Benzazepine derivatives, compositions and methods for treating cognitive disorders

Abstract

Benzazepine derivatives of formula (I), compositions containing a therapeutically effective amount of the benzazepine derivatives, and methods of using the derivatives or compositions in the treatment of cognitive disorders associated with central nervous system (CNS) disorders or associated with risk factors for cognitive disorders, particularly α5-containing GABA A R agonists (e.g., α5-containing GABA A and (ii) a therapeutic agent (containing an R-positive allosteric modulator) for the treatment of a central nervous system (CNS) disorder, including, but not limited to, age-associated cognitive impairment, mild cognitive impairment (MCI), anonymous MCI (aMCI), age-associated memory impairment (AAMI), age-associated cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer therapy-associated cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction, in a subject with risk factors associated with or associated with cognitive impairment.

Description

[Technical Field]

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

[0002] Related Applications This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 399,509, filed August 19, 2022, which is incorporated herein by reference in its entirety.

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

[0004] Background of the Disclosure Cognitive ability can decline as a normal result of aging or other risk factors, or as a result of central nervous system disorders or brain cancer.

[0005] For example, a significant proportion of elderly people experience cognitive decline that exceeds that typical of normal aging. Such age-related loss of cognitive function is clinically characterized by progressive loss of memory, cognition, reasoning, and judgment. Mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), or similar clinical classifications are associated with such age-related loss of cognitive function. According to some estimates, more than 16 million people in the United States alone have AAMI (Barker et al., 1995), and it is estimated that 5.5 to 7 million people over the age of 65 in the United States suffer from age-related MCI (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 mild cognitive impairment (MCI), amnesic mild cognitive impairment (aMCI), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (especially manic episodes), amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction. Cognitive impairment may also be associated with various brain cancers.

[0007] Thus, there is a need for effective treatments of cognitive impairment associated with both age-related and non-age-related cognitive impairment (i.e., associated with one of the many risk factors for cognitive impairment), as well as treatments for cognitive impairment associated with central nervous system (CNS) disorders, and treatments that improve cognitive function in patients diagnosed with or suffering from, or at risk of developing, cognitive impairment associated with, for example, age-related cognitive impairment, MCI, amnesic 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, obsessive-compulsive behavior and substance addiction, and other central nervous system (CNS) disorders.

[0008] GABA A Receptor (GABA A R) are pentameric assemblies derived from a pool of different subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ) that form Cl-permeable channels that are activated by the neurotransmitter γ-aminobutyric acid (GABA). Various pharmacological effects, including anxiety disorders, epilepsy, insomnia, pre-anesthetic sedation, and muscle relaxation, are attributed to the various GABA receptors. A Mediated by subtype.

[0009] Various studies have demonstrated that reduced GABA signaling leads to cognitive impairments associated with various CNS disorders. In particular, α5-containing GABA, which are relatively low in density in the mammalian brain, A Previous studies have shown that GABA R plays a role in the modification of learning and memory in rats with age-related cognitive decline. A It has been demonstrated that the expression of the α5 subunit of GABA R is reduced in the hippocampus (see International Patent Publication WO 2007 / 019312). A This suggests that upregulation of R function may be effective in treating cognitive impairments associated with said CNS disorders or associated with aging and other risk factors for cognitive decline.

[0010] Thus, α5-containing GABA receptors are useful in therapeutic preparations and medicaments for the treatment of cognitive disorders associated with CNS disorders or cognitive disorders associated with aging and other risk factors for cognitive decline, or for the treatment of subjects at risk of developing such cognitive disorders. A Positive allosteric modulators of R are needed. Summary of the Invention [Means for solving the problem]

[0011] overview The present disclosure, in some of its embodiments, provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein X is O, N, -NR 3 or -C(R 4 ) 1~2 are independently selected from W is O, N or NR 3 and V is O, NR 3 or -C(R 4 ) 1~2 and When X is O, W is N and V is -C(R 4 ) 1~2 and When X is N, W is O or -NR 3 and V is -C(R 4 ) 1~2 and X is -NR 3 , W is N and V is -C(R 4 ) 1~2 and X is -C(R 4 ) 1~2 where W is N and V is O or -NR 3 and join [ka] is either a single bond or a double bond at each occurrence, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -NCS, -NO2, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, or -(C3-C10)cycloalkenyl, wherein each (5-6 membered)heteroaryl and (3-10 membered)heterocycle is substituted with 0-4 R7; each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl-(C1-C6)alkyl or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, these two R7 groups together with the atoms to which they are attached may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, said ring being optionally substituted with 0-5 R'; Each R 8is selected from -H, -(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl or -CH2-(5-10 membered)heteroaryl; R 8 each occurrence of is independently substituted with 0 to 5 R'; Each R 9 is selected from -H, -(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, (C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -C(O)-(C6-C10)aryl; R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl, wherein said heterocyclyl has from 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and said heteroaryl has from 1 to 4 heteroatoms independently selected from N, NH, O, or S; R 3 is -H, -(C1-C6) alkyl, -(C1-C6) alkyl-(C3-C6) cycloalkyl, -(C1-C6) alkyl-OR 12 , -(C1-C6) alkyl-N(R 12)2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(5-10 membered)heteroaryl, -C(O)-(C6-C10)aryl, -C(O)-(C1-C6)alkyl or -C(O)-(C3-C6), and R 3 is 0 to 5 R 12 are independently substituted with Each R 12 -H, -halogen, -OR o , R o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2 are independently selected from R o each occurrence of is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, or -(C6-C10)aryl, wherein said heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and said heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, or S; R 4 is selected from -H or -(C1-C6)alkyl; R 6 is selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); Each occurrence of R″ is independently selected from —H, —(C1-C6)aliphatic, —(C3-C6)cycloalkyl, —(3-6 membered)heterocyclyl, —(5-10 membered)heteroaryl, —(C6-C10)aryl, —(C1-C6)alkyl-(5-10 membered)heteroaryl, —(C1-C6)alkyl-(C6-C10)aryl, —(C1-C6)alkyl-O-(5-10 membered)heteroaryl, or —(C1-C6)alkyl-O-(C6-C10)aryl, and each occurrence of R″ is independently substituted with 0-3 substituents; particularly, in some embodiments of the present disclosure, R″ is independently substituted with 1-3 substituents, the substituents being halogen, —R o , -OR o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2 is selected, R o each occurrence is independently selected from -(C1-C6)aliphatic, -O(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, or -(C6-C10)aryl, wherein said heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and said heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, or S. The present invention addresses the above-mentioned needs by providing:

[0012] In another aspect, the present disclosure provides a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6)alkyl; Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C3-C10)cycloalkenyl, [ka] is selected from each 5-6 membered heteroaryl and 3-10 membered heterocycle is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, -(C6-C10) aryl, -(C1-C6) alkyl-(C6-C10) aryl, [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R 3is independently selected from -H, -(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, or -(C1-C6)alkyl-(C6-C10)aryl; R 3 is 0 to 5 R 12 are independently substituted with Each R 12 -H, -halogen, -OR o , R o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -CF3, -OCF3 or -N(R o )2 are independently selected from R o each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-10 membered)heterocyclyl, or -(C6-C10)aryl; each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5-10 membered)heteroaryl-(C1-C6)alkyl, or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, these two R7 groups together with the atoms to which they are attached may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, said ring being optionally substituted with 0-5 R'; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); R" is selected from -Cl, -F, -(C-C)alkyl, -OMe, or -(C-C)aryl; R″ is independently substituted with 1 to 3 substituents selected from halogen, —CF3, —OCF3, —O—(C1-C6)aliphatic, or —(C1-C6)aliphatic; Each R 4 is selected from -H or -(C1-C6)alkyl; Each R 6 is selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl to provide.

[0013] In another aspect, the present disclosure provides a compound of formula I-aa: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 is halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6 alkyl); Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C3-C10)cycloalkenyl, [ka] is selected from each 5-6 membered heteroaryl and 3-10 membered heterocycle is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, (5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, -(C6-C10) aryl, -(C1-C6) alkyl-(C6-C10) aryl, [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R 3 is independently selected from -H, -(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, or -(C1-C6)alkyl-(C6-C10)aryl; R 3 is 0 to 5 R 12 are independently substituted with Each R 12 -H, -halogen, -OR o , R o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o)2, -C(O)OR o , -CF3, -OCF3 or -N(R o )2 are independently selected from R o each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-10 membered)heterocyclyl, or -(C6-C10)aryl; each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5-10 membered)heteroaryl-(C1-C6)alkyl, or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, these two R7 groups together with the atoms to which they are attached may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, said ring being optionally substituted with 0-5 R'; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); 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 to 3 substituents selected from halogen, —CF3, —OCF3, —O—(C1-C6)aliphatic, or —(C1-C6)aliphatic; Each R 4 is selected from -H or -(C1-C6)alkyl; Each R 6 is selected from -H or -(C1-C6)alkyl; Each R 13 and R 14are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl to provide.

[0014] In another aspect, the present disclosure provides a compound of formula Ib: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6)alkyl; Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, [ka] is selected from each 5- to 6-membered heteroaryl or 3- to 10-membered heterocycle is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, -(C6-C10) aryl, -(C1-C6) alkyl-(C6-C10) aryl, [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R 3 is -H, -(C1-C6) alkyl, -(C1-C6) alkyl-(C3-C6) cycloalkyl, -(C1-C6) alkyl-OR 12 , -(C1-C6) alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, or -(5-10 membered)heteroaryl; R 3 is 0 to 5 R 12 are independently substituted with Each R 12 -H, -halogen, -OR o , R o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2 are independently selected from R o each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, or -(C6-C10)aryl; each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, these two R7 groups together with the atoms to which they are attached may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, said ring being optionally substituted with 0-5 R'; each occurrence of R' is independently selected from -halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5-10 membered)heteroaryl, —(5-10 membered)heteroaryl, —(3-10 membered)heterocyclyl, —(C3-C6)cycloalkyl, or —(C6-C10)aryl; R″ is independently substituted with 1 to 3 substituents selected from halogen, —CF3, —OCF3, —O(C1-C6)aliphatic, —(C1-C6)aliphatic, or —(5-10 membered)heteroaryl; Each R 4 and R 6 are independently selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from H—, —(C1-C3)aliphatic, or —(C3-C6)cycloalkyl to provide.

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

[0016] In another aspect, the present disclosure provides a compound of formula Ic: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R1 -Halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6 alkyl); Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, [ka] is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; each occurrence of R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); each occurrence of R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C3-C6)cycloalkyl, or -(C6-C10)aryl; R" is independently substituted with 1 to 3 substituents selected from -halogen, -CF3, -OCF3, -(C1-C6)aliphatic, or -(5-10 membered)heteroaryl; Each R 4 and R 6 are independently selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl to provide.

