Benzaza derivatives, compositions and methods for treating cognitive impairment

Abstract

Benzaza # imgabs0 # derivatives of formula (I), compositions comprising therapeutically effective amounts of these benzaza # imgabs1 # derivatives, and methods of using these derivatives or compositions in the treatment of cognitive impairment associated with central nervous system (CNS) disorders or associated with cognitive impairment risk factors. In particular, the present invention relates to the use of an alpha5-containing GABAA R agonist (e.g., an alpha5-containing GABAA R positive allosteric modulator) in the treatment of cognitive impairment associated with central nervous system (CNS) disorder or having a risk factor associated with cognitive impairment in a subject in need or at risk, the subjects include, but are not limited to, subjects having or at risk of age-related cognitive impairment, mild cognitive impairment (MCI), amnetic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), proactive AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), or the like. Cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, compulsive behavior and substance addiction associated with cancer treatment. The present invention also relates to the use of [alpha] 5-containing GABAA R agonists (e.g., [alpha] 5-containing GABAA R positive allosteric modulators), as described herein, in the treatment of brain cancer, including brain tumors, e.g., myeloblastoma, and cognitive impairment associated therewith. # imgabs2 #

Description

[0001] This disclosure was made with government support from the National Institutes of Health (NIH), specifically its National Institute on Aging (NIA), an agency of the U.S. Government, under Grant No. R44 AG063607. The U.S. Government has certain rights in the described embodiments. Related applications

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 399,509, filed on August 19, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to compounds, compositions, combinations and methods for treating cognitive impairment associated with various risk factors, such as aging and APOE4 gene mutations, cognitive impairment associated with central nervous system (CNS) disorders, cognitive impairment associated with brain cancer and brain cancer itself in subjects at risk of developing or presenting with the following cognitive impairment or in need of treatment. Background Art

[0004] Cognitive abilities may decline as a normal result of aging or other risk factors, or as a result of central nervous system disease or brain cancer.

[0005] For example, a significant proportion of the elderly population experiences cognitive decline that exceeds that typical of normal aging. This age-related loss of cognitive function is clinically characterized by a progressive loss of memory, cognition, reasoning, and judgment. Mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), or similar clinical groupings are among those associated with this type of age-related loss of cognitive function. According to some estimates, more than 16 million people in the United States alone suffer from AAMI (Barker et al., 1995), and age-related MCI is estimated to affect 55 to 7 million people over the age of 65 in the United States (Plassman et al., 2008). In addition to aging, risk factors for cognitive impairment include, for example, APOE4 gene mutations or cancer treatment.

[0006] Cognitive impairment is also associated with other central nervous system (CNS) disorders (some of which are age-related), such as MCI, amnestic mild cognitive impairment (aMCI), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (particularly mania), amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction. Cognitive impairment may also be associated with various brain cancers.

[0007] Thus, there is a need for effective treatments for cognitive impairment associated with age-related and non-age-related cognitive impairment (i.e., associated with one or more risk factors for cognitive impairment), as well as for treating cognitive impairment associated with central nervous system (CNS) disorders and improving cognitive function in patients diagnosed with or suffering from, for example, age-related cognitive impairment, MCI, amnestic MCI, AAMI, ARCD, dementia, AD, prodromal AD, PTSD, schizophrenia or bipolar disorder (particularly mania), amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, compulsive behavior and substance addiction, and cognitive impairment associated with other central nervous system (CNS) disorders, or who are at risk of developing such cognitive impairment.

[0008] GABA A GABA receptors A R) is a pentameric assembly of subunits from different pools (α1-6, β1-3, γ1-3, δ, ε, π, θ) that form a Cl-permeable channel gated by the neurotransmitter γ-aminobutyric acid (GABA). Various pharmacological actions, including anxiety disorders, epilepsy, insomnia, preanesthetic sedation, and muscle relaxation, are mediated by different GABA A Isotype mediated.

[0009] Various studies have demonstrated that decreased GABA signaling is associated with cognitive impairment associated with various CNS disorders. In particular, α5-containing GABA is relatively sparse in the mammalian brain. A Previous studies have shown that GABA plays a role in altering learning and memory in rats with age-related cognitive decline. A The hippocampal expression of the α5 subunit of GABA R was reduced (see International Patent Publication WO2007 / 019312). A Upregulation of R function may be effective in treating cognitive impairment associated with such CNS disorders or other risk factors for cognitive impairment and cognitive decline associated with aging.

[0010] Therefore, GABA containing α5 is required A Positive allosteric modulators of R, which can be used in therapeutic formulations and medicaments for treating cognitive impairment associated with CNS disorders or cognitive impairment associated with aging and other risk factors for cognitive decline, or for treating subjects at risk of developing those cognitive impairments. SUMMARY OF THE INVENTION

[0011] The present disclosure, in some embodiments thereof, addresses the above needs by providing a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof: in: X is independently selected from O, N, -NR 3 or -C(R 4 ) 1-2 ; W is O, N or NR 3 ; V is O, NR 3 or -C(R 4 ) 1-2 ,in, When X is O, W is N and V is -C(R 4 ) 1-2 ; When X is N, W is O or -NR 3 , V is -C(R 4 ) 1-2 ; When X is -NR 3 When W is N, V ​​is -C(R 4 ) 1-2 ; When X is -C(R 4 ) 1-2 When W is N, V ​​is O or -NR 3 ; Each occurrence of the key " ” is a single bond or a double bond; m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -NCS, -NO2, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl or -(C3-C10)cycloalkenyl; wherein each (5- to 6-membered)heteroaryl and (3- to 10-membered)heterocyclyl is substituted by 0-4 R7; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each R 8 is selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl or -CH2-(5- to 10-membered)heteroaryl, wherein each occurrence of R 8 independently substituted with 0-5 R'; Each R 9 is selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, (C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -C(O)-(C6-C10)aryl, wherein each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O or S; R 3 Independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(5- to 10-membered)heteroaryl, -C(O)-(C6-C10)aryl, -C(O)-(C1-C6)alkyl or -C(O)-(C3-C6), wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl, or -(C6-C10)aryl, wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, or S; R 4 Selected from -H or -(C1-C6)alkyl; R 6 Selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl; wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein each occurrence of R″ is independently selected from —H, —(C1-C6)aliphatic, —(C3-C6)cycloalkyl, —(3- to 6-membered)heterocyclyl, —(5- to 10-membered)heteroaryl, —(C6-C10)aryl, —(C1-C6)alkyl-(5- to 10-membered)heteroaryl, —(C1-C6)alkyl-(C6-C10)aryl, —(C1-C6)alkyl-O-(5- to 10-membered)heteroaryl, or —(C1-C6)alkyl-O-(C6-C10)aryl, wherein each occurrence of R″ is independently substituted with 0-3 substituents, and particularly, in some aspects of the present disclosure, R″ is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, —R o , -OR o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2; and Each occurrence of R o independently selected from -(C1-C6)aliphatic, -O(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)aryl, wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O or S.

[0012] In another aspect, the present invention provides a compound of formula Ia: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, in: m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6)alkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, wherein each 5- to 6-membered heteroaryl and 3- to 10-membered heterocycle is substituted with 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 independently selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -CF3, -OCF3 or -N(R o )2, where each occurrence of R oindependently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 10-membered)heterocyclyl or -(C6-C10)aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups, together with the atoms to which they are bound, may form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 groups independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2, wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, -CF3, -OCF3, -O-(C1-C6)aliphatic or -(C1-C6)aliphatic; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0013] In another aspect, the present invention provides a compound of formula I-aa: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, in: m is an integer selected from 0-4; Each R 1 independently selected from halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, -CH2-OR 8, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, wherein each 5- to 6-membered heteroaryl and 3- to 10-membered heterocycle is substituted with 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 independently selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -CF3, -OCF3 or -N(R o )2, where each occurrence of R oindependently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 10-membered)heterocyclyl or -(C6-C10)aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(3- to 6-membered)heterocyclyl or -(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from: halogen, -CF3, -OCF3, -O-(C1-C6)aliphatic or -(C1-C6)aliphatic; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0014] In another aspect, the present invention provides a compound of formula Ib: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6)alkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5- to 6-membered heteroaryl or 3- to 10-membered heterocycle is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 Independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl or -(5- to 10-membered)heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , Ro , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from -halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5- to 10-membered)heteroaryl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C3-C6)cycloalkyl or —(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, -CF3, -OCF3, -O(C1-C6)aliphatic, -(C1-C6)aliphatic or -(5- to 10-membered)heteroaryl; Each R 4 and R 6 independently selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from H—, —(C1-C3)aliphatic or —(C3-C6)cycloalkyl.

[0015] In another aspect, the present invention provides a compound of formula I-ba: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5- to 6-membered heteroaryl or 3- to 10-membered heterocycle is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 Independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12)2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6alkyl-(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl or -(5- to 10-membered)heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)-aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from halogen, -R", -OR", oxo, CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5- to 10-membered)heteroaryl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C3-C6)cycloalkyl, —(C6-C10)aryl, —H or —C(O)CH3; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, -CF3, -OCF3, -O(C1-C6)aliphatic, -(C1-C6)aliphatic, -(5- to 10-membered)heteroaryl or oxo; Each R 4 and R 6 independently selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0016] In another aspect, the present invention provides a compound of formula Ic: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; each occurrence of R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2, wherein each occurrence of R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C6)cycloalkyl or -(C6-C10)aryl, and R″ is independently substituted with 1-3 substituents selected from -halogen, -CF3, -OCF3, -(C1-C6)aliphatic or -(5- to 10-membered)heteroaryl; Each R 4 and R 6 independently selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0017] In another aspect, the present invention provides a compound of formula Id: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6)alkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl or -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , -R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o, -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)aryl; wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from -halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0018] In another aspect, the present disclosure provides a compound of Formula 1e: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclyl or heteroaryl is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, Each occurrence of R 9 Independently by 0-5 R 11 Replace, where each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; each occurrence of R′ is wherein each occurrence of R′ is independently selected from -halogen, -R″, -OR″, oxo, -CH2OR″, -CH2NR″2, -C(O)N(R″)2, -C(O)OR″, -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R″)2, wherein each R′ is independently substituted with 0-5 R″; wherein R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; Each R 4 are independently -H or -(C1-C6)alkyl; Each R 6 are independently -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)aliphatic.

[0019] In another aspect, the present invention provides a compound of formula If: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, Each occurrence of R 9 Independently by 0-5 R 11 Replace, where each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl or -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein each R' is independently substituted by 0-5 R", wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; R 4 is -H or (C1-C6) alkyl; R 6 is -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0020] In various aspects, the present disclosure also provides pharmaceutical compositions comprising a compound of Formula I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF and If, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0021] In some embodiments, the compound of formula I is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula Ia is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula I-aa is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula Ib is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula I-ba is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula Ic is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula Id is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula Ie is GABA A α5 receptor positive allosteric modulator. In some embodiments, the compound of formula If is GABA Aα5 receptor positive allosteric modulators. In some aspects of the present disclosure, one or more compounds of Formula I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF, and If can be used to treat cognitive impairment as described herein and those at risk of cognitive impairment.

[0022] In some embodiments, the GABA described in this disclosure A Alpha 5 receptor positive allosteric modulators and one or more GABAs disclosed in PCT applications WO2015 / 095783A1, WO2016 / 205739A1, WO2018 / 130869A1 and WO2019 / 246300A1 A In some embodiments, the GABA described in this disclosure is used in combination with a positive allosteric modulator of the α5 receptor. A The α5 receptor positive allosteric modulators or the above combinations can be combined with one or more SV2a inhibitors disclosed in PCT application WO2022 / 011318 for treating cognitive impairment and risk of cognitive impairment as described herein.

[0023] In another aspect of the present disclosure, there is provided a method for treating cognitive impairment in a subject in need of treatment or at risk of cognitive impairment associated with a CNS disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, CNS disorders with cognitive impairment include, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior, and substance addiction. In another aspect of the present disclosure, there is provided a method for maintaining or improving cognitive function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In certain embodiments of the present disclosure, a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof is administered every 12 or 24 hours.

[0024] In another aspect of the present disclosure, there is provided a method for treating cognitive impairment in a subject in need of treatment or at risk of cognitive impairment associated with aging or other cognitive impairment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In another aspect of the present disclosure, there is provided a method for maintaining or improving cognitive function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In certain embodiments of the present disclosure, a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof is administered every 12 or 24 hours.

[0025] In another aspect of the present disclosure, a method for treating pediatric and adult cancers expressing α5-GABA is provided. A R method, said method comprising administering to said subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In another aspect of the present disclosure, there is provided a method for treating a disease expressing α5-GABA A In another aspect of the present disclosure, there is provided a method for maintaining or improving cognitive function in a subject suffering from brain cancer (including brain tumors, such as medulloblastoma), the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In certain embodiments of the present disclosure, a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof is administered every 12 or 24 hours.

[0026] In some embodiments, the compound of the present invention, composition or combination can be used as medicine or therapeutic agent.In some embodiments, the compound of the present invention, composition or combination and the medicine comprising them can be used for treating the cognitive impairment of the subject who needs to treat or is in the risk of cognitive impairment related to CNS disorder.In some embodiments, the CNS disorder related to cognitive impairment includes but is not limited to age-related cognitive impairment, mild cognitive impairment (MCI), amnesia MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior and substance addiction.In some embodiments, the compound of the present invention, composition or combination and the medicine comprising them can be used for treating brain cancer (including brain tumors, such as medulloblastoma). In some embodiments, the compounds, compositions, or combinations of the present disclosure, and medicaments comprising the same, can be used to treat cognitive impairment associated with brain cancer, including brain tumors such as medulloblastoma. In some embodiments, the compounds, compositions, or combinations of the present disclosure, and medicaments comprising the same, can be used to treat subjects who are at risk for developing such a disorder because the subject has one or more elevated factors for cognitive impairment, one of which is aging.

[0027] In some embodiments, present disclosure provides compound as herein described or composition for use in preparing medicine, described medicine is used for needing to treat or in the subject of the cognitive impairment risk relevant to CNS disorder to treat described cognitive impairment.In some embodiments, the CNS disorder with cognitive impairment includes but is not limited to age-related cognitive impairment, mild cognitive impairment (MCI), amnesia MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, obsessive-compulsive behavior and substance addiction.In some embodiments, compound of the present disclosure, composition or combination are used to prepare medicine for treating brain cancer (including brain tumor, such as medulloblastoma). In some embodiments, the compounds, compositions, or combinations of the present disclosure are used in the preparation of a medicament for treating cognitive impairment associated with brain cancer (including brain tumors such as medulloblastoma). In some embodiments, the compounds, compositions, or combinations of the present disclosure are used in the preparation of a medicament for treating a subject who is at risk for developing cognitive impairment because the subject has one or more elevated risk factors for such impairment, one of which is aging. Detailed Description of the Figures

[0028] Figure 1 This graph depicts the effect of methyl 3,5-diphenylpyridazine-4-carboxylate administration on spatial memory retention in 10 aged impaired (AI) rats in the eight-arm radial arm maze (RAM) test. Black bars refer to rats treated with vehicle alone; open bars refer to rats treated with different doses of methyl 3,5-diphenylpyridazine-4-carboxylate; and shaded bars refer to rats treated with a combination of TB21007 and methyl 3,5-diphenylpyridazine-4-carboxylate.

[0029] Figure 2 The graph shows the effect of 3,5-diphenylpyridazine-4-carboxylic acid methyl ester (intravenously administered) on the binding of Ro154513 in the hippocampus and cerebellum. 3,5-diphenylpyridazine-4-carboxylic acid methyl ester blocks the binding of Ro154513 in the hippocampus but does not affect the binding of Ro15413 in the cerebellum.

[0030] Figure 3 is to show that intravenously administered 3,5-diphenylpyridazine-4-carboxylic acid methyl ester has a dose-dependent effect on GABA A Figure 5. α5 receptor occupancy in the hippocampus of RO 15-4513 (high GABA Aα5 receptor density) exposure and RO 15-4513 in the cerebellum (low GABA A α5 receptor density) exposure, or by using GABA A The α5 selective compound L-655,708 (10 mg / kg, intravenously) was used to define complete occupancy.

[0031] Figure 4 This graph shows the exposure-occupancy relationship of methyl 3,5-diphenylpyridazine-4-carboxylate in the hippocampus. Methyl 3,5-diphenylpyridazine-4-carboxylate occupies approximately 32% of GABAA α5 receptors under behaviorally active exposure in aged, impaired rats.

[0032] Figure 5 3-Methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine Figure 2. Effects of ethyl-10-formate on spatial memory retention in the eight-arm radial arm maze (RAM) test in ten aged impaired (AI) rats. Figure 5 The results show that 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine Effects of ethyl-10-carboxylate on spatial memory retention in 10 aged impaired (AI) rats, in which vehicle control was tested three times and different doses of 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine -10-Ethyl formate was tested twice; Figure 5 In the figure, black bars refer to rats treated with vehicle alone, and open bars refer to rats treated with different doses of 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine. -10-Ethyl formate-treated rats.

[0033] Figure 6 is to show 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine Figure 3. Effect of ethyl-10-formate (administered intravenously) on the binding of Ro154513 in the hippocampus and cerebellum. Ethyl 10-formate blocked the binding of Ro154513 in the hippocampus but did not affect the binding of Ro15413 in the cerebellum.

[0034] Figure 7 is a method showing that intravenously administered 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine Dose-dependent GABA-10-ethylcarboxylate A Figure 5. α5 receptor occupancy by RO 15-4513 in the hippocampus (high GABA A A5 receptor density in the region) exposure and RO 15-4513 in the cerebellum (low GABA A The ratio between exposure (area of ​​a5 receptor density) was calculated to define full occupancy.

[0035] Figures 8(A)-(C) are graphs showing the effects of 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one compared to the vehicle dimethyl sulfoxide (DMSO) in aged injured rats using the Morris water maze behavioral task. Figure 8(A) shows the escape potential (ESP) of rats that received 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats that received the vehicle DMSO during training. latency) (i.e., the average time (in seconds) that rats took to find the hidden platform in the pool); Figure 8(B) shows the amount of time spent in the target ring and the opposite ring by rats that received 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats that received the vehicle DMSO; Figure 8(C) shows the number of passages in the target ring and the opposite ring by rats that received 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats that received the vehicle DMSO. Detailed Description of the Invention definition

[0036] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature and techniques used in connection with the chemistry, 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 those well known and commonly used in the art.

[0037] Unless otherwise indicated, the methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. 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); and Gilbert et al., "Developmental Biology, 6 th ed.," Sinauer Associates, Inc., Sunderland, MA (2000).

[0038] As used herein, chemical terms are used according to conventional usage in the art, as exemplified by "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0039] 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.

[0040] Throughout the specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer (or component) or group of integers (or components) but not the exclusion of any other integer (or component) or group of integers (or components).

[0041] Unless otherwise indicated herein, the description of numerical ranges herein is only intended to be used as a shorthand method for individually referring to each individual value falling within the range and including endpoints, and each individual value is incorporated into this specification as if it were individually described herein. For example, the range of 0-5 is understood to encompass each value and subrange (i.e., 0, 1, 2, 3, 4, 5, 0-1, 0-2, 0-3, 0-4, 0-5, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5 or 4-5). Unless otherwise indicated herein or clearly contradictory to the context, all methods described herein can be carried out in any suitable order. In addition, disclosed 0-3 substitutions mean unsubstituted (0) or substituted by 1, 2 or 3 substituents (1, 2 or 3).

[0042] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0043] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0044] The term "agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound (including, for example, the compounds disclosed herein), a mixture of chemical compounds). Agents include, for example, agents of known structure and agents of unknown structure. Such agents include α5-containing GABA. A R agonist activity may make it suitable as a "therapeutic agent" in the methods and compositions of the present disclosure.

[0045] "Patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cattle, pigs, etc.), companion animals (such as dogs, cats, etc.), and rodents (such as mice and rats).

[0046] "Cognitive function" or "cognitive state" means any higher-level intellectual brain process or brain state, respectively, involved in learning and / or memory, including but not limited to attention, information acquisition, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discrimination learning, decision-making, inhibitory response control, attentional set shifting, delayed reinforcement learning, reversal learning, temporal integration of autonomous behavior, expressing interest in the environment and self-care, processing speed, reasoning and problem solving, and social cognition.

[0047] In humans, cognitive function can be assessed, for example, but not limited to, by the Clinical Global Impression of Change scale (CIBIC-plus scale); Mini Mental State Exam (MMSE); Neuropsychiatric Inventory (NPI); Clinical Dementia Rating Scale (CDR); Cambridge Neuropsychological Test Automated Battery (CANTAB); Sandoz Clinical Assessment-Geriatric (SCAG), Buschke Selective Reminding Test (Buschke and Fuld, 1974); Verbal Paired Associates subtest; Logical Memory subtest; Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); Benton Visual Retention Test (Benton Visual Retention Test). Psychiatric behavior can be measured using the Psychiatric Mental Health Test (Meditation Test), the explicit three-alternative forced-choice task, or the MATRICS consensus neuropsychological battery. See Folstein et al., J Psychiatric Res 12:189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examenppendor en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994.See also Buchanan, RW, Keefe, RSE, Umbricht, D., Green, MF, Laughren, T., and Marder, SR (2011), The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr.Bull.37,1209-1217.

[0048] In animal model systems, cognitive function can be measured in various conventional ways known in the art, including using the Morris water maze (MWM), the Barnes circular maze, the elevated radial arm maze, the T maze, or any other maze in which the animal uses spatial information. Cognitive function can be assessed by reversal learning, hyperdimensional set shifting, conditional discrimination learning, and reward expectancy assessment. Other tests known in the art can also be used to assess cognitive function, such as novel object recognition and odor recognition tasks.

[0049] Cognitive function or impairment can be assessed by measuring the thickness of the cerebral cortex. The human cerebral cortex is a highly folded sheet of neurons with a thickness varying between 1 and 4.5 mm, with a total average of approximately 2.5 mm. Cortical thinning in the temporal region is associated with global cognitive changes. Cognitive function can also be measured using imaging techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT), or any other imaging technique that allows people to measure brain function. In animals, cognitive function can also be measured using electrophysiological techniques.

[0050] In addition to assessing cognitive performance, the progress of cognitive impairment and dementia can also be monitored by assessing the alternative changes in the subject's brain.Alternative changes include but are not limited to the change in local brain volume, perforant pathway degradation and 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 technology allowing to measure brain function. The example of the local brain volume that can be used to monitor age-related cognitive impairment and dementia progression includes the reduction of hippocampal volume and the reduction of volume or thickness of the entorhinal cortex. These volumes can be measured in a subject by, for example, MRI. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010). 186 perforant pathway degradations have been shown to be relevant to age and cognitive performance reduction. For example, the elderly with more perforant pathway degradation tend to perform worse in hippocampus-dependent memory tests. Ultra-high-resolution diffusion tensor imaging (DTI) can be used to monitor the degradation of perforation pathways in subjects. Yassa et al., PNAS 107: 12687-12691 (2010). Resting-state fMRI (R-fMRI) involves imaging the brain during rest and recording large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal, which are temporally correlated between functionally related areas. Seed-based functional connectivity, independent component analysis, and / or frequency domain analysis of the signal are used to reveal the functional connectivity between brain regions, particularly those whose connectivity increases or decreases with age, as well as the extent of cognitive impairment and / or dementia. FDG-PET uses the uptake of FDG as a measure of regional metabolic activity in the brain. It has been shown that the decline in FDG uptake in regions such as the posterior cingulate cortex, temporoparietal cortex, and prefrontal association cortex is associated with the extent of cognitive decline and dementia. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002).

[0051] "Promoting" cognitive function refers to affecting impaired cognitive function so that it more closely resembles the function of a normal, unimpaired, or, in some respects, age-matched subject. Cognitive function can be improved to any detectable degree, but in some embodiments of the present disclosure, in humans, cognitive function is sufficiently improved to allow an impaired subject to perform daily activities of normal life at a level of proficiency as close as possible to that of a normal, unimpaired subject or an age-matched normal, unimpaired subject.

[0052] In some cases, "promoting" cognitive function in a subject with age-related cognitive impairments refers to affecting the impaired cognitive function so that it more closely resembles the function of an age-matched normal, unimpaired subject or a young adult subject. The subject's cognitive function can be improved to any detectable degree, but in some embodiments of the present disclosure, in humans, cognitive function is sufficiently improved to allow the impaired subject to perform daily activities of normal life at a level of proficiency as close as possible to that of a normal, unimpaired subject or a young adult subject or an age-matched normal unimpaired subject.

[0053] "Maintaining" cognitive function means affecting normal or impaired cognitive function so that it does not decline or is no less than the cognitive function observed in the subject at first presentation or diagnosis, or at least delaying some degree of decline in cognitive function.

