 10 , -CH 2 -O-CH 2 -R 10 [ka] are independently selected from Each 5-10 membered heterocycle or heteroaryl is selected from 0-3 R 7 is replaced by R 3 is independently substituted with 0 to 5 R'; R 6 is selected from the group consisting of -H and -(C1-C6)alkyl; R 7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, -5-10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; R 7 each is independently substituted with 0 to 5 R'; R 8 is independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl or 5-10 membered heteroaryl, 5-10 membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl and -(C1-C6)alkyl-(C3-C6)cycloalkyl; R8 is independently substituted at each occurrence by 0 to 5 R'; R 9 is -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, [ka] is selected from the group consisting of R 9 Each has an R of 0 to 5. 11 and R 10 is -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3-10 membered heterocyclyl, (C6-C10)-aryl, 5-10 membered heteroaryl, -CH 2 -(C3-C6)cycloalkyl, -CH 2 -(C6-C10)aryl and -CH 2 - selected from the group consisting of 5 to 10 membered heteroaryl; R 10 is independently substituted at each occurrence by 0 to 5 R'; R 11 For each occurrence, -halogen, -CF 3 , -OCF 3 , -OH, OCF 2 H, -O-(C1-C6) alkyl, -(C6-C10) aryl, -(C1-C6) alkyl, -O-CH 2 independently selected from the group consisting of -(C3-C6)cycloalkyl, -CN, and -5-10 membered heteroaryl; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from the group consisting of R" at each occurrence 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-; R" at each occurrence is halogen, -R o , -OR o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 0 to 5 R independently selected from the group consisting of t and R o is independently selected at each occurrence 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 a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or GABA as part of a pharmaceutical composition A The alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is selected from the group consisting of: i) A compound of formula II: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, m is 0 to 3; R 1 are halogen, -H, -(C1-C6) alkyl, -OH, -O((C1-C6) alkyl), and -NO 2 , -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OMe, -C≡CR 8 , -CHF 2 , -CH 2 CF 3 , -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, and -(C3-C6)cycloalkyl; R 1 is independently substituted with 0 to 5 R'; R 2 teeth, -H, halogen, -OH, -(C1~C6) aliphatic, -O((C1~C6) alkyl), -C(O)O((C1~C6) alkyl), -C(O)NR 2 , -(CR 2 ) 1~3 -OR, -(CR 2 ) 1~3 -O(CR 2 ) 1~3 -R, -OR 9 , -C(O)R 8 , -CH 2 R 8 , -CH 3 , -CH 2 -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-, (5-10 membered heteroaryl)-(C1-C12)aliphatic-, (5-10 membered heteroaryl)-O-(C1-C12)aliphatic-, (5-10 membered heteroaryl)-N(R")-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-O-(C1-C12)aliphatic-, and (3-10 membered heterocyclyl)-N(R")-(C1-C12) aliphatic- is selected from the group consisting of R 2 is independently substituted with 0 to 5 R'; R 3 is -(C1-C6) alkyl, -(C2-C6) alkenyl, -C≡CH, -C≡CR 9 , -CN, halogen, -SO 2 ((C6-C10)-aryl), -SO 2 ((C1-C6) alkyl), -C(O)N((C1-C6) alkyl) 2 , -C(O)NH 2 , -C(O)O((C1-C6)alkyl), -C(O)((C1-C6)alkyl), -(C6-C10)aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, -(C1-C6)alkyl-C≡CR 10 , -CH 2 -OR 10 , -CH 2 -O-CH 2 -R 10 [ka] is selected from the group consisting of Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 3 is independently substituted with 0 to 5 R'; R4 and R 5 are each independently selected from the group consisting of -H, halogen, -(C1-C6)alkyl, or -(C1-C6)alkyl-(C6-C10)aryl, wherein (C6-C10)aryl is independently substituted with 0-5 halogens; R 6 is selected from the group consisting of -H and -(C1-C6)alkyl; R 7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl; R 7 each is independently substituted with 0 to 5 R'; R 8 are each 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; R 8 are -halogen, -(C1-C6)alkyl, -CF, excluding -H and -(C1-C6)alkyl. 3 , -OCF 3 or O-(C1-C6)alkyl; R 9 is -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 heterocycle, [ka] is selected from the group consisting of R 9 Each has an R of 0 to 5. 11 and R 10 is -H, halogen, -(C1-C6) alkyl, -(C6-C10) aryl, -5-10 membered heteroaryl, -(C3-C6) cycloalkyl, -CH 2 -(C3-C6)cycloalkyl, -CH 2 -(C6-C10)aryl and -CH 2 - 5 to 10 membered heteroaryl R 10 is each substituted with 0 to 5 R'; R 11 For each occurrence, -halogen, -CN, SCH 3 , -CF 3 , -OH, -OCF 3 , O.C.H.F. 2 , -O(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, and -5-10 membered heteroaryl; R is: 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-, 3-10 membered heterocyclyl-, (3-10 membered heterocyclyl)-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-O-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-N(R")-(C1-C12)aliphatic-, 5-10 membered heteroaryl-, (5-10 membered heteroaryl)-(C1-C12)-aliphatic-, (5-10 membered heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 membered heteroaryl)-N(R")-(C1-C12)-aliphatic- are independently selected from the group consisting of The heterocyclyl is selected from N, NH, O, S, SO and SO 2 wherein the heteroaryl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, and S; R is independently substituted at each occurrence by 0 to 5 R'; or when two R groups are attached to the same atom, the two R groups, together with the atom to which they are attached, are N, NH, O, S, SO, and SO 2 wherein the ring is optionally substituted with 0-5 R', and the ring is optionally fused to a (C6-C10)aryl, a 5-10 membered heteroaryl, a (C3-C10)cycloalkyl, or a 3-10 membered heterocyclyl; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3, -OCF 3 and -N(R") 2 are independently selected from the group consisting of R" is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl-, (C6-C10)-aryl-, (5-10 membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5-10 membered heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-; R" at each occurrence is halogen, -R o , -OR o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 and R is independently substituted with 0 to 5 substituents selected from the group consisting of o is independently selected from the group consisting of -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl- and (C6-C10)-aryl at each occurrence; and ii) A compound of formula IV: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, m is 0 to 3; R 1 are halogen, -H, -(C1-C6) alkyl, and -C≡CR. 9, -OH, -O((C1-C6) alkyl), -NO 2 , -CN, -CF 3 , -OCF 3 , -CHF 2 , -CH 2 CF 3 independently selected from the group consisting of -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 1 is independently substituted with 0 to 5 R'; R 2 -OR 8 , -SR 8 , -(CH 2 ) n OR 8 , -(CH 2 ) n O(CH 2 ) n R 8 , -(CH 2 ) p R 8 and -(CH 2 ) n N(R”)R 10 wherein n is an integer selected from 0 to 4, and p is an integer selected from 2 to 4; R 2 is independently substituted with 0 to 5 R'; R 3 are -H, -CN, halogen, -(C1-C6) aliphatic, -CH=CR 9 , -C≡CR 9 , -SO 2 ((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, -CH 2 -OR 10 , -CH2 -O-CH 2 -R 10 [ka] are independently selected from the group consisting of Each 5-10 membered heterocycle or heteroaryl is selected from 0-3 R 7 is replaced by R 3 is independently substituted with 0 to 5 R'; R 4 and R 5 are each independently selected from the group consisting of -H, halogen, and -(C1-C6)alkyl; R 6 is selected from the group consisting of -H and -(C1-C6)alkyl; R 7 is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, -5-10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl; R 7 each is independently substituted with 0 to 5 R'; R 8 is independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl or 5-10 membered heteroaryl, 5-10 membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl and -(C1-C6)alkyl-(C3-C6)cycloalkyl; R 8 is independently substituted at each occurrence by 0 to 5 R'; R 9is -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, [ka] is selected from the group consisting of R 9 Each has an R of 0 to 5. 11 and R 10 is -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, 3-10 membered heterocyclyl, (C6-C10)-aryl, 5-10 membered heteroaryl, -CH 2 -(C3-C6)cycloalkyl, -CH 2 -(C6-C10)aryl and -CH 2 - selected from the group consisting of 5 to 10 membered heteroaryl; R 10 is independently substituted at each occurrence by 0 to 5 R'; R 11 For each occurrence, -halogen, -CF 3 , -OCF 3 , OCF 2 H, -O-(C1-C6) alkyl, -(C6-C10) aryl, -(C1-C6) alkyl, -O-CH 2 independently selected from the group consisting of -(C3-C6)cycloalkyl and -5-10 membered heteroaryl; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2are independently selected from the group consisting of R" at each occurrence 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-; R" at each occurrence is halogen, -R o , -OR o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 0 to 5 R independently selected from the group consisting of t and R o is independently selected at each occurrence 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: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein m is an integer selected from 0 to 4; R 1 are halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -NCS, and -NO 2, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl and (C-C)-cycloalkenyl, each of the 5-6 membered heteroaryl and the 3-10 membered heterocycle being selected from 0-4 R 7 is replaced by R 7 are -H and -CF 3 , -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, -5-10 membered heteroaryl-(C1-C6)alkyl, and -3-10 membered heterocyclyl; R 7 are each independently substituted with 0 to 5 R'; or two R's 7 If the groups are attached to the same atom, the two R 7 The groups, together with the atoms to which they are attached, are N, NH, O, S, SO, and SO 2 and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from R 8are respectively -H, -(C1-C6 alkyl), -(5-10 membered heteroaryl), -(3-10 membered)heterocyclyl, (C3-C10)-cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -CH 2 -(C3-C6)cycloalkyl, -CH 2 -(C6-C10)aryl and -CH 2 - 5 to 10 membered heteroaryl; R 8 is independently substituted at each occurrence by 0 to 5 R'; R 9 are each selected from -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered)heterocyclyl, (C3-C10)-cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl; R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -Ome, -(C6-C10)aryl and -5-10 membered heteroaryl, wherein said heterocyclyl is selected from N, NH, O, S, SO and SO 2 and said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O and S; R 3 is -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), and R 3 is 0 to 5 R 12 and R 12 are -H, -halogen, and -OR, respectively. o , R o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 are independently selected from R o is independently selected at each occurrence from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl- and (C6-C10)-aryl, wherein said heterocyclyl is selected from N, NH, O, S, SO and SO 2 and said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O and S; R 4 is selected from -H or -(C1-C6)alkyl; R 6 is selected from -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from R″ at each occurrence is independently selected from —H, —(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl-, (C6-C10)-aryl-, (5-10 membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5-10 membered heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-; R″ at each occurrence is independently substituted with 0-3 substituents, and in particular, in some embodiments of the present disclosure, R″ is independently substituted with 1-3 substituents, the substituents being halogen, —R o , -OR o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 Selected from R o is independently selected from -(C1-C6)-aliphatic, -O(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl- and (C6-C10)-aryl-, wherein said heterocyclyl is selected from N, NH, O, S, SO and SO 2 and the heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O and S.

[0115] In some embodiments, the compound has the structure of formula Ib: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m, R 1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 is as defined in formula Ia.

[0116] In some embodiments, the compound has the structure of formula Ic: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m, R 1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 is as defined in formula Ia.

[0117] In some embodiments, the compound has the structure of formula Id: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 is as defined in formula Ia.

[0118] In some embodiments, the compound has the structure of formula Ie: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 is as defined in formula Ia.

[0119] In some embodiments, the compound has the structure of formula If: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 is as defined in formula Ia.

[0120] In some embodiments, the present disclosure provides a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; During the ceremony, m is an integer selected from 0 to 4; R 1 are halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, (C3-C10)-cycloalkenyl [ka] each of the 5- to 6-membered heteroaryl and the 3- to 10-membered heterocycle is selected from 0 to 4 R 7 is replaced by R 9 are respectively -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -(C6-C10)aryl, and -5-10 membered heteroaryl; R 3 is independently selected from -H, -(C1-C6)alkyl, -5-10 membered heteroaryl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, and -(C1-C6)alkyl-(C6-C10)aryl; R 3 is 0 to 5 R 12 and R 12 are -H, -halogen, and -OR, respectively. o , R o , oxo, -CH 2OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -CF 3 , -OCF 3 and -N(R o ) 2 are independently selected from R o is independently selected at each occurrence from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, -(3-10 membered)heterocyclyl and (C6-C10)-aryl; R 7 are respectively, -CF 3 , -(C1-C6) alkyl, -(C3-C6) cycloalkyl, -5-10 membered heteroaryl, -(C6-C10) aryl, -CH 2 -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl, and -3-10 membered heterocyclyl; R 7 are each independently substituted with 0 to 5 R'; or two R's 7 If the groups are attached to the same atom, the two R 7 The groups, together with the atoms to which they are attached, are N, NH, O, S, SO, and SO 2 and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, and —(C6-C10)aryl; R" is independently substituted with 1 to 3 substituents, the substituents being halogen, -CF 3 , -OCF 3 , -O(C1-C6)-aliphatic or -(C1-C6)-aliphatic; R 4 are each selected from -H or -(C1-C6)alkyl; R 6 are each selected from -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0121] In some embodiments of the compound of formula Ia or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, m is 0, 1 or 2; If m is 1 or 2, then the R 1 At least one of is halogen or -O((C1-C6)alkyl); R 1 are each independently selected from -halogen and -O(C1-C6)alkyl; R 2 is C≡CR 9 , (C3-C10)-cycloalkenyl [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are -(C1-C6) alkyl, [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 is independently selected at each occurrence from -(C1-C6)alkyl and -O-(C1-C6)alkyl; R 3 is independently selected from -H, -(C1-C6)alkyl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, and -(C1-C6)alkyl-(C6-C10)aryl; R 3 is 0 to 5 R 12 and R 7 -CF 3 , -(C1-C6) alkyl, -(C6-C10) aryl or -CH 2 -(C6-C10)aryl, R 7 each is independently substituted with 0 to 5 R'; R 4 and R 6 For each occurrence, -H.