[0017] In another aspect, the present disclosure provides a compound of formula Id: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R1 -Halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6 alkyl); Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, [ka] is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, -(C6-C10) aryl, -(C1-C6) alkyl-(C6-C10) aryl, [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R 3 is -H, -(C1-C6) alkyl, -(C1-C6) alkyl-(C3-C6) cycloalkyl, -(C1-C6) alkyl-OR 12, -(C1-C6) alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, or -(C1-C6)alkyl-(5-10 membered)heteroaryl; R 3 is 0 to 5 R 12 are independently substituted with Each R 12 -H, -halogen, -OR o , -R o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2 are independently selected from R o each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, or -(C6-C10)aryl; R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(3-10 membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; each occurrence of R' is independently selected from -halogen, -R'', -OR'', oxo, -CHOR'', -CHNR'', -C(O)N(R'')2, -C(O)OR'', -NO2, -NCS, -CN, -CF3, -OCF3, or -N(R'')2; R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, or —(C6-C10)aryl; Each R 4 is selected from -H or -(C1-C6)alkyl; Each R 6 is selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl to provide.

[0018] In another aspect, the present disclosure provides a compound of formula Ie: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6)alkyl; Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, [ka] is selected from each 5-membered heterocyclyl or heteroaryl is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, [ka] is selected from R 9 Each occurrence of 11 and R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl-(C1-C6)alkyl, or -(3-10 membered)heterocyclyl, each R7 being independently substituted with 0-5 R'; each occurrence of R' is independently selected from -halogen, -R'', -OR'', oxo, -CHOR'', -CHNR'', -C(O)N(R'')2, -C(O)OR'', -NO2, -NCS, -CN, -CF3, -OCF3, or -N(R'')2, and each R' is independently substituted with 0-5 R''; 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; Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl to provide.

[0019] In another aspect, the present disclosure provides a compound of formula If: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6 alkyl); Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, [ka] is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl [ka] is selected from R 9 Each occurrence of 11 and R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl or -(5-10 membered)heteroaryl-(C1-C6)alkyl or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); each R' is independently substituted with 0-5 R"; and 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, Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl to provide.

[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 thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0021] In some embodiments, the compound of formula I is GABA A In some embodiments, the compound of Formula Ia is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of formula I-aa is a GABA receptor positive allosteric modulator. AIn some embodiments, the compound of Formula Ib is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of formula I-ba is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of Formula Ic is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of formula Id is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of formula Ie is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of formula If is a GABA receptor positive allosteric modulator. A In some embodiments of the present disclosure, one or more compounds of Formula I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF, and If are useful for treating the cognitive disorders and risks of those cognitive disorders described herein.

[0022] In some embodiments, the GABA A The α5 receptor positive allosteric modulators include those disclosed in PCT applications WO2015 / 095783A1, WO2016 / 205739A1, WO2018 / 130869A1, and WO2019 / 246300A1. A In some embodiments, the GABA receptor positive allosteric modulators described in the present disclosure are used in combination with one or more of the α5 receptor positive allosteric modulators. A An alpha5 receptor positive allosteric modulator or the above combination may be used in combination with one or more of the SV2a inhibitors of the disclosed PCT application WO2022 / 011318 in the treatment of cognitive disorders and risk of cognitive disorders described herein.

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

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

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

[0026] In some embodiments, the compounds, compositions, or combinations of the present disclosure are intended for use as pharmaceuticals or therapeutic agents. In some embodiments, the compounds, compositions, or combinations of the present disclosure, and pharmaceuticals comprising them, are useful for treating cognitive disorders associated with CNS disorders in subjects in need of or at risk of such treatment. In some embodiments, CNS disorders associated with cognitive disorders include, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive disorders associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction. In some embodiments, the compounds, compositions or combinations of the present disclosure and medicaments comprising them are useful for treating brain cancer (including brain tumors, e.g., medulloblastoma). In some embodiments, the compounds, compositions or combinations of the present disclosure and medicaments comprising them are useful for treating cognitive impairment associated with brain cancer (including brain tumors, e.g., medulloblastoma). In some embodiments, the compounds, compositions or combinations of the present disclosure and medicaments comprising them are useful for treating subjects at risk of developing cognitive impairment as a result of having one or more risk factors for such cognitive impairment, and one such risk factor is aging.

[0027] In some embodiments, the present disclosure provides the use of a compound or composition described herein in the preparation of a medicament for treating a cognitive disorder associated with a CNS disorder in a subject in need of or at risk of such treatment. In some embodiments, CNS disorders associated with cognitive disorders include, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction. In some embodiments, the compound, composition, or combination of the present disclosure is for use in the preparation of a medicament for the treatment of brain cancer (including brain tumors, e.g., medulloblastoma). In some embodiments, the disclosed compounds, compositions, or combinations are for use in the preparation of a medicament for the treatment of cognitive impairment associated with brain cancer (including brain tumors, e.g., medulloblastoma). In some embodiments, the disclosed compounds, compositions, or combinations are for use in the preparation of a medicament for the treatment of a subject at risk of developing cognitive impairment as a result of having one or more predisposing factors for cognitive impairment, wherein one such risk factor is aging. [Brief explanation of the drawings]

[0028] [Figure 1] Figure 1 is a graph illustrating the effect of administration of 3,5-diphenylpyridazine-4-methyl carboxylate on the spatial memory retention of 10 aged impaired (AI) rats in an 8-run radial maze (RAM) test. Black bars refer to rats treated with vehicle alone. White bars refer to rats treated with different doses of 3,5-diphenylpyridazine-4-methyl carboxylate. Hatched bars refer to rats treated with a combination of TB21007 and 3,5-diphenylpyridazine-4-methyl carboxylate.

[0029] [Figure 2] Figure 2 is a graph showing the effect of methyl 3,5-diphenylpyridazine-4-carboxylate (intravenous administration) on the binding of Ro154513 in the hippocampus and cerebellum. 3,5-Diphenylpyridazine-4-carboxylate blocked the binding of Ro154513 in the hippocampus but did not affect the binding of Ro154513 in the cerebellum.

[0030] [Figure 3] Figure 3 is a graph showing dose-dependent GABAα5 receptor occupancy by intravenously administered methyl 3,5-diphenylpyridazine-4-carboxylate, where receptor occupancy was measured either by the ratio of RO15-4513 exposure to the hippocampus (an area with high GABAα5 receptor density) to RO15-4513 exposure to the cerebellum (an area with low GABAα5 receptor density) or by the use of the GABAα5-selective compound L-655,708 (10 mg / kg, iv) to define full occupancy.

[0031] [Figure 4] Figure 4 is a graph showing the relationship between exposure and occupancy in the hippocampus to methyl 3,5-diphenylpyridazine-4-carboxylate. 3,5-Diphenylpyridazine-4-carboxylate occupies approximately 32% of GABAA α5 receptors during behaviorally active exposure in aged impaired rats.

[0032] [Figure 5]Figure 5 is a graph illustrating the effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate on spatial memory retention of 10 aged impaired (AI) rats in the 8-run radial arm maze (RAM) test. Figure 5 shows the effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate on spatial memory retention in 10 aged impaired (AI) rats in the RAM test, where the vehicle control was tested three times and various doses of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate were tested twice. In Figure 5, black bars refer to rats treated with vehicle only, and white bars refer to rats treated with various doses of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate.

[0033] [Figure 6] Figure 6 is a graph showing the effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate (intravenous administration) on the binding of Ro154513 in the hippocampus and cerebellum. Ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate blocked the binding of Ro154513 in the hippocampus but did not affect the binding of Ro154513 in the cerebellum.

[0034] [Figure 7]Figure 7 is a graph showing dose-dependent GABAα5 receptor occupancy by intravenously administered ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate, where full occupancy is defined as the ratio of RO15-4513 exposure in the hippocampus (an area with high GABAAα5 receptor density) to RO15-4513 exposure in the cerebellum (an area with low GABAAα5 receptor density).

[0035] [Figure 8A] 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 impaired rats using the Morris water maze behavioral task. Figure 8(A) shows the escape latency (i.e., the average time (seconds) elapsed for rats to find the hidden platform in the water pool) during training in rats administered 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats administered the vehicle, DMSO. Figure 8(B) shows the length of time spent in the target and contralateral rings by rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats treated with vehicle DMSO, and Figure 8(C) shows the number of times rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats treated with vehicle DMSO crossed the target and contralateral rings. [Figure 8B]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 the Morris water maze behavioral task in aged impaired rats. Figure 8(B) shows the length of time spent in the target and contralateral rings by rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats treated with the vehicle, DMSO. [Figure 8C] 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 the Morris water maze behavioral task in aged impaired rats. Figure 8(C) shows the number of crossings of the target and contralateral rings in rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and those treated with the vehicle, DMSO. DETAILED DESCRIPTION OF THE INVENTION

[0036] Detailed Description of the Invention definition 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 used in and relating to the techniques of chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neuroscience, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein is well known and commonly used in the art.

[0037] The methods and techniques of the present disclosure generally, unless otherwise indicated, are carried out in accordance with conventional methods well known in the art and described in various general and more specific references cited and discussed throughout this specification.See, for example, "Principles of Neural Science," McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics," Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.," WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.," WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.," Sinauer Associates, Inc., Sunderland, MA (2000).

[0038] Chemical terms used herein are used in accordance with conventional usage in the art, as exemplified in "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 this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a specified integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components).

[0041] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value within that range, including the endpoints, unless otherwise indicated herein, and each separate value is incorporated herein as if set forth individually herein. For example, a range of 0 to 5 should be 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). All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Furthermore, 0-3 substitutions disclosed mean unsubstituted (0) or substituted with 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 "drug" is used herein to refer to a chemical compound (organic or inorganic compound (e.g., including compounds of the present disclosure), mixtures of chemical compounds, etc.). Drugs include, for example, drugs known in terms of structure and drugs unknown in terms of structure. Such drugs include α5-containing GABA receptors. ADue to their R agonist activity, such agents may be suitable as "therapeutic agents" in the methods and compositions of the present disclosure.

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

[0046] "Cognitive function" or "cognitive state" refers to any higher-order intellectual brain process or brain state 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, time integration of spontaneous behavior, displaying interest in the environment and self-care, processing speed, reasoning and problem-solving, and social cognition, respectively.