[0054] "Improving" cognitive function includes promoting cognitive function and / or maintaining cognitive function in a subject.

[0055] "Cognitive impairment" means that a subject's cognitive function is less robust than would be expected in a normal, unimpaired, or, in some cases, age-matched subject. In some cases, cognitive function is reduced by about 5%, about 10%, about 30% or more compared to expected cognitive function in a normal, unimpaired, or, in some aspects, age-matched subject.

[0056] " Age-related cognitive impairment " refers to the cognitive impairment in elderly subjects, wherein their cognitive function is not as strong as expected in normal subjects of age matching (i.e., subjects with the average score of a given age in cognitive tests), or in some cases not as strong as expected in young adult subjects. In some cases, compared with the cognitive function expected in normal subjects of age matching, cognitive function reduces by about 5%, about 10%, about 30% or more. In some cases, cognitive function is as expected in normal subjects of age matching, but compared with the cognitive function expected in young adult subjects, reduces by about 5%, about 10%, about 30%, about 50% or more. The cognitive function that age is related is impaired and can be relevant to, for example, mild cognitive impairment (MCI) (including amnestic MCI and non-amnestic MCI), age-related memory impairment (AAMI) and age-related cognitive decline (ARCD).

[0057] "Cognitive impairment" associated with, involving, or in AD means that a subject's cognitive function is less robust than would be expected for a subject not diagnosed with AD using conventional methods and criteria.

[0058] "Mild cognitive impairment" or "MCI" refers to a condition characterized by isolated memory impairment without other cognitive abnormalities and relatively normal functional abilities. A set of criteria for the clinical characterization of MCI specifies the following features: (1) memory complaints (as reported by the patient, informant, or physician), (2) normal activities of daily living (ADLs), (3) normal global cognitive function, (4) abnormal memory for age (defined as a score more than 1.5 standard deviations below the mean for a given age), and (5) absence of dementia indicators (as defined by DSM-IV or related guidelines). Petersen et al., Srch. Neurol. 56:303-308 (1999); Petersen, "Mild cognitive impairment: Aging to Alzheimer's Disease." Oxford University Press, NY (2003). Cognitive deficits in subjects with MCI may involve any cognitive domain or mental process, including memory, language, association, attention, perception, problem solving, executive function, and visual-spatial skills. See, for example, Winbalde et al., J. Intern. Med. 256:240-240, 2004; Meguro, Acta. Neurol. Taiwan. (China) 15:55-57, 2008; Ellison et al., CNS Spectr. 13:66-72, 2008, Petersen, Semin. Neurol. 27:22-31, 2007. MCI is further subdivided into amnestic MCI (aMCI) and non-amnestic MCI, which are particularly characterized by memory impairment (or lack thereof). If memory is found to be impaired given the subject's age and education level, MCI is defined as aMCI. On the other hand, if the subject's memory is found to be intact for age and education, but other non-memory cognitive domains (e.g., language, executive function, or visual-spatial skills) are impaired, MCI is defined as non-amnestic MCI. Both aMCI and non-amnestic MCI can be further subdivided into single-domain or multi-domain MCI. aMCI-single domain refers to a condition in which memory is impaired but no other cognitive domains are impaired. aMCI-multidomain refers to a condition in which memory and at least one other cognitive domain are impaired. Non-amnestic MCI is either single-domain or multidomain, depending on whether no more than one non-memory cognitive domain is impaired. See, e.g., Peterson and Negash, CNS Spectr. 13:45-53, 2008.

[0059] The diagnosis of MCI generally requires an objective assessment of cognitive impairment, which can be obtained using recognized neuropsychological tests, including the Mini-Mental State Examination (MMSE), the Cambridge Neuropsychological Test Automated Battery (CANTAB), and individual tests such as the Rey Auditory Verbal Learning Test (AVLT), the Logical Memory subtest of the Revised Wechsler Memory Scale (WMS-R), and the New York University (NYU) Paragraph Recall Test. See Folstein et al., J Psychiatric Res 12:189-98 (1975); Robbins et al., Dementia 5:266-81 (1994); Kluger et al., J Geriatric Psychiatry Neurol 12:168-79 (1999).

[0060] Age-associated memory impairment (AAMI) refers to memory decline due to aging. A patient is considered to have AAMI if he or she is at least 50 years old and meets all of the following criteria: a) the patient has noticed a decline in memory performance, b) the patient performs worse on standard memory tests compared to younger people, and c) all other obvious causes of memory decline other than normal aging have been ruled out (in other words, the decline cannot be attributed to other causes, such as a recent heart attack or head injury, depression, a bad reaction to medication, Alzheimer's disease, etc.).

[0061] Age-related cognitive decline (ARCD) refers to the decline in memory and cognitive abilities that is a normal consequence of aging in humans (e.g., Craik & Salthouse, 1992). This is also true in nearly all mammalian species. Age-related memory impairment refers to the objective decline in memory in older adults relative to their younger years, but normal cognitive function relative to their age peers (Crook et al., 1986). Age-related memory decline is a lesser-reviewed marker, emphasizing that these are normal developmental changes (Crook, 1993; Larrabee, 1996), not pathophysiological (Smith et al., 1991), and rarely progress to overt dementia (Youngjohn & Crook, 1993). The DSM-IV (1994) codified the diagnostic category of ARCD.

[0062] "Dementia" refers to a condition characterized by severe cognitive deficits that interfere with normal activities of daily life. Subjects with dementia also exhibit other symptoms, such as impaired judgment, personality changes, disorientation, confusion, behavioral changes, difficulty speaking, and motor deficits. There are different types of dementia, such as Alzheimer's disease (AD), vascular dementia, Lewy body dementia, and frontotemporal dementia.

[0063] Alzheimer's disease (AD) is characterized by early memory deficits. Later symptoms include impaired judgment, disorientation, confusion, behavioral changes, speech difficulties, and motor deficits. Histologically, AD is characterized by β-amyloid plaques and tau protein tangles.

[0064] Vascular dementia is caused by a stroke and has symptoms that overlap with those of AD, but without the focus on memory impairment.

[0065] Lewy body dementia is characterized by abnormal deposits of alpha-synuclein that form within neurons in the brain. Cognitive impairment can resemble AD, including memory and judgment impairments and behavioral changes.

[0066] Frontotemporal dementia is characterized by gliosis, neuronal loss, superficial spongiform degeneration in the frontal cortex and / or anterior temporal lobes, and Pick bodies. Symptoms include personality and behavioral changes, including declines in social skills and language expression / comprehension.

[0067] "Post-traumatic stress disorder (PTSD)" refers to an anxiety disorder characterized by an immediate or delayed reaction to a catastrophic event, characterized by re-experiencing the trauma, mental numbing or avoidance of stimuli associated with the trauma, and increased arousal. Re-experiencing phenomena include intrusive memories, flashbacks, nightmares, and psychological or physical distress in response to reminders of the trauma. Such reactions produce anxiety and can have significant chronic and acute effects on the patient's quality of life and physical and emotional well-being. PTSD is also associated with impaired cognitive performance, and elderly individuals with PTSD have greater cognitive decline relative to control patients.

[0068] "Schizophrenia" refers to a chronic, debilitating disorder characterized by a spectrum of psychopathology, including positive symptoms such as abnormal or distorted mental presentation (e.g., hallucinations, delusions), negative symptoms characterized by a decrease in motivation and adaptive goal-directed action (e.g., anhedonia, flat affect, asthenia), and cognitive impairment. Although abnormalities in the brain are thought to underlie the full spectrum of psychopathology in schizophrenia, currently available antipsychotic drugs are largely ineffective in treating cognitive impairment in patients.

[0069] "Bipolar disorder" or "BP" or "manic-depressive" or "manic-depressive" refers to a chronic mental / mood disorder characterized by significant mood swings, including periods of depression and euphoric-manic periods. BP can be diagnosed by a skilled physician based on personal and medical history, interview consultation, and physical examination. The term "mania" or "manic phase" or other variations refers to a period in which an individual exhibits some or all of the following characteristics: racing thoughts, rapid speech, increased activity level and agitation, as well as inflated self-esteem, euphoria, poor judgment, insomnia, impaired concentration, and aggression.

[0070] Amyotrophic lateral sclerosis, also known as ALS, is a progressive, fatal, neurodegenerative disease characterized by the degeneration of motor neurons, which are nerve cells in the central nervous system that control voluntary muscle movement. ALS is also characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and hyperexcitability of neurons in various brain regions, such as the cortex.

[0071] "Cancer therapy-associated cognitive impairment" refers to cognitive impairment that develops in subjects treated with cancer therapies such as chemotherapy (e.g., chemo-brain) and radiation therapy. The cytotoxicity and other adverse side effects of cancer therapies on the brain lead to cognitive impairment in functions such as memory, learning, and attention.

[0072] Parkinson's disease (PD) is a neurological disorder characterized by a decrease in voluntary movement. Patients experience decreased motor activity and slower voluntary movements compared to normal individuals. Patients have a characteristic "mask" facies, a tendency to jog when walking, a stooped posture, and generalized muscle weakness. Passive movement exhibits a characteristic "lead pipe" stiffness. Another key feature of the disease is tremors in the limbs that occur at rest and decrease during movement.

[0073] As used herein, "autism" refers to autism spectrum disorders characterized by neurodevelopmental disorders that result in impaired social interaction and communication through restricted and repetitive behaviors. "Autism spectrum disorder" refers to a group of developmental disorders including: autism; Asperger's syndrome; pervasive developmental disorder not otherwise specified (PDD-NOS or atypical autism); Rett syndrome; and childhood disintegrative disorder.

[0074] Mental retardation is a systemic disease characterized by significantly impaired cognitive function and adaptive behavior defects. Mental retardation is usually defined as an intelligence quotient (IQ) score of less than 70. Congenital causes are one of the many root causes of mental retardation. Dysfunction of neuronal communication is also considered to be one of the root causes of mental retardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

[0075] In some cases, mental retardation includes, but is not limited to, Down syndrome, myofacial syndrome, fetal alcohol syndrome, fragile X syndrome, Klinefelter syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat-Wilson syndrome, ciliopathies, Lowe syndrome, and Siderium-type X-linked mental retardation. Down syndrome is a condition that includes a combination of birth defects (including some degree of mental retardation, characteristic facial features, and often heart defects), increased infections, vision and hearing problems, and other health problems. Fragile X syndrome is a common form of inherited mental retardation that occurs at a frequency of 1 in 4,000 males and 1 in 8,000 females. The syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder, and autistic-like behavior. There is no effective treatment for fragile X syndrome.

[0076] Obsessive-compulsive disorder ("OCD") is a psychiatric condition most commonly characterized by intrusive, repetitive unwanted thoughts (obsessions), which lead to compulsions and mental acts (compulsions) that the individual feels driven to perform. Current epidemiological data indicate that OCD is the fourth most common psychiatric disorder in the United States. Some studies suggest that the prevalence of OCD is between 1% and 3%, although the clinically recognized prevalence of OCD is much lower, suggesting that many individuals with the condition may go undiagnosed. Patients with OCD are typically diagnosed by a psychologist, psychiatrist, or psychoanalyst using the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) (2000) diagnostic criteria, which include features of obsessions and compulsions.

[0077] Substance addiction (e.g., drug addiction, alcohol addiction) is a mental disorder. Addiction is not triggered immediately upon exposure to substances of abuse. Instead, it involves a variety of complex neural adaptations that develop over different time periods ranging from hours to days to months (Kauer JANat. Rev. Neurosci. 2007, 8, 844-858). The path to addiction typically begins with the voluntary use of one or more controlled substances, such as any one of narcotics, barbiturates, methamphetamine, alcohol, nicotine, and various other such controlled substances. Over time, with the extended use of one or more controlled substances, the voluntary ability to give up one or more controlled substances is impaired due to the effects of extended use on brain function and therefore on behavior. Therefore, the characteristic of substance addiction is typically a compulsive desire for substances that persists even in the face of negative consequences, seeking, and use. Cravings can represent changes in the patient's underlying neurobiology, and if recovery is to be achieved, this change may have to be addressed in a meaningful way. In many cases, substance addiction is also characterized by withdrawal symptoms, which are life-threatening for some substances (e.g., alcohol, barbiturates), and in other cases can lead to significant morbidity (which can include nausea, vomiting, fever, dizziness and profuse sweating), pain and a reduced ability to recover. For example, alcoholism, also known as alcohol dependence, is a type of such substance addiction. The main characteristics of alcoholism are four symptoms, including craving, loss of control, physical dependence and tolerance. These symptoms can also characterize addiction to other controlled substances. The craving for alcohol and other controlled substances is often as strong as the need for food or water. Therefore, despite serious family, health and / or legal repercussions, drinking may continue.

[0078] As used herein, the term "brain cancer" refers to a neoplasm that originates in the brain, or a metastatic brain cancer that begins elsewhere in the body and moves to the brain. As used herein, the term "brain cancer" includes both benign and malignant cancer cells. The term "expressing α5-GABA" A R brain cancer” (also referred to herein as “brain cancer expressing α5-GABA A R brain cancer”) refers to a brain cancer in which GABA pathway signaling is due to α5-GABA A Increased expression of α5-GABA R in brain cancers potentially upregulates expression of α5-GABA A R's brain cancers may include medulloblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, ependymoma, meningioma, etc.

[0079] The term "medulloblastoma" refers to a highly malignant primary brain tumor that originates in the cerebellum or posterior cranial fossa. It is one of the most common malignant brain tumors and is more common in people under 20 years of age than in adults. Medulloblastoma can spread through the CNS and often metastasize to different locations in the brain and spine. Medulloblastomas are divided into four subgroups based on the molecular characteristics of the tumor cells, namely wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. Of these types, group 3 and group 4 account for approximately 60% of medulloblastomas. Group 3 tumors share α5-GABA A High expression of R. Symptoms of medulloblastoma are primarily due to increased intracranial pressure caused by obstruction of the fourth ventricle and are primarily neurological, with other symptoms such as vomiting also occurring.

[0080] The term "risk factor for cognitive impairment" refers to one or more risks that predict or are associated with cognitive decline or cognitive impairment or the progression of decline or disorder. Such risks are associated with aging and have one or more genetic risks selected from genomic variants, mutations, or polymorphisms that are associated with changes in the 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-binding clathrin assembly protein (PICALM), phospholipase D3 (PLD3), triggering receptor 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 the APOE4 gene in the genome of the subject, the presence of one or more biofluid biomarkers selected from p-tau, t-tau, and amyloid beta in the subject, or the presence of altered hippocampal functional connectivity in the subject.

[0081] "Treatment" of a disorder or patient refers to taking steps to obtain beneficial or desired results, including but not limited to clinical results. Beneficial or desired clinical results include, but are not limited to, preventing or slowing the progression of a disease or disorder, or alleviating, improving or slowing the progression of one or more symptoms of cognitive impairment associated with a CNS disorder or risk factor of the present disclosure, such as age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior and substance addiction. In some embodiments, treatment includes preventing cognitive impairment associated with a CNS disorder or risk factor (e.g., one described herein) or slowing the progression of the cognitive impairment. In certain embodiments, treatment includes alleviating, improving one or more symptoms of cognitive impairment associated with the CNS disorder or risk factor or slowing down the progression of the one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment or cognitive deficiency. Treatment of age-related cognitive impairment also includes slowing down or delaying the conversion of age-related cognitive impairment (including but not limited to age-related MCI, ARCD and AAMI) to dementia (e.g., AD).

[0082] "Treating cognitive impairment" refers to taking steps to improve the cognitive function of a subject suffering from cognitive impairment such that the subject's performance on one or more cognitive tests improves to any detectable extent, or prevents further decline, or slows the progression of such decline. In some embodiments of the present disclosure, after treatment as described herein, the subject's cognitive function more closely resembles the function of a normal, unimpaired, or in some respects, age-matched subject. Treatment of cognitive impairment in humans can improve cognitive function to any detectable extent, but in some embodiments, is sufficiently improved to allow the impaired subject to perform the daily activities of normal life at the same level of proficiency as a normal, unimpaired subject. In some cases, "treating cognitive impairment" refers to taking steps to improve the cognitive function of a subject suffering from cognitive impairment such that the subject's performance on one or more cognitive tests improves to any detectable extent, or prevents further decline, or slows the progression of such decline. Preferably, after treatment as described herein, the subject's cognitive function more closely resembles the function of a normal, unimpaired, or in some respects, age-matched subject. In some cases, "treating cognitive impairment" in a subject affected by age-related cognitive impairment means taking steps to improve the subject's cognitive function so that, following treatment as described herein, the subject's cognitive function more closely resembles that of an age-matched normal, unimpaired subject, or in some aspects, resembles that of a young adult subject.

[0083] The "administration" or "dosing" of a substance, compound or agent according to the present disclosure can be performed on a subject using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally and transdermally (by absorption, such as through a skin catheter). The compound or agent can also be suitably introduced by a refillable or biodegradable polymer device or other device, such as a patch and pump, or a formulation that provides an extended, slow or controlled release of the compound or agent. In some embodiments of the present disclosure, the agent or compound is administered orally. It can also be administered, for example, once, multiple times and / or over one or more extended time periods. In some embodiments, the agent or compound is administered once a day. In some embodiments, the agent or compound of the present disclosure is administered in an immediate release, delayed / slow release or sustained release form. In some aspects, administration includes direct administration (including self-administration) and indirect administration (including the act of prescribing). For example, as used herein, a physician who instructs a patient to self-administer a drug or to have another person administer the drug and / or provides a patient with a prescription for a drug administers the drug to the patient.

[0084] The appropriate method of administering a substance, compound, or agent to a subject will also depend on, for example, the age of the subject, whether the subject is active or inactive at the time of administration, whether the subject is cognitively impaired at the time of administration, the degree of impairment, and the chemical and biological properties (e.g., solubility, digestibility, bioavailability, stability, and toxicity) of the compound or agent. In some embodiments, the compound or agent is administered orally, for example, by ingestion, or intravenously, for example, by injection. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or is administered using a device for such slow or extended release.

[0085] As used herein, "GABA containing α5 A R agonists," "GABA containing α5 A R agonist" or "GABA A "α5 receptor agonist" and its variants as used herein refers to a GABA receptor that enhances the activity of α5 A In some embodiments, the compound containing α5 GABA as used herein is a compound that increases the function of GABA R, i.e., a compound that increases GABA-gated Cl- current. A A GABA R agonist is a positive allosteric modulator that enhances the activity of GABA. A R agonists include α5-containing GABA of all formulas described herein. A R agonists and specific α5-containing GABA A R agonists, and hydrates, solvates, polymorphs, salts (e.g., pharmaceutically acceptable salts), isomers (e.g., stereoisomers, E / Z isomers and tautomers), and combinations thereof.

[0086] "Antipsychotic agent," "antipsychotic agent," "antipsychotic drug," or "antipsychotic compound" refers to (1) a typical or atypical antipsychotic agent; (2) an agent selected from the group consisting of a dopaminergic agent, a glutamatergic agent, an NMDA receptor positive allosteric modulator, a glycine reuptake inhibitor, a glutamate reuptake inhibitor, a metabotropic glutamate receptor (mGluRs) agonist or positive allosteric modulator (PAM) such as an mGluR2 / 3 agonist or PAM), a glutamate receptor glur5 positive allosteric modulator (PAM), an M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulator (PAM), a histamine H3 receptor antagonist, an AMPA / kainate receptor antagonist, a glutamate receptor modulator (CX-516), a glutathione prodrug, a noradrenergic agent, a serotonin receptor modulator, a cholinergic agent, a cannabinoid CB1 antagonist, a neurokinin 3 antagonist, a neurotensin agonist, an MAO B inhibitors, PDE10 inhibitors, nNOS inhibitors, neurosteroids and neurotrophic factors, alpha-7 agonists or positive allosteric modulators (PAMs) PAMs, serotonin 2C agonists; and / or (3) agents useful for treating one or more signs or symptoms of schizophrenia or bipolar disorder (particularly mania).

[0087] As used herein, "typical antipsychotics" refers to conventional antipsychotics that produce antipsychotic effects as well as motor-related side effects associated with disturbances in the nigrostriatal dopamine system. These extrapyramidal side effects (EPS) include parkinsonism, akathisia, tardive dyskinesia, and dystonia. See Baldessarini and Tarazi, Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th ed., 2001, pp. 485-520.

[0088] As used herein, "atypical antipsychotics" refer to antipsychotics that produce antipsychotic effects with little or no EPS, and include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone, and ziprasidone. "Atypical" antipsychotics differ from conventional antipsychotics in their pharmacological profile. While conventional antipsychotics are primarily characterized by D2 dopamine receptor blockade, atypical antipsychotics exhibit antagonist effects and varying degrees of receptor affinity for multiple receptors, including 5HTta and 5HTc serotonin receptors. Atypical antipsychotics are often referred to as serotonin / dopamine antagonists, reflecting the influential assumption that greater affinity for 5HT2 receptors than for D2 receptors is the basis for the action of "atypical" or "second generation" antipsychotics. However, atypical antipsychotics often exhibit side effects, including but not limited to weight gain, diabetes (e.g., type II diabetes), hyperlipidemia, QTc prolongation, myocarditis, sexual side effects, extrapyramidal side effects, and cataracts. Thus, given the differences in the ability of atypical antipsychotics to alleviate clinical symptoms and induce side effects (such as those listed above), atypical antipsychotics do not represent a homogeneous class. Furthermore, the common side effects of atypical antipsychotics, as described above, often limit the antipsychotic doses that can be used for these agents.

[0089] Memantine is chemically known as 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.13,7]decan-1-amine, which is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with moderate affinity. Proprietary names for memantine include: Axura and Akatinol (Merz),Namenda (Forest Laboratories), Ebixa and Abixa (Lundbeck) and Memox (Unipharm). Memantine is approved in the United States for the treatment of moderate to severe Alzheimer's disease (AD) at doses up to 28 mg / day. Derivatives or analogs of memantine, including compounds that are structurally or chemically similar to memantine, may also be used in the present disclosure. Such derivatives or analogs of memantine include, but are not limited to, those disclosed in U.S. Patent Nos. 3,391,142; 4,122,193; 4,273,774 and 5,061,703; U.S. Patent Application Publications US20040087658, US20050113458, US20060205822, US20090081259, US20090124659 and US20100227852; EP Patent Application Publication EP2260839A2; EP Patent EP1682109B1; and PCT Application Publication WO2005079779, all of which are incorporated herein by reference. Memantine used in the present invention includes memantine and its derivatives and analogs, as well as hydrates, polymorphs, prodrugs, salts and solvates thereof. As used herein, memantine also includes compositions comprising memantine or a derivative or analog thereof or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug thereof, wherein the composition can be optionally used in combination with at least one additional therapeutic agent (e.g., a therapeutic agent useful for treating a CNS disorder or cognitive impairment associated therewith). In some embodiments, a memantine composition suitable for use in the present invention comprises memantine and a second therapeutic agent, which is donepezil (trade name Aricept).

[0090] As used herein, "acetylcholinesterase inhibitors" or "AchEIs" refer to agents that inhibit the ability of cholinesterase to break down the neurotransmitter acetylcholine, primarily in brain synapses or neuromuscular junctions, thereby increasing the concentration and duration of acetylcholine. Suitable AChEIs for use in the present disclosure may include, for example, the following subclasses: (i) reversible noncompetitive inhibitors or reversible competitive inhibitors, (ii) irreversible, and (iii) quasi-irreversible inhibitors.

[0091] As used herein, “SV2A inhibitor” refers to any compound that binds to SV2A and reduces synaptic function by reducing presynaptic vesicle release (see, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006; Custer et al., 2006; Smedt et al., 2007; Yang et al., 2007; Meehan, “Levetiracetam has an activity-dependent effect on inhibitory transmission,” Epilepsia, January 31, 2012; Example 8 of WO 2001 / 62726, all of which are specifically incorporated herein by reference). A compound can be an SV2A inhibitor even if it does not bind to SV2A itself, as long as it causes or affects the ability of another compound to bind to SV2A or reduces synaptic function by reducing presynaptic vesicle release. SV2A inhibitors suitable for use in the methods, uses, pharmaceutical compositions or combinations of the present disclosure include specific SV2A inhibitors described herein (see also PCT application WO2022 / 011318) and pharmaceutically acceptable salts, hydrates, solvates, polymorphs or isomers thereof.