[0122] In some embodiments, the present disclosure provides a compound of formula Ib: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m is an integer selected from 0 to 4; During the ceremony, R 1 are -halogen, -(C6-C10)aryl, -Ome, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each of the 5- to 6-membered heteroaryl and the 3- to 10-membered heterocycle is selected from 0 to 4 R 7 is replaced by R 9 are respectively -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -Ome, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 3 is -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 and -5-10 membered heteroaryl; R 3 is 0 to 5 R 12 and R 12 are -H, -halogen, and -OR, respectively. o , R o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 are independently selected from R o is independently selected at each occurrence from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl; R 7 are -H and -CF 3 , -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5-10 membered heteroaryl and -3-10 membered heterocyclyl; R 7 are each independently substituted with 0 to 5 R'; or two R's 7 If the groups are attached to the same atom, the two R 7 The groups, together with the atoms to which they are attached, are N, NH, O, S, SO, and SO 2and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-5-10 membered heteroaryl, -5-10 membered heteroaryl, -3-10 membered heterocyclyl, -(C3-C6)cycloalkyl, and -(C6-C10)aryl; R" is independently substituted with 1 to 3 substituents, the substituents being halogen, -CF 3 , -OCF 3 , -O-(C1-C6)aliphatic, -(C1-C6)-aliphatic and -5-10 membered heteroaryl; R 4 and R 6 are each independently selected from -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0123] In some embodiments of the compound of formula Ib or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, m is 0, 1 or 2; If m is 1 or 2, then the R 1 At least one of is halogen or -O((C1-C6)alkyl); R 1are each independently selected from -halogen and -O(C1-C6)alkyl; R 2 is C≡CR 9 , [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each selected from -(C1-C6)alkyl; R 9 Each occurrence is 0 to 5 R 11 and R 11 is selected from -(C1-C6)alkyl at each occurrence; R 3 is -H, -(C1-C6)alkyl or -CH 2 -(C6-C10)aryl and -3- to 10-membered heterocyclyl; R 3 is 0 to 5 R 12 and R 7 is -(C1-C6) alkyl, -CH 2 -(C6-C10)aryl, -(C3-C6)cycloalkyl, and -(3-10)-membered heterocyclyl; R 7 each is independently substituted with 0 to 5 R'; R 4 and R 6 For each occurrence, -H.

[0124] In some embodiments, the present disclosure provides a compound of formula Ic: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m is an integer selected from 0 to 4; R 1are -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), or -(3-10 membered)heterocyclyl. [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -OMe, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 7 For each occurrence, -CF3 , -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5-10 membered heteroaryl and -3-10 membered heterocyclyl; R 7 each is independently substituted with 0 to 5 R'; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from R″ at each occurrence is selected from: -Cl, -F, -(C1-C6)alkyl, -Ome, -(C1-C6)alkyl-5-10 membered heteroaryl, -5-10 membered heteroaryl, -3-10 membered heterocyclyl, -(C3-C6)cycloalkyl, and -(C6-C10)aryl; R″ is independently substituted with 1 to 3 substituents, the substituents being halogen, -CF 3 , -OCF 3 , -(C1-C6)-aliphatic and -5-10 membered heteroaryl; R 4 and R 6 are each independently selected from -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0125] In some embodiments of the compound of formula Ic or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, m is 0, 1 or 2; If m is 1 or 2, then the R1 At least one of is halogen or -O((C1-C6)alkyl); R 1 are each independently selected from -halogen and -O(C1-C6)alkyl; R 2 is CO(O)R 7 , C≡CR 9 , [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each selected from H or -(C1-C6)alkyl; R 9 Each occurrence is 0 to 5 R 11 and R 11 is selected from -(C1-C6)alkyl at each occurrence; R 4 and R 6 For each occurrence, -H.

[0126] In some embodiments, the present disclosure provides a compound of formula Id: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m is an integer selected from 0 to 4; During the ceremony, R 1 are -halogen, -(C6-C10)aryl, -Ome, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are respectively -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -Ome, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 3 is -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; R 3 is 0 to 5 R 12 and R 12 are -H, -halogen, and -OR, respectively. o , R o , oxo, -CH 2 OR o , -CH 2 N(R o ) 2 , -C(O)N(R o ) 2 , -C(O)OR o , -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R o ) 2 are independently selected from R o is independently selected at each occurrence from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl; R 7 -CF 3 , -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5-10 membered heteroaryl and -3-10 membered heterocyclyl; R 7 each is independently substituted with 0 to 5 R'; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, and —(C6-C10)aryl; R 4 are each selected from -H or -(C1-C6)alkyl; R 6 are each selected from -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0127] In some embodiments of the compound of formula Id or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, m is 0, 1 or 2; If m is 1 or 2, then the R 1 At least one of is halogen or -O((C1-C6)alkyl); R 1 are each independently selected from -halogen and -O(C1-C6)alkyl; R 2 is C≡CR 9 , [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each selected from -(C1-C6)alkyl; R 9 Each occurrence is 0 to 5 R 11 and R 11 is selected from -(C1-C6)alkyl at each occurrence; R 3 is -H, -(C1-C6)alkyl or -CH 2 -(C6-C10)aryl, R 3 is 0 to 5 R 12and R 12 each is independently selected from -H or -F; R 7 is -(C1-C6) alkyl, -CH 2 -(C6-C10)aryl, -(C3-C6)cycloalkyl, and -(3-10)-membered heterocyclyl; R 7 each is independently substituted with 0 to 5 R'; R 4 and R 6 For each occurrence, -H.

[0128] In some embodiments, the present disclosure provides a compound of formula Ie: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m is an integer selected from 0 to 4; R 1 are -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), or -(3-10 membered)heterocyclyl. [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11 Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -OMe, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, -5-10 membered heteroaryl-(C1-C6)alkyl, and -3-10 membered heterocyclyl; R 7 each is independently substituted with 0 to 5 R'; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 wherein each R' is independently substituted with 0 to 5 R"; R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, and —(C6-C10)aryl; R4 are each independently -H or (C1-C6) alkyl; R 6 are each independently -H or -(C1-C6)alkyl; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0129] In some embodiments of the compound of formula Ie or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, m is 0, 1 or 2; If m is 1 or 2, then the R 1 At least one of is halogen or -O((C1-C6)alkyl); R 1 are each independently selected from -halogen and -O(C1-C6)alkyl; R 2 is CO(O)R 7 , C≡CR 9 , [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each selected from H or -(C1-C6)alkyl; R 9 Each occurrence is 0 to 5 R 11 and R 11 is selected from -(C1-C6)alkyl at each occurrence; R 4 and R 6 Both of these are -H.

[0130] In some embodiments, the present disclosure provides a compound of formula If: [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; m is an integer selected from 0 to 4; R 1 are -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , CO(O)R 7 , C.H. 2 -OR 8 independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl and -(C3-C6)cycloalkyl; R 8 are each independently selected from -H or -(C1-C6 alkyl); R 2 are CO(O)R, respectively. 7 , C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), or -(3-10 membered)heterocyclyl. [ka] is selected from R 9 Each occurrence is 0 to 5 R 11 and R 11Each occurrence represents -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF 3 , -OCF 3 , -OMe, -(C6-C10)aryl, and -5-10 membered heteroaryl; R 7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, -5-10 membered heteroaryl-(C1-C6)alkyl, and -3-10 membered heterocyclyl; R 7 each is independently substituted with 0 to 5 R'; R' at each occurrence is halogen, -R", -OR", oxo, -CH 2 OR”, -CH 2 N.R.” 2 , -C(O)N(R”) 2 , -C(O)OR”, -NO 2 , -NCS, -CN, -CF 3 , -OCF 3 and -N(R") 2 are independently selected from each R' is independently substituted with 0-5 R" where 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; R 13 and R 14 are each independently selected from H-, (C1-C3)-aliphatic- or (C3-C6)-cycloalkyl.

[0131] In some embodiments of the compound of formula If, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, m is 0, 1, or 2; If m is 1 or 2, then the R1 At least one of is halogen or -O((C1-C6)alkyl); R 1 are each independently selected from -halogen and -O(C1-C6)alkyl; R 2 is CO(O)R 7 , C≡CR 9 , [ka] is selected from Each 5-membered heterocycle or heteroaryl is selected from 0 to 4 R 7 is replaced by R 9 are each selected from H or -(C1-C6)alkyl; R 9 Each occurrence is 0 to 5 R 11 and R 11 is selected from -(C1-C6)alkyl at each occurrence; R 4 and R 6 Both of these are -H.

[0132] In some embodiments, GABA Athe alpha5 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 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 as above, or Compound 606 Form A, Compound 606 Form B, Compound 606 Form C, Compound 606 Form E or Compound 606 Form F, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. See pages 284-305 of WO2022011318, which is incorporated by reference in its entirety, particularly in the context of the compounds described, their synthesis and properties.

[0133] In some embodiments, GABA A α5 receptor agonists, or pharma- ceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof, or the GABA A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof included as part of the pharmaceutical composition of the present disclosure is a compound of formula II as described in paragraph 19, or a compound of formula II as described in paragraph 20, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In other embodiments, GABA Aα5 receptor agonists, or pharma- ceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof, or the GABA A The α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof included as part of the pharmaceutical composition of the present disclosure is a compound of formula IV as described in paragraph 19, or a compound of formula IV as described in paragraph 20, or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments, the GABA A α5 receptor agonists or pharma- ceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof, or GABA receptor agonists included as part of the pharmaceutical compositions of the present disclosure. A The alpha 5 receptor agonist or a pharma- ceutically 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 The crystalline form of the α5 receptor agonist or its pharma- ceutically acceptable salt, hydrate, solvate or isomer. Such crystalline form may be selected from the group consisting of, for example, Compound 606 Form A (polymorphic crystalline form), Compound 606 Form B (polymorphic crystalline form), Compound 606 Form C (solvate crystalline form), Compound 606 Form E (polymorphic crystalline form) and Compound 606 Form F (hydrate crystalline form). In other embodiments of the methods and uses of the present disclosure, the pharmaceutical composition comprises GABA AThe crystalline form of the alpha5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate or isomer thereof may be one of a plurality of crystal forms, including, for example, those selected from the group consisting of compound 606 form A (polymorphic crystal form), compound 606 form B (polymorphic crystal form), compound 606 form C (solvate crystal form), compound 606 form E (polymorphic crystal form) and compound 606 form F (hydrate crystal form). In some embodiments, the crystal form is compound 606 form A. In some embodiments, the crystal form is compound 606 form B. In some embodiments, the crystal form is compound 606 form C. In some embodiments, the crystal form is compound 606 form E. In some embodiments, the crystal form is compound 606 form F. See WO2022011318, the entirety of which is incorporated herein by reference, particularly in the context of the compounds described, their synthesis and properties.

[0135] In some embodiments, the crystalline form is an anhydrous crystalline form of compound 606, where 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, where 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 Form A of compound 606 characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in Figure 29 of WO2022011318 having at least one of 3.0 and / or 21.0 degrees 2θ ± 0.2 degrees 2θ and further including one or more additional peaks selected from 9.1, 10.7, 13.8, 22.0, 23.1, 23.9, 24.4 and 27.1 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, the crystalline form is Form A of compound 606 characterized by a C2 / c single crystal X-ray diffraction space group. In some embodiments, the crystalline form has the following parameters: a=58.1415(14) Å, b=4.03974(8) Å, c=17.1204(3) Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14) Å 3 In some embodiments, the crystalline form is Form A of compound 606, characterized by a single crystal X-ray diffraction unit cell having: In some embodiments, the crystalline form is Form A of compound 606, characterized by a differential scanning calorimetry (DSC) curve substantially as set forth in Figure 27B of WO2022011318. In some embodiments, the crystalline form is Form A of compound 606, characterized by a differential scanning calorimetry (DSC) curve having an exotherm with an onset at about 207 °C. In some embodiments, the crystalline form has (a) an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 29 of WO2022011318; (b) a C2 / c single crystal X-ray diffraction space group; and (c) parameters: a=58.1415(14) Å, b=4.03974(8) Å, c=17.1204(3) Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14) Å. 3 and (d) a differential scanning calorimetry (DSC) curve substantially as set forth in Figure 27B of WO2022011318; and (e) Form A of compound 606, characterized by two or more of the following: (a) a single crystal X-ray diffraction unit cell having a crystal structure of

[0137] In some embodiments of the methods and uses of the present disclosure, the crystalline form is Form B of compound 606 characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 34 of WO2022011318 having at least one peak selected from 13.0 and / or 15.3 degrees 2θ ± 0.2 degrees 2θ, and further including one or more 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 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, the crystalline form is Form B of compound 606 characterized by a single crystal X-ray diffraction monoclinic unit cell. In some embodiments, the crystalline form is Form B of compound 606 characterized by a single crystal X-ray diffraction monoclinic unit cell. 3 In some embodiments, the crystalline form is Form B of compound 606 characterized by a single crystal X-ray diffraction formula unit volume of about 497 Å. In some embodiments, the crystalline form is Form B of compound 606 characterized by a differential scanning calorimetry (DSC) curve having an exotherm with an onset at about 190° C. In some embodiments, the crystalline form is Form B of compound 606 characterized by: (a) an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 34 of WO2022011318; (b) a single crystal X-ray diffraction formula unit volume of about 497 Å. 3 and (c) a differential scanning calorimetry (DSC) curve having an exotherm with an onset at about 190° C.