[0047] In humans, cognitive function can be measured, for example, but not limited to, by the Clinical Global Impression of Change Scale (CIBIC-plus scale); Mini-Mental State Examination (MMSE); Neuropsychiatric Assessment (NPI); Clinical Dementia Scale (CDR); Cambridge Neuropsychological Test Battery (CANTAB); Sandoz Clinical Assessment-Geriatric (SCAG), Buschke Selective Reminding Test (Buschke and Fuld, 1974); Verbal Paired Associations subtest; Logical Memory subtest; Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); Benton Visual Retention Test or explicit 3-alternative forced choice task, or the MATRICS Consensus Neuropsychological Test Battery. Folstein et al., J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, L'examenppendor en psychology, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); See Marquis et al., 2002 and Masur et al., 1994. See also Buchanan, RW, Keefe, RSE, Umbricht, D., Green, MF, Laughren, T., and Marder, SR (2011), The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209-1217.

[0048] In animal model systems, cognitive function can be measured by a variety of conventional methods known in the art, including the use of the Morris Water Maze (MWM), Barnes Circular Maze, Elevated Radial Arm Maze, T-Maze, or any other maze in which animals use spatial information. Cognitive function can be measured by reversal learning, extradimensional set shifting, conditioned discrimination learning, and It can be assessed by assessing reward expectancy. Other tests known in the art may also be used to assess cognitive function, such as novel object recognition tasks 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, whose thickness varies from 1 to 4.5 mm, with an overall average of approximately 2.5 mm. Cortical thinning in the temporal region has been associated with overall cognitive changes. Cognitive function may also be measured using imaging techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single-photon emission computed tomography (SPECT), or any other imaging technique that allows for the measurement of brain function. In animals, cognitive function may also be measured using electrophysiological techniques.

[0050] In addition to assessing cognitive ability, the progression of cognitive impairment and dementia can be monitored by assessing surrogate changes in the subject's brain. Surrogate changes include, but are not limited to, changes in regional brain volume, degradation of perforant passage fibers, and changes in brain function observed by resting-state fMRI (R-fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), fluorodeoxyglucose positron emission tomography (FDG-PET), or any other imaging technique that allows for measurement of brain function. Examples of regional brain volumes useful for monitoring the progression of age-related cognitive impairment and dementia include a decrease in hippocampal volume and a decrease in the volume or thickness of the entorhinal cortex. These volumes can be measured in subjects, for example, by MRI. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010). 186 Degradation of perforant passage fibers has been shown to be associated with age and cognitive decline. For example, elderly people with more degradation of perforant passage fibers tend to perform worse on hippocampus-dependent memory tests. Perforant path degradation can be monitored in subjects using ultra-high-resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting-state fMRI (R-fMRI) involves imaging the brain at rest and recording large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated between functionally related regions. Seed-based functional connectivity, signal independent component analysis, and / or frequency-domain analysis are used to reveal functional connectivity between brain regions, particularly those whose connectivity increases or decreases with age, as well as the degree of cognitive impairment and / or dementia. FDG-PET uses FDG uptake as a measure of regional metabolic activity in the brain. Decreased FDG uptake in areas such as the posterior cingulated cortex, temporoparietal cortex, and frontal association cortex has been shown to be associated with cognitive decline and the degree of dementia.Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002).

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

[0052] In some cases, "promotion" of cognitive function in a subject affected by age-related cognition refers to affecting the impaired cognitive function so that it closely resembles the function of an intact, normal, age-matched subject or a young adult subject. The cognitive function of the subject can be promoted to any detectable degree, but in some embodiments of the present disclosure, in humans, the cognitive function is promoted sufficiently to enable the impaired subject to perform the daily activities of normal life at a level of proficiency as close as possible to that of an intact, normal, age-matched subject or a young adult subject or an intact, normal, age-matched subject.

[0053] "Protecting" cognitive function refers to affecting normal or impaired cognitive function so that it does not decline or does not decline below that observed in the subject at the time of initial presentation or diagnosis, or to slow the decline of cognitive function to at least some level.

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

[0055] "Cognitive impairment" refers to cognitive function in a subject that is not as robust as expected in an intact, normal, 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 an intact, normal, or in some embodiments, age-matched subject.

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

[0057] "Cognitive impairment" associated with, or related to, or in AD refers to cognitive function in a subject that is less robust than would be expected in 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 ability. A set of diagnostic criteria for clinically characterizing MCI specifies the following features: (1) memory complaints (reported by the patient, informant, or physician), (2) normal activities of daily living (ADL), (3) normal overall cognitive function, (4) abnormal memory for age (defined as a score more than 1.5 standard deviations below the mean for a given age), and (5) the absence of indicators of dementia (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). Agnosia in subjects with MCI can involve any cognitive domain or mental process, including memory, language, association, attention, perception, problem-solving, executive function, and visuospatial skills. For example, see Winbald et al., J. Intern. Med. 256:240-240, 2004; Meguro, Acta. Neurol. Taiwan. 15:55-57, 2008; Ellison et al., CNS Spectr. 13:66-72, 2008, Petersen, Semin. Neurol. 27:22-31, 2007. MCI is further subdivided into amnestic MCI (aMCI) and non-amnestic MCI, which are characterized by memory impairment (or loss), in particular. MCI is defined as aMCI when memory is found to be impaired, taking into account the subject's age and education level. On the other hand, when the subject's memory is found to be intact for age and education, but other non-memory cognitive domains (such as language, executive function or visuospatial skills) are impaired, MCI is defined as non-amnestic MCI. Both aMCI and non-amnestic MCI can be further subdivided into single-domain MCI or multi-domain MCI. aMCI-single-domain refers to a condition in which memory is intact but other cognitive domains are impaired.aMCI-multiple domain refers to the state that memory and at least one other cognitive domain are impaired.Non-amnestic MCI is single domain or multi-domain, depending on whether more than one non-memory cognitive domain is impaired.For example, see Peterson and Negash, CNS Spectr.13:45-53,2008.

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

[0060] "Age-Associated Memory Impairment (AAMI)" refers to memory decline due to aging. A patient can be considered to have AAMI if they are at least 50 years old and meet all of the following diagnostic criteria: a) the patient is aware of a decline in memory abilities, b) the patient performs worse on standard memory tests than younger adults, and c) all other causes of apparent memory decline except normal aging are excluded (in other words, the memory decline cannot be attributed to other causes, such as a recent heart attack or head injury, depression, an adverse reaction to a medication, or Alzheimer's disease).

[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). It also applies to virtually all mammalian species. Age-associated memory impairment refers to older individuals who have objective memory declines relative to younger individuals but normal cognitive function relative to their age-matched peers (Crook et al., 1986). Age-consistent memory decline is a less pejorative classification that emphasizes that these are normal developmental changes (Crook, 1993; Larrabee, 1996), are not pathophysiological (Smith et al., 1991), and rarely progress to overt dementia (Youngjohn & Crook, 1993). DSM-IV (1994) codifies the diagnostic classification of ARCD.

[0062] " Dementia " refers to a condition characterized by severe agnosia that interferes with normal daily activities. Subjects with dementia also show other symptoms, such as impaired judgment, personality changes, disorientation, confusion, behavioral changes, speech difficulties and movement disorders. There are various types of dementia, such as Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies and frontotemporal dementia.

[0063] Alzheimer's disease (AD) is characterized by memory loss in its early stages. Later symptoms include impaired judgment, disorientation, confusion, behavioral changes, speech difficulties, and movement disorders. Histologically, AD is characterized by beta-amyloid plaques and tau protein tangles.

[0064] Vascular dementia is caused by stroke. Symptoms overlap with those of AD, but are not focused on memory loss.

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

[0066] Frontotemporal dementia is characterized by gliosis, neuronal loss, superficial spongiform degeneration in the frontal 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 acute or delayed reactions to a tragic event, characterized by re-experiencing the trauma, mental numbness or avoidance of trauma-related stimuli, and increased arousal. Re-experiencing events can include intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to reminders of the trauma. Such reactions can lead to anxiety and have significant both chronic and acute effects on patients' quality of life and physical and emotional well-being. PTSD is also associated with impaired cognitive abilities, with older individuals with PTSD experiencing greater cognitive decline compared to control patients.

[0068] "Schizophrenia" refers to a chronic, debilitating disorder characterized by a range of psychopathology, including negative symptoms characterized by abnormal or distorted mental representations (e.g., hallucinations, delusions), decreased motivation and diminished adaptive goal-directed behavior (e.g., anhedonia, flat affect, loss of motivation), and positive symptoms such as cognitive impairment. Abnormalities in the brain have been proposed to underlie the broad range of psychopathology in schizophrenia, but currently available antipsychotic medications are often ineffective in treating cognitive impairment in patients.

[0069] "Bipolar disorder" or "BP" or "manic-depressive disorder" or "manic depression" refers to a chronic psychological / mood disorder that can be characterized by marked mood changes, including periods of depression and periods of euphoric mania. BP can be diagnosed by a skilled physician based on personal and medical history, a medical examination, and a physical examination. The term "mania" or "manic period" or other variations refer to a period during which an individual exhibits some or all of the following features: competitiveness, rapid speech, increased levels of activity and agitation, as well as feelings of inflated self-esteem, euphoria, impaired judgment, insomnia, impaired concentration, and aggressiveness.

[0070] Amyotrophic lateral sclerosis (ALS), 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 neuronal hyperexcitability in various brain regions, such as the cortex.

[0071] "Cancer treatment-related cognitive impairment" refers to cognitive impairment that occurs in subjects who are treated with cancer treatments such as chemotherapy (e.g., chemobrain) and radiation. The cytotoxic and other harmful side effects of cancer treatment on the brain result in cognitive impairment in functions such as memory, learning, and attention.

[0072] Parkinson's disease (PD) is a neurological disorder characterized by decreased voluntary movement. Affected patients have reduced motor activity and slower voluntary movements compared to normal individuals. Patients have a characteristic "mask-like" facial appearance, a tendency to hurry while walking, a hunched posture, and generalized muscle weakness. There is a typical "lead-pipe" rigidity of passive movements. Another important feature of the disease is tremor in the limbs, which occurs at rest and decreases during movement.