[0092] As used herein, the term "simultaneous administration" means that GABA containing α5 A R agonists (e.g., GABA containing α5 A R positive allosteric modulator) or a combination thereof with a second therapeutic agent (e.g., an antipsychotic, memantine AChEI or SV2A inhibitor) or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered with a time interval of no more than about 15 minutes, and in some embodiments, no more than about 10 minutes. When the drugs are administered simultaneously, they can be administered at the same dose (e.g., including α5-containing GABA A R agonists (e.g., GABA containing α5 A R positive allosteric modulator) and a second therapeutic agent (e.g., an antipsychotic, memantine, AChEI or SV2A inhibitor)) in a unit dosage form comprising a GABA containing α5 A R agonists (e.g., GABA containing α5 A R positive allosteric modulator) and a second therapeutic agent (e.g., an antipsychotic, memantine, an AChEI or an SV2A inhibitor) or a salt, hydrate, solvate or polymorph thereof, or in discrete doses in one dosage form comprising, for example, a GABA containing α5 A R agonists (e.g., GABA containing α5 AR positive allosteric modulator) or a salt, hydrate, solvate or polymorph thereof and in another dosage form comprises a second therapeutic agent (e.g., an antipsychotic, memantine, AChEI or SV2A inhibitor) or a salt, hydrate, solvate or polymorph thereof).

[0093] As used herein, the term "sequential administration" means that GABA containing α5 A R agonists (e.g., GABA containing α5 A R positive allosteric modulator) and the second therapeutic agent (e.g., an antipsychotic, memantine AChEI or SV2A inhibitor) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph thereof are administered with a time interval of more than about 15 minutes, and in some embodiments, more than about 1 hour or up to 12-24 hours. GABA containing α5 may be administered first A R agonists (e.g., GABA containing α5 A R positive allosteric modulator) or a second therapeutic agent (e.g., an antipsychotic, memantine, AChEI or SV2A inhibitor). A R agonists (e.g., GABA containing α5 A R positive allosteric modulator) and a second therapeutic agent (e.g., an antipsychotic, memantine, AChEI or SV2A inhibitor) or a salt, hydrate, solvate or polymorph thereof can be contained in discrete dosage forms, optionally contained in the same container or package.

[0094] The "therapeutically effective amount" of a drug or agent disclosed herein is an amount of a drug or agent that will have an expected therapeutic effect when administered to a subject, such as a subject's (e.g., a patient with cognitive impairment associated with a CNS disorder) cognitive function. A complete therapeutic effect does not necessarily occur by administering one dose, and may occur only after administering a series of doses. Therefore, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount required for the subject will depend on, for example, the subject's size, health, and age, cognitive impairment, or other symptoms of a CNS disorder (e.g., age-related cognitive impairment, mild cognitive impairment (MCI), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, ALS, cancer therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior, and substance addiction) properties and extent, as well as the therapeutic agent or combination of therapeutic agents selected for administration, and mode of administration. Technicians can easily determine the effective amount in a given situation by routine experiments.

[0095] The compounds of the present disclosure also include prodrugs, analogs or derivatives. The term "prodrug" is art-recognized and is intended to include compounds that are converted to α5-containing GABA under physiological conditions. A A common method for preparing a prodrug is to select a moiety that is hydrolyzed or metabolized under physiological conditions to provide the desired compound or agent. In other embodiments, the prodrug is converted to GABA containing α5 by the enzymatic activity of the host animal. A R positive allosteric modulator.

[0096] As used herein, the term "aliphatic" refers to a straight or branched chain alkyl, alkenyl, or alkynyl group. It should be 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 carbon atoms, such as 1 (or 2) to 4 carbon atoms.

[0097] The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic aromatic ring system. As used herein, aryl includes (C6-C12)-aryl-. For example, as used herein, aryl can be a C6-C10 monocyclic or C8-C12 bicyclic carbocyclic aromatic ring system. In some embodiments, as used herein, aryl 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, such as naphthyl, and systems in which only one of the two rings is aromatic, such as tetralin.

[0098] The term "heterocycle" as used herein refers to a chemically stable monocyclic or bicyclic non-aromatic ring system having 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH, S, SO or SO2. As used herein, heterocycle includes 3- to 12-membered heterocyclyl groups having 1-4 heteroatoms independently selected from O, N, NH, S, SO or SO2. For example, as used herein, heterocycle can be a chemically stable monocyclic or 8- to 12-membered bicyclic non-aromatic ring system having 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH, S, SO or SO2. In some embodiments, heterocycle as used herein can be a 3- to 10-membered heterocyclyl- having 1-4 heteroatoms independently selected from O, N, NH, S, SO or SO2. In the embodiment of the bicyclic non-aromatic ring system of "heterocyclyl", one or both rings may contain the heteroatom or heteroatom group. In another bicyclic "heterocyclyl" embodiment, one of the two rings may be aromatic. In another heterocyclic ring system embodiment, a non-aromatic heterocyclic ring may be optionally fused to an aromatic carbocyclic ring.

[0099] Examples of heterocycles 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-piperazinyl, pyridinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzotetrahydrothiophene, benzodithiane and 1,3-dihydro-imidazol-2-one.

[0100] The term "heteroaryl" as used herein refers to a monocyclic or bicyclic aromatic ring system having 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH or S in a chemically stable arrangement. Heteroaryl as used herein includes 5- to 12-membered heteroaryl groups having 1-4 heteroatoms independently selected from O, N, NH or S. In some embodiments, heteroaryl as used herein can be a 5- to 10-membered heteroaryl group having 1-4 heteroatoms independently selected from O, N, NH or S. For example, heteroaryl as used herein can be a 5- to 10-membered monocyclic or 8- to 12-membered bicyclic aromatic ring system having 1-4 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 rings may contain said heteroatom or heteroatom group.

[0101] Examples of heteroaryl rings include 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), ), 2-thienyl, 3-thienyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl) and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).

[0102] The term "cycloalkyl or cycloalkenyl" refers to a non-aromatic monocyclic or fused or bridged bicyclic carbocyclic ring system. For example, as used herein, a cycloalkyl or cycloalkenyl group can be a non-aromatic C3-C10 monocyclic or fused or bridged C8-C12 bicyclic carbocyclic ring system. The cycloalkenyl ring has one or more unsaturated units. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl, and decahydronaphthyl.

[0103] The term "heteroaralkyl" refers to an alkyl group in which a heteroaryl group replaces an alkyl H atom. For example, an alkyl group is any straight chain hydrocarbon and can include 1 to 12 carbon atoms (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl), wherein the alkyl group can be substituted with any heteroaryl group, including but not limited to 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4- Thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl) and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).

[0104] When a substituted moiety is described without indicating the atom via which the moiety is bonded to the substituent, the substituent may be bonded via any suitable atom in the moiety. For example, for a substituted 5- to 10-membered heteroaryl, a substituent on the heteroaryl may be bonded to any substitutable ring-forming atom of the heteroaryl ring (i.e., an atom bonded to one or more hydrogen atoms).

[0105] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then the substituent may be bonded to any substitutable ring atom in the ring (i.e., an atom bonded to one or more hydrogen atoms), unless the context indicates otherwise or implies otherwise. For example, when the R group is defined as pyridine, and the pyridine is described as follows: When the pyridine ring can bind to the benzodiazepine through any ring carbon atom of the pyridine ring, As another example, when the R group is defined as pyrazole, and the pyrazole is described as follows: When the pyrazole ring is connected to the benzodiazepine ring, any ring carbon atom of the pyrazole ring can be connected to the benzodiazepine ring. Derivative bonding, or with sp 3 N-atom bonding.

[0106] As used herein, carbon atom designations may have the specified integer and any intermediate integers. For example, the number of carbon atoms in a (C1-C4)alkyl group is 1, 2, 3, or 4. It should be understood that these designations refer to the total number of atoms in the appropriate group. For example, in a (3- to 10-membered)heterocyclyl group, the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.

[0107] "Pharmaceutically acceptable salts" are used herein to refer to therapeutically active, non-toxic base and acid salt forms of the agents or compounds according to the present invention. Acid addition salt forms of compounds that exist in their free form as bases can be obtained by treating the free base form with an appropriate acid, such as an inorganic acid, for example, a hydrohalic acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid, for example, acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclopentane, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. See, for example, WO 01 / 062726.

[0108] Compounds containing acidic protons can be converted into their therapeutically active, non-toxic base addition salt forms, such as metal or amine salts, by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth metal salts, such as alkali metal salts and alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, and the like, salts with organic bases, such as N-methyl-D-glucamine, hepatocarboxamide, and salts with amino acids (e.g., arginine, lysine, etc.). Conversely, the salt forms can be converted into the free form by treatment with an appropriate base or acid.

[0109] The compounds and their salts may be in the form of solvates, which are included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, etc. See, for example, WO01 / 062726.

[0110] The term "hydrate" as used herein refers to a combination of water and a compound wherein the water maintains its molecular state as water and is absorbed, adsorbed, or contained within the crystal lattice of the substrate compound.

[0111] As used herein, the term "polymorph" refers to different crystalline forms and other solid molecular forms of the same compound, including pseudopolymorphs, such as hydrates (e.g., bound water present in the crystal structure) and solvates (e.g., bound solvents instead of water) of the same compound. Due to the different packing of molecules in the crystal lattice, different crystalline polymorphs have different crystal structures. This results in different crystal symmetries and / or unit cell parameters, which directly affect their physical properties, such as the X-ray diffraction characteristics of crystals or powders. For example, different polymorphs will typically diffract at different angles and will give different intensity values. Therefore, X-ray powder diffraction can be used to identify different polymorphs or solid forms comprising more than one polymorph in a reproducible and reliable manner. Crystalline polymorphic forms are of interest to the pharmaceutical industry, particularly those related to the development of suitable dosage forms. If the polymorphic form does not remain constant during clinical or stability studies, the exact dosage form used or studied may not be comparable between one batch and another. When a compound is used in clinical studies or commercial products, it is also desirable to have a method for producing the compound in a selected polymorphic form in high purity, as the presence of impurities may produce undesirable toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more easily manufactured in large quantities at high purity, and therefore be more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may display other advantageous physical properties, such as a lack of hygroscopic tendency due to different lattice energies, improved solubility, and enhanced dissolution rate.

[0112] The term "substituted with 0-X substituents" means that the base moiety is unsubstituted (0) or independently substituted with 1, 2, 3, etc. or more X substituents, i.e., substituted with, for example, 1 substituent, 2 substituents, 3 substituents, etc.

[0113] The present disclosure relates to all isomers of compounds of formula I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF and If. "Isomer" as used herein includes optical isomers (e.g., stereoisomers, such as enantiomers and diastereomers), Z (zusammen) or E (entgegen) isomers and tautomers. Many compounds that can be used in the methods and compositions of the present disclosure have at least one stereocenter in their structure. The stereocenter can exist in R or S configuration, and the R and S symbols are used according to the rules described in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure also relates to all stereoisomeric forms of a compound or its mixture, such as enantiomers and diastereoisomeric forms (including all possible stereoisomer mixtures). See, for example, WO01 / 062726. In addition, certain compounds containing alkenyl groups can exist as Z (zusammen) or E (entgegen) isomers. In each case, the present disclosure includes both mixtures and separate individual isomers. Multiple substituents on the piperidinyl or azepanyl ring can also be in a cis or trans relationship relative to the plane of the piperidinyl or azepanyl ring. Some compounds can also exist in tautomeric forms. Such forms, although not explicitly indicated in the formula described herein, are intended to be included within the scope of the present invention. With respect to the methods and compositions of the present disclosure, mention of one or more compounds is intended to encompass compounds of each possible isomeric form and mixtures thereof, unless specific isomeric forms are specifically mentioned. See, for example, WO01 / 062726.

[0114] The compounds disclosed herein enhance the activity of GABA containing α5 A The function of R, that is, they are GABA containing α5 A R agonists (e.g., GABA containing α5 A R positive allosteric modulator) and is able to increase GABA-gated Cl- currents.

[0115] The present disclosure also provides pharmaceutical compositions comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical compositions of the present disclosure can be used in combination with a second therapeutic agent such as an antipsychotic, memantine, AChEI or SV2A inhibitor.

[0116] In some aspects, the present disclosure also provides methods for treating cognitive impairment associated with said CNS disorders or with α5-containing GABA. AMethods for treating cognitive impairment associated with various risk factors for cognitive impairment that are responsive to positive allosteric modulators of R, such as age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, compulsive behavior and substance addiction. In certain embodiments, the method is a method for treating the following diseases: age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior and substance addiction. In certain embodiments, treatment includes preventing cognitive impairment associated with CNS disorders or risk factors (such as those described herein) or slowing down the progression of the cognitive impairment. In certain embodiments, treatment includes alleviating, improving one or more impaired cognitive symptoms associated with CNS disorders or risk factors or slowing down the progression of the one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment or cognitive deficit. In another aspect of the present disclosure, there is provided a method of maintaining or improving cognitive function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, or a pharmaceutical composition of one or more thereof.

[0117] The cognitive impairment treated according to the present disclosure may be associated with various CNS disorders or cognitive impairment risks, such as age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, obsessive-compulsive behavior and substance addiction. These diseases may have multiple causes. However, the cognitive impairment associated with each of the above-mentioned diseases or risks may have overlapping reasons. Therefore, compounds, compositions or methods for treating the cognitive impairment associated with a CNS disorder or risk factor can also treat the cognitive impairment of another CNS disorder or risk factor. Benzazepines of the present disclosure derivative

[0118] The present disclosure provides compounds of formula I: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein: X is independently selected from O, N, -NR 3 or -C(R 4 ) 1-2 ; W is O, N, or NR 3 ; V is O, NR 3 or -C(R 4 ) 1-2 ,in, When X is O, W is N and V is -C(R 4 ) 1-2 ; When X is N, W is O or -NR 3 , V is -C(R 4 ) 1-2 ; When X is -NR 3 When W is N, V ​​is -C(R 4 ) 1-2 ; When X is -C(R 4 ) 1-2 When W is N, V ​​is O or -NR 3 ; Each occurrence of the key " ” is a single bond or a double bond; m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -NCS, -NO2, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl or -(C3-C10)cycloalkenyl; wherein each (5- to 6-membered)heteroaryl and (3- to 10-membered)heterocyclyl is substituted by 0-4 R7; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each R 8 is selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl or -CH2-(5- to 10-membered)heteroaryl, wherein each occurrence of R 8 independently substituted with 0-5 R'; Each R 9is selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, (C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -C(O)-(C6-C10)aryl, wherein each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O or S; R 3 Independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(5- to 10-membered)heteroaryl, -C(O)-(C6-C10)aryl, -C(O)-(C1-C6)alkyl or -C(O)-(C3-C6), wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R oindependently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl, or -(C6-C10)aryl, wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, or S; R 4 Selected from -H or -(C1-C6)alkyl; R 6 Selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl; wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein each occurrence of R″ is independently selected from —H, —(C1-C6)aliphatic, —(C3-C6)cycloalkyl, —(3- to 6-membered)heterocyclyl, —(5- to 10-membered)heteroaryl, —(C6-C10)aryl, —(C1-C6)alkyl-(5- to 10-membered)heteroaryl, —(C1-C6)alkyl-(C6-C10)aryl, —(C1-C6)alkyl-O-(5- to 10-membered)heteroaryl, or —(C1-C6)alkyl-O-(C6-C10)aryl, wherein each occurrence of R″ is independently substituted with 0-3 substituents, and particularly, in some aspects of the present disclosure, R″ is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, —R o , -OR o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2; and Each occurrence of R oindependently selected from -(C1-C6)aliphatic, -O(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)aryl, wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O or S.

[0119] In some embodiments of the compound of Formula I, the compound has the structure of Formula IA; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

[0120] In some embodiments of the compound of Formula IA, the compound has the structure of Formula Ia: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, in: m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6)alkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, wherein each 5- to 6-membered heteroaryl and 3- to 10-membered heterocycle is substituted with 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 independently selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 10-membered)heterocyclyl or -(C6-C10)aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2, wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, -CF3, -OCF3, -O-(C1-C6)aliphatic or -(C1-C6)aliphatic; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0121] In some embodiments, the compound of Formula Ia, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, has the structure of Formula Ia: Where: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is -halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -C≡CR 9 ,-(C3-C10)cycloalkenyl, wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R11 independently selected from -(C1-C6)alkyl and -O-(C1-C6)alkyl; R 3 independently selected from: -H, -(C1-C6)alkyl, -(3- to 10-membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl and -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C6-C10)aryl or -CH2-(C6-C10)aryl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R 4 and R 6 is -H; and where R 11 , R 12 , R 13 and R 14 , R′ and R″ are as defined in Formula Ia.

[0122] In some embodiments of the compound of Formula IA, the compound has the structure of Formula I-aa: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, in: m is an integer selected from 0-4; Each R 1 independently selected from halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, wherein each 5- to 6-membered heteroaryl and 3- to 10-membered heterocycle is substituted with 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 independently selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 10-membered)heterocyclyl or -(C6-C10)aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(3- to 6-membered)heterocyclyl or -(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from: halogen, -CF3, -OCF3, -O-(C1-C6)aliphatic or -(C1-C6)aliphatic; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0123] In some embodiments, the compound of Formula I-aa, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, has the structure of Formula I-aa: Where: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is -halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -C≡CR 9 ,-(C3-C10)cycloalkenyl, wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl and -O-(C1-C6)alkyl; R 3 independently selected from: -H, -(C1-C6)alkyl, -(3- to 10-membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl and -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C6-C10)aryl or -CH2-(C6-C10)aryl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R 4 and R 6 is -H; and where R 11 , R 12 , R 13 and R 14 , R' and R" are as defined in Formula I-aa.

[0124] In some embodiments of the compound of Formula I, the compound has the structure of Formula IB: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

[0125] In some embodiments of the compound of Formula IB, the compound has the structure of Formula Ib: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6)alkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5- to 6-membered heteroaryl or 3- to 10-membered heterocycle is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 Independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl or -(5- to 10-membered)heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o)2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from -halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5- to 10-membered)heteroaryl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C3-C6)cycloalkyl or —(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, -CF3, -OCF3, -O(C1-C6)aliphatic, -(C1-C6)aliphatic or -(5- to 10-membered)heteroaryl; Each R 4 and R 6 independently selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from H—, —(C1-C3)aliphatic or —(C3-C6)cycloalkyl.

[0126] In some embodiments, the compound of Formula Ib, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, has the structure of Formula Ib: Where: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is -halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -C≡CR 9 , wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 Selected from -(C1-C6)alkyl; R 3 are independently selected from: -H, -(C1-C6)alkyl or -CH2-(C6-C10)aryl and -(3 to 10-membered)heterocyclyl, wherein R 3 Independently by 0-5 R 12 replace; wherein R7 is selected from -(C1-C6)alkyl, -CH2-(C6-C10)aryl, -(C3-C6)cycloalkyl and -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R 4 and R 6 is -H; and where R 11 , R 12 , R 13 , R 14 and R' are as defined in Formula Ib.

[0127] In some embodiments of the compound of Formula IB, the compound has the structure of Formula I-ba: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5- to 6-membered heteroaryl or 3- to 10-membered heterocycle is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 Independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6alkyl-(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl or -(5- to 10-membered)heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o)2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)-aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from halogen, -R", -OR", oxo, CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2, wherein R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5- to 10-membered)heteroaryl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C3-C6)cycloalkyl, —(C6-C10)aryl, —H or —C(O)CH3; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, -CF3, -OCF3, -O(C1-C6)aliphatic, -(C1-C6)aliphatic, -(5- to 10-membered)heteroaryl or oxo; Each R 4 and R 6 independently selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0128] In some embodiments, the compound of Formula I-ba, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, has the structure of Formula I-ba: Where: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is -halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -C≡CR 9 , wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 Selected from -(C1-C6)alkyl; R 3 independently selected from: -H, -(C1-C6)alkyl or -CH2-(C6-C10)aryl and -(3 to 10-membered)heterocyclyl, wherein R 3 Independently by 0-5 R 12 replace; wherein R7 is selected from -(C1-C6)alkyl, -CH2-(C6-C10)aryl, -(C3-C6)cycloalkyl and -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R 4 and R 6 is -H; and where R 11 , R 12 , R 13 , R 14 and R' are as defined in formula I-ba.

[0129] In some embodiments of the compound of Formula I, the compound has the structure of Formula IC: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

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

[0131] In some embodiments, the compound of Formula Ic, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, has the structure of Formula Ic: Where: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is -halogen or -O-(C1-C6)alkyl; Each R 1 independently selected from: -halogen and -O(C1-C6)alkyl; R 2 Selected from: -CO(O)R7, -C≡CR 9 , wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H or -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 Selected from -(C1-C6)alkyl; Each occurrence of R 4 and R 6 is -H; and Among them, R7, R 13 , R14 , R' and R" are as defined in Formula Ic.

[0132] In some embodiments of the compound of Formula I, the compound has the structure of Formula ID: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

[0133] In some embodiments of the compound of Formula ID, the compound has the structure of Formula Id: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl or -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , -R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)aryl; wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from -halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0134] In some embodiments, the compound of Formula Id, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, has the structure of Formula Id: Where: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -C≡CR 9 , wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 Replace, where each occurrence of R 11 Selected from -(C1-C6)alkyl; R 3 are independently selected from: -H, -(C1-C6)alkyl or -CH2-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 Substitute, where each R 12 Independently selected from: -H or -F, wherein R7 is selected from -(C1-C6)alkyl, -CH2-(C6-C10)aryl, -(C3-C6)cycloalkyl and -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R 4 and R 6 is -H; and where R 11 , R 12 R 13 , R 14 and R' are as defined in Formula Id.

[0135] In some embodiments of the compound of Formula I, the compound has the structure of Formula IE: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

[0136] In some embodiments of the compound of Formula IE, the compound has the structure of Formula Ie: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6)alkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclyl or heteroaryl is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, Each occurrence of R 9 Independently by 0-5 R 11 Replace, where each occurrence of R 11independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; each occurrence of R′ is wherein each occurrence of R′ is independently selected from -halogen, -R″, -OR″, oxo, -CH2OR″, -CH2NR″2, -C(O)N(R″)2, -C(O)OR″, -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R″)2, wherein each R′ is independently substituted with 0-5 R″; wherein R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; Each R 4 are independently -H or -(C1-C6)alkyl; Each R 6 are independently -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)aliphatic.

[0137] In some embodiments, the compound of Formula Ie, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, has the structure of Formula Ie: Where: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is halogen or -O-(C1-C6)alkyl; Each R 1 independently selected from -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -CO(O)R7, -C≡CR 9 , wherein each 5-membered heterocyclic ring or heteroaryl group is substituted by 0-4 R7; Each R 9 is selected from -H or -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R11 replace; Each occurrence of R 11 Selected from -(C1-C6)alkyl; R 4 and R 6 Both -H; and R7, R 13 , R 14 and R' are as defined in Formula le.

[0138] In some embodiments of the compound of Formula I, the compound has the structure of Formula IF: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

[0139] In some embodiments of the compound of Formula IF, the compound has the structure of Formula If: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9Selected from: -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, Each occurrence of R 9 Independently by 0-5 R 11 Replace, where each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl or -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein each R' is independently substituted by 0-5 R", wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; R 4 is -H or (C1-C6) alkyl; R 6 is -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

[0140] In some embodiments, the compound of Formula If, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, has the structure of Formula If: Where: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from -CO(O)R7, -C≡CR 9 , wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 is selected from -H or -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 Replace, and each occurrence of R 11 Selected from -(C1-C6)alkyl; R 4 and R 6 Both -H; and Among them, R7, R 13 , R 14 and R' are as defined in Formula If.

[0141] Examples of specific compounds of the present disclosure include: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0142] Basic nitrogen groups present in the compounds of the present invention can be quaternized with lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides, such as benzyl and phenethyl bromides, and others, thereby obtaining water-soluble or oil-soluble or dispersible products.

[0143] Unless otherwise indicated, any embodiment described herein is also intended to represent both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I. The present invention includes various isotopically labeled compounds as defined herein, for example, those in which radioactive isotopes such as 3 H, 13 C and 14 Such isotope-labeled compounds can be used for metabolic studies (preferably with 14 C), reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determinations, or radiotherapy for patients. In particular, 18 Compounds labeled with F or α-F may be particularly preferred for use in PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes or Examples and Preparations described below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0144] Any individual embodiment described herein in the context of Formula I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF, and If is part of the present disclosure. In addition, the various substituents recited at specific residues in those individual embodiments may be combined with one of the substituents recited at other specific residues without departing from the scope of the present disclosure. General synthetic methods

[0145] Compounds of the present disclosure can generally be prepared by methods known to those skilled in the art. Schemes 1-4 below provide general synthetic routes for preparing compounds of Formula I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF and If. Other equivalent schemes apparent to ordinary organic chemists can alternatively be used to synthesize various parts (or all) of the molecule, as shown in the general scheme below. Scheme 1. General Synthesis of Compounds of Formula IA, Ia and I-aa Wherein X, W and V Form a Pyrazole Ring Scheme 2. General synthesis of compounds of formula IB, Ib and I-ba wherein X, W and V form a methylpyrazole ring. Scheme 3-A. General synthesis of compounds of formula IB, Ib and I-ba wherein X, W and V form a pyrazole ring. Scheme 3-B. Alternative synthesis of compounds of formula IB, Ib and I-ba (main) starting from intermediate A, wherein X, W and V form a pyrazole ring.