[0138] In some embodiments of the methods and uses of the present disclosure, the crystalline form is Form C of compound 606 characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 41 of WO2022011318 having at least one peak selected from 8.5 and / or 18.9 degrees 2θ ± 0.2 degrees 2θ, and further including one or more 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 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, the crystalline form is Form C of compound 606 characterized by a single crystal X-ray diffraction monoclinic unit cell. In some embodiments, the crystalline form is Form C of compound 606 characterized by a single crystal X-ray diffraction monoclinic unit cell. 3In some embodiments, the crystalline form is Form C of compound 606, characterized by a differential scanning calorimetry (DSC) curve substantially as set forth in Figure 42B of WO2022011318. In some embodiments, the crystalline form is Form C of compound 606, characterized by a differential scanning calorimetry (DSC) curve having an exotherm with an onset at about 190°C. In some embodiments, the crystalline form is Form C of compound 606, characterized by (a) an X-ray powder diffraction (XRPD) pattern substantially as set forth in Figure 41 of WO2022011318, (b) a single crystal X-ray diffraction monoclinic unit cell, (c) a molecular weight of about 544 Å. 3 and (d) a differential scanning calorimetry (DSC) curve substantially as set forth in Figure 42B of WO2022011318; and (e) Form C of compound 606, characterized by two or more of the following: (a) a single crystal X-ray diffraction formula unit volume of 1000 nm; (b) a differential scanning calorimetry (DSC) curve substantially as set forth in Figure 42B of WO2022011318; and (c) a differential scanning calorimetry (DSC) curve having an exotherm with an onset at about 190°C.

[0139] In some embodiments of the methods and uses of the present disclosure, the crystalline form is Form E of compound 606 characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in Figure 45 of WO2022011318 having at least one peak selected from 11.4, 18.1 and / or 21.6 degrees 2θ ± 0.2 degrees 2θ, and further including one or more additional peaks selected from 7.2, 22.0, 23.0, 24.2, 25.0 and 26.6 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, the crystalline form is Form E of compound 606 characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in Figure 45 of WO2022011318 having at least one peak selected from 11.4, 18.1 and / or 21.6 degrees 2θ ± 0.2 degrees 2θ, and further including one or more additional peaks selected from 7.2, 22.0, 23.0, 24.2, 25.0 and 26.6 degrees 2θ ± 0.2 degrees 2θ. 1 / n single crystal X-ray diffraction space group, is Form E of compound 606. In some embodiments, the crystalline form has the parameters: a=11.83974(13) Å, b=23.5195(2) Å, c=14.48807(17) Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7) Å 3In some embodiments, the crystalline form is Form E of compound 606, characterized by a single crystal X-ray diffraction unit cell having: In some embodiments, the crystalline form is Form E of compound 606, characterized by a differential scanning calorimetry (DSC) curve substantially as set forth in Figure 36B of WO2022011318. In some embodiments, the crystalline form is Form E of compound 606, characterized by a differential scanning calorimetry (DSC) curve having an exotherm with an onset at about 201 °C. In some embodiments, the crystalline form is Form E of compound 606, characterized by: (a) an X-ray powder diffraction (XRPD) pattern substantially as set forth in Figure 35 of WO2022011318; (b) a P2 1 / n Single crystal X-ray diffraction space group, (c) Parameters: a=11.83974(13)Å, b=23.5195(2)Å, c=14.48807(17)Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7)Å 3 and (d) a differential scanning calorimetry (DSC) curve substantially as set forth in Figure 36B of WO2022011318; and (e) a differential scanning calorimetry (DSC) curve having an exotherm with an onset at about 201°C.

[0140] In some embodiments of the methods and uses of the present disclosure, the crystalline form is Form F of compound 606 characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 37 of WO2022011318 having at least one peak selected from 9.9, 11.9, 17.3, 19.4 and / or 25.7 degrees 2θ ± 0.2 degrees 2θ, and further including one or more additional peaks selected from 9.7, 12.1, 20.8, 23.2, 23.7, 24.2, 25.0 and 26.4 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, the crystalline form is Form F of compound 606 characterized by a single crystal X-ray diffraction triclinic unit cell. In some embodiments, the crystalline form is Form F of compound 606 characterized by a single crystal X-ray diffraction triclinic unit cell having at least one peak selected from 9.9, 11.9, 17.3, 19.4 and / or 25.7 degrees 2θ ± 0.2 degrees 2θ. 3In some embodiments, the crystalline form is Form F of compound 606 characterized by a differential scanning calorimetry (DSC) curve having an exotherm at greater than about 120° C. In some embodiments, the crystalline form is Form F of compound 606 characterized by (a) an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 37 of WO2022011318; (b) a single crystal X-ray diffraction triclinic unit cell; and (c) a molecular weight of about 511 Å. 3 and (d) a differential scanning calorimetry (DSC) curve having an exotherm at or above about 120° C.

[0141] The pharmaceutical compositions or combinations (or their components) of the disclosed methods and uses may be administered by buccal and oral delivery (including sublingual and buccal administration, see, for example, Danckwerts (2003). Intraoral Drug Delivery: A Comparative Review. American Journal of Drug Delivery. 1. 171-186). Such delivery may be in the form of bioadhesive polymers, tablets, patches, thin films, liquids and semi-solids (see, for example, Smart JD. Buccal drug delivery. Expert Opin Drug Deliv. 2005 May; 2(3):507-17).

[0142] Those skilled in the art, such as physicians, can use the compositions and methods of the present disclosure to determine whether GABA receptor antagonists are effective in treating a subject. A The required amount of α5 receptor agonist can be readily determined. The dosage regimen can be determined, for example, by administering a selected GABA A It will be understood that the effect of the alpha5 receptor agonist will be determined for each individual, taking into account various factors that modify the effect of the alpha5 receptor agonist, the severity or stage of the disease, the route of administration, and characteristics specific to that individual, such as age, weight, size, and degree of cognitive impairment.

[0143] In certain embodiments of the present disclosure, GABAA The daily dose of the α5 receptor agonist or a pharma- ceutically 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, the GABA A The dosage of the α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is about 0.1 to 500 mg / day. In some embodiments of the present disclosure, the GABA A The dose of the α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is about 1-250 mg / day. In some embodiments of the present disclosure, the GABA A The dosage of the α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is about 10-100 mg / day. In some embodiments of the present disclosure, the GABA AThe dose of the α5 receptor agonist or its pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer is about 1-10 mg / day. Daily doses 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, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 ... / kg, 0.6mg / 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 / kg, 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 g, 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, 5 In some embodiments, the GABA may be administered in the form of a 200 mg, 300 mg, 400 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 2500 mg, 3500 mg, or 5000 mg. A The dose of the α5 receptor agonist or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is AThe amount of alpha5 receptor agonist 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 about 5000 mg. Other doses higher than, intermediate or lower than these doses may be used and can be determined by those skilled in the art according to the methods of the present disclosure.

[0144] In certain embodiments, GABA A Doses of α5 receptor agonists are between 0.0001 and 100 mg / kg / day in rodents (which, assuming a typical human subject of 70 kg, 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 hours or 24 hours.In some embodiments, administration is used once a day.In some embodiments, administration at more frequent intervals, such as once every 6 hours, can also be used.In the case of repeated administration over several days or weeks or longer, treatment is continued until a sufficient level of cognitive function is achieved, depending on the condition.

[0146] Dosing at less frequent intervals may also be used. A For example, when administered by implant, device, or slow or sustained release formulation, α5 receptor agonist can be administered once, or periodically once or multiple times throughout the patient's life, as needed.Other administration intervals between or shorter than these administration intervals can also be used and can be determined by those skilled in the art according to the method of the present invention.

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

[0148] In some embodiments of the methods and uses of the present disclosure, levetiracetam, brivaracetam or seletracetam or pharma- ceutically acceptable salts thereof, and / or 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 to 12, 44 to 56, 101 to 268, 270 to 644, 646 to 687, 689 to 698, 700 to 703, 705, 707 to 721, 723 to 740, 742 to 755, 758 to 763, 765 to 779, 781 to 795, 797 to 810, 813 to 828, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 995, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 13 Compounds, pharmaceutical compositions, combinations and medicaments comprising one or more compounds, pharmaceutical compositions, pharmaceutical combinations (e.g., comprising levetiracetam, brivaracetam or seletracetam), or pharma- ceutically acceptable salts thereof, hydrates, solvates, polymorphs or isomers thereof, useful in the methods and uses of the present disclosure, such as GABA, levetiracetam, brivaracetam or seletracetam, or pharma- ceutically acceptable salts thereof, hydrates, solvates, polymorphs or isomers thereof, may be in solid dosage forms such as capsules, tablets, medicinal dragees, pills, lozenges, cachets, powders, troches, wafers or granules. In such forms, compounds, pharmaceutical compositions, pharmaceutical combinations (e.g., comprising levetiracetam, brivaracetam or seletracetam), or pharma- ceutically 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 to 12, 44 to 56, 101 to 268, 270 to 644, 646 to 687, 689 to 698, 700 to 703, 705, 707 to 721, 723 to 740, 742 to 755, 758 to 763, 765 to 779, 781 to 795 above) , 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 pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof), is / are prepared by the steps of: (1) administering to the patient a medicament ... (1) fillers or extenders such as gluten, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants such as glycerol; (4) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) colorants. In the case of capsules, tablets and pills, the pharmaceutical compositions or combinations (or components thereof) may also comprise buffering agents.Solid pharmaceutical compositions or combinations of a similar type (or components thereof) may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0149] Pharmaceutical compositions or combinations (or components thereof) useful in the methods and uses of the present disclosure (e.g., levetiracetam, brivaracetam or seletracetam, or pharma- ceutically acceptable salts thereof, and / or 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 to 12, 44 to 56, 101 to 268, 270 to 644, 646 to 687, 689 to 698, 700 to 703, 705, 707 to 721, 723 to 740, 742 to 755, 758 to 763, 765 to 779, 781 to 795, 797 to 810, 813 to 828, 830, 831, 833 to 846 above) , 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 pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof) of the pharmaceutical composition or combination (or components thereof)) may be in an aqueous or non-aqueous liquid dosage form, including a solution, emulsion, microemulsion, suspension, syrup, pastille or elixir. In some embodiments, the pharmaceutical composition or combination (or components thereof) is in an aqueous solution. In some embodiments, the pharmaceutical composition or combination (or components thereof) is in a suspension form.

[0150] Where appropriate, the pharmaceutical compositions or combinations (or components thereof) may be prepared with coatings, such as enteric coatings, or they may be coated with one or more compounds useful in the methods and uses of the present disclosure (e.g., levetiracetam, brivaracetam or seletracetam), or pharma- ceutically acceptable salts thereof and / or GABA, in accordance with methods well known to those skilled in the art. 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 to 12, 44 to 56, 101 to 268, 270 to 644, 646 to 687, 689 to 698, 700 to 703, 705, 707 to 721, 723 to 740, 742 to 755, 758 to 763, 765 to 779, 781 to 795, 79 or Form A of Compound 606; Form B of Compound 606; Form C of Compound 606; Form E of Compound 606; or Form F of Compound 606) or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph, or isomer thereof). 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), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, 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 contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, aromatic agents and preservatives. The suspensions contain a compound useful in the methods and uses of the present disclosure (e.g., levetiracetam, brivaracetam, or seletracetam) or a pharma- ceutically 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 to 12, 44 to 56, 101 to 268, 270 to 644, 646 to 687, 689 to 698, 700 to 703, 705, 707 to 721, 723 to 740, 742 to 755, 758 to 763, 765 to 779, 781 to 795, 797 to 810, 813 to 828, 830, 831, 833 to 846, 848 to 89 Compound 606 Form A; Compound 606 Form B; Compound 606 Form C; Compound 606 Form E; or Compound 606 Form F), or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof), may also include a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0151] The pharmaceutical composition or combination (or its components) useful for the disclosed method and use may be formulated for respiratory delivery (pulmonary and nasal delivery).In such form, the pharmaceutical composition or combination may be delivered by device and in forms including, but not limited to, various pressurized metered dose inhalers, dry powder inhalers, nebulizers, aqueous mist inhalers, droplets, solutions, suspensions, sprays, powders, gels, ointments, and specialized systems such as liposomes and microspheres (see, for example, Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabet Med. 2003 Nov; 20(11):886-98 and Martini G, Ciani L. Electron spin resonance spectroscopy in drug delivery. Phys Chem Phys. 2009).