[0073] "Autism" as used herein refers to autism spectrum disorder, characterized by neurodevelopmental disorders that lead to impaired social interaction and communication due to 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 global disability characterized by significantly impaired cognitive function and deficits in adaptive behavior. Mental retardation is often defined as an intelligence quotient (IQ) score below 70. Congenital causes are the primary cause of many cases of mental retardation. Dysfunction in neuronal connections is also thought to be one of the primary causes of mental retardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

[0075] In some instances, mental retardation includes, but is not limited to, Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, fragile X syndrome, Klinefelter syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat-Wilson syndrome, ciliopathies, Lowe syndrome, and siderium-type X-linked mental retardation. Down syndrome is a disorder involving some degree of mental retardation, distinctive facial features, and a combination of birth defects, often including heart defects, numerous infections, vision and hearing problems, and other health issues. Fragile X syndrome is a common form of inherited mental retardation, occurring in 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 mental condition characterized most commonly by intrusive, repetitive, and unwanted thoughts (obsessions) that individuals feel compelled to act on (compulsions), leading to compulsive behaviors and mental acts. Current epidemiological data indicate that OCD is the fourth most common mental disorder in the United States. Some studies suggest that the prevalence of OCD is between 1 and 3 percent, but the prevalence of clinically recognized OCD is lower, suggesting that many individuals with the disorder may be undiagnosed. Patients with OCD are often diagnosed by psychologists, psychiatrists, or psychoanalysts according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) (2000), which includes features of obsessions and compulsions.

[0077] Substance addiction (e.g., drug addiction, alcohol addiction) is a mental disorder. This addiction is not triggered instantly upon exposure to the substance of abuse. Rather, it requires multiple, complex neuronal adaptations that occur over a period of time ranging from hours to days to months (Kauer JA Nat. Rev. Neurosci. 2007, 8, 844-858). The path to addiction generally begins with the voluntary use of one or more controlled substances (such as narcotics, barbiturates, methamphetamine, alcohol, nicotine, and various other such controlled substances). Over time, persistent use of these controlled substances impairs the voluntary ability to abstain from them due to the effects of long-term use on brain function and therefore behavior. Therefore, substance addiction is generally characterized by compulsive substance craving, seeking, and use that persist despite negative consequences. The cravings may represent changes in the patient's underlying neurobiology, which must likely be addressed in a meaningful way if recovery is to be achieved. Substance addiction is also often characterized by life-threatening withdrawal symptoms for some substances (e.g., alcohol, barbiturates), and in other cases, substantial morbidity (which can include nausea, vomiting, fever, dizziness, and profuse sweating), distress, and a diminished ability to recover. For example, alcoholism, also known as alcohol dependence, is one such substance addiction. Alcoholism is primarily characterized by four symptoms: craving, loss of control, physical dependence, and tolerance. These symptoms can also characterize addiction to other controlled substances. Cravings for alcohol and other controlled substances are often as strong as cravings for food or water. Thus, alcoholics may continue to drink despite significant family, health, and / or legal consequences.

[0078] The term "brain cancer," as used herein, refers to a neoplasm that originates in the brain or a metastatic brain cancer that originates elsewhere in the body and migrates to the brain. The term "brain cancer," as used herein, includes both benign and malignant cancer cells. The term "α5-GABA A R-expressing brain cancer (referred to herein as "α5-GABA A α5-GABA receptor-expressing brain cancers (also called α5-GABA receptor-expressing brain cancers) A This refers to brain cancers in which GABA pathway signaling is potentially upregulated due to increased expression of α5-GABA. A R-expressing brain cancers include medulloblastoma, glioblastoma multiforme, astrocytoma, oligodendroglioma, ependymoma, and meningioma.

[0079] The term "medulloblastoma" refers to an aggressive primary brain tumor that arises in the cerebellum or posterior fossa. Medulloblastoma is one of the most common malignant brain tumors, occurring more frequently in people under 20 years of age than in adults. Medulloblastoma can spread throughout the CNS, often metastasizing to various locations in the brain and spine. Medulloblastomas are classified into four subgroups based on the molecular characteristics of the tumor cells: Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4. Of these types, Groups 3 and 4 account for approximately 60% of medulloblastomas. Group 3 tumors are α5-GABAergic. A They share high expression of R. Symptoms of medulloblastoma are primarily neurological, due to increased intracranial pressure caused by obstruction of the fourth ventricle, although other symptoms such as vomiting may also occur.

[0080] The term "risk factor for cognitive impairment" refers to one or more risks that predict or are associated with the onset or progression of cognitive decline or impairment. Such risks may be associated with aging, one or more genetic risks selected from the group consisting of genomic variants, mutations, or polymorphisms associated with altered expression of a gene 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 subject's genome, the presence of at least one allele of the APOE4 gene in the subject's genome, the presence of one or more biofluid biomarkers selected from the group consisting of p-tau, t-tau, and amyloid beta, or the presence of altered hippocampal functional connectivity in the subject.

[0081] "Treating" a condition 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, prevention or slowing the progression of a disease or disorder, or reducing, ameliorating, or slowing the progression of one or more symptoms of a CNS disorder or cognitive impairment associated with a risk factor of the disclosure, such as age-associated cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-associated memory impairment (AAMI), age-associated cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, Fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction. In some embodiments, treatment includes preventing or slowing the progression of cognitive impairment (such as those described herein) associated with CNS disorders or risk factors. In certain embodiments, treatment includes alleviating, improving, or slowing the progression of one or more symptoms of cognitive impairment associated with CNS disorders or risk factors. In certain embodiments, the symptom being treated is cognitive impairment or agnosia. Treatment of age-related cognitive impairment further includes slowing 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 cognitive function in a subject with cognitive impairment, so that the performance of the subject in one or more cognitive tests is improved to any detectable degree, or further decline is prevented, or the progression to such decline is slowed. In some embodiments of the present disclosure, the cognitive function of the subject after the treatment described in the present disclosure closely resembles that of an intact, normal, or in some aspects, age-matched subject. Treatment of cognitive impairment in humans can improve cognitive function to any detectable degree, but in some embodiments, is improved enough to allow the impaired subject to perform the daily activities of normal life at the same proficiency level as an intact, normal subject. In some cases, " treating cognitive impairment " refers to taking steps to improve cognitive function in a subject with cognitive impairment, so that the performance of the subject in one or more cognitive tests is improved to any detectable degree, or further decline is prevented, or such decline is delayed. Preferably, the subject's cognitive functioning closely resembles that of an intact, normal, or in some embodiments, age-matched subject after treatment as described herein. In some cases, "treating cognitive impairment" in a subject affected by age-related cognitive impairment refers to taking steps to improve cognitive function in the subject such that the subject's cognitive functioning closely resembles that of an intact, normal, age-matched subject, or in some embodiments, that of a young adult subject after treatment as described herein.

[0083] "Administering" a substance, compound, or agent to a subject in accordance with the present disclosure, or "administering" a substance, compound, or agent to a subject, can be carried out 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, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intrathecally, intracerebrally, and transdermally (by absorption, e.g., through skin channels). The compound or agent can be suitably introduced by a rechargeable or biodegradable polymeric or other device, such as a patch or pump, or a formulation that provides sustained, slow, or controlled release of the compound or agent. In some embodiments of the present disclosure, the agent or compound is administered orally. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods. In some embodiments, the agent or compound is administered once daily. 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 embodiments, administering includes both direct administration (including self-administration) and indirect administration (including the act of prescribing a drug). For example, as used herein, a physician who instructs a patient to self-administer a drug or to have another administer the drug, and / or who provides a patient with a prescription for the drug, is administering a drug to a patient.

[0084] The appropriate method of administering a substance, compound or drug to a subject also depends on, for example, the age of the subject, whether the subject is active or inactive at the time of administration, whether the subject has cognitive impairment at the time of administration, the degree of functional impairment, and the chemical and biological properties (for example, solubility, digestibility, bioavailability, stability and toxicity) of the compound or drug.In some embodiments, the compound or drug is administered orally, for example, by ingestion, or intravenously, for example, by injection into the subject.In some embodiments, the orally administered compound or drug is a sustained-release or slow-release formulation, or is administered using a device for such slow or sustained release.

[0085] As used herein, "α5-containing GABA A R agonist, α5-containing GABA A R agonist" or "GABA A "α5 receptor agonist," and other variations thereof as used herein, refers to an α5-containing GABA A In some embodiments, the α5-containing GABA receptor is a compound that enhances the function of α5-containing GABA receptors, i.e., compounds that increase GABAergic Cl- currents. A As used herein, an R agonist refers to a positive allosteric modulator that activates the activity of GABA. A R agonists include α5-containing GABA receptor antagonists of all formulas described herein. A R agonists and specific α5-containing GABA A Included are R agonists, as well as their hydrates, solvates, polymorphs, salts (e.g., pharmaceutically acceptable salts), isomers (e.g., stereoisomers, E / Z isomers and tautomers), and combinations thereof.

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

[0087] "Typical antipsychotics," as used herein, are drugs that have antipsychotic effects as well as effects on the substantia nigra. Refers to conventional antipsychotic medications that produce movement-related adverse effects related to impairment of the striatal dopamine system. These extrapyramidal side effects (EPS) include parkinsonism, akathisia, tardive dyskinesia, and dystonia. See Baldessarini and Tarazi in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, 2001, pp. 485-520.

[0088] "Atypical antipsychotics," as used herein, refer to antipsychotic drugs that produce antipsychotic effects with little or no EPS, including, but not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone, and ziprasidone. "Atypical" antipsychotic drugs differ from conventional antipsychotic drugs in their pharmacological profile. While conventional antipsychotic drugs are primarily characterized by blockade of D2 dopamine receptors, atypical antipsychotic drugs block the 5HT a and 5HT c They exhibit antagonistic effects and varying degrees of receptor affinity for multiple receptors, including serotonin receptors. Atypical antipsychotics, also commonly referred to as serotonin / dopamine antagonists, reflect the tempting hypothesis that a higher affinity for 5HT2 receptors than for D2 receptors is the basis for the action of "atypical" antipsychotics 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, prolongation of the QTc interval, myocarditis, sexual side effects, extrapyramidal side effects, and cataracts. Therefore, atypical antipsychotics are not a homogeneous class, considering differences in both the relief of clinical symptoms and the potential for inducing side effects, such as those listed above. Furthermore, the common side effects of atypical antipsychotics described above often limit the antipsychotic dose that can be used for these drugs.

[0089] Memantine is a 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.1 3,7] It is chemically known as decan-1-amine and is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with moderate affinity. Trade 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 structurally or chemically similar to memantine, are also useful in the present disclosure. Such memantine derivatives or analogs include, but are not limited to, those compounds disclosed in U.S. Pat. Nos. 3,391,142; 4,122,193; 4,273,774 and 5,061,703; U.S. Patent Application Publications US20040087658, US20050113458, US20060205822, US20090081259, US20090124659 and US20100227852; European Patent Application Publication EP2260839A2; European Patent EP1682109B1; and PCT Application Publication WO2005079779, all of which are incorporated herein by reference. Memantine, as used herein, also includes compositions comprising memantine or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof, optionally in combination with at least one additional therapeutic agent, such as a therapeutic agent useful for treating a CNS disorder or cognitive impairment associated therewith. In some embodiments, memantine compositions suitable for use in the present invention comprise memantine and a second therapeutic agent that is donepezil (trade name Aricept).