[0146] As will be appreciated by those skilled in the art, compounds of Formula I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF and If having variables other than those described above can be prepared by varying the chemical reagents or synthetic routes. Pharmaceutical compositions and administration methods disclosed herein

[0147] The present disclosure provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of Formula I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF and If, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof. In some embodiments, the GABA described in the present disclosure A α5 receptor positive allosteric modulators and GABA disclosed in PCT applications WO2015 / 095783A1, WO2016 / 205739A1, WO2018 / 130869A1 and WO2019 / 246300A1 A In some embodiments, the GABA described in the present disclosure is used in combination with one or more of the α5 receptor positive allosteric modulators. A The α5 receptor positive allosteric modulators or the combinations described above can be used in combination with one or more SV2a inhibitors disclosed in PCT application WO2022 / 011318, in particular levetiracetam or brivaracetam, for the treatment of such cognitive impairment and other conditions described herein.

[0148] It will be appreciated that the compounds and agents used in the compositions of the present disclosure should preferably readily penetrate the blood-brain barrier when administered peripherally. However, compounds that are unable to penetrate the blood-brain barrier may still be effectively administered directly into the central nervous system, for example, via intraventricular or other neurocompatible routes.

[0149] In some embodiments of the present disclosure, the α5-containing GABA of the present disclosure A The R positive allosteric modulator or combination is formulated in a pharmaceutical composition together with a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers that can be used in these compositions and combinations include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. In other embodiments, no carrier is used. For example, GABA containing α5 A R agonists (e.g., GABA containing α5 A R positive allosteric modulators) can be administered alone or as a component of a pharmaceutical formulation (therapeutic composition). GABA containing α5 AR agonists (e.g., GABA containing α5 A R positive allosteric modulators) can be formulated for administration in any convenient way used in human medicine.

[0150] In some embodiments, the methods of treatment of the present invention include topical, systemic or topical administration of a pharmaceutical composition of the present invention or a combination of the present invention in some embodiments, or a compound or agent of the present invention. For example, the therapeutic composition of a compound or agent of the present invention can be formulated for administration by, for example, injection (e.g., intravenous, subcutaneous or intramuscular), inhalation or insufflation (through the mouth or nose) or oral, oral, sublingual, transdermal, nasal or parenteral administration. In some embodiments, the composition of the compound or agent or combination described herein can also be formulated as a part of an implant or device, or formulated for slow or extended release. When parenteral administration, the therapeutic composition or compound or agent of the present invention is preferably in a physiologically acceptable form without pyrogen. Technology and formulations can generally be found in Remington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA.

[0151] In certain embodiments, pharmaceutical compositions suitable for parenteral administration may include α5-containing GABA A The R positive allosteric modulator is combined with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or a sterile powder that can be reconstituted into a sterile injectable solution or dispersion before use, which may contain antioxidants, buffers, bacteriostats, solutes or suspending agents or thickening agents that make the preparation isotonic with the blood of the intended recipient. Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate). For example, appropriate fluidity can be maintained by using a coating material such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant.

[0152] Contains GABA containing α5 A Compositions of R positive allosteric modulators may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Protection against the action of microorganisms may be ensured by including various antibacterial and antifungal agents, such as 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 composition. In addition, prolonged absorption of the injectable pharmaceutical form may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0153] In certain embodiments of the present disclosure, the GABA comprising α5 A The compositions of the R positive allosteric modulators can be administered orally, for example, in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, typically sucrose and gum arabic or gum tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic), etc., each containing a predetermined amount of α5-containing GABA A R positive allosteric modulator as the active ingredient.

[0154] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), one or more GABA-containing A Compositions of R positive allosteric modulators are combined with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. The capsules use excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, and solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules.

[0155] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. AIn addition to the R positive allosteric modulator, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, colorants, fragrances and preservatives.

[0156] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0157] As described herein, the compounds of the present disclosure, compositions or combinations thereof can be used for slow, controlled or extended release. The term "sustained release" is widely recognized in the field of pharmaceutical science and is used herein to refer to the controlled release of an active compound or agent from a dosage form to an environment over an extended period of time (e.g., greater than or equal to one hour) (whole or during). A sustained-release dosage form will release the drug at a substantially constant rate over an extended period of time, or will gradually release a substantially constant amount of the drug over an extended period of time. The term "extended release" used herein includes the terms "controlled release," "long-term release," "sustained release," "delayed release," or "slow release," because these terms are used in pharmaceutical science. In some embodiments, the sustained-release dose is administered in the form of a patch or pump.

[0158] A person of ordinary skill in the art, such as a physician, can readily determine the amount of α5-containing GABA required to treat a subject using the compositions and methods of the present disclosure. A It will be appreciated that varying the amount of the selected α5-containing GABA A Individual dosage regimens will be determined based on factors such as the effect of the R positive allosteric modulator, the severity or stage of the disease, the route of administration, and unique characteristics of the individual, such as age, weight, size, and degree of cognitive impairment.

[0159] In certain embodiments of the present disclosure, α5-containing GABA A The daily dose of the R positive allosteric modulator or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is in the range of 0.0015 mg to 5000 mg or 5 mg to 1000 mg. In some embodiments of the present disclosure, the α5-containing GABA AThe dosage of the R positive allosteric modulator or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is about 0.1-500 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. 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, 10mg / kg, 14mg / kg, 18mg / kg, 36mg / kg, 50mg / kg or 70mg / kg.

[0160] In some embodiments of the present disclosure, α5-containing GABA A The daily dose of the R positive allosteric modulator, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof, is 0.1 mg, 0.15 mg, 0.18 mg, 0.35 mg, 0.7 mg, 1.5 mg, 2.0 mg, 2.5 mg, 2.8 mg, 3.0 mg, 3.5 mg, 4.2 mg, 5 mg, 5.5 mg, 6.0 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 25 mg, 28 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg In some embodiments, the α5-containing GABA is administered in an amount of 1 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 125 mg, 140 mg, 150 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 225 mg, 250 mg, 280 mg, 300 mg, 350 mg, 400 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 2500 mg, 3500 mg, or 5000 mg. AThe amount of a daily dose of an R positive allosteric modulator or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is about 0.5 mg, about 5 mg, about 20 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 2500 mg, about 3500 mg or 5000 mg of α5-containing GABA A R positive allosteric modulator.

[0161] In certain embodiments of the present disclosure, α5-containing GABA A The dosage of the R positive allosteric modulator is 0.1 to 5 mg / kg / day (7 to 350 mg / day for a typical 70 kg human subject). In certain embodiments of the present disclosure, the α5-containing GABA A The daily dose of the positive allosteric modulator is 7 to 350 mg. In some embodiments, the α5-containing GABA may be used. A The daily dose of the R positive allosteric modulator includes, but is not limited to, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5 mg / kg / day. In some embodiments, the α5-containing GABA may be used. A The daily dose of the positive allosteric modulator of R includes but is not limited to 7, 35, 70, 110, 150, 180, 220, 300, 350 mg. In some embodiments of the present disclosure, GABA containing α5 A The dosage of the positive allosteric modulator of R is 1-2 mg / kg / day. In some embodiments of the present disclosure, the GABA containing α5 A The daily dose of the positive allosteric modulator of R is 70-140 mg. In other embodiments of the present disclosure, the GABA containing α5 A The dosage of the positive allosteric modulator of R is 0.1 to 0.2 mg / kg / day. In other embodiments of the present disclosure, the GABA containing α5 A The daily dosage of the R positive allosteric modulator is 7 to 14 mg. Other dosages above, between, or below these daily dosages may also be used and can be determined by one skilled in the art using the methods disclosed herein.

[0162] In certain embodiments of the present disclosure, the dosing interval is 12 or 24 hours. It can also be administered at a less frequent interval, such as once every 6 hours. In some embodiments, GABA containing α5 A The R positive allosteric modulator is administered at a total daily dose of 0.1 to 5 mg / kg every 12 or 24 hours (e.g., at a daily dose of 2 mg / kg every 12 hours, each administration is 1 mg / kg). In some embodiments, the α5-containing GABA AR positive allosteric modulators are administered in a total daily dose of 7 to 350 mg every 12 or 24 hours. In some embodiments, the α5-containing GABA A R positive allosteric modulators are administered at a daily dose of 1 to 2 mg / kg every 24 hours. In some embodiments, the α5-containing GABA A In another embodiment, the α5-containing GABA A In another embodiment, the α5-containing GABA A R is administered at a daily dose of 7 to 15 mg every 24 hours. In some embodiments, α5-containing GABA A The R positive allosteric modulator is administered at a daily dose of 0.01 to 2.5 mg / kg every 12 or 24 hours (e.g., 0.4 mg / kg per administration at a daily dose of 0.8 mg / kg every 12 hours). In another embodiment, the α5-containing GABA A R positive allosteric modulators are administered at a daily dose of 0.7 to 15 mg every 24 hours. In some embodiments, the α5-containing GABA A In another embodiment, the α5-containing GABA A R positive allosteric modulators are administered at a daily dose of 7 to 15 mg every 24 hours. In some embodiments, the α5-containing GABA A R positive allosteric modulators are administered at a daily dose of 25-180 mg every 12 or 24 hours. In some embodiments, the α5-containing GABA A R positive allosteric modulators are administered at a daily dose of 0.6 to 1.8 mg / kg every 12 or 24 hours. In some embodiments, the α5-containing GABA A R positive allosteric modulators are administered at a daily dose of 40 to 130 mg every 12 or 24 hours.

[0163] In some embodiments, GABA A The dosing interval of the α5 receptor agonist or its pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer, or a pharmaceutical composition comprising any of the foregoing is once every 12 hours (twice a day) or once every 24 hours (once a day). Administration at intervals with lower frequencies, for example, once every 6 hours, can also be used. Other doses higher, intermediate or lower than these doses can also be used and can be determined by those skilled in the art according to the methods disclosed herein. For repeated administration for several days or weeks or longer, depending on the condition, treatment is continued until a sufficient level of cognitive function is achieved.

[0164] In certain embodiments of the present disclosure, the administration interval is once every 12 or 24 hours, and in some embodiments, once daily. Administration at less frequent intervals, such as once every 6 hours, may also be used.

[0165] If administered by implant, device, or slow-release or extended-release formulation, GABA containing α5 A The R positive allosteric modulator can be administered once, or periodically, or more frequently throughout the patient's life as needed. For clinical use, other dosing intervals intermediate to or shorter than these dosing intervals can also be used and can be determined by those skilled in the art following the methods of the present invention.

[0166] Those skilled in the art can determine the desired administration time by routine experiments. A The R positive allosteric modulator can be administered for a period of 1-4 weeks, 1-3 months, 3-6 months, 6-12 months, 1-2 years, or longer, up to the lifetime of the patient.

[0167] In addition to GABA containing α5 A In addition to the R positive allosteric modulators, the compositions of the present disclosure can be used in combination with other therapeutically useful agents, but are not limited to antipsychotics, memantine AChEIs or SV2A inhibitors (e.g., levetiracetam or brivaracetam), or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs. According to the methods of the present disclosure, these other therapeutically useful agents can be administered in a single formulation or in a separate formulation with α5-containing GABA. A The R positive allosteric modulator is administered simultaneously or sequentially. In some embodiments, two or more formulations are packaged together. In other embodiments, they are packaged separately.

[0168] It will be understood by those skilled in the art that the compositions described herein can be adjusted and modified according to the application involved, and the compositions described herein can be used in other suitable applications. For example, the compositions of the present disclosure can be used in combination with a second therapeutic agent. Such other additions and modifications will not depart from the scope of the present invention. Pharmaceutical compositions / combinations with antipsychotic drugs

[0169] In some embodiments, the compounds, compositions or combinations of the present disclosure can be used in combination with antipsychotics for treating cognitive impairment associated with schizophrenia or bipolar disorder (e.g., mania) in a subject suffering from or at risk of schizophrenia or bipolar disorder (e.g., mania). Antipsychotics or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof that can be used in the methods and compositions of these embodiments of the present disclosure include both typical and atypical antipsychotics. In some embodiments, the compounds, compositions or combinations of the present disclosure can be used to treat one or more positive and / or negative symptoms and cognitive impairment associated with schizophrenia. In some embodiments, the compounds, compositions or combinations of the present disclosure can be used to treat one or more symptoms and cognitive impairment associated with bipolar disorder (particularly mania). In some embodiments of the present disclosure, the compounds, compositions or combinations of the present disclosure prevent or slow the progression of cognitive impairment in schizophrenia or bipolar disorder (particularly mania) in the subject.

[0170] In some embodiments, the antipsychotics suitable for use in the present disclosure are selected from atypical antipsychotics. Such atypical antipsychotics include, but are not limited to, those disclosed in, for example, U.S. Patents 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573; 5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and 5,312,925, as well as EP Patents EP402644 and EP368388, and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[0171] In some embodiments, atypical antipsychotics suitable for use herein include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone, and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. In some embodiments, antipsychotics suitable for use herein are selected from aripiprazole (Bristol-Myers Squibb), olanzapine (Lilly), and ziprasidone (Pfizer), and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[0172] In some embodiments, antipsychotics suitable for use in the present disclosure are typical antipsychotics, including but not limited to acepromazine, phenperidol, bromazepam, bromperidol, chlorpromazine, cloprothixol, clotiapine, cyanomemazine, diazepam, dixylazine, droperidol, flupentixol, fluphenazine, fluspirine, haloperidol, heptamine, iodine isopropylamide, levomepromazine, levosulpride, loxapine, meperone, mesoridazine , molindone, hydroxyperidine, hydroxypropylthiapine, penfluridol, piperazine, perazine, perphenazine, pimozide, pipoperone, pipotiazide, prochlorperazine, promethazine, promethazine, prothiopentidine, pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine, sulpiride, thiothixene, trifluoperazine, triflupromazine, trihexyphenidyl and zuclothixene and their medically acceptable salts, hydrates, solvates and polymorphs.

[0173] In some embodiments of the present disclosure, the antipsychotic drug or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof can be selected from the following compounds: dopaminergic agents (e.g., dopamine D1 receptor antagonists or agonists, dopamine D2 receptor antagonists or partial agonists, dopamine D3 receptor antagonists or partial agonists, dopamine D4 receptor antagonists), glutamatergic agents, N-methyl-D-aspartate (NMDA) receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitors, metabotropic glutamate receptor (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluRs) GluR2 / 3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) / kainate receptor antagonists, glutamate receptor modulators (CX-516), glutathione prodrugs, noradrenergic agents (such as α-2 adrenergic receptor agonists or antagonists and catechol-O-methyltransferase (COMT) inhibitors), serotonin receptor modulators (such as 5-HT 2A Receptor antagonist, 5-HT 1A Partial agonist of 5-HT receptor 2C agonists and 5-HT6 antagonists, serotonin 2C agonists), cholinergic agents (such as alpha-7 nicotinic receptor agonists or PAMs, alpha4-beta2 nicotinic receptor agonists, allosteric modulators of nicotinic receptors and acetylcholinesterase inhibitors, muscarinic receptor agonists and antagonists), cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, monoamine oxidase (MAO) B inhibitors, PDE10 inhibitors, neuronal nitric oxide synthase (nNOS) inhibitors, neurosteroids and neurotrophic factors.

[0174] In some embodiments, the α5-containing GABA as described herein A The R positive allosteric modulator and the antipsychotic agent as described herein or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs are administered simultaneously or sequentially or in a single formulation or in separate formulations packaged together or in separate formulations packaged separately. In other embodiments, the α5-containing GABA A The R positive allosteric modulator and the antipsychotic agent or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof are administered by different routes. As used herein, "combination" includes packaging and administration by any of these formulations or routes of administration. Pharmaceutical compositions / combinations with memantine

[0175] The compounds, compositions or combinations of the present disclosure can be used in combination with memantine or a derivative or analog thereof for the treatment of cognitive impairment associated with central nervous system (CNS) disorders in a subject in need thereof or at risk thereof, including but not limited to, subjects having or at risk of: age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI, age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS) and cognitive impairment associated with cancer treatment.

[0176] Memantine, also known chemically as 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.1 3,7 ]Decan-1-amine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with moderate affinity. Proprietary names of memantine include: Axura and Akatinol (Merz),Namenda (Forest Laboratories), Ebixa and Abixa (Lundbeck) and Memox (Unipharm). Memantine is currently available in the United States and over 42 countries worldwide. In the United States, it is approved for the treatment of moderate to severe Alzheimer's disease (AD) at doses up to 28 mg / day. Memantine and certain derivatives and analogs thereof useful in the present disclosure are disclosed in U.S. Patent Nos. 3,391,142; 4,122,193; 4,273,774; and 5,061,703, all of which are incorporated herein by reference. Other memantine derivatives or analogs that can be used in the present disclosure include, but are not limited to, those disclosed in U.S. Patent Application Publications US20040087658, US20050113458, US20060205822, US20090081259, US20090124659, and US20100227852; EP Patent Application Publication EP2260839A2; EP Patent EP1682109B1; and PCT Application Publication WO2005079779, all of which are incorporated herein by reference. Memantine used in the present disclosure includes memantine and its derivatives and analogs, as well as hydrates, polymorphs, prodrugs, salts, and solvates thereof. As used herein, memantine also includes compositions comprising memantine or a derivative or analog thereof or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug thereof, wherein the composition can be optionally used in combination with at least one additional therapeutic agent (e.g., a therapeutic agent useful for treating a CNS disorder or cognitive impairment associated therewith). In some embodiments, a memantine composition suitable for use in the present disclosure comprises memantine and a second therapeutic agent, the second therapeutic agent being donepezil (trade name Aricept).

[0177] In other embodiments of the present disclosure, α5-containing GABA A The R positive allosteric modulator and memantine (or memantine derivative / analog) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof are administered simultaneously or sequentially, or in a single formulation or in separate formulations packaged together or separately. In other embodiments, the α5-containing GABA A The R positive allosteric modulator and memantine (or memantine derivative / analog) or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof are administered by different routes. As used herein, "combination" includes packaging or administration by any of these formulations or administration routes. Pharmaceutical compositions / combinations with acetylcholinesterase inhibitors (AChEI)

[0178] The compounds, compositions or combinations of the present disclosure can be used in combination with an acetylcholinesterase inhibitor ("AChEI") for the treatment of cognitive impairment associated with central nervous system (CNS) disorders in a subject in need thereof or at risk thereof, including but not limited to subjects having or at risk of: age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI, age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS) and cognitive impairment associated with cancer treatment.

[0179] AChEIs known to those of ordinary skill in the art may belong to the following subclasses: (i) reversible noncompetitive inhibitors or reversible competitive inhibitors, (ii) irreversible, and / or (iii) quasi-irreversible inhibitors.

[0180] In certain embodiments, AChEIs useful in the present disclosure include PCT applications WO2014039920 and WO2002032412; European Patent Nos. 468187; 481429-A; and U.S. Patent Nos. 4,816,456; 4,895,841; 5,041,455; 5,106,856; 5,602,176; 6,677,330; 7,340,299; 7,635,709; 8,058,268; 8,741,808; and 8,853,219, all of which are incorporated herein by reference.

[0181] In certain embodiments, exemplary AChEIs that can be used in accordance with the present disclosure include, but are not limited to, ugremin, ladostigid, demecarium, exepectate (diethoxythiocholine), etorphinium (Tensilon), tacrine (Cognex), pralidoxime (2-PAM), pyridostigmine (Mestinon), physostigmine (serine, antilim), abenate bromide (Mytelase), galantamine (Reminyl, Razadyn) and dapoxetine (Dapoxetine). e), rivastigmine (Exelon, SZD-ENA-713), huperzine A, icopezil, neostigmine (Prostigmin, Vagostigmin), donepezil (Donepezil, E2020), lactucin, monoamine acridine and its derivatives, piperidine and piperazine derivatives, benzyl piperidine derivatives, piperidinyl-alkanoyl heterocyclic compounds, 4-(1-benzyl: piperidinyl)-substituted fused quinoline derivatives and cyclic amide derivatives. Other typical AChEIs include carbamate and organic phosphonate compounds, such as metrifonate (trichlorfon). Benzazepines Alcohols such as galantamine are also useful AChEIs. In some embodiments, AChEIs suitable for use in combination with the compounds and compositions of the present application include donepezil (aricept), galantamine (razadyne), or rivastigmine (exelons).

[0182] In other embodiments of the present disclosure, α5-containing GABA A The R positive allosteric modulator and the AChEI or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs are administered simultaneously or sequentially, or in a single formulation or in separate formulations packaged together or separately. In other embodiments, the α5-containing GABA A The R positive allosteric modulator and the AChEI or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug thereof are administered via different routes. As used herein, "combination" includes packaging or administration by any of these formulations or administration routes. Pharmaceutical compositions / combinations with SV2A inhibitors

[0183] The compounds, compositions or combinations of the present disclosure can be used in combination with an SV2A inhibitor for treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need thereof or at risk thereof, including but not limited to subjects having or at risk of: age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI, age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS) and cognitive impairment associated with cancer treatment.

[0184] In certain embodiments, SV2A inhibitors useful in the present disclosure include those described in PCT applications WO2001 / 062726, WO2002 / 094787, WO2004 / 087658, WO2007 / 065595, WO2006 / 128692, WO2006 / 128693, and WO2022 / 011318. In certain embodiments, SV2A inhibitors useful in the present disclosure include those described in U.S. Patent No. 7,244,747, U.S. Patent Application No. 2008 / 0081832. In certain embodiments, SV2A inhibitors useful in the present disclosure include those described in British Patent No. 1,039,113 and British Patent No. 1,309,692, all of which are incorporated herein by reference.

[0185] In some embodiments of the present disclosure, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is selected from levetiracetam, brivaracetam and celecoxib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or isomer of any of the foregoing. In some embodiments of the present disclosure, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. In some embodiments of the present disclosure, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. Brivaracetam refers to the compound (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide (IUPAC name). In some embodiments of the present disclosure, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof is celecracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or isomer thereof. Celecracetam refers to the compound (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]butanamide (IUPAC name). In certain embodiments of the present invention, the SV2A inhibitor is selected from levetiracetam, brivaracetam and celecracetam or a pharmaceutically acceptable salt thereof.

[0186] In certain embodiments, levetiracetam, brivaracetam or celecoxib or a pharmaceutically acceptable salt thereof can be administered at a dose disclosed in, for example, U.S. Patent Application 12 / 580,464 (Publication No. US-2010-0099735), U.S. Patent Application 13 / 287,531 (Publication No. US-2012-0046336), U.S. Patent Application 13 / 370,253 (Publication No. US-2012-0214859), WO2010 / 044878, WO2012 / 109491, WO2014 / 144663 and WO2022 / 011318. Each of these publications is incorporated herein by reference in its entirety.

[0187] In certain embodiments of the present disclosure, the dose of the SV2A inhibitor (e.g., levetiracetam, brivaracetam, or celecoxib) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer thereof is 0.0015 to 7 mg / kg / day. In certain embodiments of the present disclosure, the dose of the SV2A inhibitor (e.g., levetiracetam, brivaracetam, or celecoxib) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer thereof is about 0.1-500 mg / day. Daily doses that may 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, 0.4mg / kg, 0.5mg / 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 or 7.0mg / 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, 50mg, 55mg, 60mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 140mg, 150mg, 170mg, 175mg, 180mg, 190mg, 200mg, 210mg, 225mg, 250mg, 280mg, 300mg, 350mg, 400mg or 500mg.