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

[0153] In some embodiments of the disclosed methods and uses, one or more of the compounds, pharmaceutical compositions or medicaments may be packaged together. In other embodiments, one or more of the compounds, pharmaceutical compositions or medicaments may be packaged separately. Combinations useful in the disclosed methods and uses also include levetiracetam, brivaracetam or seletracetam or pharma- ceutical acceptable salts 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 to 12, 44 to 56, 101 to 268, 270 to 644, 646 to 687, 689 to 698, 700 to 703, 705, 707 to 721, 723 to 740, 742 to 755, 758 to 763, 765 to 779, 781 to 795, Compound 606, Form A; Compound 606, Form B; Compound 606, Form C; Compound 606, Form E; or Compound 606, Form F), or a pharma- ceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, or a formulation of a pharmaceutical composition containing each of them together in a formulation or in separate formulations.

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

[0155] Pharmaceutical compositions or combinations (or their components) useful for the disclosed methods and uses may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of microbial action can be brought about by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the pharmaceutical compositions or combinations (or their components). In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0156] Pharmaceutical compositions, medicaments or combinations (or components thereof) useful in the methods and uses of the present disclosure can be prepared by methods well known in the art of pharmacy, for example, those described in Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th Edition Edited by JG Hardman, LE Limbird, 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 edition (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 method of the present disclosure comprises administering to the subject levetiracetam, brivaracetam or seletracetam, or a pharmaceutically acceptable salt. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam or seletracetam, or a pharmaceutical salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the method comprises administering to the subject levetiracetam or a pharmaceutically acceptable salt. In some embodiments, the method comprises administering to the subject brivaracetam or a pharmaceutically acceptable salt. In some embodiments, the method comprises administering to the subject seletracetam or a pharmaceutically acceptable salt. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising a daily dose of levetiracetam or a pharmaceutical salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising a daily dose of brivaracetam or a pharmaceutical salt thereof and a pharmaceutically acceptable carrier.In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising a daily dose of seletracetam or a pharmaceutical salt thereof and a pharmaceutically acceptable carrier. General synthesis method

[0158] The compounds of the present disclosure can generally be prepared by methods known to those skilled in the art. The following schemes 1-4 provide general synthetic routes for the preparation of compounds of formula Ia-If. Other equivalent schemes, readily apparent to an organic chemist of ordinary skill in the art, may be used instead to synthesize various portions (or the entirety) of the molecules illustrated by the following general schemes. Scheme 1. General synthesis of compounds of formula Ia where X, W and V form a pyrazole ring [ka] Scheme 2. General synthesis of compounds of formula Ib where X, W and V form a methylpyrazole ring [ka] Scheme 3-A. General synthesis of compounds of formula Ib where X, W and V form a pyrazole ring [ka] Scheme 3-B. Alternative synthesis of compounds of formula Ib (primary) starting from intermediate A, where X, W and V form a pyrazole ring [ka] Scheme 3-C. Alternative synthesis of compounds of formula Ic starting from intermediate A, where X, W and V form an isoxazole ring [ka]

[0159] As will be recognized by the skilled practitioner, compounds of Formula I, Ia, Ib, Ic, Id, Ie, and If having variables other than those illustrated above can be prepared by varying the chemical reagents or synthetic routes. Predictive risk factors for cognitive decline or impairment in subjects who exhibit or demonstrate cognitive performance within the normal range for their age

[0160] In some embodiments, subjects treated in the methods and uses of the present disclosure (subjects who exhibit or exhibit cognitive abilities within the normal range for the subject's age) are at risk of developing cognitive decline or impairment, which risk is associated with aging.

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

[0162] In some embodiments, the subject treated in the methods and uses of the present disclosure (subjects who exhibit or exhibit cognitive abilities within the normal range for the subject's age) is at risk of developing cognitive decline or cognitive impairment, the risk being a genetic risk associated with the presence of one or more genomic variants, mutations or polymorphisms in the subject's genome that are associated with changes in 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, the risk being associated with the presence of one or more genomic variants, mutations or polymorphisms in the subject's genome that are associated with ABCA7. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, the risk being associated with the presence of one or more genomic variants, mutations or polymorphisms in the subject's genome that are associated with CLU. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, the risk being associated with the presence of one or more genomic variants, mutations or polymorphisms in the subject's genome that are associated with CR1. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, and this risk is associated with the presence of one or more genomic variants, 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, and this risk is associated with the presence of one or more genomic variants, 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, and this risk is associated with the presence of one or more genomic variants, 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, and this risk is associated with the presence of one or more genomic variants, 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, and this risk is associated with the presence of at least one allele of APOE4 gene in the genome of the subject.In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, and this risk is associated with the presence of one allele of APOE4 gene in the genome of the subject.In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, and this risk is associated with the presence of both alleles of APOE4 in the genome of the subject.

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

[0165] Example 1 Composition of Levetiracetam Compositions containing levetiracetam can be made by the process illustrated in the flow diagram of Figure 4. Briefly, silicified microcrystalline cellulose ProSolv™ SMCC HD90 (or Encompress, anhydrous dicalcium phosphate) is sieved through a deagglomerate #30 US mesh sieve and then blended with colloidal silicon dioxide (16qt V-shell blender; 75 rpm ± 5 rpm). The blended sample is then passed through a round 1601 impeller (2A024R screen). 220 mg of levetiracetam and hypromellose 2208 (Methocel™ K15M Premium CR) (or Methocel™ K100M Premium CR) are also sieved through a deagglomerated #30 U.S. mesh sieve and then mixed with 1 ft of milled silicified microcrystalline cellulose ProSolv™ HD90 and colloidal silicon dioxide. 3 The blended sample is then passed through a round 1601 impeller (2A024R screen) and then mixed with sieved magnesium stearate (HyQual®) (sieved through a deagglomerated #30 U.S. mesh sieve) in a 1 ft 3 The tablets are blended in a 500 ml pitch cone blender (125 rpm ± 5 rpm). The blended sample is compressed into tablets. If necessary, the tablets are further film coated with a hypromellose-based (HPMC-based) coating such as Opadry® complete film coating system. A similar process can be used for compositions containing 190 mg of levetiracetam. Example 2 Assessment of levetiracetam plasma levels

[0166] The effective steady-state levetiracetam plasma concentration range for treating cognitive impairment was previously established using the aMCI clinical trial and aged rat study disclosed in WO2016191288, the entire contents of which are incorporated herein by reference. In one embodiment, the concentration range of levetiracetam is between 2.9-4.4 μg / mL. In another embodiment, the concentration range of levetiracetam is between 1.9-4.4 μg / mL. In another aspect, the effective plasma concentration is between 1.9-3.9 μg / mL. See FIG. 1.

[0167] This example further describes a two-arm, single-dose, two-period, two-way crossover, food effect study of two extended release formulations of levetiracetam, namely, 190 mg tablet A of Table 1 and 220 mg tablet D of Table 2. Test Design

[0168] This is an open-label, randomized, two-arm, single-dose, two-period crossover, food-effect study. 56 healthy subjects will be enrolled. Subjects who successfully complete the screening process will check into the study site the evening before their first dose. Subjects who continue to meet the inclusion / exclusion criteria the morning of dosing will be assigned a number based on the order in which they successfully completed the required screening processes and procedures. Dosing days will be separated by a washout period of at least 7 days. Subjects will be randomly assigned to one of two groups: [Table 6] Summary of clinical procedures

[0169] During each study period, 6 mL of blood samples are obtained before each dose and after each dose at selected times over the 24-hour period after each dose.A total of 34 pharmacokinetic blood samples are collected from each subject, 17 samples during each study period.In addition, blood is drawn and urine is collected for clinical testing at screening and at the end of the study.

[0170] During each study period, subjects will be admitted to the study unit the afternoon prior to the scheduled dosing. Subjects will remain in the study facility for the duration of each study period until completion of 24-hour blood sampling and other study procedures. Procedures for collecting samples for pharmacokinetic analysis

[0171] Blood samples (1 x 6 mL) are collected into evacuated tubes containing K2-EDTA as a preservative at pre-dose (0) and at 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 post-dose. Summary of biological analysis

[0172] Analyze plasma samples for levetiracetam using a validated LC MS MS procedure. The method has been validated for a range of 0.0500-30.0 µg / mL for levetiracetam based on the analysis of 0.200 mL of human EDTA plasma. Data are stored in the Watson Laboratory Information Management System (LIMS; version 7.2.0.03, Thermo Fisher Scientific). Pharmacokinetic analysis

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

[0174] The following pharmacokinetic parameters are calculated: peak plasma concentration (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). Additionally, Cmax, AUClast, and AUCinf are normalized to dose. Steady-State Modeling

[0175] Consistent with steady-state modeling of the PK profile for the 190 mg tablet A, plasma concentrations of levetiracetam were between 1.9 and 4.4 μg / mL for a substantial portion of the 24-hour post-dose period. See Figure 2.

[0176] Based on steady-state modeling of the PK profile for the 220 mg tablet D, plasma concentrations of levetiracetam were between 2.9 and 4.4 μg / mL for a substantial portion of the 24-hour post-dose period. See Figure 3. Example 3 Effects of levetiracetam on hippocampal functional connectivity: The Alzheimer's disease-related LEV-HFC study subject

[0177] To evaluate the potential effect of levetiracetam on hippocampal functional connectivity (a risk marker for cognitive decline and impairment, and progression to AD), we conducted a phase II randomized, double-blind, placebo-controlled, crossover clinical trial in 26 CN subjects (age range 55-75 years). Thirty-five patients were recruited, assessed for eligibility, and 26 eligible subjects were divided into treatment groups, group A or group B. Subjects in group A took oral placebo tablets daily for 2 weeks, followed by a 4-week washout period, after which the subjects took oral levetiracetam tablets daily for 2 weeks (i.e., 2 weeks of placebo treatment, 4 weeks of washout period, and 2 weeks of levetiracetam treatment). Subjects in group B received treatment using the opposite order (i.e., 2 weeks of levetiracetam treatment, 4 weeks of washout period, and 2 weeks of placebo treatment). The tablets were characterized with levetiracetam 220 mg in sustained release form, namely tablet D as above (Table 2). The flow diagram of the study design is shown in FIG. MRI protocol

[0178] For each scanning session, imaging was performed on a 3T GE MR750 whole-body scanner (GE Healthcare, Waukesha WI) equipped with a body transmit coil and a 32-channel head receive coil (Nova Medical, Wilmington MA). Imaging acquisitions included T1- and T2-weighted high-resolution anatomical images (TR=2521.27ms, TE=3.596ms, voxel resolution: 0.5×0.5×0.8mm3, FOV: 25.6cm, flip angle: 8°). Functional images included episodic memory (300s duration), finger tap (192s duration), and two resting states (480s duration, one AP axial and one PA axial scan). Functional imaging parameters included TE: 33.5 ms, TR: 800 ms, 50° flip angle, 128 × 128 acquisition matrix, 20.8 cm axial FOV, 2 mm thick slices, 8-band simultaneous multislice acceleration, 1 / 3 blip CAIPI field of view shift, and a total of 72 slices conforming to the Lifespan Human Connectome Project acquisition protocol. T2 flare: voxel resolution: 0.5 × 0.5 × 0.8 mm3, FOV: 25.6 cm, TR: 4002 ms, TE: 161.893 ms, 90° flip angle. Perfusion images (pcASL) included 72 frames, voxel resolution: 1.875 × 1.875 × 4 mm3, 24 cm FOV, TR: 4667 ms, TE: 56.32 ms. Pre-processing of resting state images

[0179] Image pre-processing was performed using Analysis of Functional Neuroimaging (AFNI) software (http: / / afni.nimh.nih.gov / afni / ), SPM8 (Wellcome Trust, London, United Kingdom) and MATLAB® (MathWorks, Natick, Massachusetts). Pre-processing allows for T1 equilibration (excluding the first 15 s of R-fMRI data); slice-acquisition-dependent time shift correction (3dTshift); motion correction (3dvolreg); trend removal (3dDetrend); despiking (3dDespike); spatial normalization (original space to Montreal Neurological Institute [MNI] space, SPM8); averaging of white matter and CSF recovered signals using standard SPM white matter and cerebrospinal fluid (CSF) masks, in MNI space (3dROIstats); removal of white matter, CSF signals and motion effects (3dDeconvolve); checking for the need for global signal removal (if necessary, global signal is removed) (see, e.g., Chen et al., 2012); and low-frequency band-pass filtering (3dFourier, 0.015–0.1 Hz). Total functional connectivity index

[0180] The total functional connectivity index (TFCI) was obtained based on a conventional region of interest (ROI)-based method (Chen et al., 2011), in which individual cerebral cortices were automatically parcellated 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 a seed region and all of the other regions in the cerebral cortex. Specifically, the entire cerebral cortex was first divided into 90 regions based on the AAL template, and the blood oxygen level-dependent (BOLD) time series of each region was extracted using the AAL template mask from the preprocessed resting-state dataset published in Tzourio-Mazoyer et al. (2002). Then, the functional connectivity between each ROI and other brain regions was calculated using Pearson cross-correlation analysis. Thus, a vector consisting of 89 cross-correlation coefficient (CC) values ​​was obtained for each ROI. Finally, the FCI value of each ROI was calculated by summing the 89 CC values ​​within each ROI vector. In addition to removing the effects of outliers, the median functional connectivity index (MFCI) was calculated by the median value of the 89 CC values ​​within each ROI vector. TFCI and MFCI were calculated for the 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 enrolled subject had no detectable levetiracetam in his blood sample and was discarded upon analysis. A total of 25 participants (15 females with a mean [SD] age of 65.9 [3.8] years and 10 males with a mean [SD] age of 66.7 [5.5] years) were enrolled and randomized (12 participants to group A and 13 participants to group B) to complete the study. See Table 3. Overall, treatment with levetiracetam significantly reduced functional connectivity of the hippocampal network compared to placebo (paired t-test, t=-2.8044, p<0.0098; Figure 6). [Table 3-1] [Table 3-2]

[0182] In Table 3, in columns for Periods I and II, * Numbers with a * indicate functional connectivity from subjects receiving 2 weeks of placebo treatment, all other numbers indicate functional connectivity from subjects receiving 2 weeks of levetiracetam treatment.