[0090] "Acetylcholinesterase inhibitors" or "AchEIs," as used herein, refer to agents that inhibit the ability of cholinesterase enzymes to break down the neurotransmitter acetylcholine, thereby increasing and prolonging the concentration of acetylcholine primarily at brain synapses or neuromuscular junctions. AchEIs suitable for use in the present disclosure can include, for example, the following subclassifications: (i) reversible noncompetitive inhibitors or reversible competitive inhibitors, (ii) irreversible inhibitors, 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, for example, Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006; Custer et al., 2006; Smedt et al., 2007; Yang et al., 2007; Meehan, "Levetiracetam has an activity-dependent effect on inhibitory transmission," Epilepsia, 2012 Jan 31; and Example 8 of WO2001 / 62726, all of which are specifically incorporated herein by reference).A compound can be an SV2A inhibitor even if it does not itself bind to SV2A, as long as it causes or affects the ability of another compound to reduce synaptic function by binding to SV2A or reducing presynaptic vesicle release. SV2A inhibitors suitable for the methods, uses, pharmaceutical compositions or combinations of the present disclosure include the specific SV2A inhibitors described herein (see also PCT application WO2022 / 011318), and pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof or isomers thereof.

[0092] The term "co-administration," as used herein, refers to administration of α5-containing GABA AR agonists (e.g., α5-containing GABA A This means that the α5-containing GABA receptor antagonist or a combination thereof with a second therapeutic agent (e.g., an antipsychotic, memantine, an AChEI, or an SV2A inhibitor) or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered at intervals of no more than about 15 minutes, and in some embodiments, no more than about 10 minutes. When the drugs are administered simultaneously, the α5-containing GABA receptor antagonist or a combination thereof with a second therapeutic agent (e.g., an antipsychotic, memantine, an AChEI, or an SV2A inhibitor) or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered at intervals of no more than about 15 minutes, and in some embodiments, no more than about 10 minutes. A R agonists (e.g., α5-containing GABA A and a second therapeutic agent (e.g., an antipsychotic, memantine, an AChEI, or an SV2A inhibitor) or a salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof, in the same dosage form (e.g., an α5-containing GABA A R agonists (e.g., α5-containing GABA A The first therapeutic agent (e.g., an α5-containing GABA receptor positive allosteric modulator) and the second therapeutic agent (e.g., an antipsychotic, memantine, an AChEI, or an SV2A inhibitor) may be contained in a single unit dosage form, or may be contained in separate dosage forms (e.g., an α5-containing GABA receptor positive allosteric modulator). A R agonists (e.g., α5-containing GABA A R positive allosteric modulator) or a salt thereof, hydrate thereof, solvate thereof or polymorph thereof is included in one dosage form, and a second therapeutic agent (e.g., an antipsychotic, memantine, AChEI or SV2A inhibitor) or a salt thereof, hydrate thereof, solvate thereof or polymorph thereof is included in another dosage form.

[0093] The term "sequential administration," as used herein, refers to administration of α5-containing GABA A R agonists (e.g., α5-containing GABA AR positive allosteric modulator) and a second therapeutic agent (e.g., an antipsychotic, memantine, AChEI, or SV2A inhibitor) or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, are administered at intervals of more than about 15 minutes, and in some embodiments, at intervals of more than about 1 hour or up to 12-24 hours. A R agonists (e.g., α5-containing GABA A Either the α5-containing GABA receptor antagonist (a GABA receptor-positive allosteric modulator) or the second therapeutic agent (e.g., an antipsychotic, memantine, an AChEI, or an SV2A inhibitor) may be administered first. A R agonists (e.g., α5-containing GABA A The R positive allosteric modulator) and the second therapeutic agent (e.g., an antipsychotic, memantine, an AChEI or an SV2A inhibitor) or a salt thereof, a hydrate thereof, a solvent thereof, or a polymorph thereof may be contained in separate dosage forms, optionally in the same container or package.

[0094] A "therapeutically effective amount" of a drug or agent of the present disclosure is an amount of drug or agent that, when administered to a subject, has the intended therapeutic effect, e.g., improvement of cognitive function, in a subject, e.g., a patient with cognitive impairment associated with a CNS disorder. The full therapeutic effect does not necessarily occur by administering a single dose, but may occur only after administering a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount required for a subject will depend, for example, on the subject's size, health, and age, the nature and extent of the 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, cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction), the therapeutic agent or combination of therapeutic agents selected for administration, and the mode of administration. One of ordinary skill in the art can readily determine the effective amount for a given situation using routine experimentation.

[0095] The compounds of the present invention also include prodrugs, analogs, or derivatives. The term "prodrug" is art-recognized and refers to a compound that inhibits the production of α5-containing GABA receptors under physiological conditions. A The term "prodrug" is intended to encompass compounds or drugs that are converted to R-positive allosteric modulators. A common method for generating prodrugs is to select a moiety that is hydrolyzed or metabolized under physiological conditions to yield the desired compound or drug. In other embodiments, prodrugs are converted to α5-containing GABA receptors by the enzymatic activity of a host animal. A R converted to a positive allosteric modulator.

[0096] The term "aliphatic," as used herein, refers to a straight-chain or branched alkyl, alkenyl, or alkynyl. It is understood that alkenyl or alkynyl embodiments require at least two carbon atoms in the aliphatic chain. Aliphatic groups typically contain 1 (or 2) to 12 carbons, such as 1 (or 2) to 4 carbons.

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

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

[0099] Heterocyclic rings include 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl These include 1,3-dihydro-imidazol-2-one, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro-imidazol-2-one.

[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 having 1 to 4 heteroatoms independently selected from O, N, NH, or S. In some embodiments, heteroaryl, as used herein, can be 5 to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from O, N, NH, or S. For example, heteroaryl, as used herein, can be a 5 to 10-membered monocyclic or 8 to 12-membered bicyclic aromatic ring system having 1 to 4 heteroatoms or heteroatom groups independently 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 heteroatoms or heteroatomic groups.

[0101] Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), azolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

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

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

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

[0105] When a bond to a substituent is depicted as crossing a bond connecting two atoms in a ring, such substituent may be attached to any of the substitutable ring-forming atoms in that ring (i.e., an atom bonded to one or more hydrogen atoms) unless otherwise specified or otherwise implied by the context. For example, if the R group is defined as pyridine, said pyridine may be: [ka] In another example, when the R group is defined as pyrazole, the pyrazole may be represented by the following: [ka] When the pyrazole ring is depicted as 3 The N atom may be bonded to a benzodiazepine derivative.

[0106] As used herein, carbon atom designations can have the indicated integers and any integers therebetween. For example, the number of carbon atoms in a (C1-C4) alkyl group can be 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, 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 salt " is used herein to refer to the agent or compound according to the present invention, which is the therapeutically active non-toxic base and acid salt form of the compound.The acid addition salt form of the compound that exists as a base in its free form can be obtained by treating the free base form with suitable acid such as inorganic acid, for example, hydrohalic acid (such as hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acid (such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.).For example, see WO01 / 062726.

[0108] Compounds containing acidic protons can be converted into their therapeutically active non-toxic base addition salt forms, such as metal salts or amine salts, by treating them 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 lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, and salts with organic bases, such as N-methyl-D-glucamine salts, hydrabamine salts, and salts with amino acids, such as arginine and lysine. Conversely, the salt forms can be converted into their free forms by treating them with appropriate bases or acids.

[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] As used herein, the term "hydrate" refers to a combination of water and a compound where the water retains its molecular state and is either 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-state molecular forms (including pseudopolymorphs) of the same compound, such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound. Different crystalline polymorphs have different crystal structures due to different molecular packing within the lattice. This results in different crystal symmetries and / or unit cell parameters, which directly affect their physical properties, such as the X-ray diffraction characteristics of the crystal or powder. For example, different polymorphs generally diffract at a different set of angles, resulting in different values ​​for their intensities. Therefore, powder X-ray diffraction can be used to identify different polymorphs, or solid forms containing more than one polymorph, in a reproducible and reliable manner. Crystalline polymorphic forms are of interest to the pharmaceutical industry, and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not kept constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from lot to lot. It is also desirable to have a process for producing a compound having a selected polymorphic form in high purity, since impurities present may result in undesirable toxicological effects when the compound is used in clinical studies or products. Certain polymorphic forms may exhibit improved thermodynamic stability or may be more easily manufactured in large quantities at high purity, and therefore more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may exhibit other beneficial physical properties, such as a lack of hygroscopic tendency, improved solubility, and enhanced dissolution rate due to different lattice energies.

[0112] The term "substituted with 0 to 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 1 substituent, 2 substituents, 3 substituents, etc.

[0113] The present disclosure contemplates all isomers of the compounds of Formulas I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF, and If. As used herein, "isomer" includes optical isomers (stereoisomers, such as enantiomers and diastereoisomers), Z (zusammen) or E (entgegen) isomers, and tautomers. Many of the compounds useful in the methods and compositions of the present disclosure have at least one stereogenic center in their structure. This stereogenic center can exist in the R or S configuration, and the R and S designations are used according to the rules set forth in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure also relates to all stereoisomers, such as enantiomers and diastereoisomers of the present compounds, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO01 / 062726. Furthermore, certain compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each case, the present disclosure includes both mixtures and separate individual isomers. Multiple substituents on the piperidinyl or azepanyl ring may also be in a cis or trans relationship to each other relative to the plane of the piperidinyl or azepanyl ring. Some of the present compounds may also exist in tautomeric forms. Although such forms are not explicitly shown in the formulas described herein, they are intended to be included within the scope of the present invention. With respect to the methods and compositions of the present disclosure, when a compound(s) is mentioned, it is intended to encompass the compound in each of its possible isomers and mixtures thereof, unless a specific isomer is specifically mentioned. See, for example, WO01 / 062726.

[0114] The compounds of the present disclosure are α5-containing GABA A They enhance the function of α5-containing GABA receptors. A R agonists (e.g., α5-containing GABA AR positive allosteric modulator) and can increase GABAergic Cl- currents.