[0188] In some embodiments, the daily dose of an SV2A inhibitor (e.g., levetiracetam, brivaracetam, or celecoxib) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer thereof that can be used in the methods, uses, pharmaceutical compositions for use, or combinations for use of the present disclosure includes, but is not limited to, 0.0015-5 mg / kg, 0.05-4 mg / kg, 0.05-2.0 mg / kg, 0.05-1.5 mg / kg, 0.1-1.0 mg / kg, 1-5 mg / kg, 1.5-4.0 mg / kg, 1.8-3.6 mg / kg, 0.01-0.8 mg / kg, 0.01-1 mg / kg, 0.01-1.5 mg / kg, 0. 01-2mg / kg, 0.01-2.5mg / kg, 0.01-3mg / kg, 0.01-3.5mg / kg, 0.01-4mg / kg, 0.01-5mg / kg, 0.025-0.8mg / kg, 0.025-1mg / kg, 0.025-1.5mg / kg, 0.025-2m g / kg, 0.025-2.5mg / kg, 0.025-3mg / kg, 0.025-3.5mg / kg, 0.025-4mg / kg, 0.05-0.8mg / kg, 0.05-1mg / kg, 0.05-1.5mg / kg, 0.05-2mg / kg, 0.05-2.5mg / k g, 0.05-3mg / kg, 0.05-3.5mg / kg, 0.05-4mg / kg, 0.075-0.8mg / kg, 0.075-1mg / kg, 0.075-1.5mg / kg, 0.075-2mg / kg, 0.075-2.5mg / kg, 0.075-3mg / kg, 0 .075-3.5mg / kg, 0.075-4mg / kg, 0.1-0.8mg / kg, 0.1-1mg / kg, 0.1-1.5mg / kg, 0.1-2mg / kg, 0.1-2.5mg / kg, 0.1-3mg / kg, 0.1-3.5mg / kg, 0.1-4mg / kg, 0. 2-0.8mg / kg, 0.2-1mg / kg, 0.2-1.5mg / kg, 0.2-2mg / kg, 0.2-2.5mg / kg, 0.2-3mg / kg, 0.2-3.5mg / kg, 0.2-4mg / kg, 0.5-0.8mg / kg, 0.5-1mg / kg, 0.5-1.5 mg / kg, 0.5-2mg / kg, 0.5-2.5mg / kg, 0.5-3mg / kg, 0.5-3.5mg / kg or 0.5-4mg / kg; or 0.1-350mg, 0.7-50mg, 0.7-75mg, 0.7-100mg, 0.7-150mg, 0.7-180mg, 0.7-225mg, 0.7-250mg, 0.7-280mg, 1.8-50mg, 1.8-75mg, 1.8-100mg, 1.8-150mg, 1 .8-180mg, 1.8-225mg, 1.8-250mg, 1.8-280mg, 3.5-50mg, 3.5-75mg, 3.5-100mg, 3.5-150mg, 3.5-180mg, 3.5-225mg, 3.5-250mg, 3.5-280mg, 5-50mg, 5-75mg, 5-1 00mg, 5-150mg, 5-180mg, 5-225mg, 5-250mg, 5-280mg, 7-50mg, 7-75mg, 7-100mg, 7 -150mg, 7-180mg, 7-225mg, 7-250mg, 7-280mg, 15-50mg, 15-75mg, 15-100mg, 15-150mg, 15-180mg, 15-225mg, 15-250mg, 15-280mg, 35-50mg, 35-75mg, 35-100mg, 35-150mg, 35-180mg, 35-225mg, 35-250mg, 35-280mg, 0.1-500mg, 3-300mg, 3-150mg, 3-110mg, 7-70mg, 70-350mg, 100-300mg, 190-220mg, 190-240mg or 125-250mg. .

[0189] In certain embodiments of the present invention, the SV2A inhibitor is selected from levetiracetam, brivaracetam and celecoxib or a pharmaceutically acceptable salt thereof. In certain embodiments of the present invention, the SV2A inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 to 5 mg / kg, or about 1 to 2 mg / kg, or about 0.1 to 0.2 mg / kg, or about 0.01 to 2.5 mg / kg, or about 0.1-2.5 mg / kg, or about 0.4-2.5 mg / kg, or about 0.6-1.8 mg / kg, or about 0.04-2.5 mg / kg or about 0.06-1.8 mg / kg every 12 or 24 hours.

[0190] In certain embodiments of the present invention, the SV2A inhibitor is present in an amount of 5-140 mg. In other embodiments of the present invention, the SV2A inhibitor is present in an amount of 0.7-180 mg. In certain embodiments of the present invention, the SV2A inhibitor is present in an amount of 3-50 mg. In other embodiments of the present invention, the SV2A inhibitor is present in an amount of 0.07-50 mg.

[0191] In some embodiments, levetiracetam, brivaracetam, or celecatham, or a pharmaceutically acceptable salt thereof, is administered at a daily dose of 0.7-350 mg, or comprises administering to a subject a pharmaceutical composition comprising a daily dose of levetiracetam, brivaracetam, or celecatham, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the daily dose of levetiracetam or celecatham, or a pharmaceutically acceptable salt thereof, is 7-350 mg. In some embodiments, the daily dose of brivaracetam or a pharmaceutically acceptable salt thereof is 0.7-180 mg. In other embodiments, the daily dose of levetiracetam or celecatham, or a pharmaceutically acceptable salt thereof, is 125-250 mg. In some embodiments, the daily dose of levetiracetam or celecatham, or a pharmaceutically acceptable salt thereof, is 220 mg. In some embodiments, the daily dose of levetiracetam or celecatham, or a pharmaceutically acceptable salt thereof, is 190 mg.

[0192] In certain embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt thereof is administered to the subject in a therapeutically effective amount. In certain embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 1-2 mg / kg. In certain embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 70-150 mg. In some embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.1-2.5 mg / kg. In some embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 7-180 mg. In some embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.4-2.5 mg / kg. In some embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 25-180 mg every 12 or 24 hours. In some embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 0.6-1.8 mg / kg every 12 or 24 hours. In some embodiments of the present invention, levetiracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 40-130 mg every 12 or 24 hours.

[0193] In certain embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt thereof is administered to the subject in a therapeutically effective amount. In certain embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.1-0.2 mg / kg. In certain embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 7-15 mg. In some embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.01-2.5 mg / kg. In some embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.7-180 mg. In some embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt thereof is administered every 12 or 24 hours at a daily dose of about 0.04-2.5 mg / kg. In some embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 2.5-180 mg every 12 or 24 hours. In some embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 0.06-1.8 mg / kg every 12 or 24 hours. In some embodiments of the present invention, brivaracetam or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 4-130 mg every 12 or 24 hours.

[0194] In some embodiments, the daily dose of the SV2A inhibitor (e.g., levetiracetam, brivaracetam, or celecoxib) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer thereof that can be used in the methods, uses, pharmaceutical compositions for use, or combinations of the present disclosure comprises 0.1-350 mg / day. In some embodiments, the daily dose of the SV2A inhibitor (e.g., levetiracetam, brivaracetam, or celecoxib) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer thereof that can be used in the methods, uses, pharmaceutical compositions for use, or combinations of the present disclosure comprises 220 mg / day. In some embodiments, the daily dose of levetiracetam is 220 mg in an extended release form (see, e.g., US10925834B2). Other doses above, between, or below these doses may also be used and can be determined by one skilled in the art according to the methods of the present disclosure.

[0195] In other embodiments of the present disclosure, α5-containing GABA A The R positive allosteric modulator and the SV2A inhibitor or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs are administered simultaneously or sequentially, or in a single formulation or in separate formulations packaged together or separately. In other embodiments, the α5-containing GABA AThe R positive allosteric modulator and the SV2A inhibitor or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof are administered by different routes. As used herein, "combination" includes packaging or administration by any of these formulations or routes of administration. Methods for assessing cognitive impairment and evaluating its treatment

[0196] Animal models are an important resource for developing and evaluating treatments for cognitive impairment associated with CNS disorders. The characteristics of cognitive impairment in animal models are generally extended to human cognitive impairment. Therefore, those skilled in the art will interpret the efficacy in such animal models as a reasonable prediction of efficacy in humans. The degree of cognitive impairment in animal models of CNS disorders and the efficacy of methods for treating the CNS disorders can be tested and confirmed using a variety of cognitive tests.

[0197] The radial arm maze (RAM) behavioral task is an example of a cognitive test, particularly testing spatial memory (Chappell et al. Neuropharmacology 37:481-487, 1998). The RAM device consists of, for example, eight equally spaced arms. The maze arms protrude from each small facet of the central platform. A food well is located at the distal end of each arm. Food is used as a reward. Blocks can be positioned to prevent entry into any arm. Many additional maze cues around the device can also be provided. After the adaptation and training phase, the spatial memory of the model animal can be tested in the RAM under conditions of control or test compound treatment. As part of the test, animals are pretreated with a vehicle control or a series of doses of the test compound before the test. At the beginning of each trial, a subset of the arms of the eight-arm maze is blocked. Animals are allowed to obtain food on the unblocked arm and are allowed to approach the unblocked arm during this initial "information phase" of the trial. Then, between the information phase and the subsequent "retention test", the animal is taken out of the maze for a delay period, such as a 60-second delay, a 15-minute delay, a 1-hour delay, a 2-hour delay, a 6-hour delay, a 24-hour delay or longer, during which the barrier on the maze is removed, thereby allowing access to all eight arms. After the delay period, the animal is placed back on the central platform (the barrier of the previously blocked arm has been removed) and is allowed to obtain the remaining food rewards during this retention test phase of the trial. The identity and construction of the blocking arms are different in the trial. The number of "errors" generated by the animal during the retention test phase is tracked. If the animal enters the arm from which food has been retrieved in the pre-delay portion of the trial, or if the animal revisits the arm already visited in the post-delay phase, an error occurs in the trial. A smaller number of errors indicates better spatial memory. The number of errors generated by the test animal under various test compound treatment regimens can then be compared to assess the efficacy of the test compound in the cognitive impairment associated with CNS disorders in the treatment model.

[0198] Another cognitive test that can be used to assess the effects of test compounds on cognitive impairment in CNS disorder model animals is the Morris water maze. A water maze is a pool surrounded by a set of novel patterns relative to a maze. The training regimen for a water maze can be based on an improved water maze task (de Hoz et al., Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999) that has been shown to be hippocampal-dependent. The test animals are trained to locate a submerged escape platform hidden below the pool surface. During the training trial, the animals are released into the maze (pool) from a random starting position around the pool periphery. The starting position varies from trial to trial. If the animal does not locate the escape platform within the set time, the experimenter guides and places the animal on the platform to "teach" the position of the platform. After the delay period after the last training trial, a retention test is performed in the absence of an escape platform to assess spatial memory. The level of preference of the animal for the location of the (now absent) escape platform (as measured, for example, by the time spent in that location or the number of times the animal crosses that location) indicates better spatial memory, i.e., treatment of cognitive impairment. Preference for the location of the escape platform under different treatment conditions can then be compared to assess the efficacy of the test compound in treating cognitive impairment associated with CNS disorders in the model.

[0199] Various tests are known in the art for assessing human cognitive function, such as, but not limited to, the Clinical Global Impression of Change scale (CIBIC-plus scale); the Mini-Mental State Examination (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating (CDR); the Cambridge Neuropsychological Automated Test Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric (SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); the Benton Visual Retention Test, or the MATRICS Consensus Neuropsychological Battery, which includes tests of working memory, processing speed, attention, verbal learning, visual learning, reasoning and problem solving, and social cognition. See Folstein et al., J Psychiatric Res 12:189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994. See also Buchanan, RW, Keefe, RSE, Umbricht, D., Green, MF, Laughren, T. and Marder, SR (2011) The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr.Bull.37,1209-1217. Another example of a human cognitive test is the explicit 3-alternative forced-choice task. In this test, subjects are presented with color photographs of common objects consisting of a mixture of three types of image pairs (similar pairs, identical pairs, and unrelated foils). The second of the pair of similar objects is called a "lure." These image pairs are completely randomized and presented individually as a series of images. Subjects are instructed to judge whether the object they are seeing is new, old, or similar. A "similar" response to the presentation of the lure stimulus indicates successful memory retrieval by the subject. In contrast, calling the lure stimulus "old" or "new" indicates that no correct memory retrieval has occurred.

[0200] In addition to assessing cognitive performance, it is also possible to monitor age-related and other cognitive impairments and the progression of dementia, as well as age-related and other cognitive impairments to dementia by assessing the substitution changes in the subject's brain. Substitution changes include but are not limited to changes in local brain volume, perforant pathway degradation, and the changes seen in brain function by resting state fMRI (R-fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). Examples of local brain volumes that can be used to monitor cognitive impairment and dementia progression include a reduction in hippocampal volume and a reduction in the volume or thickness of the entorhinal cortex. These volumes can be measured in a subject by, for example, MRI. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010). Perforant pathway degradation has been shown to be relevant to age and cognitive function reduction. For example, elderly people with more perforant pathway degradation tend to perform worse in hippocampus-dependent memory tests. Perforant pathway degradation in a subject can be monitored by ultra-high resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107: 12687-12691 (2010). Resting state fMRI (R-fMRI) involves imaging the brain during rest and recording large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related regions. Seed-based functional connectivity, independent component analysis, and / or frequency domain analysis of the signal are used to reveal functional connectivity between brain regions, particularly those regions whose connectivity increases or decreases with age, as well as the extent of cognitive impairment and / or dementia. FDG-PET uses the uptake of FDG as a measure of local metabolic activity in the brain. It has been shown that the decline in FDG uptake in regions such as the posterior cingulate cortex, temporoparietal cortex, and prefrontal association cortex is associated with the extent of cognitive decline and dementia. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002). Risk factors for cognitive impairment

[0201] In some embodiments, the subject to be treated in the methods and uses of the present disclosure (a subject who displays or exhibits cognitive performance within the normal range for the subject's age) is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with aging.

[0202] In some embodiments of the methods of the present disclosure, the subject to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of altered hippocampal functional connectivity in the subject. In some embodiments of the methods of the present disclosure, the subject to be treated is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of increased hippocampal functional connectivity in the subject.

[0203] In some embodiments, the subject to be treated in the methods and uses of the present disclosure (a subject who displays or presents cognitive performance within the normal range for the subject's age) is at risk of developing cognitive decline or cognitive impairment, wherein the risk is a genetic risk associated with the presence of one or more genomic variants, mutations, or polymorphisms that are associated with changes in the expression of genes selected from the group consisting of ABCA7, CLU, CR1, PICALM, PLD3, TREM2, and SORL1 in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variants, mutations, or polymorphisms associated with ABCA 7 in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variants, mutations, or polymorphisms associated with CLU in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic variants, mutations, or polymorphisms associated with CR1 in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more genomic 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, wherein the 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, wherein the 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, wherein the risk is associated with the presence of one or more genomic variants, mutations, or polymorphisms associated with SORL1 in the subject's genome.

[0204] In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of at least one allele of the APOE4 gene in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one allele of the APOE4 gene in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of two APOE4 alleles in the subject's genome.

[0205] In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of one or more biofluid biomarkers selected from p-tau, t-tau, and amyloid beta in the subject. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of the biofluid biomarker p-tau in the subject. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of the biofluid biomarker t-tau in the subject. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, wherein the risk is associated with the presence of the biofluid biomarker amyloid beta in the subject.

[0206] In some embodiments, the compounds, compositions or combinations of the present disclosure are used to treat the cognitive impairment in a subject in need of treatment of cognitive impairment associated with a CNS disorder. In some embodiments, the CNS disorder associated with cognitive impairment includes but is not limited to age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior and substance addiction.

[0207] In some embodiments, the compounds, compositions or combinations of the present disclosure are used to treat cognitive impairment associated with the cognitive impairment risk factors in subjects at risk of cognitive impairment. In some embodiments, cognitive impairment associated with risk factors includes but is not limited to age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior and substance addiction.

[0208] In some embodiments, the compounds, compositions or combinations of the present disclosure are used as a drug for treating cognitive impairment associated with CNS disorders in a subject in need of treatment for cognitive impairment. In some embodiments, the CNS disorders associated with cognitive impairment include but are not limited to age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior and substance addiction.

[0209] In some embodiments, the compounds, compositions or combinations of the present disclosure are used as a medicament for treating cognitive impairment associated with risk factors for cognitive impairment in subjects at risk of cognitive impairment. In some embodiments, cognitive impairment associated with risk factors includes but is not limited to age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior and substance addiction.

[0210] In some embodiments, the present disclosure provides the use of a compound, composition or combination as described herein in the preparation of a medicament for treating cognitive impairment in a subject in need of treatment for cognitive impairment associated with a CNS disorder. In some embodiments, the CNS disorder associated with cognitive impairment includes but is not limited to age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior and substance addiction.

[0211] In some embodiments, the present disclosure provides a compound as described herein, a composition or a combination for use in the preparation of a medicament for treating cognitive impairment associated with the cognitive impairment risk factor in a subject at risk of cognitive impairment. In some embodiments, cognitive impairment associated with risk factors includes but is not limited to age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X chromosome disorder, Rett syndrome, compulsive behavior and substance addiction. Age-related cognitive impairment

[0212] The present disclosure provides methods for using GABA containing α5 A Methods and compositions for treating age-related cognitive impairment or risk thereof with positive allosteric modulators of GABA R (i.e., compounds of the present disclosure), wherein the α5-containing GABA AR positive allosteric modulators are, for example, selected from one of the compounds as described herein or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In certain embodiments, treatment includes preventing age-related cognitive impairment or slowing down the progression of the cognitive impairment. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with age-related cognitive impairment or slowing down the progression of the one or more symptoms. In certain embodiments, the treatment of age-related cognitive impairment includes slowing down the conversion of age-related cognitive impairment (including but not limited to MCI, ARCD and AAMI) to dementia (e.g. AD). The methods and compositions can be used for clinical applications in human patients for treating age-related cognitive impairment or its risk in conditions such as age-related MCI, ARCD and AAMI. As described herein, the dosage and dosage interval of the composition of the method are dosages and dosage intervals that are safe and effective in those applications. In some embodiments of the present disclosure, there is provided a method for maintaining or improving cognitive function in a subject suffering from age-related cognitive impairment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0213] In some embodiments, the subject treated by the methods and compositions of the present disclosure exhibits age-related cognitive impairment or is at risk of such a disorder. In some embodiments, age-related cognitive impairment includes but is not limited to age-related memory impairment (AAMI), age-related mild cognitive impairment (MCI), and age-related cognitive decline (ARCD).

[0214] Animal models serve as an important resource for developing and evaluating treatments for age-related cognitive impairment. Features that characterize age-related cognitive impairment in animal models often extend to age-related cognitive impairment in humans. Therefore, efficacy in such animal models is reasonably predictive of efficacy in humans.

[0215] Various animal models of age-related cognitive impairment are known in the art. For example, extensive behavioral characterization has identified naturally occurring forms of cognitive impairment in outbred strains of elderly Lone-Evans rats (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107: 618-626, (1993)). In behavioral assessments using the Morris Water Maze (MWM), rats learn and remember the location of an escape platform guided by a configuration of spatial cues around the maze. In a probe trial, measurements of spatial bias in the animals' search for the location of the escape platform were used to test the cognitive basis of performance. The elderly rats in the study group had no difficulty swimming to the visible platform, but age-dependent impairments were detected when the platform was camouflaged, requiring the use of spatial information. In outbred Lone-Evans strains, the performance of individual elderly rats varied greatly. For example, some of these rats performed comparable to young adults. However, approximately 40-50% fell outside the range of young people's performance. This variability between elderly rats reflects reliable individual differences. Thus, in an elderly population, some animals are cognitively impaired and designated as age-impaired (AI), and other animals are unimpaired and designated as age-unimpaired (AU). See, e.g., Colombo et al., Proc. Natl. Acad. Sci. 94:14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10:691-708, (1989); Gallagher et al. Behav. Neurosci. 107:618-626, (1993); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al., Neuroscience 74:741-756, (1996); Nicolle et al., Neuroscience 74:741-756, (1996). et al., J. Neurosci. 19:9604-9610, (1999); International Patent Publication No. WO 2007 / 019312 and International Patent Publication No. WO 2004 / 048551. This animal model of age-related cognitive impairment can be used to determine the effectiveness of the methods and compositions of the present disclosure in treating age-related cognitive impairment.

[0216] The efficacy of the methods and compositions of the present invention in treating age-related cognitive impairment can be assessed using a variety of cognitive tests, including the Morris water maze and the radial arm maze, as discussed herein. Mild cognitive impairment

[0217] In some embodiments, a subject treated by the methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use of the present disclosure exhibits non-age-related MCI or is at risk of such impairment. The methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use can be used in clinical applications in human patients for the treatment of non-age-related MCI (including amnestic MCI and non-amnestic MCI).

[0218] The present disclosure provides a method for using GABA containing α5 A R positive allosteric modulators (i.e., compounds of the present disclosure), for example, selected from one of the compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof, for use in treating mild cognitive impairment or its risk, methods, uses, combinations, pharmaceutical compositions, combinations for use or pharmaceutical compositions for use. In certain embodiments, treatment comprises improving cognitive function in a patient with mild cognitive impairment. In certain embodiments, treatment comprises slowing or delaying the progression of mild cognitive impairment. In certain embodiments, treatment comprises reducing the rate of decline of cognitive function associated with mild cognitive impairment. In certain embodiments, treatment comprises preventing mild cognitive impairment or slowing the progression of the mild cognitive impairment. In certain embodiments, treatment comprises alleviating, improving one or more symptoms associated with mild cognitive impairment or slowing the progression of the one or more symptoms. dementia

[0219] The present disclosure also provides for the use of GABA containing α5 A Methods and compositions for treating cognitive impairment associated with dementia using a positive allosteric modulator of GABA R, said α5-containing AR positive allosteric modulators are, for example, selected from one of the compounds as described herein or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In certain embodiments, treatment includes preventing cognitive impairment associated with dementia or slowing the progression of the cognitive impairment associated with dementia. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with dementia or slowing the progression of the one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment. In some embodiments of the present disclosure, there is provided a method for maintaining or improving cognitive function in a subject with dementia, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In certain embodiments, dementia is Alzheimer's disease (AD), prodromal AD, vascular dementia, Lewy body dementia or frontotemporal dementia. The methods and compositions can be used in clinical applications for the treatment of cognitive impairment associated with dementia and these embodiments thereof in human patients. As described herein, the doses and dose intervals of the compositions of the method are doses and dose intervals that are safe and effective in those applications.

[0220] Animal models serve as an important resource for developing and evaluating treatments for dementia and cognitive impairment associated therewith. Features characterized in animal models of dementia and cognitive impairment associated therewith are generally extrapolated to dementia and cognitive impairment associated therewith in humans. Therefore, efficacy in such animal models is reasonably predictive of efficacy in humans. For example, various animal models of dementia are known in the art, such as PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg, and APP+PS1 transgenic mice. Sankaranarayanan, Curr. Top. Medicinal Chem. 6:609-627, 2006; Kobayashi et al. Genes Brain Behav. 4:173-196, 2005; Ashe and Zahns, Neuron. 66:631-45, 2010. Such animal models of dementia and cognitive impairment associated therewith can be used to determine the effectiveness of the methods and compositions of the present invention disclosed herein in treating cognitive impairment associated with dementia.

[0221] The efficacy of the methods and compositions of the present disclosure in treating cognitive impairment associated with dementia can be assessed in animal models of dementia as well as in human subjects with dementia using various cognitive tests known in the art as discussed herein. Post-traumatic stress disorder

[0222] The present invention also provides a method for using GABA containing α5 AMethods and compositions for treating cognitive impairment associated with post-traumatic stress disorder (PTSD) using positive allosteric modulators of GABA R, the α5-containing A R positive allosteric modulators are, for example, selected from one of the compounds as described herein or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In certain embodiments, treatment includes preventing cognitive impairment associated with PTSD or slowing the progression of cognitive impairment associated with PTSD. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with PTSD or slowing the progression of one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment. In some embodiments of the present disclosure, there is provided a method for maintaining or improving cognitive function in a subject with PTSD, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. The methods and compositions can be used in clinical applications in human patients to treat cognitive impairment associated with PTSD. As described herein, the doses and dose intervals of the compositions of the method are doses and dose intervals that are safe and effective in those applications.

[0223] Patients with PTSD (and, to a lesser extent, patients who have been exposed to trauma but do not have PTSD) have smaller hippocampal volumes (Woon et al., Prog. Neuro-Psychopharm. & Biological Psych. 34, 1181-1188; Wang et al., Arch. Gen. Psychiatry 67:296-303, 2010). PTSD is also associated with impaired cognitive performance. Elderly individuals with PTSD have greater cognitive decline than controls (Yehuda et al., Bio. Psych. 60:714-721, 2006) and are more likely to develop dementia (Yaffe et al., Arch. Gen. Psych. 678:608-613, 2010).

[0224] Animal models serve as an important resource for developing and evaluating treatments for PTSD and its associated cognitive impairment. Features characterizing PTSD in animal models are often extrapolated to human PTSD. Therefore, efficacy in such animal models reasonably predicts efficacy in humans. Various animal models of PTSD are known in the art.

[0225] A rat model of PTSD is time-dependent sensitization (TDS). TDS involves exposing animals to severe stress events, followed by situational reminders of previous stress. The following is an example of TDS. Rats are placed in a restrainer, then placed in a swimming pool and allowed to swim for a period of time, such as 20 min. After this, each rat is immediately exposed to a gaseous anesthetic until it loses consciousness and finally dried. The animals are left to stand for several days, such as a week. The rats are then exposed to a "re-stress" phase consisting of the initial stressor, such as a swimming phase in a swimming pool (Liberzon et al., Psychoneuroendocrinology 22:443-453, 1997; Harvery et al., Psychopharmacology 175:494-502, 2004). TDS causes an enhancement of the auditory startle response (ASR) in rats, which is comparable to the exaggerated auditory startle as a prominent symptom of PTSD (Khan and Liberzon, Psychopharmacology 172:225-229, 2004). This animal model of PTSD can be used to determine the effectiveness of the methods and compositions of the present invention in treating PTSD and the cognitive impairment associated therewith.