[0183] Table 3 shows the individual scores for each participant. Briefly, the columns of the table display, from left to right, 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 score for dementia, the subject's APOE genotype, the subject's baseline hippocampal functional connectivity, the hippocampal functional connectivity during the first 2 weeks of treatment (levetiracetam or placebo), the hippocampal functional connectivity during the second 2 week treatment period after washout (levetiracetam or placebo) and the blood levetiracetam levels 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 are not intended to be limiting.

Claims

1. A composition or pharmaceutical composition for preventing or slowing the progression of cognitive impairment in a subject, or for preventing or reducing the onset of cognitive decline, wherein the composition contains 0.7 to 350 mg of levetiracetam, brivalacetam, or ceretracetam, or a pharmaceutically acceptable salt thereof, in a daily dose, and the pharmaceutical composition comprises the daily dose of levetiracetam, brivalacetam, or ceretracetam, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the subject exhibits or displays cognitive abilities within the normal range for the subject's age.

2. The composition or pharmaceutical composition according to claim 1, wherein the daily dose of levetiracetam or ceretracetam or the pharmaceutically acceptable salt thereof is 7 to 350 mg.

3. The composition or pharmaceutical composition according to claim 1, wherein the daily dose of buribaracetam or a pharmaceutically acceptable salt thereof is 0.7 to 180 mg.

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

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

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

7. The composition or pharmaceutical composition according to claim 1, wherein the composition or pharmaceutical composition is formulated in one or more of the following forms: oral form, sustained-release form, single-dose dosage form, or once-daily administration form.

8. The composition or pharmaceutical composition according to claim 7, wherein the sustained-release mode is a controlled-release mode, a long-term release mode, a sustained-release mode, a delayed-release mode, or a slow-release mode.

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

10. The composition or pharmaceutical composition according to claim 9, wherein the composition or 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 composition or pharmaceutical composition according to claim 9, wherein the composition or 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 composition or pharmaceutical composition according to claim 1, wherein the daily dose of levetiracetam or a pharmaceutically acceptable salt thereof in the composition or pharmaceutical composition is 190 mg, and the composition or pharmaceutical composition further comprises 300 mg of hydroxypropyl methylcellulose, 1.2 mg of colloidal silicon dioxide, 102.8 mg of silicified microcrystalline cellulose or anhydrous dicalcium phosphate and 6 mg of magnesium stearate.

13. The composition or pharmaceutical composition according to claim 9, wherein the hydroxypropyl methylcellulose is hypromellose 2208.

14. The composition or pharmaceutical composition according to claim 9, wherein the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC90.

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

16. The composition or pharmaceutical composition according to claim 15, wherein the composition or pharmaceutical composition yields the steady-state plasma concentration of levetiracetam that lasts for at least 13 hours of a 24-hour period after administration, within 2 hours after administration.

17. The composition or pharmaceutical composition according to claim 15, wherein the composition or pharmaceutical composition yields the steady-state plasma concentration of levetiracetam that lasts for at least 13 hours within a 24-hour period after administration, within one hour after administration.

18. The composition or pharmaceutical composition according to claim 15, wherein the composition or pharmaceutical composition yields the steady-state plasma concentration of levetiracetam that lasts for at least 13 to 16 hours within a 24-hour period after administration, within one hour after administration.

19. The composition or pharmaceutical composition according to claim 15, wherein the composition or pharmaceutical composition is formulated in one or more of the following forms: oral form, sustained-release form, single-dose dosage form, or once-daily administration form.

20. The composition or pharmaceutical composition according to claim 19, wherein the sustained-release mode is a controlled-release mode, a long-term release mode, a sustained-release mode, a delayed-release mode, or a slow-release mode.

21. A composition or pharmaceutical composition for preventing or slowing the progression of cognitive impairment in a subject, or for preventing or reducing the onset of cognitive decline, wherein the composition comprises a GABAA α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, and the pharmaceutical composition comprises a GABAA α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharmaceutically acceptable carrier, wherein the subject exhibits or displays cognitive abilities within the normal range for the subject's age.

22. The GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers, or polymorphs thereof, as follows: i) Compounds of formula II: 【Transformation 87】 or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof [in the formula, m is between 0 and 3. R １ 、R ２ 、R ４ 以及R ５ 每次出现时,如下:卤素、-R、-OR、-NO ２ 、-NCS、-CN、-CF ３ 、-OCF ３ 、-SiR ３ 、-N(R) ２ 、-SR、-SOR、-SO ２ R、-SO ２ N(R) ２ 、-SO ３ R、-(CR ２ ) １～３ R、-(CR ２ ) １～３ -OR、-(CR ２ ) ０～３ -C(O)NR(CR ２ ) ０～３ R、-(CR ２ ) ０～３ -C(O)NR(CR ２ ) ０～３ OR、-C(O)R、-C(O)C(O)R、-C(O)CH ２ C(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 、-(CR[[ID=6I]] ２ ) ０～３ NHC(O)R、-N(R)N(R)COR丶-N(R)N(R)C(O)OR、-N(R)N(R)CON(R) ２ 、-N(R)SO ２ R、-N(R)SO ２ N(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 are independently selected from -P(O)(H)(OR), R ３ は、ハロゲン、-R、-OR、-NO ２ 、-NCS、-CN、-CF ３ 、-OCF ３ 、-SiR ３ 、-N(R) ２ 、-SR、-SOR、-SO ２ R、-SO ２ N(R) ２ 、-SO ３ R、-(CR ２ ) １～３ R、-(CR ２ ) １～３ -OR、-(CR ２ ) ０～３ -C(O)NR(CR ２ ) ０～３ R、-(CR ２ ) ０～３ -C(O)NR(CR ２ ) ０～３ OR、-C(O)R、-C(O)C(O)R、-C(O)CH ２ C(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 、-(CR ２ ) 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)SO ２ R、-N(R)SO ２ N(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 ien-CH ２ -O-R １０ ien-CH ２ -O-CH ２ -R １０ 【Chemical 88】 Selected from the group consisting of, The five-membered complex ring or heteroaryl is each substituted by 0 to 4 R ７ and R ３ These are independently substituted by 0 to 5 R' values. R ６ It is selected from the group consisting of -H and -(C1-C6) alkyl groups, R ７ R is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl, ７ Each of these is independently substituted by 0 to 5 R' values. R ８ Each is independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 member heteroaryl, and -(C1-C6)alkyl-5-10 member heteroaryl. R ８ each independently substituted, except for -H and -(C1-C6)alkyl, by 0 to 5 of -halogen, -(C1-C6)alkyl, -CF ３ , -OCF ３ or O-(C1-C6)alkyl; R ９ -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 heterocycle, 【Chemistry 89】 Selected from the group consisting of, R ９ Each of these has 0 to 5 R's. １１ It is independently replaced by, R １０ These include -H, halogen, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 member heteroaryl, -(C3-C6)cycloalkyl, and -CH ２ - (C3-C6) cycloalkyl, -CH ２ - (C6-C10) aryl and - CH ２ - Selected from the group consisting of 5 to 10-membered heteroaryls R １０ Each of these is substituted by 0 to 5 R' values. R １１ Each instance of -halogen, -CN, SCH ３ , -CF ３ -OH, -OCF ３ , OCHF ２ Independently selected from the group consisting of -O(C1-C6) alkyl, -(C6-C10) aryl, -(C1-C6) alkyl, and -5-10 member heteroaryl, R stands for: H-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl-, (C3-C10)-cycloalkenyl-, [(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic- [(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic- [(C3-C10)-cycloalkyl]-O-(C1-C12)-aliphatic-, [(C3-C10)-cycloalkenyl]-O-(C1-C12)-aliphatic- (C6-C10) -Ayl-, (C6-C10)-aryl-(C1-C12) aliphatic-, (C6-C10)-aryl-O-(C1-C12) aliphatic-, (C6-C10)-aryl-N(R”)-(C1-C12) aliphatic-, 3-10 member heterocyclines, (3-10 member heterocyclyl) - (C1-C12) aliphatic - (3-10 member heterocyclyl)-O-(C1-C12) aliphatic-, (3-10 member heterocyclyl)-N(R'')-(C1-C12) aliphatic-, 5-10 member heteroaryl complex (5-10 member heteroaryl)-(C1-C12)-aliphatic- (5-10 member heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 member heteroaryl)-N(R'')-(C1-C12)-aliphatic- Independently selected from the group consisting of, The heterocyclil is N, NH, O, S, SO and SO ２ It has 1 to 4 heteroatoms independently selected from the group consisting of, and the heteroaryl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, and S, Each instance of R is either independently substituted by 0 to 5 R' elements, Or, if two R groups are bonded to the same atom, the two R groups, together with the atom to which they are bonded, form N, NH, O, S, SO and SO ２ The ring may form a 3-10 member aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from the group consisting of the following, the ring may be optionally substituted with 0-5 R' atoms, and the ring may be optionally condensed with (C6-C10)aryl, 5-10 member heteroaryl, (C3-C10)cycloalkyl or 3-10 member heterocyclyl. Each instance of R' corresponds to halogen, -R'', -OR'', oxo, or -CH. ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ Independently selected from the group consisting of, Each instance of R'' is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 member heterocyclyl, 5-10 member heteroaryl-, (C6-C10)-aryl-, (5-10 member heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5-10 member heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-. Each instance of "R" is halogen, -R ｏ , -OR ｏ , oxo, -CH ２ OR ｏ ien-CH ２ N(R) ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R ｏ ) ２ R is independently substituted by 0 to 5 substituents selected from the group consisting of the following: ｏ Each occurrence is independently selected from the group consisting of -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 member heterocyclyl, 5-10 member heteroaryl- and (C6-C10)-aryl, and ii) Compounds of formula IV: [Chemical 90] or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof [in the formula, m is between 0 and 3. R １ , R ４ and R ５ Each is independently selected from the following: R １ , R ４ and R ５ Each occurrence corresponds to halogen, -R, -OR, -NO ２ , -NCS, -CN, -CF ３ , -OCF ２ H-OCF ３ , -SiR ３ , -N(R) ２ , -SR, -SOR, -SO ２ R, -SO ２ N(R) ２ , -SO ３ R, -(CR ２ ) １～３ R, -(CR ２ ) １～３ -OR, -(CR ２ ) １～３ -O(CR ２ ) １～３ -R, -(CR ２ ) ０～３ -C(O)NR(CR ２ ) ０～３ R, -(CR ２ ) ０～３ -C(O)NR(CR ２ ) ０～３ OR, -C(O)R, -C(O)C(O)R, -C(O)CH ２ C(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 ,-(CR ２ ) 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)SO ２ R, -N(R)SO ２ N(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 ,CH ２ CF ３ or CHF ２ Each is independently selected from, R ２ is, -OR ８ ,-SR ８ ,-(CH ２ ) ｎ OR ８ ,-(CH ２ ) ｎ O(CH ２ ) ｎ R ８ ,-(CH ２ ) ｐ R ８ or - (CH ２ ) ｎ N(R")R １０ n is an integer selected from 0 to 4, and p is an integer selected from 2 to 4. R ２ These are independently substituted by 0 to 5 R' values. R ３ These are -H, -CN, halogen, -(C1-C6) aliphatic, and -CH=CR respectively. ９ -C≡CR ９ , -SO ２ ((C1-C6) alkyl), -C(O)N((C1-C6) alkyl) ２ ), -C(O)NH((C1-C6)aliphatic), (C6-C10)-aryl-(C1-C12)aliphatic-, -C(O)((C1-C6)alkyl), -C(O)O((C1-C6)alkyl), 5-membered or 6-membered heterocyclyl, 5-membered or 6-membered heteroaryl, -(C1-C6)alkyl-C≡C-R １０ ien-CH ２ -O-R １０ ien-CH ２ -O-CH ２ -R １０ 【Chemistry 91】 Selected independently from, Each of the 5- to 10-membered heterocyclic rings or heteroaryls contains 0 to 3 R atoms. ７ It has been replaced by, R ３ These are independently substituted by 0 to 5 R' values. R ６ It is selected from the group consisting of -H and -(C1-C6) alkyl groups, R ７ This is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, and -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl, R ７ Each of these is independently substituted by 0 to 5 R' values. R ８ These are independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl or 5-10 membered heteroaryl, 5-10 membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl and -(C1-C6)alkyl-(C3-C6)cycloalkyl, R ８ Each instance is independently substituted by 0 to 5 R' values. R ９ -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, 【Chemistry 92】 Selected from the group consisting of, R ９ Each of these has 0 to 5 R's. １１ It is independently replaced by, R １０ These include -H, -(C1-C6) alkyl, -(C3-C10)-cycloalkyl, 3-10 member heterocyclyl, -(C6-C10)-aryl, 5-10 member heteroaryl, and -CH ２ - (C3-C6) cycloalkyl, -CH ２ - (C6-C10) aryl and - CH ２ - Selected from the group consisting of 5 to 10-membered heteroaryls, R １０ Each instance is independently substituted by 0 to 5 R' values. R １１ Each occurrence of -halogen, -CF ３ , -OCF ３ -OH,OCF ２ H, -O-(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, -O-CH ２ - Independently selected from the group consisting of (C3-C6) cycloalkyl, -CN, and -5-10 member heteroaryl, Each instance of R' corresponds to halogen, -R'', -OR'', oxo, or -CH. ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ Independently selected from the group consisting of, Each instance of R'' is independently selected from the group consisting of H, -(C1-C6)-aliphatic, -(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3-6 member heterocyclyl, 5-10 member heteroaryl-, (C6-C10)-aryl-, (5-10 member heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5-10 member heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-. Each instance of "R" is halogen, -R ｏ , -OR ｏ , oxo, -CH ２ OR ｏ ien-CH ２ N(R) ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R ｏ ) ２ 0 to 5 R independently selected from the group consisting of ｔ It is independently substituted by R ｏ Each instance is independently selected from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3--6 member heterocyclyl, 5--10 member heteroaryl, and (C6-C10)-aryl. A composition or pharmaceutical composition according to claim 21, selected from the group consisting of the following.