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

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

[0117] The cognitive disorders treated according to the present disclosure may be associated with various CNS disorders or cognitive disorders, such as age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-associated memory impairment (AAMI), age-associated cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction risk. These disorders may have different etiologies. However, cognitive disorders associated with each of the above-mentioned disorders or risk factors may have overlapping causes. Thus, compounds, compositions, or treatment methods that treat cognitive disorders associated with one CNS disorder or risk factor can also treat cognitive disorders in another. Benzazepine Derivatives of the Present Disclosure

[0118] The present disclosure provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein X is O, N, -NR 3 or -C(R 4 ) 1~2 are independently selected from W is O, N or NR 3 and V is O, NR 3 or -C(R 4 ) 1~2 and When X is O, W is N and V is -C(R 4 ) 1~2 and When X is N, W is O or -NR 3 and V is -C(R 4 ) 1~2 and X is -NR 3 , W is N and V is -C(R 4 )1~2 and X is -C(R 4 ) 1~2 where W is N and V is O or -NR 3 and join [ka] is either a single bond or a double bond at each occurrence, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -NCS, -NO2, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, or -(C3-C10)cycloalkenyl, wherein each (5-6 membered)heteroaryl and (3-10 membered)heterocycle is substituted with 0-4 R7; each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl-(C1-C6)alkyl or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, these two R7 groups together with the atoms to which they are attached may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, said ring being optionally substituted with 0-5 R'; Each R 8 is selected from -H, -(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl or -CH2-(5-10 membered)heteroaryl; R 8 each occurrence of is independently substituted with 0 to 5 R'; Each R 9 is selected from -H, -(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, (C3-C10)cycloalkenyl, -(C6-C10)aryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(C1-C6)alkyl-(C3-C6)cycloalkyl or -C(O)-(C6-C10)aryl; R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence of is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl, wherein said heterocyclyl has from 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and said heteroaryl has from 1 to 4 heteroatoms independently selected from N, NH, O, or S; R 3is -H, -(C1-C6) alkyl, -(C1-C6) alkyl-(C3-C6) cycloalkyl, -(C1-C6) alkyl-OR 12 , -(C1-C6) alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(5-10 membered)heteroaryl, -C(O)-(C6-C10)aryl, -C(O)-(C1-C6)alkyl or -C(O)-(C3-C6), and R 3 is 0 to 5 R 12 are independently substituted with Each R 12 -H, -halogen, -OR o , R o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2 are independently selected from R o each occurrence of is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, or -(C6-C10)aryl, wherein said heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and said heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, or S; R 4 is selected from -H or -(C1-C6)alkyl; R 6 is selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); Each occurrence of R″ is independently selected from —H, —(C1-C6)aliphatic, —(C3-C6)cycloalkyl, —(3-6 membered)heterocyclyl, —(5-10 membered)heteroaryl, —(C6-C10)aryl, —(C1-C6)alkyl-(5-10 membered)heteroaryl, —(C1-C6)alkyl-(C6-C10)aryl, —(C1-C6)alkyl-O-(5-10 membered)heteroaryl, or —(C1-C6)alkyl-O-(C6-C10)aryl, and each occurrence of R″ is independently substituted with 0-3 substituents; particularly, in some embodiments of the present disclosure, R″ is independently substituted with 1-3 substituents, the substituents being halogen, —R o , -OR o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2 is selected, R o each occurrence is independently selected from -(C1-C6)aliphatic, -O(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, or -(C6-C10)aryl, wherein said heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and said heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, or S. to provide.

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

[0120] In some embodiments of the compound of formula IA, the compound has the structure of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6)alkyl; Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C3-C10)cycloalkenyl, [ka] is selected from each 5-6 membered heteroaryl and 3-10 membered heterocycle is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, -(C6-C10) aryl, -(C1-C6) alkyl-(C6-C10) aryl, [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R 3 is independently selected from -H, -(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, or -(C1-C6)alkyl-(C6-C10)aryl; R 3 is 0 to 5 R 12 are independently substituted with Each R 12 -H, -halogen, -OR o , R o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -CF3, -OCF3 or -N(R o )2 are independently selected from R o each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-10 membered)heterocyclyl, or -(C6-C10)aryl; each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5-10 membered)heteroaryl-(C1-C6)alkyl, or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, these two R7 groups together with the atoms to which they are attached may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, said ring being optionally substituted with 0-5 R'; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); R" is selected from -Cl, -F, -(C-C)alkyl, -OMe, or -(C-C)aryl; R″ is independently substituted with 1 to 3 substituents selected from halogen, —CF3, —OCF3, —O—(C1-C6)aliphatic, or —(C1-C6)aliphatic; Each R 4 is selected from -H or -(C1-C6)alkyl; Each R 6 is selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl It has.

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

[0122] In some embodiments of the compound of formula IA, the compound has the structure of formula I-aa: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 is halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF2, -CF3, -OCF3, -OCHF2, CO(O)R7, CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6 alkyl); Each R 2 is CO(O)R7, C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C3-C10)cycloalkenyl, [ka] is selected from each 5-6 membered heteroaryl and 3-10 membered heterocycle is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, (5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, -(C6-C10) aryl, -(C1-C6) alkyl-(C6-C10) aryl, [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R 3 is independently selected from -H, -(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, or -(C1-C6)alkyl-(C6-C10)aryl; R 3 is 0 to 5 R 12 are independently substituted with Each R 12 -H, -halogen, -OR o , R o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -CF3, -OCF3 or -N(R o )2 are independently selected from R o each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-10 membered)heterocyclyl, or -(C6-C10)aryl; each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -CH2-(C6-C10)aryl, -(5-10 membered)heteroaryl-(C1-C6)alkyl, or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, these two R7 groups together with the atoms to which they are attached may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, said ring being optionally substituted with 0-5 R'; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); 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 to 3 substituents selected from halogen, —CF3, —OCF3, —O—(C1-C6)aliphatic, or —(C1-C6)aliphatic; Each R 4 is selected from -H or -(C1-C6)alkyl; Each R 6 is selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl It has.

[0123] In some embodiments, the compound of formula I-aa or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof has the structure of formula I-aa: (wherein m is 0, 1 or 2; When m is 1 or 2, R 1 at least one occurrence of is -halogen or -O-(C1-C6)alkyl; Each R 1 is independently selected from -halogen and -O-(C1-C6)alkyl; R 2 is -C≡CR9 , -(C3-C10)cycloalkenyl, [ka] is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R 9 is -(C1-C6) alkyl, [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence of is independently selected from —(C1-C6)alkyl and —O—(C1-C6)alkyl; R 3 is independently selected from -H, -(C1-C6)alkyl, -(3-10 membered)heterocyclyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, and -(C1-C6)alkyl-(C6-C10)aryl; R 3 is 0 to 5 R 12 are independently substituted with R7 is selected from -CF3, -(C1-C6)alkyl, -(C6-C10)aryl, or -CH2-(C6-C10)aryl; each R7 is independently substituted with 0 to 5 R'; R 4 and R 6 Each occurrence of is -H, R 11 , R 12 , R 13 and R 14 , R' and R'' are as defined in formula I-aa) It has.

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

[0125] In some embodiments of the compound of formula IB, the compound has the structure of formula Ib: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6)alkyl; Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, [ka] is selected from each 5- to 6-membered heteroaryl or 3- to 10-membered heterocycle is substituted with 0-4 R7; Each R 9is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, -(C6-C10) aryl, -(C1-C6) alkyl-(C6-C10) aryl, [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R 3 is -H, -(C1-C6) alkyl, -(C1-C6) alkyl-(C3-C6) cycloalkyl, -(C1-C6) alkyl-OR 12 , -(C1-C6) alkyl-N(R 12 )2, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, or -(5-10 membered)heteroaryl; R 3 is 0 to 5 R 12 are independently substituted with Each R 12 -H, -halogen, -OR o , R o , oxo, -CH2OR o , -CHN(R o )2, -C(O)N(R o )2, -C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 or -N(R o )2 are independently selected from R o each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, or -(C6-C10)aryl; each R7 is selected from -H, -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, these two R7 groups together with the atoms to which they are attached may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, said ring being optionally substituted with 0-5 R'; each occurrence of R' is independently selected from -halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5-10 membered)heteroaryl, —(5-10 membered)heteroaryl, —(3-10 membered)heterocyclyl, —(C3-C6)cycloalkyl, or —(C6-C10)aryl; R″ is independently substituted with 1 to 3 substituents selected from halogen, —CF3, —OCF3, —O(C1-C6)aliphatic, —(C1-C6)aliphatic, or —(5-10 membered)heteroaryl; Each R 4 and R 6 are independently selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from H—, —(C1-C3)aliphatic, or —(C3-C6)cycloalkyl It has.

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

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

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

[0129] In some embodiments of the compound of Formula I, the compound has the structure of Formula IC: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (wherein m, R1 , R 2 , R 3 , R 4 , R 6 , R 13 and R 14 is as defined in formula I).

[0130] In some embodiments of the compound of formula IC, the compound has the structure of formula Ic: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6 alkyl); Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, [ka] is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl, [ka] is selected from R 9 Each occurrence of 11 and are independently substituted by R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; each occurrence of R7 is selected from -CF3, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); each occurrence of R" is selected from -Cl, -F, -(C1-C6)alkyl, -OMe, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(C3-C6)cycloalkyl, or -(C6-C10)aryl; R" is independently substituted with 1 to 3 substituents selected from -halogen, -CF3, -OCF3, -(C1-C6)aliphatic, or -(5-10 membered)heteroaryl; Each R 4 and R 6 are independently selected from -H or -(C1-C6)alkyl; Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl It has.

[0131] In some embodiments, the compound of Formula Ic or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof has the structure of Formula Ic: (wherein m is 0, 1 or 2; When m is 1 or 2, R 1 at least one occurrence of is -halogen or -O-(C1-C6)alkyl; Each R 1 is independently selected from -halogen and -O(C1-C6)alkyl; R 2 is -CO(O)R7, -C≡CR 9 , [ka] is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R 9 is selected from -H or -(C1-C6) alkyl, and R 9 Each occurrence of 11 are independently substituted by R 11 each occurrence of is selected from -(C1-C6)alkyl; R 4 and R 6 Each occurrence of is -H, R7, R 13 , R 14 , R' and R'' are as defined in formula Ic) It has.

[0132] In some embodiments of the compound of Formula I, the compound has the structure of Formula ID: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (wherein m, R 1 , R 2 , R4 , R 6 , R 13 and R 14 is as defined in formula I).

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

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

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

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

[0137] In some embodiments, the compound of formula Ie or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof has the structure of formula Ie: (wherein m is 0, 1 or 2; When m is 1 or 2, R 1 at least one occurrence of is halogen or —O—(C1-C6)alkyl; Each R 1is independently selected from -halogen and -O-(C1-C6)alkyl; R 2 is -CO(O)R7, -C≡CR 9 , [ka] is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R 9 is selected from -H or -(C1-C6) alkyl, and R 9 Each occurrence of 11 are independently substituted by R 11 each occurrence of is selected from -(C1-C6)alkyl; R 4 and R 6 are both -H, R7, R 13 , R 14 and R' is as defined in formula Ie. It has.