[0226] The efficacy of methods and compositions of the present invention in treating cognitive impairment associated with PTSD can also be assessed in animal models of PTSD as well as in human subjects with PTSD using various cognitive tests known in the art as discussed herein. Schizophrenia and bipolar disorder

[0227] The present disclosure further provides for the use of GABA containing α5 A Methods and compositions for treating cognitive impairment associated with schizophrenia or bipolar disorder (particularly mania) using a positive allosteric modulator of GABA R, wherein the α5-containing AR positive allosteric modulator, for example, selected from one of the compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof. In certain embodiments, treatment includes preventing cognitive impairment associated with schizophrenia or bipolar disorder (particularly mania) or slowing down the progression of the cognitive impairment. Schizophrenia is characterized by a wide spectrum of psychopathology, including positive symptoms, such as abnormal or distorted mental manifestations (e.g., hallucinations, delusions) or dopamine dysregulation-related symptoms (e.g., dopaminergic responses, dopaminergic behavioral responses, dopaminergic hyperactivity or excessive motor activity or psychosis), negative symptoms characterized by reduced motivation and adaptive goal-directed actions (e.g., lack of pleasure, flat affect, asymptomatic) and cognitive impairment. In certain embodiments, treatment includes alleviating, improving one or more positive and / or negative symptoms associated with schizophrenia and cognitive impairment or slowing down the progression of one or more positive and / or negative symptoms associated with schizophrenia and cognitive impairment. In addition, there are many other mental illnesses, such as schizotypal and schizoaffective disorders, other acute and chronic psychoses and bipolar disorders (particularly mania), which have overlapping symptoms with schizophrenia, including cognitive impairment. In some embodiments, treatment includes alleviating, improving or slowing down the progression of one or more symptoms associated with bipolar disorder (particularly mania). In some embodiments of the present disclosure, there is provided a method for maintaining or improving cognitive function in a subject suffering from schizophrenia or bipolar disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. The methods and compositions can be used in human patients in clinical applications for the treatment of cognitive impairment associated with schizophrenia or bipolar disorder (particularly mania). As described herein, the dosage and dosage interval of the composition of the method are dosages and dosage intervals that are safe and effective in those applications.

[0228] Cognitive impairments are associated with schizophrenia. They precede the onset of psychosis and are present in unaffected relatives. Cognitive impairments associated with schizophrenia are good predictors of functional outcome and are a core feature of the disorder. The cognitive features of schizophrenia reflect dysfunction in frontal cortical and hippocampal circuits. Patients with schizophrenia also exhibit hippocampal pathology, such as reduced hippocampal volume, decreased neuronal size, and dysfunctional hyperactivity. Imbalances in excitation and inhibition in these brain regions have also been documented in schizophrenia patients, suggesting that drugs targeting inhibitory mechanisms may be therapeutic. See, for example, Guidotti et al., Psychopharmacology 180:191-205, 2005; Zierhut, Psych. Res. Neuroimag. 183:187-194, 2010; Wood et al., NeuroImage 52:62-63, 2010; Vinkers et al., Expert Opin. Investig. Drugs 19:1217-1233, 2009; Young et al., Pharmacol. Ther. 122:150-202, 2009.

[0229] Animal models serve as an important resource for developing and evaluating treatments for schizophrenia and its associated cognitive impairment. Features characterizing schizophrenia in animal models are often extended to human schizophrenia. Therefore, efficacy in such animal models reasonably predicts efficacy in humans. Various animal models of schizophrenia are known in the art.

[0230] An animal model of schizophrenia is long-term treatment with methionine. Mice treated with methionine show defective expression of GAD67 in the frontal cortex and hippocampus, similar to those reported in the brains of postmortem schizophrenia patients. They also show prepulse inhibition of startle and social interaction defects (Tremonlizzo et al., PNAS, 99:17095-17100, 2002). Another animal model of schizophrenia is methoxymethanol acetate (MAM) treatment in rats. MAM (20 mg / kg, intraperitoneal) is administered to pregnant female rats on the 17th day of gestation. MAM treatment summarizes the pathological development process of schizophrenia-like phenotypes in offspring, including anatomical changes, behavioral defects and altered neuronal information processing. More specifically, rats treated with MAM show a decrease in the density of parvalbumin-positive GABAergic interneurons in part of the prefrontal cortex and hippocampus. In behavioral tests, rats treated with MAM show reduced potential inhibition. Potential inhibition is a behavioral phenomenon in which learning about previously exposed stimuli with any consequences is reduced. This tendency to ignore previously benign stimuli and reduce the formation of associations with such stimuli is thought to prevent sensory overload. Low latent inhibition indicates psychosis. Potential inhibition can be tested in rats in the following way. The rats were divided into two groups. One group was pre-exposed to a tone over multiple trials. The other group was not presented with a tone. Both groups were then exposed to an auditory fear conditioning procedure, in which the same tone was presented simultaneously with a noxious stimulus, such as an electric shock to the foot. Subsequently, the tone was presented to both groups, and changes in the rats' motor activity during the tone presentation were monitored. After fear conditioning, the rats responded to the tone presentation by strongly reducing their motor activity. However, the group that had been exposed to the tone before the conditioning period showed strong latent inhibition: the inhibition of motor activity in response to the tone presentation was reduced. In contrast, rats treated with MAM showed impaired latent inhibition. In other words, exposure to the tone before the fear conditioning procedure had no significant effect on inhibiting fear conditioning (see Lodge et al., J. Neurosci., 29:2344-2354, 2009). This animal model of schizophrenia can be used to determine the effectiveness of the methods and compositions of the present invention in treating cognitive impairment associated with schizophrenia or bipolar disorder (particularly mania).

[0231] The rat of MAM process shows the motor response (or abnormal motor activity) of remarkable enhancement to low-dose D-amphetamine administration.The rat of MAM process also shows the spontaneous discharge ventral tegmental dopamine (DA) neuron of remarkable greater number.These results are considered to be the result of excessive hippocampal activity, because in the rat of MAM process, ventral hippocampus (vHipp) inactivation (for example, by applying sodium channel blocker tetrodotoxin (TTX) in MAM rat vHipp) reversed the DA neuron population activity of raising completely, and also normalized the motor behavior of enhanced amphetamine induction. The correlation of the hyperresponsiveness of hippocampal dysfunction and DA system is considered to be the basis of the psychosis of the animal of MAM process to the reaction enhancement of amphetamine and schizophrenia patient.Referring to Lodge DJ et al.Neurobiology of Disease (2007), 27 (42), 11424-11430.In above-mentioned research, use the rat of MAM process to be applicable to measuring the effectiveness of method and composition of the present disclosure in treating schizophrenia or bipolar disorder (particularly mania) and the cognitive impairment associated therewith. For example, methods and compositions of the invention can be evaluated using MAM-treated animals for their effects on central hippocampal (vHipp) modulation, on elevated DA neuron population activity, and on hyperactive locomotor responses to amphetamine in MAM-treated animals.

[0232] In MAM-treated rats, hippocampal (HPC) dysfunction leads to hyperactivity of the dopamine system. A The α5 subunit of R is selective for benzodiazepines - Effects of the positive allosteric modulator (PAM), SH-053-2'FR-CH3, on hippocampal (HPC) output. The effects of SH-053-2'FR-CH3 on the hyperactive locomotor response to amphetamine in MAM-treated animals were also examined. When administered systemically and directly infused into the ventral HPC, α5-GABA A R PAM reduced the number of spontaneously active DA neurons in the ventral tegmental area (VTA) of MAM rats to the level observed in saline-treated rats (control group). In addition, HPC neurons in both saline-treated and MAM-treated animals showed a 5-GABA A Furthermore, the increased locomotor responses to amphetamine observed in MAM-treated rats were attenuated by α5-GABA AR PAM is processed after and reduces.Referring to Gill KM et al.Neuropsychopharmacology (2011), 1-9.The rat using MAM to process in the above-mentioned study is applicable to the present disclosure, to measure the effectiveness of the method and composition of the present invention in treating schizophrenia or bipolar disorder (particularly mania) and the cognitive impairment associated therewith.For example, the animal of MAM process can be used to evaluate the method and composition of the present invention, their output to hippocampus (HPC) and the influence of the overactive motor response to amphetamine in the animal of MAM process.

[0233] Administration of MAM to pregnant rats at embryonic day 15 (E15) severely impaired the spatial memory of offspring or the ability to learn the spatial location of four items on an eight-arm radial maze. In addition, rats treated with MAM at embryonic day 17 (E17) were able to reach the performance level of control rats in the initial stages of training, but could not process and retrieve spatial information when a 30-minute delay was inserted, indicating that working memory was significantly impaired. Referring to Gourevitch R. et al. (2004). Behav. Pharmacol, 15, 287-292. This animal model of schizophrenia can be used to measure the effectiveness of the methods and compositions of the present invention in treating cognitive impairments relevant to schizophrenia or bipolar disorder (particularly mania).

[0234] Apomorphine-induced climbing (AIC) and stereotypy (AIS) in mice is another animal model useful in the present disclosure. The agent is administered to mice at the desired dose level (e.g., by intraperitoneal administration). Subsequently, for example, thirty minutes later, the experimental mice are challenged with apomorphine (e.g., 1 mg / kg sc). Five minutes after the injection of apomorphine, each animal is scored and the sniff-lick-bite syndrome (stereotypic behavior) and climbing behavior induced by apomorphine are recorded. During the 30-minute test period, the scores of each animal can be totaled for each syndrome (stereotypic behavior and climbing). If the effect reaches at least 50% inhibition, the ID is calculated using a nonlinear least squares calculation with inverse prediction. 50 Values ​​(95% confidence interval). Mean climbing and stereotyping scores can be expressed as a percentage of the control value observed in mice treated with a vehicle (e.g., saline) receiving apomorphine. See Grauer SM et al. Psychopharmacology (2009) 204, 37-48. This mouse model can be used to determine the effectiveness of the methods and compositions of the present invention in treating cognitive impairment associated with schizophrenia or bipolar disorder (particularly mania).

[0235] In another well-established preclinical model of schizophrenia, chronic exposure to ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, produces positive and negative psychotic symptoms and cognitive impairment in rats. Male Lon-Evans rats were given intraperitoneal injections of ketamine (30 mg / kg twice daily) for two weeks during adolescence (2 months of age). When the rats reached adulthood (approximately 4-5 months of age), they were behaviorally tested to assess the behavioral symptoms of ketamine exposure and the efficacy of treatment in alleviating these symptoms. See, for example, Enomoto et al. Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 668-675.

[0236] The efficacy of the disclosed methods and compositions in treating schizophrenia and the cognitive impairment associated therewith can also be assessed in animal models of schizophrenia or bipolar disorder (particularly mania), as well as in human subjects with schizophrenia, using various cognitive tests known in the art as discussed herein. Amyotrophic lateral sclerosis (ALS)

[0237] The present disclosure further provides for the use of GABA containing α5 A Methods and compositions for treating cognitive impairment associated with ALS using a positive allosteric modulator of GABA R, said α5-containing A R positive allosteric modulators are, for example, selected from one of the compounds as described herein or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In certain embodiments, treatment includes preventing cognitive impairment associated with ALS or slowing the progression of the cognitive impairment. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with ALS or slowing the progression of the one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment. In some embodiments of the present disclosure, there is provided a method for maintaining or improving cognitive function in a subject with ALS, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. The methods and compositions can be used in clinical applications for the treatment of cognitive impairment associated with ALS in human patients. As described herein, the doses and dose intervals of the compositions of the method are doses and dose intervals that are safe and effective in those applications.

[0238] In addition to motor neuron degeneration, ALS is also characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and neuronal hyperexcitability in different brain regions such as the cortex.

[0239] The efficacy of the methods and compositions of the present disclosure in treating cognitive impairment associated with ALS can also be assessed in animal models of ALS as well as in human subjects with ALS using various cognitive tests known in the art as discussed herein. Cancer treatment-related cognitive impairment

[0240] The present disclosure further provides for the use of GABA containing α5 A Methods and compositions for treating cognitive impairment associated with cancer therapy using a positive allosteric modulator of GABA R, said α5 A R positive allosteric modulators are, for example, selected from one of the compounds as described herein or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In certain embodiments, treatment includes preventing cognitive impairment associated with cancer therapy or slowing the progression of the cognitive impairment. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with cognitive impairment associated with cancer therapy or slowing the progression of the one or more symptoms. In some embodiments, the symptom is cognitive impairment. In some embodiments of the present invention, there is provided a method for maintaining or improving cognitive function in a subject suffering from cognitive impairment associated with cancer therapy, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. The methods and compositions can be used in clinical applications in human patients to treat cognitive impairment associated with cancer therapy. As described herein, the doses and dose intervals of the compositions of the method are doses and dose intervals that are safe and effective in those applications.

[0241] Cancer treatment therapies, including chemotherapy, radiation therapy, or a combination thereof, can lead to cognitive impairment in patients, affecting functions such as memory, learning, and attention. The cytotoxicity and other adverse side effects of cancer therapy on the brain underlie this form of cognitive impairment, which can persist for decades (Dietrich et al., Oncologist 13:1285-95, 2008; Soussain et al., Lancet 374:1639-51, 2009).

[0242] Cognitive impairment after cancer treatment reflects dysfunction of the frontal cortex and hippocampal circuits necessary for normal cognition. In animal models, exposure to chemotherapy or radiation adversely affects the performance of cognitive tests that are particularly dependent on these brain systems, especially the hippocampus (Kim et al., J. Radiat. Res. 49: 517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93: 487-494, 2010). Therefore, drugs targeting these cortical and hippocampal systems can be neuroprotective in patients receiving cancer therapy and are effective in treating symptoms of cognitive impairment that may persist beyond the intervention used as cancer therapy.

[0243] Animal models serve as an important resource for developing and evaluating treatments for cognitive impairment associated with cancer therapy. Features characterizing cognitive impairment associated with cancer therapy in animal models are generally extrapolated to cognitive impairment associated with cancer therapy in humans. Therefore, efficacy in such animal models is reasonably predictive of efficacy in humans. Various animal models of cognitive impairment associated with cancer therapy are known in the art.

[0244] Examples of animal models of cognitive impairment associated with cancer treatment include treatment with antitumor agents such as cyclophosphamide (CYP) or with radiation, such as 60 Animals are treated with Co gamma rays (Kim et al., J. Radiat. Res. 49: 517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93: 487-494, 2010). Cognitive tests can then be used to test the cognitive function of animal models of cancer therapy-related cognitive impairment to determine the effectiveness of the methods and compositions of the present invention in treating cancer therapy-related cognitive impairment. Using various cognitive tests known in the art as discussed herein, the efficacy of the methods and compositions of the present invention in treating cancer therapy-related cognitive impairment and human subjects with cancer therapy-related cognitive impairment can be determined. Parkinson's disease (PD)

[0245] Parkinson's disease (PD) is a neurological disorder characterized by a decrease in voluntary movement. Patients with PD experience decreased motor activity and slower voluntary movements compared to normal individuals. Patients have a characteristic "mask" facies, a tendency to jog when walking, a stooped posture, and generalized muscle weakness. Passive movement exhibits a characteristic "lead pipe" stiffness. Another key feature of the disease is tremors in the limbs that occur at rest and decrease during movement.

[0246] Parkinson's disease, of unknown etiology, belongs to a group of the most common movement disorders called parkinsonism, which affects approximately one in every 1,000 people. These other diseases classified as parkinsonism may be caused by viral infections, syphilis, arteriosclerosis and trauma, as well as exposure to toxic chemicals and narcotics. Nevertheless, it is believed that inappropriate loss of synaptic stability may lead to the destruction of neuronal circuits and brain diseases. Whether due to genetics, drug use, the aging process, viral infection or other various causes, neuronal communication dysfunction is believed to be the root cause of many neurological diseases (such as PD) (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

[0247] Regardless of the cause of the disease, the primary pathological feature is the degeneration of dopamine cells in the basal ganglia, particularly the substantia nigra. Due to the premature death of dopamine-producing neurons in the substantia nigra, the striatum, the largest ganglia of the basal ganglia, receives reduced input from the substantia nigra, resulting in decreased dopamine release. Understanding the underlying pathology led to the introduction of the first successful treatments that can alleviate Parkinson's disease. Virtually all approaches to treating the disease are based on dopamine replacement. Currently available drugs can convert dopamine into dopamine after crossing the blood-brain barrier, or they can promote dopamine synthesis and reduce its breakdown. Unfortunately, the primary pathological event, the degeneration of cells in the substantia nigra, has not been alleviated. The disease continues to progress, and often, after a certain period of time, dopamine replacement therapy loses its effectiveness.

[0248] The present disclosure provides a method for using GABA containing α5 A R positive allosteric modulators, for example, selected from one of the compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof, methods and compositions for treating cognitive impairment associated with PD. In certain embodiments, treatment includes preventing cognitive impairment associated with PD or slowing the progression of the cognitive impairment. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with PD or slowing the progression of the one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to improve the motor / cognitive impairment symptoms of Parkinson's disease. In addition, the methods and compositions of the present disclosure can be used to treat memory impairment symptoms of Parkinson's disease. In some embodiments of the present disclosure, a method for maintaining or improving cognitive function in a subject with PD is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0249] There are many animal models of PD. Exemplary animal models of PD include reserpine model, methamphetamine model, 6-hydroxydopamine (6-OHDA) model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model, paraquat (PQ)-Maneb model, rotenone model, 3-nitrotyrosine model and genetic models using transgenic mice. Transgenic models include mice that overexpress α-synuclein, mice that express a human mutant form of α-synuclein, or mice that express LRKK2 mutations. See Ranjita B. et al. for a review of these models (Ranjita B. et al. BioEssays 2002, 24, 308-318). Additional information about these animal models can be easily obtained from Jackson Laboratories (see also http: / / research.jax.org / grs / parkinsons.html) and many publications that disclose the use of these validated models.

[0250] The efficacy of the disclosed methods and compositions in treating PD or cognitive impairment associated with PD can be assessed in any of the aforementioned animal models of PD, as well as in human subjects with PD, using various cognitive tests known in the art as discussed herein. autism

[0251] Autism is a neurodevelopmental disorder characterized by dysfunction across three core behavioral dimensions: repetitive behaviors, social deficits, and cognitive deficits. The repetitive behavior dimension includes compulsive behaviors, unusual attachment to objects, strict adherence to routines or rituals, and repetitive motor habits such as stereotypy and self-stimulatory behaviors. The social deficit dimension includes deficits in reciprocal social interaction, lack of eye contact, reduced ability to engage in conversation, and impaired skills in everyday interactions. Cognitive deficits may include language abnormalities. Autism and the related autism spectrum disorders are disabling neurological disorders that affect thousands of Americans and encompass many subtypes with various presumed causes and few documented treatment improvements. Autism spectrum disorders can be present at birth or have a later onset, such as at age two or three. There are no definitive biomarkers for autism. The diagnosis of the disorder is made by considering the extent to which a child fits a behavioral syndrome characterized by poor communication skills, idiosyncratic social and cognitive abilities, and maladaptive behavior patterns. Dysfunction of neuronal communication is considered to be one of the root causes of autism (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). Recent studies have shown that GABA is involved in autism spectrum disorder (ASD).A α5 deficiency and supports further investigation of the GABA system in this disorder (Mendez MA, et al. Neuropharmacology. 2013, 68:195-201).

[0252] The present disclosure also provides for the use of GABA containing α5 A R positive allosteric modulators, for example, selected from one of the compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof, methods and compositions for treating cognitive impairment associated with autism. In certain embodiments, treatment includes preventing autism or cognitive impairment associated therewith or slowing the progression of the autism or cognitive impairment associated therewith. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with autism or slowing the progression of the one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment or cognitive deficiency. For example, the methods and compositions of the present disclosure can be used to improve motor / cognitive deficiency symptoms of autism. In some embodiments of the present disclosure, a method for maintaining or improving cognitive function in a subject with autism is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0253] Using in vitro electrophysiological techniques established by Rodier et al. (Rodier, PM et al. Reprod. Toxicol. 1997, 11, 417-422), the valproic acid (VPA) rat model of autism is one of the most thoroughly established animal models of autism based on damage, and is based on the observation that pregnant women treated with VPA in the 1960s had a much higher risk of giving birth to autistic children than the normal population during a limited time window of embryogenesis. The offspring of pregnant rats exposed to VPA showed several anatomical and behavioral symptoms unique to autism, such as a reduction in the number of cerebellar Purkinje neurons, impaired social interaction, repetitive behaviors, and other symptoms of autism, including enhanced fear memory processing. See Rinaldi T. et al. Frontiers in Neural Circuits, 2008, 2, 1-7. The efficacy of GRN-529, a selective negative allosteric modulator of the mGluR5 receptor, was investigated using another mouse model, the BTBR T+tf / J (BTBR) mouse, an established model with a robust behavioral phenotype associated with the three diagnostic behavioral symptoms of autism: unusual social interactions, impaired communication, and repetitive behaviors. See, e.g., Silverman J. Letal. Sci Transl. Med. 2012, 4, 131. The efficacy of the disclosed methods and compositions in treating autism or cognitive deficits associated with autism can be assessed in VPA-treated rat models or BTBR T+tf / J (BTBR) mouse models of autism, as well as in human subjects with autism, using various cognitive tests known in the art, as discussed herein. Mental retardation

[0254] Mental retardation is a systemic disease characterized by significantly impaired cognitive function and adaptive behavior defects. Mental retardation is usually defined as an intelligence quotient (IQ) score of less than 70. Congenital causes are one of the many root causes of mental retardation. Dysfunction of neuronal communication is also considered to be one of the root causes of mental retardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

[0255] In some cases, mental retardation includes, but is not limited to, Down syndrome, velomaxillofacial syndrome, fetal alcohol syndrome, fragile X syndrome, Klinefelter syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat-Wilson syndrome, ciliopathies, Lowe syndrome, and Siderium-type X-linked mental retardation. Down syndrome is a condition that includes a combination of birth defects (including some degree of mental retardation, characteristic facial features, and often heart defects), increased infection, vision and hearing problems, and other health problems. Fragile X syndrome is a common form of inherited mental retardation that occurs at a frequency of 1 in 4,000 males and 1 in 8,000 females. The syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder, and autistic-like behavior. There is no effective treatment for fragile X syndrome.

[0256] The present disclosure relates to the treatment of cognitive impairment associated with mild mental retardation, moderate mental retardation, severe mental retardation, profound mental retardation and unspecified mental retardation severity. Such mental retardation may, but is not necessarily, associated with chromosomal changes (e.g., Down syndrome due to trisomy 21), genetics, pregnancy and perinatal problems and other serious mental disorders. The present disclosure provides a method for treating cognitive impairment associated with mild mental retardation, moderate mental retardation, severe mental retardation, profound mental retardation and unspecified mental retardation severity. Such mental retardation may, but is not necessarily, associated with chromosomal changes (e.g., Down syndrome due to trisomy 21), genetics, pregnancy and perinatal problems and other serious mental disorders. A R positive allosteric modulators, for example, selected from one of the compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof, methods and compositions for treating cognitive impairment associated with mental retardation. In certain embodiments, treatment comprises preventing cognitive impairment associated with mental retardation or slowing the progression of said cognitive impairment. In certain embodiments, treatment comprises alleviating, improving one or more symptoms associated with mental retardation or slowing the progression of said one or more symptoms. In certain embodiments, the symptom to be treated is a cognitive deficit / disorder. For example, the methods and compositions of the present disclosure can be used to improve motor / cognitive impairment symptoms of mental retardation. In some embodiments of the present disclosure, a method for maintaining or improving cognitive function in a subject suffering from mental retardation is provided, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0257] Several animal models for mental retardation have been developed. For example, a knockout mouse model for Fragile X syndrome has been developed. Fragile X syndrome is a common form of mental retardation caused by a deficiency of the FMR1 protein FMRP. Two homologs of FMRP have been identified, FXR1P and FXR2P. FXR2P, like FMRP, is expressed highly in the brain and testes. Fxr2 and Fmr1 knockout mice, as well as Fmr1 / Fxr2 double knockout mice, are considered useful models for mental retardation such as Fragile X syndrome. See, Bontekoe CJ Metal. Hum. Mol. Genet. 2002, 11(5): 487-498. The efficacy of the methods and compositions of the present invention in treating mental retardation or cognitive deficits / disorders associated with mental retardation can be assessed in these mouse models and other animal models developed for mental retardation, as well as in human subjects with mental retardation, using various cognitive tests known in the art, as discussed herein. Compulsive behaviors (OCD)

[0258] Obsessive-compulsive disorder ("OCD") is a psychiatric disorder most commonly characterized by intrusive, repetitive unwanted thoughts (obsessions) that result in compulsions and mental acts (compulsions) that the individual feels driven to perform. Current epidemiological data indicate that OCD is the fourth most common psychiatric disorder in the United States. Some studies have suggested that the prevalence of OCD is between 1% and 3%, although the prevalence of clinically recognized OCD is much lower, suggesting that many individuals with the disorder may go undiagnosed. Patients with OCD are typically diagnosed by a psychologist, psychiatrist, or psychoanalyst using the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) (2000) diagnostic criteria, which include features of obsessions and compulsions. Features of OCD include: (1) frequent and persistent thoughts, urges, or images that are experienced as intrusive and cause significant anxiety or distress; (2) the thoughts, urges, or images are not simply excessive worries about real-life problems; and (3) the person attempts to ignore or suppress such thoughts, urges, or images, or to counteract them with some other thought or action. The person recognizes that the obsessive thoughts, impulses, or images are products of his or her own mind and are not based in reality. Characteristics of obsessive-compulsive disorder include: (1) the person feels driven to perform repetitive behaviors or mental acts in response to compulsions or according to rules that must be applied strictly; (2) the behaviors or mental acts are intended to prevent or reduce distress or to avert some frightening event or situation; however, the behaviors or mental acts are not actually related to the problem or they are excessive.