23. The GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers, or polymorphs thereof, as follows: i) Compounds of formula II: 【Chemistry 93】 or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof [in the formula, m is between 0 and 3. R １ These are halogen, -H, -(C1-C6)alkyl, -OH, -O((C1-C6)alkyl), and -NO, respectively. ２ -CN, -CF ３ , -OCF ３ , -OCHF ２ , -OMe, -C≡C-R ８ ,-CHF ２ ien-CH ２ CF ３ , independently selected from the group consisting of -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 member heteroaryl, -(C1-C6)alkyl-5-10 member heteroaryl, and -(C3-C6)cycloalkyl, R １ These are independently substituted by 0 to 5 R' values. R ２ teeth, -H, halogen, -OH, -(C1-C6) aliphatic, -O((C1-C6) alkyl), -C(O)O((C1-C6) alkyl), -C(O)NR ２ ,-(CR ２ ) １～３ -OR, -(CR ２ ) １～３ -O(CR ２ ) １～３ -R, -OR ９ , -C(O)R ８ ien-CH ２ R ８ ien-CH ３ ien-CH ２ -OR ８ , (C6-C10) -Ayl-, (C6-C10)-aryl-(C1-C12) aliphatic-, (C6-C10)-aryl-O-(C1-C12) aliphatic-, (C6-C10)-aryl-N(R”)-(C1-C12) aliphatic-, (5-10 member heteroaryl) - (C1-C12) aliphatic - (5-10 member heteroaryl)-O-(C1-C12) aliphatic-, (5-10 member heteroaryl)-N(R'')-(C1-C12) aliphatic-, (3-10 member heterocyclyl) - (C1-C12) aliphatic - (3-10 member heterocyclyl)-O-(C1-C12)aliphatic-, and (3-10 member heterocyclyl)-N(R'')-(C1-C12) aliphatic- Selected from the group consisting of, R ２ These are independently substituted by 0 to 5 R' values. R ３ These are -(C1-C6) alkyl, -(C2-C6) alkenyl, -C≡CH, and -C≡CR. ９ -CN, halogen, -SO ２ ((C6-C10)-aryl),-SO ２ ((C1-C6) alkyl), -C(O)N((C1-C6) alkyl) ２ , -C(O)NH ２ -C(O)O((C1-C6)alkyl), -C(O)((C1-C6)alkyl), -(C6-C10)aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, -(C1-C6)alkyl-C≡C-R １０ ien-CH ２ -O-R １０ ien-CH ２ -O-CH ２ -R １０ 【Chemical 94】 Selected from the group consisting of, Each five-membered heterocyclic ring or heteroaryl has 0 to 4 R atoms. ７ It has been replaced by, R ３ These are independently substituted by 0 to 5 R' values. 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, and the (C6-C10)aryl is independently substituted with 0 to 5 halogens. R ６ It is selected from the group consisting of -H and -(C1-C6) alkyl groups, R ７ R is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl, ７ Each of these is independently substituted by 0 to 5 R' values. R ８ Each is independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 member heteroaryl, and -(C1-C6)alkyl-5-10 member heteroaryl. R ８ Excluding -H and -(C1-C6)alkyl, these are -halogen, -(C1-C6)alkyl, and -CF respectively. ３ , -OCF ３ Alternatively, it may be independently substituted by 0 to 5 of the O-(C1-C6) alkyl groups. R ９ -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 heterocycle, 【Chemical 95】 Selected from the group consisting of, R ９ Each of these has 0 to 5 R's. １１ It is independently replaced by, R １０ These include -H, halogen, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 member heteroaryl, -(C3-C6)cycloalkyl, and -CH ２ - (C3-C6) cycloalkyl, -CH ２ - (C6-C10) aryl and - CH ２ - Selected from the group consisting of 5 to 10-membered heteroaryls R １０ Each of these is substituted by 0 to 5 R' values. R １１ Each instance of -halogen, -CN, SCH ３ , -CF ３ -OH, -OCF ３ , OCHF ２ Independently selected from the group consisting of -O(C1-C6) alkyl, -(C6-C10) aryl, -(C1-C6) alkyl, and -5-10 member heteroaryl, R stands for: H-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl-, (C3-C10)-cycloalkenyl-, [(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic- [(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic- [(C3-C10)-cycloalkyl]-O-(C1-C12)-aliphatic-, [(C3-C10)-cycloalkenyl]-O-(C1-C12)-aliphatic- (C6-C10) -Ayl-, (C6-C10)-aryl-(C1-C12) aliphatic-, (C6-C10)-aryl-O-(C1-C12) aliphatic-, (C6-C10)-aryl-N(R”)-(C1-C12) aliphatic-, 3-10 member heterocyclines, (3-10 member heterocyclyl) - (C1-C12) aliphatic - (3-10 member heterocyclyl)-O-(C1-C12) aliphatic-, (3-10 member heterocyclyl)-N(R'')-(C1-C12) aliphatic-, 5-10 member heteroaryl complex (5-10 member heteroaryl)-(C1-C12)-aliphatic- (5-10 member heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 member heteroaryl)-N(R'')-(C1-C12)-aliphatic- Independently selected from the group consisting of, The heterocyclil is N, NH, O, S, SO and SO ２ It has 1 to 4 heteroatoms independently selected from the group consisting of, and the heteroaryl has 1 to 4 heteroatoms independently selected from the group consisting of N, NH, O, and S, Each instance of R is either independently substituted by 0 to 5 R' elements, Or, if two R groups are bonded to the same atom, the two R groups, together with the atom to which they are bonded, form N, NH, O, S, SO and SO ２ The ring may form a 3-10 member aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from the group consisting of the following, the ring may be optionally substituted with 0-5 R' atoms, and the ring may be optionally condensed with (C6-C10)aryl, 5-10 member heteroaryl, (C3-C10)cycloalkyl or 3-10 member heterocyclyl. Each instance of R' corresponds to halogen, -R'', -OR'', oxo, or -CH. ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ Independently selected from the group consisting of, Each instance of R'' is independently selected from the group consisting of H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 member heterocyclyl, 5-10 member heteroaryl-, (C6-C10)-aryl-, (5-10 member heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5-10 member heteroaryl)-O-(C1-C6)-alkyl-, (C6-C10)-aryl-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-. Each instance of "R" is halogen, -R ｏ , -OR ｏ , oxo, -CH ２ OR ｏ ien-CH ２ N(R) ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R ｏ ) ２ R is independently substituted by 0 to 5 substituents selected from the group consisting of the following: ｏ Each occurrence is independently selected from the group consisting of -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 member heterocyclyl, 5-10 member heteroaryl- and (C6-C10)-aryl, and ii) Compounds of formula IV: 【Chemistry 96】 or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof [in the formula, m is between 0 and 3. R １ These are halogen, -H, -(C1-C6) alkyl, and -C≡C-R, respectively. ９ -OH, -O ((C1-C6) alkyl), -NO ２ -CN, -CF ３ , -OCF ３ ,-CHF ２ ien-CH ２ CF ３ Independently selected from the group consisting of -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -5-10 member heteroaryl, -(C1-C6)alkyl-5-10 member heteroaryl, and -(C3-C6)cycloalkyl, R １ These are independently substituted by 0 to 5 R' values. R ２ is, -OR ８ ,-SR ８ ,-(CH ２ ) ｎ OR ８ ,-(CH ２ ) ｎ O(CH ２ ) ｎ R ８ ,-(CH ２ ) ｐ R ８ and - (CH ２ ) ｎ N(R")R １０ Selected from the group consisting of, where n is an integer selected from 0 to 4, and p is an integer selected from 2 to 4. R ２ These are independently substituted by 0 to 5 R' values. R ３ These are -H, -CN, halogen, -(C1-C6) aliphatic, and -CH=CR respectively. ９ -C≡CR ９ , -SO ２ ((C1-C6) alkyl), -C(O)N((C1-C6) alkyl) ２ ), -C(O)NH((C1-C6)aliphatic), (C6-C10)-aryl-(C1-C12)aliphatic-, -C(O)((C1-C6)alkyl), -C(O)O((C1-C6)alkyl), 5-membered or 6-membered heterocyclyl, 5-membered or 6-membered heteroaryl, -CH ２ -O-R １０ ien-CH ２ -O-CH ２ -R １０ 【Chemistry 97】 Independently selected from the group consisting of, Each of the 5- to 10-membered heterocyclic rings or heteroaryls contains 0 to 3 R atoms. ７ It has been replaced by, R ３ These are independently substituted by 0 to 5 R' values. R ４ and R ５ These are independently selected from the group consisting of -H, halogens, and -(C1-C6) alkyl groups. R ６ It is selected from the group consisting of -H and -(C1-C6) alkyl groups, R ７ This is selected from the group consisting of -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl, and -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl, R ７ Each of these is independently substituted by 0 to 5 R' values. R ８ These are independently selected from the group consisting of -H, -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl or 5-10 membered heteroaryl, 5-10 membered heteroaryl-(C1-C6)alkyl-, -(C1-C6)alkyl-(C6-C10)aryl and -(C1-C6)alkyl-(C3-C6)cycloalkyl, R ８ Each instance is independently substituted by 0 to 5 R' values. R ９ -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-5-10 membered heteroaryl, 5-10 membered heterocycle, -C(O)-(C6-C10)aryl, 【Chem.98】 Selected from the group consisting of, R ９ Each of these has 0 to 5 R's. １１ It is independently replaced by, R １０ These include -H, -(C1-C6) alkyl, -(C3-C10)-cycloalkyl, 3-10 member heterocyclyl, -(C6-C10)-aryl, 5-10 member heteroaryl, and -CH ２ - (C3-C6) cycloalkyl, -CH ２ - (C6-C10) aryl and - CH ２ - Selected from the group consisting of 5 to 10-membered heteroaryls, R １０ Each instance is independently substituted by 0 to 5 R' values. R １１ Each occurrence of -halogen, -CF ３ , -OCF ３ OCF ２ H, -O-(C1-C6)alkyl, -(C6-C10)aryl, -(C1-C6)alkyl, -O-CH ２ - Independently selected from the group consisting of (C3-C6) cycloalkyl and -5-10 member heteroaryl groups, Each instance of R' corresponds to halogen, -R'', -OR'', oxo, or -CH. ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ Independently selected from the group consisting of, Each instance of R'' is independently selected from the group consisting of H, -(C1-C6)-aliphatic, -(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3-6 member heterocyclyl, 5-10 member heteroaryl-, (C6-C10)-aryl-, (5-10 member heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5-10 member heteroaryl)-O-(C1-C6)-alkyl-, and (C6-C10)-aryl-O-(C1-C6)-alkyl-. Each instance of "R" is halogen, -R ｏ , -OR ｏ , oxo, -CH ２ OR ｏ ien-CH ２ N(R) ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R ｏ ) ２ 0 to 5 R independently selected from the group consisting of ｔ It is independently substituted by R ｏ Each instance is independently selected from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3--6 member heterocyclyl, 5--10 member heteroaryl, and (C6-C10)-aryl. A composition or pharmaceutical composition according to claim 22, selected from the group consisting of the following.

24. The GABA Ａ The composition or pharmaceutical composition according to claim 23, wherein the α5 receptor agonist or the 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 GABA Ａ The composition or pharmaceutical composition according to claim 23, wherein the α5 receptor agonist or the 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 GABA Ａ The composition or pharmaceutical composition according to claim 21, wherein the α5 receptor agonist or the 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 pharmaceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof.