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

[0139] In some embodiments of the compound of formula IF, the compound has the structure of formula If: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (In the formula, m is an integer selected from 0 to 4; Each R 1 -Halogen, -(C6-C10)aryl, -OMe, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -CO(O)R7, -CH2-OR 8 , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R 8 are independently selected from -H or -(C1-C6 alkyl); Each R 2 is -CO(O)R7, -C≡CR 9 , -(C1-C6) alkyl-C≡CR 9 , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, [ka] is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R 9 is -H, -(C1-C6) alkyl, -(5-10 membered) heteroaryl, -(3-10 membered) heterocyclyl [ka] is selected from R 9 Each occurrence of 11 and R 11 each occurrence is independently selected from -(C1-C6)alkyl, -O-(C1-C6)alkyl, -halogen, -CF3, -OCF3, -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl or -(5-10 membered)heteroaryl-(C1-C6)alkyl or -(3-10 membered)heterocyclyl, and each R7 is independently substituted with 0-5 R'; each occurrence of R' is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, or -N(R"); each R' is independently substituted with 0-5 R"; and 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, Each R 13 and R 14 are independently selected from -H, -(C1-C3)aliphatic, or -(C3-C6)cycloalkyl It has.

[0140] In some embodiments, the compound of formula If or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof has the structure of formula If: (wherein m is 0, 1 or 2; When m is 1 or 2, R 1 at least one occurrence of is halogen or —O—(C1-C6)alkyl; Each R 1 is independently selected from -halogen and -O-(C1-C6)alkyl; R 2 is -CO(O)R7, -C≡CR 9 , [ka] is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R 9 is selected from -H or -(C1-C6) alkyl, and R 9 Each occurrence of 11 and R 11 each occurrence of is selected from -(C1-C6)alkyl; R 4 and R 6 are both -H, R7, R 13 , R 14 and R' is as defined in formula If It has.

[0141] Examples of specific compounds of the present disclosure include the following: [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10]

Table 8-11

Table 8-12

Table 8-13

Table 8-14

Table 8-15

Table 8-16

Table 8-17

Table 8-18

Table 8-19

Table 8-20

Table 8-21

Table 8-22

Table 8-23

Table 8-24

Table 8-25

Table 8-26

Table 8-27

Table 8-28

Table 8-29

Table 8-30

Table 8-31

Table 8-32

Table 8-33

Table 8-34

Table 8-35

Table 8-36

Table 8-37

Table 8-38

Table 8-39

Table 8-40

Table 8-41

Table 8-42

Table 8-43

Table 8-44

[0142] The basic nitrogen-containing group present in the compounds of the present disclosure can be quaternized with agents such as lower alkyl halides, for example, methyl chloride, ethyl chloride, propyl chloride and butyl chloride, methyl bromide, ethyl bromide, propyl bromide and butyl bromide, and methyl iodide, ethyl iodide, propyl iodide and butyl iodide; dialkyl sulfates, for example, dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate, long-chain halides, for example, decyl chloride, lauryl chloride, myristyl chloride and stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide and stearyl bromide, and decyl iodide, lauryl iodide, myristyl iodide and stearyl iodide; aralkyl halides, for example, benzyl bromide and phenethyl bromide.This can result in water-soluble or oil-soluble or water-dispersible or oil-dispersible products.

[0143] Any embodiment described herein is also intended to correspond to both unlabeled and isotopically labeled forms of the compound, unless otherwise indicated. Isotopically labeled compounds have the structure depicted by the formulas shown herein, except that one or more atoms are replaced by atoms with selected atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds of the present invention include, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 The present invention includes various isotopically labeled compounds as defined herein, for example, those in which: 3 H, 13 C and 14 Such isotopically labeled compounds may be used in metabolic studies (preferably in 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 assays), or radioactive treatment of patients. 18 F or labeled compounds may be particularly preferred for 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 the preparations described below by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0144] Any of the individual embodiments listed herein in the context of general formulas I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF, and If are part of the present disclosure. Furthermore, the various substituents listed at particular residues in those individual embodiments may be combined with one of the substituents listed at other particular residues without departing from the scope of the present disclosure. General synthesis method

[0145] The compounds of the present disclosure can be prepared by methods generally known to those skilled in the art. Schemes 1-4 below present general synthetic routes for the preparation of compounds of formula I, IA, Ia, I-aa, IB, Ib, I-ba, IC, Ic, ID, Id, IE, Ie, IF, and If. Other equivalent schemes will be readily apparent to an organic chemist of ordinary skill in the art and can alternatively be used to synthesize various portions (or the entire) of the molecules, as exemplified by the following general schemes. Scheme 1. General synthesis of compounds of formula IA, Ia and I-aa where X, W and V form a pyrazole ring. [ka] Scheme 2. General synthesis of compounds of formula IB, Ib and I-ba where X, W and V form a methylpyrazole ring. [ka] Scheme 3 - General synthesis of compounds of formula IB, Ib and I-ba where AX, W and V form a pyrazole ring. [ka] Scheme 3-B. Alternative synthesis of compounds of formula IB, Ib and I-ba (major) starting from intermediate A, where X, W and V form a pyrazole ring. [ka]

[0146] As will be recognized by one of ordinary skill 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 illustrated above can be prepared by varying the chemical reagents or synthetic routes. Pharmaceutical Compositions and Modes of Administration of the Present Disclosure

[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 a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In some embodiments, the GABA compound described in the present disclosure is A The α5 receptor positive allosteric modulators include those disclosed in PCT applications WO2015 / 095783A1, WO2016 / 205739A1, WO2018 / 130869A1, and WO2019 / 246300A1. A In some embodiments, the GABA receptor positive allosteric modulators described in the present disclosure are used in combination with one or more of the α5 receptor positive allosteric modulators. A The alpha5 receptor positive allosteric modulators or the above combinations may be used in combination with one or more of the SV2a inhibitors disclosed in PCT application WO2022 / 011318, specifically levetiracetam or brivaracetam, in the treatment of such cognitive disorders and other conditions described herein.

[0148] It is recognized that the compounds and drugs used in the compositions of the present disclosure should preferably be easily passed through the blood-brain barrier when administered peripherally.However, compounds that cannot pass through the blood-brain barrier can still be effectively administered directly to the central nervous system, for example, by intraventricular or other neurocompatible routes.

[0149] In some embodiments of the present disclosure, the α5-containing GABA A The R positive allosteric modulator or combination is formulated into pharmaceutical compositions with pharmaceutically acceptable carriers or excipients.The 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 silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.In other embodiments, no carrier is used.For example, α5-containing GABA A R agonists (e.g., α5-containing GABA A α5-containing GABA receptors (positive allosteric modulators) can be administered alone or as a component of a pharmaceutical formulation (therapeutic composition). A R agonists (e.g., α5-containing GABA A R positive allosteric modulators) can be formulated for use in human medicine for administration in any convenient way.

[0150] In some embodiments, the therapeutic methods of the present disclosure include administering a pharmaceutical composition of the present disclosure, or in some embodiments, a combination of the present disclosure, or a compound or agent of the present disclosure locally, systemically, or locally. For example, a therapeutic composition of a compound or agent of the present disclosure may be formulated for administration by, for example, injection (e.g., intravenous, subcutaneous, or intramuscular), inhalation or insufflation (through either the mouth or nose), or oral, buccal, sublingual, transdermal, nasal, or parenteral administration. The compound or agent compositions or combinations described herein may also be formulated in some embodiments as part of an implant or device, or may be formulated for slow or sustained release. When administered parenterally, the therapeutic composition of a compound or agent for use in the present disclosure is preferably in a pyrogen-free, physiologically acceptable form. Techniques and formulations can generally be found in Remington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA.

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

[0152] α5-containing GABA A The compositions containing R positive allosteric modulators may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenanthrene, benzoyl perfluorooctanoic acid, benzocaine, benzoyl perfluorooctanoic acid ... This can be ensured by the inclusion of isotonic agents, such as sugars, sodium chloride, and the like, in the composition. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0153] In certain embodiments of the present disclosure, α5-containing GABA A Compositions containing R-positive allosteric modulators can be orally administered, for example, in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as 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 a troche (using an inert base such as gelatin and glycerin, or sucrose and acacia), each of which contains a predetermined amount of α5-containing GABA. A It contains an R positive allosteric modulator as the active ingredient.

[0154] In the solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), α5-containing GABA AOne or more compositions comprising an R-positive allosteric modulator may be mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate), and / or any of the following: (1) a filler or extender (such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid); (2) a binder (such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia); (3) a humectant (such as glycerol); (4) Disintegrants (such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate); (5) solution retarders (such as paraffin); (6) absorption enhancers (such as quaternary ammonium compounds); (7) wetting agents (such as cetyl alcohol and glycerol monostearate); (8) absorbents (such as kaolin and bentonite clay); (9) lubricants (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof); and (10) coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[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 composition may contain inert diluents commonly used in the art (such as water or other solvents), solubilizers and emulsifiers (e.g., ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants (e.g., wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, coloring agents, fragrances, and preservatives).

[0156] Suspensions may contain, in addition to the active compound, suspending agents (such as 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, compositions and combinations thereof of the present disclosure can be administered in a slow-release, controlled-release or sustained-release manner.The term "sustained-release" is widely recognized in the field of pharmaceutical science and is used herein to refer to the controlled release of active compounds or drugs from a dosage form into an environment for an extended period of time, for example, over or equal to one hour (for an extended period of time or during).A sustained-release dosage form releases drugs at a substantially constant rate over an extended period of time, or a substantially constant amount of drugs is released incrementally over an extended period of time.The term "sustained-release" used herein includes the terms "controlled release", "extended release", "sustained release", "delayed release" or "slow release", as these terms are used in pharmaceutical science.In some embodiments, sustained-release dosage forms are administered in the form of a patch or pump.

[0158] Those skilled in the art, such as physicians, can utilize the disclosed compositions and methods to treat subjects with α5-containing GABA receptors. A The required amount of R-positive allosteric modulator can be readily determined. The dosage regimen can be determined, for example, by administering a selected α5-containing GABA A It is understood that the effect of the R-positive allosteric modulator will be determined for each individual, taking into account various factors that modify the effect of the R-positive allosteric modulator, the severity or stage of the disease, the route of administration, and characteristics specific to that individual, such as age, weight, size, and the 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 its pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer is an amount 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 its pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer is about 0.1 to 500 mg / day. Daily dosages that can be used include 0.0015 mg / kg, 0.002 mg / kg, 0.0025 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, and 1 mg / kg. / 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 AThe daily dose of an R-positive allosteric modulator or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or an 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, 5 ... mg, 45 mg, 50 mg, 55 mg, 60 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 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. A The daily dose of an R-positive allosteric modulator or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof is an α5-containing GABA receptor antagonist in an amount of 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. A It is an R-positive allosteric modulator.