[0259] Individuals with OCD often perform tasks (or compulsions) to seek relief from the anxiety associated with their obsessions. Repetitive behaviors such as washing hands, counting, checking, or cleaning are often performed in the hope of preventing the obsessive thoughts or making them go away. However, performing these "rituals" only provides temporary relief. People with OCD may also be diagnosed with a range of other psychiatric disorders, such as generalized anxiety disorder, anorexia nervosa, panic attacks, or schizophrenia.

[0260] Dysfunction of neuronal communication is believed to be one of the root causes of obsessive-compulsive disorder (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). Studies have shown that OCD may be related to abnormal levels of a neurotransmitter called serotonin. First-line treatments for obsessive-compulsive disorder include behavioral therapy, cognitive therapy, and medication. Medications used for treatment include serotonin reuptake inhibitors (SRIs), such as paroxetine (Seroxetine). TM , Paxil , Xetanor TM , ParoMerck TM , Rexetin TM ), sertraline (Zoloft , Stimuloton TM ), fluoxetine (Prozac ,Bioxetin TM ), escitalopram (Lexapro ) and fluvoxamine (Luvox ) and tricyclic antidepressants, especially clomipramine (Anafranil ). Benzodiazepine However, as many as 40% to 60% of patients fail to adequately respond to SRI therapy, and an even larger proportion fail to experience complete relief of their symptoms.

[0261] The present disclosure provides a method for using GABA containing α5 A R agonists (e.g., GABA containing α5 AR positive allosteric modulator), for example, selected from the compound or one of its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations, methods and compositions for treating OCD and cognitive impairment associated therewith. In certain embodiments, treatment includes preventing OCD and cognitive impairment associated therewith or slowing the progression of the cognitive impairment. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with OCD or slowing the progression of the one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment or cognitive deficit. For example, the methods and compositions of the present disclosure can be used to treat cognitive deficits in OCD, and / or improve cognitive function in patients with OCD. In some embodiments of the present disclosure, a method for maintaining or improving cognitive function in a subject with OCD is provided, the method comprising the step of administering to the subject a therapeutically effective amount of a compound of the present disclosure or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations.

[0262] A quinpirole-sensitized rat model for OCD has been developed. The compulsive checking behavior of quinpirole-sensitized rats is disturbed, which is a characteristic feature of obsessive-compulsive disorder. In addition, the schedule-induced thirst (SIP) rodent model of obsessive-compulsive disorder is used to evaluate the effect of the novel 5-HT2C receptor agonist WAY-163909. See, for example, Rosenzweig-Lipson S. et al. Psychopharmacology (Berl) 2007, 192, 159-70. The efficacy of the methods and compositions of the present invention in treating OCD or cognitive impairment or cognitive deficits associated with OCD can be evaluated in the above-mentioned animal models and other animal models developed for OCD, as well as human subjects with OCD, using various cognitive tests known in the art as discussed herein. Substance addiction

[0263] Substance addiction (e.g., drug addiction, alcohol addiction) is a mental disorder. Substance addiction is not triggered immediately upon exposure to a substance of abuse. Instead, it involves a variety of complex neural adaptations that develop over different time periods ranging from hours to days to months (Kauer JANat. Rev. Neurosci. 2007, 8, 844-858). The pathway to substance addiction typically begins with the voluntary use of one or more controlled substances, such as narcotics, barbiturates, methamphetamine, alcohol, nicotine, and any of a variety of other such controlled substances. Over time, with the extended use of one or more controlled substances, the voluntary ability to give up one or more controlled substances is impaired due to the effects of extended use on brain function and therefore on behavior. Therefore, substance addiction is typically characterized by compulsive cravings, seeking, and use of substances that persist even in the face of negative consequences. Cravings can represent changes in the patient's underlying neurobiology, which may have to be addressed in a meaningful way if recovery is to be achieved. In many cases, substance addiction is also characterized by withdrawal symptoms, which are life-threatening for some substances (e.g., alcohol, barbiturates), and in other cases can lead to significant morbidity (which can include nausea, vomiting, fever, dizziness, and profuse sweating), distress, and a reduced ability to recover. For example, alcoholism, also known as alcohol dependence, is one such substance addiction. The main characteristics of alcoholism are four symptoms, including cravings, loss of control, physical dependence, and tolerance. These symptoms can also characterize substance addiction to other controlled substances. The craving for alcohol and other controlled substances is often as strong as the need for food or water. Therefore, despite serious family, health, and / or legal repercussions, alcoholics may continue to drink.

[0264] Recent work investigating the effects of alcohol abuse, stimulants, and opiates on the central nervous system (CNS) has demonstrated a variety of adverse effects associated with mental health, including substance-induced cognitive impairment. See Nyberg F. Cognitive Impairments in Drug Addicts, Chapter 9. In some laboratories and clinics, it has been observed that these drugs cause substantial impairment of brain function. One of the harmful effects of drug abuse on the brain is that it causes accelerated aging. An observation that has received particular attention in recent years is that chronic drug users show significant impairment in brain regions associated with executive and memory functions. A noteworthy neuroadaptation caused by addictive drugs (such as alcohol, stimulants, and opiates) involves reduced neurogenesis in the subgranular zone (SGZ) of the hippocampus. In fact, it has been proposed that reduced adult neurogenesis in the SGZ can alter hippocampal function in such a way that it contributes to relapse and the maintenance of addictive behavior. It also raises the possibility that reduced neurogenesis may contribute to the cognitive deficits caused by these drugs of abuse.

[0265] The present disclosure provides a method for using GABA containing α5 A R positive allosteric modulators, such as one selected from the compounds as described herein or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof, methods and compositions for treating cognitive impairment associated with substance addiction. In certain embodiments, treatment includes preventing substance addiction and cognitive impairment associated therewith or slowing the progression of the substance addiction and cognitive impairment associated therewith. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with substance addiction or slowing the progression of one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to treat cognitive impairment and / or improve cognitive function in patients with substance addiction. In some embodiments of the present disclosure, a method for maintaining or improving cognitive function in a subject with substance addiction is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

[0266] Several animal models have been developed to study substance addiction. For example, the genetically selected Marchigian Sardinian Alcohol-Preferring (msP) rat model was developed to study the neurobiology of alcoholism. See, Ciccocioppo R. et al. Substance Addiction Biology 2006, 11, 339-355. The efficacy of the methods and compositions of the present disclosure in treating substance addiction or cognitive impairment associated with substance addiction can also be evaluated in animal models of substance addiction as well as in human subjects with substance addiction using various cognitive tests known in the art as discussed herein. brain cancer

[0267] Brain cancer is the growth of abnormal cells in brain tissue, often associated with the growth of malignant brain tumors. Brain tumors grow and press on nearby areas of the brain, which can prevent that part of the brain from functioning as it should. Brain cancer rarely spreads to other tissues outside the brain. The grade of a tumor can be used to distinguish between slow-growing tumors and fast-growing tumors based on how abnormal the cancer cells appear under a microscope. Brain tumors are classified according to the type of cells from which the tumor appears to originate. Diffuse fibrillary astrocytomas are the most common type of primary brain tumor in adults. These tumors are histopathologically divided into three grades of malignancy: World Health Organization (WHO) grade II astrocytomas, WHO grade III anaplastic astrocytomas, and WHO grade IV glioblastoma multiforme (GBM). WHO grade II astrocytomas are the most indolent of the diffuse astrocytoma spectrum. Astrocytomas show a significant tendency to infiltrate the surrounding brain, thus thwarting treatment attempts at local control. These invasive capabilities are often evident in both low-grade and high-grade tumors.

[0268] Glioblastoma multiforme is the most malignant stage of astrocytoma, with most patients surviving less than 2 years. Histologically, these tumors are characterized by dense cellularity, a high proliferation index, endothelial proliferation, and focal necrosis. The highly proliferative nature of these lesions is likely due to multiple mitogenic factors. One of the hallmarks of GBM is endothelial proliferation. Numerous angiogenic growth factors and their receptors have been identified in GBM.

[0269] There are biological subgroups of astrocytomas that may reflect the clinical heterogeneity observed in these tumors. These subgroups include brainstem gliomas, which are a form of diffuse fibrillary astrocytoma in children that generally follows a malignant course. Brainstem GBMs share genetic characteristics with those adult GBMs that affect young patients. Pleomorphic xanthoastrocytoma (PXA) is a superficial low-grade astrocytic tumor that primarily affects young adults. Although these tumors have a bizarre histological appearance, they are typically slow-growing tumors that may be amenable to surgical cure. However, some PXAs may regenerate as GBMs. Pilocytic astrocytomas are the most common astrocytic tumors in children and are clinically and histopathologically distinct from diffuse fibrillary astrocytomas that affect adults. Pilocytic astrocytomas do not have the same genomic alterations as diffuse fibrillary astrocytomas. Subependymal giant cell astrocytomas (SEGAs) are periventricular, low-grade astrocytic tumors that are often associated with tuberous sclerosis (TS) and are histologically identical to the so-called "candle-gutterings" that line the ventricles of TS patients. Similar to other neoplastic lesions in TS, these lesions grow slowly and may more closely resemble hamartomas than true tumors. Desmoplastic cerebral astrocytomas of infancy (DCAI) and desmoplastic infantile gangliogliomas (DIGGs) are large, superficial, often cystic, benign astrocytomas that affect children in their first year or two of life.

[0270] Oligodendrogliomas and oligoastrocytomas (mixed gliomas) are diffuse, usually brain tumors that are most closely related clinically and biologically to diffuse fibrillary astrocytomas. However, these tumors are far less common than astrocytomas and generally have a better prognosis than diffuse astrocytomas. Oligodendrogliomas and oligoastrocytomas can progress to WHO grade III anaplastic oligodendrogliomas or anaplastic oligoastrocytomas, or WHO grade IV GBMs. Therefore, genetic changes that lead to oligodendroglial tumors constitute another pathway to GBM.

[0271] Ependymomas are a clinically diverse group of gliomas, ranging from aggressive intraventricular tumors in children to benign spinal cord tumors in adults. Transformation of ependymomas to GBMs is rare. Choroid plexus tumors are also a variable group of tumors that preferentially arise in the ventricular system, ranging from aggressive supratentorial intraventricular tumors in children to benign cerebellopontine angle tumors in adults. Choroid plexus tumors have occasionally been reported in patients with Li-Fraumeni syndrome and von Hippel-Lindau (VHL) disease.

[0272] Medulloblastoma is a highly malignant, primitive tumor that arises in the posterior cranial fossa, primarily in children. It is the most common malignant brain tumor in children. Medulloblastoma can spread through the central nervous system (CNS) and often metastasize to different locations in the brain and spine.

[0273] Meningiomas are common intracranial tumors that arise in the meninges and compress the underlying brain. Meningiomas are usually benign, but some "atypical" meningiomas may recur locally, and some meningiomas are truly malignant and may invade the brain or metastasize. Atypical and malignant meningiomas are less common than benign meningiomas. Schwannomas are benign tumors that arise on peripheral nerves. Schwannomas may arise on cranial nerves, particularly the vestibular portion of the eighth cranial nerve (vestibular schwannomas, acoustic neuromas), where they present as cerebellopontine angle masses. Hemangioblastomas are tumors of uncertain origin composed of endothelial cells, pericytes, and so-called stromal cells. These benign tumors most commonly occur in the cerebellum and spinal cord of young adults. Multiple hemangioblastomas are a characteristic of von Hippel-Lindau disease (VHL). Hemangiopericytomas (HPCs) are dural tumors that can exhibit locally aggressive behavior and can metastasize. The histogenesis of dural-based hemangiopericytoma (HPC) has long been controversial, with some authors classifying it as a distinct entity and others as a subtype of meningioma.

[0274] Group 3 tumors shared α5-containing GABA A High expression of R. α5-containing GABA A R is present in patient-derived Group 3 cells and tumor tissues and contributes to functional α5-containing GABA A Assembly of R. GABA expressed by the most lethal medulloblastoma subtype A High expression of the Rα5 subunit gene and MYC amplification. See, for example, J. Biomed. Nanotechnol. 2016 Jun; 12(6): 1297-302.

[0275] The present invention provides a method for using GABA containing α5 A R positive allosteric modulators, such as one selected from the compounds described herein or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof, for treating GABA expressing α5 AR's brain cancer (e.g., a brain tumor as described herein) and methods and compositions for cognitive impairment associated therewith. In certain embodiments, treatment includes preventing brain cancer and cognitive impairment associated therewith or slowing down the progression of the brain cancer and cognitive impairment associated therewith. In certain embodiments, treatment includes alleviating, improving one or more symptoms associated with brain cancer or slowing down the progression of the one or more symptoms. In certain embodiments, the symptom to be treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to treat cognitive impairment and / or improve cognitive function in brain cancer patients. In some embodiments of the present disclosure, there is provided a method for maintaining or improving cognitive function in a subject with brain cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof. In some embodiments, the brain tumor is medulloblastoma. Research Domain Criteria Framework (RdoC)

[0276] The present disclosure also provides for the use of α5-containing GABA as described herein. A R positive allosteric modulators or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers or combinations thereof, methods and compositions for treating cognitive impairment associated with neurological disorders and neuropsychiatric conditions. In certain embodiments, treatment includes alleviating, improving, or slowing the progression of one or more symptoms associated with the disorder. In another aspect of the present disclosure, methods and compositions for maintaining or improving cognitive function in subjects in need thereof using a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof are provided.

[0277] Research Domain Criteria (RdoC) are used to augment clinical criteria, such as the DSM and ICD, for diagnosing diseases and disorders affecting the nervous system (see, e.g., Am. J. Psychiatry 167:7 (2010)). RdoC aims to provide a classification based on findings from genomics and neuroscience, as well as clinical observations. A High levels of R expression in specific neural circuits in the nervous system are therapeutic targets for neural circuit dysfunction identified under RdoC. GABA A Determination of α5 subunit binding and receptor positive allosteric modulator activity

[0278] Any receptor binding assay known in the art can be used to determine the effect of a test compound on a GABA-containing receptor. A α5 subunit of GABA AAffinity for R. See, e.g., U.S. Patent 7,642,267 and U.S. Patent 6,743,789, which are incorporated herein by reference.

[0279] The test compound can be used as a GABA containing α5 by electrophysiological methods known in the art. A The activity of a positive allosteric modulator of R can be tested. See, for example, U.S. Patent 7,642,267 and Guidotti et al., Psychopharmacology 180:191-205, 2005. A α5 subunit of GABA A Positive allosteric modulator activity can be tested by measuring the GABA-induced chloride conductance of a receptor. Cells expressing such receptors can be exposed to an effective amount of a compound of the present disclosure. Such cells can be exposed to the compound in vivo by contacting it with a body fluid containing the compound of the present disclosure, for example, by contacting it with cerebrospinal fluid. In vitro testing can be performed by contacting cells with a compound of the present disclosure in the presence of GABA. In the presence of a test compound, cells expressing a compound containing GABA A α5 subunit of GABA A An increase in GABA-induced chloride conductance in cells expressing R would indicate positive allosteric modulator activity of the compound. This can be achieved, for example, by using a GABA-injected A R subunit mRNA (including GABA A α5 subunit RNA) in Xenopus oocytes, encoding GABA A Such conductance changes can be detected by voltage clamp assays performed on HEK 293 cells transfected with plasmids expressing R subunits, or on neurons in vivo, in vitro, or in culture.

[0280] Those skilled in the art will appreciate that the methods described herein may be adapted and modified according to the applications described, and that the methods described herein may be used for other suitable applications, and that such other additions and modifications will not depart from the scope of the present invention.

[0281] The present disclosure will be better understood through the following examples. However, those skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the present disclosure, as more fully described in the embodiments that follow. Example 1: Synthesis of Compound 18 Option 4

[0282] At 0 ° C, to a stirred solution of methyl 2-amino-5-methoxybenzoate (12.7 g, 70.2 mmol) in pyridine (5.6 g) and THF (200 ml) was added dropwise acyl chloride 4.2 (21.4 g, 130 mmol). After the addition was complete, the ice bath was removed and the reaction was allowed to proceed at ambient temperature for 20 h. The reaction mixture was concentrated under reduced pressure to a thick slurry and saturated NaHCO (120 ml) was added. After stirring for 30 min, the precipitate was collected by filtration, washed with water and dried to give 21.4 g of product 4.3 as a pink solid.

[0283] To a stirred solution of methyl-ethyl-diester 4.3 (10.6 g, 33.7 mmol) in THF (80 ml) at 0° C., potassium hexamethyldisilazide (1 M THF; 74.1 ml) was slowly added. The reaction was allowed to proceed overnight at ambient temperature and then diluted with water (200 ml) and 1N HCl (150 ml). After stirring for 2 h, the precipitate was collected by filtration, washed with water, and dried to afford 8.1 g of the cyclized product 4.4 as a mixture of methyl and ethyl esters in a ratio of approximately 1:1.

[0284] The above ester 4.4 (2.54 g) was treated with DMSO (50 ml) and water (1 ml) at 160° C. for about 5 h, cooled to room temperature, and ice-water mixture (200 g) was added with stirring. The precipitate was collected by filtration and washed with water. The filtrate was repeatedly extracted with Et2O; the combined ethereal solution was washed with water, brine, and dried over MgSO4, filtered, and the solvent was removed to provide additional crude product. This was combined with the above precipitate and purified by column chromatography (0 to 100% EtOAc in hexanes gradient) to provide 1.4 g of 4.5.

[0285] 1.25 g of compound 4.5 was treated with N,N-dimethylformamide dimethoxyacetal (10 ml) at 100° C. for 2 h, then cooled and diluted with Et2O (20 ml) with stirring. The precipitate was collected by filtration, washed with a small amount of Et2O and dried to give 1.20 g of ketoenamine (Intermediate A, R1 = OMe).

[0286] A solution of the above intermediate A (525.9 mg, 2.0 mmol) and 1-boc-1-methylhydrazine (886.2 mg, 6.0 mmol) in isopropanol (10 ml) was stirred at room temperature for 30 min and then heated to 80° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO 3 , brine, and dried over MgSO 4 . The mixture was filtered and concentrated, then subjected to silica gel column chromatography using a gradient of 0 to 8% MeOH in DCM as eluent to give a brown foamy solid, which was dissolved in DCM (30 ml) and treated with TFA (20 ml) at room temperature for 16 h. The mixture was concentrated, diluted with EtOAc, and washed with saturated NaHCO 3 ; the aqueous layer was back-extracted with EtOAc (2x), combined with the previous organic layer, washed with brine, and then dried over MgSO 4 . Filtration and concentration followed by silica gel column chromatography using a 0 to 100% EtOAc in hexanes gradient afforded 218.0 mg of N11-methyllactam (4.6).

[0287] To a stirred suspension of 4.6 (258.1 mg, 1.06 mmol) in an anhydrous solvent mixture of THF (6 ml) and DMF (1 ml) under nitrogen at -20° C. was added t-BuOK powder (192 mg). After stirring at -20° C. for 20 min, diethyl chlorophosphate (329.5 mg, 1.91 mmol) was added dropwise, and the reaction was allowed to slowly warm to about +5° C. over 2 h with stirring.

[0288] The reaction mixture was cooled back to -20°C and ethyl isocyanoacetate (239.8 mg, 2.12 mmol) was slowly added. The reaction was further cooled to -78°C and t-BuOK powder (192 mg) was added. The reaction was allowed to proceed to room temperature overnight. After quenching with saturated NaHCO (50 ml), the reaction solution was further diluted with EtOAc (50 ml) and stirred. The precipitate from the two-phase solution was collected by filtration, washed with water and dried to give 141.2 mg of the desired product 4.7. The aqueous layer of the filtrate was separated and extracted with EtOAc, combined with the previous organic layer, washed with water (2x), brine (1x), and dried over MgSO. Silica gel column chromatography using a 0 to 100% EtOAc in hexane gradient gave 121.1 mg of additional product. The total product weight of 4.7 was 262.3 mg (73%).

[0289] Acetamide oxime (R2=Me) was azeotroped three times in toluene before use. At 0°C, NaH 60% (11.7 mg, 0.293 mmol) in an oil dispersion was added to a suspension of acetamide oxime (43.3 mg, 0.58 mmol) in THF (0.5 mL). The suspension was stirred for 10 min and the above-mentioned ester 4.7 (16.5 mg, 0.049 mmol) was added. The ice bath was removed and the resulting suspension was stirred at ambient temperature for 30 min, then heated at 70°C for 40 min. The reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc, which was then washed with brine and dried over MgSO4. Preparative TLC (using 80% EtOAc in hexane) gave 11.7 mg of the desired product, Example 1 compound 18, as a light yellow solid. MS:[M+1]=349. H 1 NMR(CDCl3)δ7.76(1H,s),7.51(1H,br d,J=8Hz), 7.47(1H,s), 7.07(2H,m), 4.92(1H,d,J=16Hz), 4.01(3H,s), 3.91(3H,s), 3.51(1H,d,J=16Hz) and 2.46(3H,s). Example 2: Synthesis of Compound 19

[0290] Example 2 was prepared similarly to Example 1 using N'-hydroxypivalamidine in the final oxadiazole cyclization step. MS: [M+1] = 391. 1 NMR(CDCl3)7.75(1H,s),7.50(1H,d,J=12Hz),7.43(1H,s),7.07(2H,m),4.90 (1H,d,J=16Hz), 4.00(3H,s), 3.91(3H,s), 3.50(1H,d,J=16Hz) and 1.43(9H,s). Example 2a: Synthesis of Compound 329 Example 2a was prepared analogously to Example 1 using N'-hydroxy-2-(4-morpholinyl)acetamidine in the final oxadiazole ring formation step. MS: [M+1]=434. Example 3: Synthesis of Compound 03

[0291] In the first step of the synthetic sequence, Example 3 was prepared analogously to Example 1 starting from methyl 2-amino-5-chlorobenzoate. MS: [M+1]=353. Example 4: Synthesis of Compound 04

[0292] Example 4 was prepared analogously to Example 1 starting from methyl 2-amino-5-chlorobenzoate in the first step and using isobutyramide oxime in the final oxadiazole-forming step. MS: [M+1]=381. Option 5 Example 5: Synthesis of Compound 07

[0293] A solution of intermediate A (R1 = OMe; 827 mg, 3.18 mmol) and benzylhydrazine di-HCl salt (2.48 g, 12.7 mmol) in isopropanol (20 ml) was stirred at room temperature for 30 min and then heated to 90° C. for 5 h. After cooling, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, brine, and dried over MgSO4. Filtered and concentrated, then subjected to silica gel column chromatography using a 0 to 100% EtOAc in hexanes gradient as the eluent to afford 523 mg of benzylpyrazololactam 5.1 as a light yellow solid. At -20 ° C, under nitrogen, to a stirred suspension of lactam 5.1 (505.1 mg, 1.58 mmol) in an anhydrous solvent mixture of THF (7 ml) and DMF (2 ml) was added tBuOK powder (284 mg). After stirring at -20 ° C for 20 min, diethyl chlorophosphate (0.411 mL, 2.85 mmol) was added dropwise, and the reaction was slowly warmed to about +50 ° C within 2 h of stirring. The reaction mixture was cooled back to -20 ° C, and ethyl isocyanoacetate (357.5 mg, 3.16 mmol) was slowly added. The reaction was further cooled to -78 ° C, and tBuOK powder (284 mg) was added. The reaction was allowed to proceed to room temperature overnight. After quenching with saturated NaHCO 3 , the reaction mixture was extracted with EtOAc, washed with water and brine, and dried over MgSO 4 . Silica gel column chromatography with a 0 to 100% EtOAc in hexanes gradient afforded 391.2 mg of the imidazole product Intermediate B (R1 = Ome, R = H).