27. ​​The GABA Ａ An α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof, structure: 【Chem.99】 The composition or pharmaceutical composition according to claim 26, which is a compound having, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof.

28. The GABA Ａ An α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof, structure: 【Chemistry 100】 The polymorphic crystalline form of a compound having the following characteristics: The polymorphic crystalline form is form A, and the following: a. At least one peak selected from 3.0 and 21.0 degrees (2θ) ± 0.2 degrees (2θ), and b. At least one additional peak selected from the group consisting of 9.1, 10.7, 13.8, 22.0, 23.1, 23.9, 24.4, and 27.1 degrees (2θ) ± 0.2 degrees (2θ). The composition or pharmaceutical composition according to claim 27, which contains XRPD.

29. The GABA Ａ An α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof, structure: 【Chemistry 101】 The polymorphic crystalline form of a compound having the above crystalline form is form B, and the following applies: a. At least one peak selected from 13.0 and 15.3 degrees (2θ) ± 0.2 degrees (2θ), and b. At least one additional peak selected from the group consisting of 7.0, 9.3, 10.2, 10.4, 12.5, 13.6, 14.0, 22.0, 23.0, 23.6, and 27.3 degrees (2θ) ± 0.2 degrees (2θ). The composition or pharmaceutical composition according to claim 27, which contains XRPD.

30. The GABA Ａ An α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof, structure: 【Chemical Engineering 102】 The solvate crystal form of a compound having the following characteristics, wherein the solvate crystal form is form C, and the following applies: a. At least one peak selected from 8.5 and 18.9 degrees (2θ) ± 0.2 degrees (2θ), and b. At least one additional peak selected from the group consisting of 7.1, 9.4, 10.3, 12.3, 12.5, 14.2, 20.7, 22.1, 23.2, 23.7, 24.0, and 26.4 degrees (2θ) ± 0.2 degrees (2θ). The composition or pharmaceutical composition according to claim 27, which contains XRPD.

31. The GABA Ａ An α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof, structure: 【Chemistry 103】 The polymorphic crystalline form of a compound having the following characteristics: The polymorphic crystalline form is form E, and the following: a. At least one peak selected from the group consisting of 11.4, 18.1 and 21.6 degrees (2θ) ± 0.2 degrees (2θ), and b. At least one additional peak selected from the group consisting of 7.2, 22.0, 23.0, 24.2, 25.0, and 26.6 degrees (2θ) ± 0.2 degrees (2θ). The composition or pharmaceutical composition according to claim 27, which contains XRPD.

32. The GABA Ａ An α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof, structure: 【Chemical 104】 The hydrate crystal form of a compound having the following characteristics, wherein the hydrate crystal form is form F, and the following applies: a. At least one peak selected from the group consisting of 9.9, 11.9, 17.3, 19.4 and 25.7 degrees (2θ) ± 0.2 degrees (2θ), and b. At least one additional peak selected from the group consisting of 9.7, 12.1, 20.8, 23.2, 23.7, 24.2, 25.0, and 26.4 degrees (2θ) ± 0.2 degrees (2θ). The composition or pharmaceutical composition according to claim 27, which contains XRPD.

33. The GABA Ａ The composition or pharmaceutical composition according to claim 21, wherein an 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 GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers, or polymorphs thereof, as follows: i) Compounds of formula I-a: 【Chemistry 105】 Alternatively, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. [In the formula, m is an integer selected from 0 to 4. R １ These are halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, and -CHF, respectively. ２ , -CF ３ , -OCF ３ , -OCHF ２ CO(O)R ７ ,CH ２ -OR ８ Independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 member heteroaryl, -(C1-C6)alkyl-5-10 member heteroaryl, and -(C3-C6)cycloalkyl, R ８ Each is independently selected from -H or -(C1-C6 alkyl), R ２ These are CO(O)R respectively. ７ , C≡C-R ９ ,-(C1-C6)alkyl-C≡C-R ９ -(5-10 member) heteroaryl, -(3-10 member) heterocyclyl, (C3-C10)-cycloalkenyl 【Chemistry 106】 Selected from, 5-6 member heteroaryls and 3-10 member heterocycles each have 0-4 R groups. ７ It has been replaced by, R ９ These are respectively -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered) heterocyclyl, -(C6-C10)aryl, and -(C1-C6)alkyl-(C6-C10)aryl. 【Chemistry 107】 Selected from, R ９ Each appearance produces 0 to 5 R １１ It is independently replaced by, R １１ Each instance is -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF ３ , -OCF ３ , independently selected from -(C6-C10)aryls and -5-10 member heteroaryls, R ３ R is independently selected from -H, -(C1-C6)alkyl, -5-10 membered heteroaryl, -(3-10 membered) heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, and -(C1-C6)alkyl-(C6-C10)aryl. ３ These are 0 to 5 R's. １２ It is independently replaced by, R １２ These are -H, -Halogen, and -OR respectively. ｏ , R ｏ , oxo, -CH ２ OR ｏ ien-CH ２ N(R) ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -CF ３ , -OCF ３ and -N(R ｏ ) ２ Selected independently from, R ｏ Each instance is independently selected from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, -(3-10 membered) heterocyclyl, and (C6-C10)-aryl. R ７ -H and -CF respectively ３ -(C1-C6) alkyl, -(C1-C6) alkyloxy, (C1-C6) alkylamino, -(C3-C6) cycloalkyl, -5-10 member heteroaryl, -(C6-C10) aryl, -CH ２ - Selected from (C6-C10)aryl, -5-10 member heteroaryl-(C1-C6)alkyl and -3-10 member heterocyclyl, R ７ Each of these is independently substituted by 0 to 5 R's, or two R's ７ When the group is bonded to the same atom, the two R groups ７ The groups, together with the atoms to which they are bonded, form N, NH, O, S, SO and SO ２ They may form a 3-10 member aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from, the ring being optionally substituted with 0-5 R' atoms. R' appears each time, R' appears each time, halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ R'' is independently selected from -Cl, -F, -(C1-C6) alkyl, -OMe, and -(C6-C10) aryl. R'' is independently substituted by 1 to 3 substituents, the substituents being halogens, -CF ３ , -OCF ３ , selected from -O-(C1-C6)-aliphatic or -(C1-C6)-aliphatic, R ４ Each is selected from -H or -(C1-C6) alkyl, R ６ Each is selected from -H or -(C1-C6) alkyl, R １３ and R １４ Each of these is independently selected from H-, (C1-C3)-aliphatic-, or (C3-C6)-cycloalkyl. ii) Compounds of formula I-b: 【Chemistry 108】 Alternatively, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. [m is an integer selected from 0 to 4, During the ceremony, R １ These are -halogen, -(C6-C10)aryl, -ome, -CN, and -CHF, respectively. ２ , -CF ３ , -OCF ３ , -OCHF ２ CO(O)R ７ ,CH ２ -OR ８ Independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 member heteroaryl, -(C1-C6)alkyl-5-10 member heteroaryl, and -(C3-C6)cycloalkyl, R ８ Each is independently selected from -H or -(C1-C6 alkyl), R ２ These are CO(O)R respectively. ７ , C≡C-R ９ ,-(C1-C6)alkyl-C≡C-R ９ , -(5-10 member) heteroaryl, -(3-10 member) heterocyclyl, 【Chemistry 109】 Selected from, Each of the 5-6 member heteroaryls or 3-10 member heterocycles has 0-4 R groups. ７ It has been replaced by, R ９ These are respectively -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered) heterocyclyl, -(C6-C10)aryl, and -(C1-C6)alkyl-(C6-C10)aryl. 【Chemical 110】 Selected from, R ９ Each appearance produces 0 to 5 R １１ It is independently replaced by, R １１ Each instance is -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF ３ , -OCF ３ Independently selected from -OMe, -(C6-C10)aryls and -5-10 member heteroaryls, R ３ -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR １２ ,-(C1-C6)alkyl-N(R １２ ) ２ , independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 member heteroaryl, -3-10 member heterocyclyl, and -5-10 member heteroaryl, R ３ These are 0 to 5 R's. １２ It is independently replaced by, R １２ These are -H, -Halogen, and -OR respectively. ｏ , R ｏ , oxo, -CH ２ OR ｏ ien-CH ２ N(R) ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R ｏ ) ２ Selected independently from, R ｏ Each instance is independently selected from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl-, and (C6-C10)-aryl. R ７ -H and -CF respectively ３ Selected from -(C1-C6)alkyl, -(C1-C6)alkyloxy, (C1-C6)alkylamino, -(C3-C6)cycloalkyl, -5-10 member heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5-10 member heteroaryl and -3-10 member heterocyclyl, R ７ Each of these is independently substituted by 0 to 5 R's, or two R's ７ When the group is bonded to the same atom, the two R groups ７ The groups, together with the atoms to which they are bonded, form N, NH, O, S, SO and SO ２ They may form a 3-10 member aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from, the ring being optionally substituted with 0-5 R' atoms. R' appears each time, R' appears each time, halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ Selected independently from, R'' is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-5-10 member heteroaryl, -5-10 member heteroaryl, -3-10 member heterocyclyl, -(C3-C6)cycloalkyl, and -(C6-C10)aryl. R'' is independently substituted by 1 to 3 substituents, the substituents being halogens, -CF ３ , -OCF ３ Selected from -O(C1-C6)aliphatic, -(C1-C6)-aliphatic, and -5-10 membered heteroaryls, R ４ and R ６ Each is independently selected from -H or -(C1-C6) alkyl groups, R １３ and R １４ Each of these is independently selected from H-, (C1-C3)-aliphatic-, or (C3-C6)-cycloalkyl. iii) Compounds of formula I-c: 【Chemistry 111】 Alternatively, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. [m is an integer selected from 0 to 4, R １ These are -halogen, -(C6-C10)aryl, -OMe, -CN, and -CHF, respectively. ２ , -CF ３ , -OCF ３ , -OCHF ２ CO(O)R ７ ,CH ２ -OR ８ Independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 member heteroaryl, -(C1-C6)alkyl-5-10 member heteroaryl, and -(C3-C6)cycloalkyl, R ８ Each is independently selected from -H or -(C1-C6 alkyl), R ２ These are CO(O)R respectively. ７ , C≡C-R ９ ,-(C1-C6)alkyl-C≡C-R ９ , -(5-10 member) heteroaryl, -(3-10 member) heterocyclyl, 【Chemistry 112】 Selected from, Each five-membered heterocyclic ring or heteroaryl has 0 to 4 R atoms. ７ It is replaced by R ９ These are respectively -H, -(C1-C6) alkyl, (5-10 member heteroaryl), and -(3-10 member) heterocycline. 【Chemistry 113】 Selected from, R ９ Each appearance produces 0 to 5 R １１ It is independently replaced by, R １１ Each instance is -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF ３ , -OCF ３ Independently selected from -OMe, -(C6-C10)aryls and -5-10 member heteroaryls, R ７ Each time it appears, -CF ３ Selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 member heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5-10 member heteroaryl and -3-10 member heterocyclyl, R ７ Each of these is independently substituted by 0 to 5 R' values. R' appears each time, R' appears each time, halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ Selected independently from, Each instance of R'' is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-5-10 member heteroaryl, -5-10 member heteroaryl, -3-10 member heterocyclyl, -(C3-C6)cycloalkyl, and -(C6-C10)aryl, and R'' is independently substituted by 1-3 substituents, the substituents being halogens, -CF ３ , -OCF ３ Selected from -(C1-C6)-aliphatic and -5-10 membered heteroaryls, R ４ and R ６ Each is independently selected from -H or -(C1-C6) alkyl groups, R １３ and R １４ Each of these is independently selected from H-, (C1-C3)-aliphatic-, or (C3-C6)-cycloalkyl. iv) Compounds of formula I-d: 【Chemical 114】 Alternatively, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. [m is an integer selected from 0 to 4, During the ceremony, R １ These are -halogen, -(C6-C10)aryl, -OMe, -CN, and -CHF, respectively. ２ , -CF ３ , -OCF ３ , -OCHF ２ CO(O)R ７ ,CH ２ -OR ８ Independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 member heteroaryl, -(C1-C6)alkyl-5-10 member heteroaryl, and -(C3-C6)cycloalkyl, R ８ Each is independently selected from -H or -(C1-C6 alkyl), R ２ These are CO(O)R respectively. ７ , C≡C-R ９ ,-(C1-C6)alkyl-C≡C-R ９ , -(5-10 member) heteroaryl, -(3-10 member) heterocyclyl, 【Chemical 115】 Selected from, Each five-membered heterocyclic ring or heteroaryl has 0 to 4 R atoms. ７ It is replaced by R ９ These are respectively -H, -(C1-C6)alkyl, (5-10 membered heteroaryl), -(3-10 membered) heterocyclyl, -(C6-C10)aryl, and -(C1-C6)alkyl-(C6-C10)aryl. 【Chemistry 116】 Selected from, R ９ Each appearance produces 0 to 5 R １１ It is independently replaced by, R １１ Each instance is -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF ３ , -OCF ３ Independently selected from -OMe, -(C6-C10)aryls and -5-10 member heteroaryls, R ３ -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR １２ ,-(C1-C6)alkyl-N(R １２ ) ２ , independently selected from -(C1-C6)alkyl-(C6-C10)aryl and -(C1-C6)alkyl-5-10 member heteroaryl, R ３ These are 0 to 5 R's. １２ It is independently replaced by, R １２ These are -H, -Halogen, and -OR respectively. ｏ , R ｏ , oxo, -CH ２ OR ｏ ien-CH ２ N(R) ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R ｏ ) ２ Selected independently from, R ｏ Each occurrence is independently selected from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl-, and (C6-C10)-aryl. R ７ -CF ３ Selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 member heteroaryl, -(C6-C10)aryl, (C6-C10)aryl-(C1-C6)alkyl-, -(C1-C6)alkyl-5-10 member heteroaryl and -3-10 member heterocyclyl, R ７ Each of these is independently substituted by 0 to 5 R' values. R' appears each time, R' appears each time, halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ Selected independently from, R'' is selected from -Cl, -F, -(C1-C6) alkyl, -OMe, and -(C6-C10) aryl. R ４ Each is selected from -H or -(C1-C6) alkyl, R ６ Each is selected from -H or -(C1-C6) alkyl, R １３ and R １４ Each of these is independently selected from H-, (C1-C3)-aliphatic-, or (C3-C6)-cycloalkyl. v) Compounds of formula I-e: 【Chemistry 117】 Alternatively, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. [m is an integer selected from 0 to 4, R １ These are -halogen, -(C6-C10)aryl, -OMe, -CN, and -CHF, respectively. ２ , -CF ３ , -OCF ３ , -OCHF ２ CO(O)R ７ ,CH ２ -OR ８ Independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 member heteroaryl, -(C1-C6)alkyl-5-10 member heteroaryl, and -(C3-C6)cycloalkyl, R ８ Each is independently selected from -H or -(C1-C6 alkyl), R ２ These are CO(O)R respectively. ７ , C≡C-R ９ ,-(C1-C6)alkyl-C≡C-R ９ , -(5-10 member) heteroaryl, -(3-10 member) heterocyclyl, 【Chemistry 118】 Selected from, Each five-membered heterocyclic ring or heteroaryl has 0 to 4 R atoms. ７ It is replaced by R ９ These are respectively -H, -(C1-C6) alkyl, (5-10 member heteroaryl), and -(3-10 member) heterocycline. 【Chemical 119】 Selected from, R ９ Each appearance produces 0 to 5 R １１ It is independently substituted by R １１ Each instance is -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF ３ , -OCF ３ Independently selected from -OMe, -(C6-C10)aryls and -5-10 member heteroaryls, R ７ R is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5-10 membered heteroaryl-(C1-C6)alkyl and -3-10 membered heterocyclyl, ７ Each of these is independently substituted by 0 to 5 R' values. R' appears each time, R' appears each time, halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ R' is independently selected from and each R' is independently substituted by 0 to 5 R''. R'' is selected from -Cl, -F, -(C1-C6) alkyl, -OMe, and -(C6-C10) aryl. R ４ Each of these is independently -H or (C1-C6) alkyl, R ６ Each of these is independently -H or -(C1-C6)alkyl, R １３ and R １４ Each of these is independently selected from H-, (C1-C3)-aliphatic-, or (C3-C6)-cycloalkyl, and vi) Compounds of formula I-f: 【Chemical 120】 Alternatively, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. [m is an integer selected from 0 to 4, R １ These are -halogen, -(C6-C10)aryl, -OMe, -CN, and -CHF, respectively. ２ , -CF ３ , -OCF ３ , -OCHF ２ CO(O)R ７ ,CH ２ -OR ８ Independently selected from -(C1-C6)alkyl-(C6-C10)aryl, -5-10 member heteroaryl, -(C1-C6)alkyl-5-10 member heteroaryl, and -(C3-C6)cycloalkyl, R ８ Each is independently selected from -H or -(C1-C6 alkyl), R ２ These are CO(O)R respectively. ７ , C≡C-R ９ ,-(C1-C6)alkyl-C≡C-R ９ , -(5-10 member) heteroaryl, -(3-10 member) heterocyclyl, 【Chemistry 121】 Selected from, Each five-membered heterocyclic ring or heteroaryl has 0 to 4 R atoms. ７ It is replaced by R ９ These are respectively -H, -(C1-C6) alkyl, (5-10 member heteroaryl), and -(3-10 member) heterocycline. 【Chemistry 122】 Selected from, R ９ Each appearance produces 0 to 5 R １１ It is independently substituted by R １１ Each instance is -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF ３ , -OCF ３ Independently selected from -OMe, -(C6-C10)aryls and -5-10 member heteroaryls, R ７ R is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5-10 membered heteroaryl-(C1-C6)alkyl and -3-10 membered heterocyclyl, ７ Each of these is independently substituted by 0 to 5 R' values. R' appears each time, R' appears each time, halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR” ２ , -C(O)N(R”) ２ , -C(O)OR", -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ and -N(R'') ２ Selected independently from, Each R' is independently substituted by 0 to 5 R'', where 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, R １３ and R １４ Each of these is independently selected from H-, (C1-C3)-aliphatic-, or (C3-C6)-cycloalkyl. A composition or pharmaceutical composition according to claim 21, selected from the group consisting of the following.

35. The GABA Ａ The composition or pharmaceutical composition according to claim 34, wherein the α5 receptor agonist or the pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof is a compound selected from the group consisting of formulas I-a, I-b, I-c, I-d, I-e and I-f, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer thereof, or a combination thereof.

36. The GABA Ａ The composition or pharmaceutical composition according to claim 21, wherein the α5 receptor agonist or the 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 pharmaceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof.

37. A combination for preventing or slowing the progression of cognitive impairment in a subject, or preventing or reducing the onset of cognitive decline, wherein the subject exhibits or displays cognitive abilities within the normal range for the subject's age, and the combination is A) Levetiracetam, brivalacetam or celetracetam, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising levetiracetam, brivalacetam or celetracetam, or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier; and B) GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or 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 C) Pharmaceutical composition comprising A and B and a pharmaceutically acceptable carrier A combination that includes this.

38. A levetiracetam, celetracetam, or brivalacetam or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising levetiracetam, brivalacetam, or celetracetam or a pharmaceutically acceptable salt thereof, and B the GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA Ａ The combination according to claim 37, characterized in that the pharmaceutical composition comprising an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or the pharmaceutical composition of C, is administered orally.

39. A levetiracetam, celetracetam, or brivalacetam or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising levetiracetam, brivalacetam, or celetracetam or a pharmaceutically acceptable salt thereof, and B the GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA Ａ The combination according to claim 37, characterized in that the pharmaceutical composition comprising an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof, or the pharmaceutical composition of C, is administered once daily.

40. A levetiracetam, celetracetam, or brivalacetam or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising levetiracetam, brivalacetam, or celetracetam or a pharmaceutically acceptable salt thereof, and B the GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA Ａ The combination according to claim 37, characterized in that the pharmaceutical composition comprising an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof, or the pharmaceutical composition of C, is administered twice daily.

41. A levetiracetam, celetracetam, or brivalacetam or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising levetiracetam, brivalacetam, or celetracetam or a pharmaceutically acceptable salt thereof, and B the GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA Ａ The combination according to claim 37, characterized in that the pharmaceutical composition comprising an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof is administered simultaneously.

42. A levetiracetam, celetracetam, or brivalacetam or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising levetiracetam, brivalacetam, or celetracetam or a pharmaceutically acceptable salt thereof, and B the GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or GABA Ａ The combination according to claim 37, characterized in that the pharmaceutical composition comprising an α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof is administered sequentially.

43. The combination according to claim 37, characterized in that the levetiracetam, brivalacetam, or ceretracetam of A or C, or a pharmaceutically acceptable salt thereof, is administered in a daily dose of 0.7 to 350 mg.

44. The combination according to claim 43, characterized in that the levetiracetam or ceretracetam of A or C, or the pharmaceutically acceptable salt thereof, is administered in a daily dose of 125 to 250 mg.

45. The combination according to claim 44, characterized in that the levetiracetam or ceretracetam or a pharmaceutically acceptable salt thereof of A or C is administered in a daily dose of 220 mg.

46. The combination according to claim 44, characterized in that the levetiracetam or ceretracetam or a pharmaceutically acceptable salt thereof of A or C is administered in a daily dose of 190 mg.

47. The combination according to claim 43, characterized in that the brivalacetam of A or C or the pharmaceutically acceptable salt thereof is administered in a daily dose of 0.7 to 180 mg.

48. The combination according to claim 43, characterized in that the levetiracetam or ceretracetam of A, or the pharmaceutically acceptable salt thereof, is administered in a daily dose of 7 to 350 mg.

49. The combination according to claim 37, wherein the pharmaceutical composition A and the pharmaceutical composition B, or the pharmaceutical composition C, are formulated in one or more of the following forms: oral form, sustained-release form, single-dose dosage form, or once-daily administration.

50. The combination according to claim 49, wherein the sustained release mode is a controlled release mode, a long-term release mode, a continuous release mode, a delayed release mode, or a slow release mode.

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

52. The combination according to 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 combination according to claim 37, wherein the pharmaceutical composition contains 190 mg of levetiracetam or a pharmaceutically acceptable salt thereof, 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 anhydrous dicalcium phosphate and 6 mg of magnesium stearate.

54. The combination according to claim 51, wherein the hydroxypropyl methylcellulose is hypromellose 2208.

55. The combination according to claim 51, wherein the silicified microcrystalline cellulose is silicified microcrystalline cellulose SMCC90.

56. The combination according to claim 37, wherein the pharmaceutical composition comprising levetiracetam A or C or a pharmaceutically acceptable salt thereof is in a sustained-release form and, in a subject, results in a steady-state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL lasting for at least 8 hours within a 24-hour period after administration, within 3 hours after administration, a steady-state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL lasting for at least 13 hours within a 24-hour period after administration, within 2 hours after administration, a steady-state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL lasting for at least 13 hours within a 24-hour period after administration, or within 1 hour after administration, a steady-state plasma concentration of levetiracetam between 1.9 μg / mL and 4.4 μg / mL lasting for at least 13 to 16 hours within a 24-hour period after administration.

57. The aforementioned GABA Ａ α5 receptor agonists or pharmaceutically acceptable salts, hydrates, solvates, isomers or polymorphs thereof, or the GABA in the pharmaceutical composition Ａ The combination according to claim 37, wherein an 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. A composition, pharmaceutical composition, or combination according to any one of claims 1 to 57, wherein the subject is at risk of developing cognitive decline or cognitive impairment, and the risk is related to the presence of altered functional connectivity in the hippocampus in the subject.

59. A composition, pharmaceutical composition, or combination according to any one of claims 1 to 57, wherein the subject is at risk of developing cognitive decline or cognitive impairment, and the risk is related to the presence of one or more genomic variants, mutations, or polymorphisms in the genome of the subject that are related to changes in the expression of genes selected from the group consisting of ABCA7, CLU, CR1, PICALM, PLD3, TREM2, and SORL1.

60. The composition, pharmaceutical composition, or combination according to any one of claims 1 to 57, wherein the subject is at risk of developing cognitive decline or cognitive impairment, and the risk is related to the presence of one or more genomic variants, mutations, or polymorphisms in the genome of the subject that are associated with changes in TREM2 expression.

61. A composition, pharmaceutical composition, or combination according to any one of claims 1 to 57, wherein the subject is at risk of developing cognitive decline or cognitive impairment, and the risk is related to the presence of at least one allele of the APOE4 gene in the genome of the subject.

62. The composition, pharmaceutical composition, or combination according to any one of claims 1 to 57, wherein the subject is at risk of developing cognitive decline or cognitive impairment, and the risk is related to the presence of one of more biomarkers selected from the group consisting of p-tau, t-tau, and amyloid β42 in the subject.

63. The composition, pharmaceutical composition, or combination according to any one of claims 1 to 57, wherein the subject is a human.

64. A composition or pharmaceutical composition for preventing or slowing the progression of cognitive impairment in a subject, or for preventing or reducing the onset of cognitive decline, wherein the composition comprises levetiracetam, brivalacetam, or celetracetam, or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprises levetiracetam, brivalacetam, or celetracetam, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the subject exhibits or has cognitive abilities within the normal range for the subject's age, and the composition or pharmaceutical composition is A pharmaceutical composition comprising a GABAA α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, or a GABAA α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharmaceutically acceptable carrier. A composition or pharmaceutical composition characterized by being administered in combination with [another substance].

65. A composition or pharmaceutical composition for preventing or slowing the progression of cognitive impairment in a subject, or for preventing or reducing the onset of cognitive decline, wherein the composition comprises a GABA A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof, and the pharmaceutical composition comprises a GABA A α5 receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, isomer or polymorph thereof and a pharmaceutically acceptable carrier, and the subject exhibits or has cognitive abilities within the normal range for the subject's age, and the composition or pharmaceutical composition is A pharmaceutical composition comprising levetiracetam, brivalacetam, or ceretracetam, or pharmaceutically acceptable salts thereof, or levetiracetam, brivalacetam, or ceretracetam, or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. A composition or pharmaceutical composition characterized by being administered in combination with [another substance].

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