[0294] Acetamide oxime (R2=Me) was azeotroped three times in toluene before use. At 0°C, NaH 60% (9.0 mg, 0.225 mmol) in an oil dispersion was added to a suspension of acetamide oxime (40.0 mg, 0.539 mmol) in THF (0.4 mL). The suspension was stirred for 10 min. The above-mentioned ester intermediate B (18.6 mg, 0.0449 mmol) was added. The ice bath was removed and the resulting suspension was stirred at ambient temperature for 30 min, then heated at 70°C for 30 min. The reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc, which was then washed with brine and dried with MgSO4. Using 5% MeOH in premixed solvent EtOAc / DCM (1: 1), preparative TLC was performed to obtain 9.5 mg of the desired product, Example 5 compound 07, as a light yellow solid. MS:[M+1]=425. H 1 NMR(CDCl3)δ7.75(1H,s),7.61(1H,s),7.45(1H,d,J=8Hz),7.35-7.25(3H,m),7.11(2H,br d,J=8Hz),7.00(1H,dd,J=4,12Hz),6.85(1H,d,J=4Hz),5.60(1H,d,J=16Hz),5.37( 1H,d,J=16Hz), 4.97(1H,d,J=16Hz), 3.55(1H,d,J=16Hz), 3.49(3H,s) and 2.48(3H,s). Example 6: Synthesis of Compound 08

[0295] Example 6 was prepared analogously to Example 5 using isobutyramide oxime in the final oxadiazole formation step. MS: [M+1]=453. Example 7: Synthesis of Compound 01

[0296] In the first step, Example 7 was prepared analogously to Example 5 starting from methyl 2-amino-5-chlorobenzoate. MS: [M+1]=429. Example 8: Synthesis of Compound 02

[0297] Example 8 was prepared analogously to Example 5 starting from methyl 2-amino-5-chlorobenzoate in the first step and isobutyramide oxime in the final oxadiazole-forming step. MS: [M+1]=457. Example 9: Synthesis of Compound 09

[0298] Step 1: 76.5 mg of intermediate B (R1 = OMe, R = H) was stirred with Pd(OH)2 (20% wt on carbon; catalytic amount) in EtOAc (2 ml) and MeOH (1 ml) under a hydrogen atmosphere for 4 days in the presence of HCl (1 N aqueous solution; 50 uL). The catalyst was removed by passing through celite and rinsed with 5% MeOH in DCM; the solvent of the filtrate was removed in vacuo to give 63.4 mg of the debenzylated pyrazolo ester as a light yellow solid.

[0299] Step 2: Acetamide oxime was azeotroped three times in toluene before use. A solution of acetamide oxime (41.0 mg, 0.553 mmol) and the above-mentioned debenzylated ester (14.9 mg, 0.046 mmol) in THF (0.45 ml) was cooled to 0°C and NaH (60% suspension in mineral oil, 11.0 mg) was added. The ice bath was removed and stirring was continued at ambient temperature for 30 min, and then the reaction was heated at 70°C for 30 min. After cooling, the reaction was diluted with EtOAc, washed with saturated NaHCO3, brine, and dried over MgSO4. Preparative TLC was performed using 7% MeOH in DCM as eluent to give Example 9 Compound 09 as an off-white solid. Weight: 5.6 mg. MS: [M+1] = 335. H 1 NMR (CDCl3 + trace CD3OD) δ 7.77 (1H, s), 7.51 (1H, s), 7.43 (1H, br d, J = 8 Hz), 7.38 (1H, br s), 6.99 (1H, br d, J = 12 Hz), 4.25 (2H, br s), 3.85 (3H, s) and 2.41 (3H, s). Example 10: Synthesis of Compound 10

[0300] Example 10 was prepared analogously to Example 9 using isobutyramide oxime in the final oxadiazole formation step. MS: [M+1]=363. Example 11: Synthesis of Compound 11

[0301] Example 11 was prepared analogously to Example 9 using N'-hydroxypivalamidine in step 2. MS: [M+1]=377. Example 12: Synthesis of Compound 100

[0302] Example 12 was prepared analogously to Example 9 using N-hydroxytetrahydrofuran-3-carboximidamide in step 2. MS: [M+1]=391. Example 13: Synthesis of Compound 45

[0303] 2,2,2-Trifluoro-N'-hydroxyacetamidine (~170 mg) was dried over P2O5 in vacuo for 24 h, then suspended in THF (0.7 ml) and intermediate B (R1 = OMe, R = OMe; 30 mg) was added. The mixture was cooled to 0 ° C and NaH (60% suspension in mineral oil, 28 mg) was added. After stirring for 20 min, the ice bath was removed and the reaction mixture was heated to 60 ° C for 16 h and quenched with saturated NaHCO3. It was extracted with EtOAc (3x), and the combined extracts were washed with brine and dried over MgSO4. After filtration and removal of the solvent, the 4-methoxybenzyl group was removed by treatment with TfOH (35 mg) in TFA (0.7 ml) and DCM (0.7 ml) at 40 ° C for 5 h. After concentration, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, brine and dried (MgSO4). Example 13 compound 45 was isolated by preparative TLC using 5% MeOH in DCM / EtOAc (1:1). Weight: 8.6 mg. MS: [M+1] = 389. 1 NMR (CDCl3 + a few drops of CD3OD) δ 7.83 (1H, s), 7.54 (1H, s), 7.47 (1H, d, J = 12 Hz), 7.42 (1H, br d, J = 4 Hz), 7.03 (1H, dd, J = 4, 12 Hz), 4.32 (2H, br s) and 3.89 (3H, s). Example 14: Synthesis of Compound 33

[0304] Intermediate B (R1 = Cl, R = OMe) was prepared in the same manner as Intermediate B (R1 = OMe, R = H) using methyl 2-amino-5-chlorobenzoate instead of methyl 2-amino-5-methoxybenzoate and 4-methoxybenzylhydrazine HCl instead of benzylhydrazine 2HCl in each reaction step. Step 1: Intermediate B (R1 = Cl, R = Ome; 100.8 mg) was treated with trifluoromethylsulfonic acid (68 mg) in a mixture of trifluoroacetic acid (1.1 ml) and DCM (1.1 ml) at room temperature for 2 days, or until all 4-methoxybenzyl groups were removed. The reaction mixture was concentrated, treated with saturated NaHCO3, and extracted with EtOAc (3x). The combined organic extracts were washed with water, brine, and dried over MgSO4. Filtration and removal of the solvent gave 88.2 mg of the crude debenzylated ester as a light yellow solid. This was used without further purification.

[0305] Step 2: Acetamide oxime was azeotroped three times in toluene before use. A solution of acetamide oxime (51.8...

Claims

1. A compound having the structure of Formula I: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein: X is independently selected from O, N, -NR 3 or -C(R 4 ) 1-2 ; W is O, N or NR 3 ; V is O, NR 3 or -C(R 4 ) 1-2 ,in, When X is O, W is N and V is -C(R 4 ) 1-2 ; When X is N, W is O or -NR 3 , V is -C(R 4 ) 1-2 ; When X is -NR 3 When W is N, V ​​is -C(R 4 ) 1-2 ; When X is -C(R 4 ) 1-2 When W is N, V ​​is O or -NR 3 ; Each key that appears Is a single bond or a double bond; m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -NCS, -NO2, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl or -(C3-C10)cycloalkenyl; wherein each (5- to 6-membered)heteroaryl and (3- to 10-membered)heterocyclyl is substituted by 0-4 R7; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each R 8 is selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl or -CH2-(5- to 10-membered)heteroaryl, wherein each occurrence of R 8 independently substituted with 0-5 R'; Each R 9 is selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, (C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -C(O)-(C6-C10)aryl, wherein each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O or S; R 3 Independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(5- to 10-membered)heteroaryl, -C(O)-(C6-C10)aryl, -C(O)-(C1-C6)alkyl or -C(O)-(C3-C6), wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl, or -(C6-C10)aryl, wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, or S; R 4 Selected from -H or -(C1-C6)alkyl; R 6 Selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl; wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein each occurrence of R″ is independently selected from —H, —(C1-C6)aliphatic, —(C3-C6)cycloalkyl, —(3- to 6-membered)heterocyclyl, —(5- to 10-membered)heteroaryl, —(C6-C10)aryl, —(C1-C6)alkyl-(5- to 10-membered)heteroaryl, —(C1-C6)alkyl-(C6-C10)aryl, —(C1-C6)alkyl-O-(5- to 10-membered)heteroaryl, or —(C1-C6)alkyl-O-(C6-C10)aryl, wherein each occurrence of R″ is independently substituted with 0-3 substituents, and particularly, in some aspects of the present disclosure, R″ is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, —R o , -OR o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2; and Each occurrence of R o independently selected from -(C1-C6)aliphatic, -O(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)aryl, wherein the heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, and the heteroaryl has 1-4 heteroatoms independently selected from N, NH, O or S.

2. The compound according to claim 1, which has the structure of Formula IA: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

3. The compound according to claim 2, which has the structure of Formula Ia: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, in: m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6)alkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, wherein each 5- to 6-membered heteroaryl and 3- to 10-membered heterocycle is substituted with 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 independently selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 10-membered)heterocyclyl or -(C6-C10)aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2, wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, -CF3, -OCF3, -O-(C1-C6)aliphatic or -(C1-C6)aliphatic; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

4. The compound according to claim 2, which has the structure of formula I-aa: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, in: m is an integer selected from 0-4; Each R 1 independently selected from halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from CO(O)R7, C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, wherein each 5- to 6-membered heteroaryl and 3- to 10-membered heterocycle is substituted with 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, (5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 independently selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from: -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 10-membered)heterocyclyl or -(C6-C10)aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(3- to 6-membered)heterocyclyl or -(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from: halogen, -CF3, -OCF3, -O-(C1-C6)aliphatic or -(C1-C6)aliphatic; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

5. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is -halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -C≡CR 9 ,-(C3-C10)cycloalkenyl, wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl and -O-(C1-C6)alkyl; R 3 independently selected from: -H, -(C1-C6)alkyl, -(3- to 10-membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl and -(C1-C6)alkyl-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 replace; wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C6-C10)aryl or -CH2-(C6-C10)aryl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R 4 and R 6 is -H; and where R 11 , R 12 , R 13 and R 14 , R' and R" are as defined in Formula I-aa.

6. The compound according to claim 1, which has the structure of Formula IB: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

7. The compound according to claim 6, which has the structure of Formula Ib: or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers thereof or a combination, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6)alkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5- to 6-membered heteroaryl or 3- to 10-membered heterocycle is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 Independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl or -(5- to 10-membered)heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from -halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5- to 10-membered)heteroaryl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C3-C6)cycloalkyl or —(C6-C10)aryl; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, -CF3, -OCF3, -O(C1-C6)aliphatic, -(C1-C6)aliphatic or -(5- to 10-membered)heteroaryl; Each R 4 and R 6 independently selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from H—, —(C1-C3)aliphatic or —(C3-C6)cycloalkyl.

8. The compound according to claim 6, which has the structure of formula I-ba: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5- to 6-membered heteroaryl or 3- to 10-membered heterocycle is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 Independently selected from -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6alkyl-(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl or -(5- to 10-membered)heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)-aryl; wherein each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5- to 10-membered heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are bound to the same atom, the two R7 groups may be taken together with the atoms to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO or SO2, wherein the ring is optionally substituted with 0-5 R'; Each occurrence of R' is independently selected from halogen, -R", -OR", oxo, CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5- to 10-membered)heteroaryl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C3-C6)cycloalkyl, —(C6-C10)aryl, —H or —C(O)CH3; R" is independently substituted with 1-3 substituents, wherein the substituents are selected from halogen, -CF3, -OCF3, -O(C1-C6)aliphatic, -(C1-C6)aliphatic, -(5- to 10-membered)heteroaryl or oxo; Each R 4 and R 6 independently selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

9. The compound according to claim 7 or 8, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is -halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -C≡CR 9 , wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 replace; in Each occurrence of R 11 Selected from -(C1-C6)alkyl; R 3 are independently selected from: -H, -(C1-C6)alkyl or -CH2-(C6-C10)aryl and -(3 to 10-membered)heterocyclyl, wherein R 3 Independently by 0-5 R 12 replace; wherein R7 is selected from -(C1-C6)alkyl, -CH2-(C6-C10)aryl, -(C3-C6)cycloalkyl and -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R 4 and R 6 is -H; and where R 11 , R 12 , R 13 , R 14 and R' are as defined in formula I-ba.

10. The compound according to claim 1, which has the structure of Formula IC: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

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

12. The compound according to claim 11 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is -halogen or -O-(C1-C6)alkyl; Each R 1 independently selected from: -halogen and -O(C1-C6)alkyl; R 2 Selected from: -CO(O)R7, -C≡CR 9 , wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H or -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 Selected from -(C1-C6)alkyl; Each occurrence of R 4 and R 6 is -H; and Among them, R7, R 13 , R 14 , R' and R" are as defined in Formula Ic.

13. The compound according to claim 1, having the structure of Formula ID: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

14. The compound according to claim 13, which has the structure of Formula Id: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; in: Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, Each occurrence of R 9 Independently by 0-5 R 11 replace; Each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; R 3 Independently selected from: -H, -(C1-C6)alkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-OR 12 , -(C1-C6)alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl or -(C1-C6)alkyl-(5- to 10-membered)heteroaryl, wherein R 3 Independently by 0-5 R 12 replace; Each R 12 Independently selected from -H, -halogen, -OR o , -R o , oxo, -CH2OR o ,-CH2N(R o )2,-C(O)N(R o )2,-C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2, where each occurrence of R o independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl or -(C6-C10)aryl; wherein R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from -halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; Each R 4 Selected from -H or -(C1-C6)alkyl; Each R 6 selected from -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -C≡CR 9 , wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 Replace, where each occurrence of R 11 Selected from -(C1-C6)alkyl; R 3 are independently selected from: -H, -(C1-C6)alkyl or -CH2-(C6-C10)aryl, wherein R 3 Independently by 0-5 R 12 Substitute, where each R 12 Independently selected from: -H or -F, wherein R7 is selected from -(C1-C6)alkyl, -CH2-(C6-C10)aryl, -(C3-C6)cycloalkyl and -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R 4 and R 6 is -H; and where R 11 , R 12 R 13 , R 14 and R' are as defined in Formula Id.

16. The compound according to claim 1, which has the structure of Formula IE: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

17. The compound according to claim 16, which has the structure of Formula Ie: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6)alkyl; Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclyl or heteroaryl is substituted by 0-4 R7; Each R 9 Selected from -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, Each occurrence of R 9 Independently by 0-5 R 11 Replace, where each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; each occurrence of R′ is wherein each occurrence of R′ is independently selected from -halogen, -R″, -OR″, oxo, -CH2OR″, -CH2NR″2, -C(O)N(R″)2, -C(O)OR″, -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R″)2, wherein each R′ is independently substituted with 0-5 R″; wherein R″ is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; Each R 4 are independently -H or -(C1-C6)alkyl; Each R 6 are independently -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)aliphatic.

18. The compound of claim 17, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is -halogen or -O-(C1-C6)alkyl; Each R 1 independently selected from -halogen and -O-(C1-C6)alkyl; R 2 Selected from: -CO(O)R7, -C≡CR 9 , wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 is selected from -H or -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 replace; in Each occurrence of R 11 Selected from -(C1-C6)alkyl; R 4 and R 6 Both -H; and R7, R 13 , R 14 and R' are as defined in Formula le.

19. The compound according to claim 1, which has the structure of Formula IF: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, wherein m, R 1 , R 2 , R 4 , R 6 , R 13 and R 14 As defined in Formula I.

20. The compound according to claim 19, which has the structure of Formula If: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, m is an integer selected from 0-4; Each R 1 independently selected from -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5- to 10-membered)heteroaryl, -(C1-C6)alkyl-(5- to 10-membered)heteroaryl or -(C3-C6)cycloalkyl; Each R 8 Independently selected from -H or -(C1-C6 alkyl); Each R 2 Selected from -CO(O)R7, -C≡CR 9 , -(C1-C6)alkyl-C≡CR 9 ,-(5- to 10-membered)heteroaryl,-(3- to 10-membered)heterocyclyl, wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 Selected from: -H, -(C1-C6)alkyl, -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, Each occurrence of R 9 Independently by 0-5 R 11 Replace, where each occurrence of R 11 independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl or -(5- to 10-membered)heteroaryl; wherein R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5- to 10-membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl or -(5- to 10-membered)heteroaryl-(C1-C6)alkyl or -(3- to 10-membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; Each occurrence of R' is wherein each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CH2OR", -CH2NR"2, -C(O)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R")2; wherein each R' is independently substituted by 0-5 R", wherein R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe or -(C6-C10)aryl; R 4 is -H or (C1-C6) alkyl; R 6 is -H or -(C1-C6)alkyl; and Each R 13 and R 14 Independently selected from -H, -(C1-C3)aliphatic or -(C3-C6)cycloalkyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein: m is 0, 1 or 2; When m is 1 or 2, at least one occurrence of R 1 is halogen or -O-(C1-C6)alkyl; Each R 1 Independently selected from: -halogen and -O-(C1-C6)alkyl; R 2 Selected from -CO(O)R7, -C≡CR 9 , wherein each 5-membered heterocyclic or heteroaryl group is substituted by 0-4 R7; Each R 9 is selected from -H or -(C1-C6)alkyl, wherein each occurrence of R 9 Independently by 0-5 R 11 Replace, and each occurrence of R 11 Selected from -(C1-C6)alkyl; R 4 and R 6 Both -H; and Among them, R7, R 13 , R 14 and R' are as defined in Formula If.

22. A compound selected from any one of the following groups: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

23. A compound selected from any one of the following groups: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof, and an acceptable carrier, excipient or vehicle, wherein the compound or pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof is present in the composition in a therapeutically effective amount.

25. A combination comprising the pharmaceutical composition of claim 24 and a second therapeutic agent.

26. The combination of claim 25, wherein the second therapeutic agent is administered once or twice daily.

27. The combination of claim 25, wherein the second therapeutic agent is administered sequentially or simultaneously with the pharmaceutical composition.

28. The combination of claim 25, wherein the second therapeutic agent is administered in one or more of an oral form, a sustained release form, or a single unit dosage form or for once-daily administration.

29. The combination according to claim 25, wherein 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.

30. The combination according to any one of claims 25 to 29, wherein the second therapeutic agent is selected from an antipsychotic, memantine, an acetylcholinesterase inhibitor (AChEI), an Sv2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer or combination thereof.

31. The combination of claim 30, wherein the second therapeutic agent is an antipsychotic selected from aripiprazole, olanzapine, ziprasidone, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

32. The combination of claim 30, wherein the second therapeutic agent is memantine or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

33. The combination of claim 30, wherein the second therapeutic agent is an AChEI selected from donepezil, galantamine, rivastigmine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

34. The combination of claim 30, wherein the second therapeutic agent is an Sv2A inhibitor selected from levetiracetam, brivaracetam, seletracetam, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or polymorph thereof.

35. The combination according to claim 34, wherein levetiracetam, seletracetam, brivaracetam or a pharmaceutically acceptable salt thereof is administered once or twice daily.

36. The combination according to claim 34, wherein levetiracetam, seletracetam, brivaracetam or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with the pharmaceutical composition.

37. The combination according to claim 34, wherein levetiracetam, seletracetam, brivaracetam or a pharmaceutically acceptable salt thereof is administered in a sustained release form or a single unit dosage form or is administered once daily.

38. The combination according to claim 37, wherein 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.

39. The combination according to any one of claims 34-37, wherein the levetiracetam, seletracetam, brivaracetam or a pharmaceutically acceptable salt thereof is administered in a daily dose of 0.7-350 mg.

40. The combination according to claim 39, wherein levetiracetam, seletracetam or a pharmaceutically acceptable salt thereof is administered in a daily dose of 125-250 mg.

41. The combination according to claim 40, wherein levetiracetam, seletracetam or a pharmaceutically acceptable salt thereof is administered in a daily dose of 220 mg.

42. The combination according to claim 40, wherein levetiracetam, seletracetam or a pharmaceutically acceptable salt thereof is administered in a daily dose of 190 mg.

43. The combination according to claim 40, wherein brivaracetam or a pharmaceutically acceptable salt thereof is administered in a daily dose of 0.7-180 mg.

44. The combination according to claim 39, wherein levetiracetam, seletracetam or a pharmaceutically acceptable salt thereof is administered in a daily dose of 7-350 mg.

45. A method of treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising the step of administering a compound according to any one of claims 1-23, a pharmaceutical composition according to claim 24, or a combination according to any one of claims 25-44.

46. ​​The method of claim 45, wherein the CNS disorder is age-related cognitive impairment.

47. The method of claim 45, wherein the CNS disorder is mild cognitive impairment (MCI).

48. The method of claim 45, wherein the CNS disorder is amnestic mild cognitive impairment (aMCI).

49. The method of claim 45, wherein the CNS disorder is dementia.

50. The method of claim 45, wherein the CNS disorder is Alzheimer's disease.

51. The method of claim 45, wherein the CNS disorder is schizophrenia or bipolar disorder.

52. The method of claim 45, wherein the CNS disorder is amyotrophic lateral sclerosis (ALS).

53. The method of claim 45, wherein the CNS disorder is post-traumatic stress disorder (PTSD).

54. The method of claim 45, wherein the CNS disorder is associated with cancer therapy.

55. The method of claim 45, wherein the CNS disorder is mental retardation.

56. The method of claim 45, wherein the CNS disorder is Parkinson's disease (PD).

57. The method of claim 45, wherein the CNS disorder is autism.

58. The method of claim 45, wherein the CNS disorder is compulsive behavior.

59. The method of claim 45, wherein the CNS disorder is substance addiction.

60. The method of claim 45, wherein the CNS disorder is prodromal AD.

61. A method of treating brain cancer in a subject in need thereof, comprising the step of administering a compound according to any one of claims 1-23, a pharmaceutical composition according to claim 24, or a combination according to any one of claims 25-44.

62. A method of treating cognitive impairment associated with brain cancer in a subject in need thereof, comprising the step of administering a compound according to any one of claims 1-23, a pharmaceutical composition according to claim 24, or a combination according to any one of claims 25-44.

63. The method of claim 61 or 62, wherein the brain cancer is medulloblastoma.

64. A method of treating cognitive impairment associated with neurological disorders and neuropsychiatric conditions in a subject in need thereof comprising the step of administering a compound according to any one of claims 1-23 or a pharmaceutical composition according to claim 24 or a combination according to any one of claims 25-44.

65. The method of claim 64, wherein treating comprises alleviating, ameliorating, or slowing the progression of one or more symptoms associated with the damage.

66. The method of claim 64, wherein treating comprises maintaining or improving cognitive function in a subject in need thereof.

67. A method of treating cognitive impairment associated with a risk factor for cognitive impairment in a subject at risk of said cognitive impairment, said method comprising the step of administering a compound according to any one of claims 1-23, or a pharmaceutical composition according to claim 24, or a combination according to any one of claims 25-44.

68. The method of claim 67, wherein the risk factor for cognitive impairment is: Related to aging; associated with the presence of altered hippocampal functional connectivity; associated with increased hippocampal functional connectivity; a genetic risk associated with the presence of one or more genomic variants, mutations or polymorphisms that are associated with altered expression of a gene selected from the group consisting of ABCA7, CLU, CR1, PICALM, PLD3, TREM2 and SORL1 in the genome of the subject; is associated with the presence of at least one allele of the APOE4 gene in the genome of the subject; or Correlating with the presence of one or more biological fluid biomarkers selected from the group consisting of p-tau, t-tau, and amyloid beta in the subject.

69. The method of any one of claims 45-68, wherein the compound, composition or combination is administered at a dose of 0.0015 mg-5000 mg.

70. The method of claim 69, wherein the compound, composition or combination is administered at a dose of 5 mg to 1000 mg.

71. The method of claim 69, wherein the compound, composition or combination is administered at a dose of 0.1 mg to 500 mg.

72. The method of any one of claims 45-71, wherein the compound, composition or combination is administered once or twice daily.

73. The method of any one of claims 45-72, wherein the compound, composition or combination is administered topically, intravenously, subcutaneously, intramuscularly, orally, buccally, sublingually, transdermally, nasally or parenterally.

74. The method of claim 73, wherein the compound, composition or combination is administered orally.

75. The method of any one of claims 45-74, wherein the compound, composition, or combination is administered as a sustained release dosage form.

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