[0161] In certain embodiments of the present disclosure, α5-containing GABA A The dose of the R-positive allosteric modulator is 0.1-5 mg / kg / day (7-350 mg / day for a typical human subject weighing 70 kg). In certain embodiments of the present disclosure, the α5-containing GABA A The daily dose of the R-positive allosteric modulator is 7 to 350 mg. In some embodiments, α5-containing GABA may be used. ADaily doses of R-positive allosteric modulators include, but are not limited to, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 4, and 5 mg / kg / day. In some embodiments, α5-containing GABA receptors may be used. A Daily doses of the R-positive allosteric modulator include, but are not limited to, 7, 35, 70, 110, 150, 180, 220, 300, and 350 mg. In some embodiments of the present disclosure, the α5-containing GABA A The dose of the R-positive allosteric modulator is 1-2 mg / kg / day. In some embodiments of the present disclosure, the α5-containing GABA A The daily dose of the R-positive allosteric modulator is 70-140 mg. In another embodiment of the present disclosure, the α5-containing GABA A The dose of the R-positive allosteric modulator is 0.1 to 0.2 mg / kg / day. In another embodiment of the present disclosure, the α5-containing GABA A The daily dose of the R-positive allosteric modulator is 7-14 mg. Other doses higher, intermediate, or lower than these daily doses may also be used and may be determined by one of skill in the art following the methods of the present disclosure.

[0162] In certain embodiments of the present disclosure, the interval between administrations is 12 hours or 24 hours. Less frequent administration intervals, such as once every 6 hours, may also be used. In some embodiments, the α5-containing GABA A The R-positive allosteric modulator is administered every 12 or 24 hours at a total daily dose of 0.1 to 5 mg / kg (e.g., if a daily dose of 2 mg / kg is administered every 12 hours, each administration is 1 mg / kg). A The R-positive allosteric modulator is administered every 12 or 24 hours at a total daily dose of 7 to 350 mg. A The R-positive allosteric modulator is administered at a daily dose of 1-2 mg / kg every 24 hours. AThe R-positive allosteric modulator is administered at a daily dose of 70 to 150 mg every 24 hours. A The R-positive allosteric modulator is administered at a daily dose of 0.1 to 0.2 mg / kg every 24 hours. In another embodiment, the α5-containing GABA A The R-positive allosteric modulator is administered at a daily dose of 7 to 15 mg every 24 hours. A The R-positive allosteric modulator is administered every 12 or 24 hours at a daily dose of 0.01 to 2.5 mg / kg (e.g., at a daily dose of 0.8 mg / kg administered every 12 hours, each administration is 0.4 mg / kg). A The R-positive allosteric modulator is administered at a daily dose of 0.7 to 15 mg every 24 hours. A The R-positive allosteric modulator is administered at a daily dose of 0.1 to 2.5 mg / kg every 12 or 24 hours. A The R-positive allosteric modulator is administered at a daily dose of 7 to 15 mg every 24 hours. A The R-positive allosteric modulator is administered at a daily dose of 25 to 180 mg every 12 or 24 hours. A The R-positive allosteric modulator is administered at a daily dose of 0.6-1.8 mg / kg every 12 or 24 hours. A R-positive allosteric modulators are administered at daily doses of 40–130 mg every 12 or 24 hours.

[0163] In some embodiments, GABA AThe administration interval of α5 receptor agonist or its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph or its isomer, or pharmaceutical composition containing any of the above is once every 12 hours (twice a day) or once every 24 hours (once a day).Administration at less frequent intervals, such as once every 6 hours, can also be used.Other doses higher than, intermediate or lower than these doses can also be used, and can be determined by those skilled in the art according to the method of the present disclosure.Depending on the condition, when repeated administration is carried out for several days or weeks or longer, treatment is continued until a sufficient level of cognitive function is achieved.

[0164] In certain embodiments of the present disclosure, the interval between doses is once every 12 or 24 hours, and in some embodiments, once a day. Less frequent doses, such as once every 6 hours, may also be used.

[0165] α5-containing GABA when administered via implant, device, or slow- or sustained-release formulation A The R-positive allosteric modulator can be administered once, or, if necessary, once or more periodically throughout the patient's life. Other administration intervals intermediate or shorter than these administration intervals for clinical use may also be used and can be determined by one skilled in the art according to the methods of the present invention.

[0166] The desired administration time can be determined by one of ordinary skill in the art through routine experimentation. A The R-positive allosteric modulator may be administered for 1-4 weeks, 1-3 months, 3-6 months, 6-12 months, 1-2 years or more, up to the patient's lifetime.

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

[0168] It is understood by those skilled in the art that the compositions described herein can be adapted and modified to be suitable for the intended use, and the compositions described herein can be used in other suitable uses.For example, the compositions of the present disclosure can be used in combination with a second therapeutic agent.Such other additions and modifications do not depart from the scope of the present invention. Pharmaceutical compositions / combinations containing antipsychotic drugs

[0169] In some embodiments, the compounds, compositions, or combinations of the present disclosure can be used in combination with antipsychotic drugs to treat cognitive impairment associated with schizophrenia or bipolar disorder (e.g., mania) in subjects with or at risk of schizophrenia or bipolar disorder. Antipsychotic drugs or pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, or polymorphs thereof useful in the methods and compositions of these embodiments of the present disclosure include both typical and atypical antipsychotic drugs. 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 invention prevent or slow the progression of cognitive impairment in schizophrenia or bipolar disorder (particularly mania) in said subject.

[0170] In some embodiments, the antipsychotic suitable for use in the present disclosure is selected from atypical antipsychotics.Such atypical antipsychotics include but are not limited to those disclosed in, for example, United States Patent No. 4,734,416; United States Patent No. 5,006,528; United States Patent No. 4,145,434; United States Patent No. 5,763,476; United States Patent No. 3,539,573; United States Patent No. 5,229,382; United States Patent No. 5,532,372; United States Patent No. 4,879,288; United States Patent No. 4,804,663; United States Patent No. 4,710,500; United States Patent No. 4,831,031; and United States Patent No. 5,312,925; and European Patent EP402644 and European Patent EP368388, and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs.

[0171] In some embodiments, atypical antipsychotics suitable for use in the present disclosure 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, antipsychotic drugs suitable for use in the present disclosure include, but are not limited to, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clothipine, cyamemazine, diazepam, dixyrazine, droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepin, penfluridol, perazine, pericyazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine , thioridazine, tiapride, thiothixene, trifluoperazine, triflupromazine, trihexyphenidyl, and zuclopenthixol, and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[0173] In some embodiments of the present disclosure, the antipsychotic drug or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is selected from the group consisting of a dopaminergic agent (such as a dopamine D1 receptor antagonist or agonist, a dopamine D2 receptor antagonist or partial agonist, a dopamine D3 receptor antagonist or partial agonist, a dopamine D4 receptor antagonist), a glutamatergic agent, an N-methyl-D-aspartate (NMDA) receptor positive allosteric modulator, a glycine reuptake inhibitor, a glutamate reuptake inhibitor, a metabotropic glutamate receptor (mGluR) agonist or positive allosteric modulator (PAM) (e.g., mGluR uR2 / 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, ampakines (CX-516), glutathione prodrugs, noradrenergic agents (such as alpha-2 adrenoceptor agonists or antagonists and catechol-O-methyltransferase (COMT) inhibitors), serotonin receptor modulators (5-HT 2A Receptor antagonist, 5-HT 1A Receptor partial agonist, 5-HT 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 A The R-positive allosteric modulator and the antipsychotic drug described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof may be administered simultaneously or sequentially, or in a single formulation, or in separate formulations packaged together, or in separate formulations packaged separately. A The R-positive allosteric modulator and the antipsychotic drug or its pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof are administered via different routes. As used herein, "combination" includes packaging and administration by any of these formulations or administration routes. Pharmaceutical compositions / combinations containing memantine

[0175] The compounds, compositions, or combinations of the present disclosure may be used in combination with memantine, or a derivative or analog thereof, in treating cognitive impairment associated with central nervous system (CNS) disorders in subjects in need of or at risk of such treatment (including, but not limited to, subjects with or at risk of age-related cognitive impairment, mild cognitive impairment (MCI), amnesic 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 is a 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.1 3,7 ] also known chemically as decan-1-amine, It is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with moderate affinity. Trade names for 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 more than 42 countries worldwide. Memantine is approved in the United States for the treatment of moderate to severe Alzheimer's disease (AD) at doses of up to 28 mg / day. Some of the memantine and its derivatives and analogs 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 useful in the present disclosure include, but are not limited to, the compounds disclosed in U.S. Patent Application Publications US20040087658, US20050113458, US20060205822, US20090081259, US20090124659 and US20100227852; European Patent Application Publication EP2260839A2; European Patent EP1682109B1; and PCT Application Publication WO2005079779, all of which are incorporated herein by reference.As used in the present disclosure, memantine includes memantine and its derivatives and analogs, as well as their hydrates, polymorphs, prodrugs, salts and solvates. Memantine, as used herein, also includes compositions comprising memantine or a derivative or analog, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof, optionally in combination with at least one additional therapeutic agent, such as 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 that is donepezil (trade name Aricept).

[0177] In another embodiment of the present disclosure, α5-containing GABA AThe R-positive allosteric modulator and memantine (or a memantine derivative / analog) or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a prodrug 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 a memantine derivative / analog) or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a prodrug thereof are administered via different routes. As used herein, "combination" includes packaging or administration via any of these formulations or administration routes. Pharmaceutical compositions / combinations containing acetylcholinesterase inhibitors (AchEIs)

[0178] The compounds, compositions or combinations of the present disclosure may be used in combination with an acetylcholinesterase inhibitor ("AChEI") in treating cognitive impairment associated with central nervous system (CNS) disorders in subjects in need of or at risk for such treatment (including, but not limited to, subjects with or at risk for age-related cognitive impairment, mild cognitive impairment (MCI), amnesic 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 skilled in the art can belong to the subclassification of (i) reversible non-competitive inhibitors or reversible competitive inhibitors, (ii) irreversible inhibitors, and / or (iii) quasi-irreversible inhibitors.

[0180] In certain embodiments, AChEIs useful in the present disclosure include those described in 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, ungeremine, ladostigil, demecarium, echothiophate (Phospholine), edrophonium (Tensilon), tacrine (Cognex), pralidoxime (2-PAM), pyridostigmine (Mestinon), physostigmine (Serine, Antilirium), ambenonium (Mytelase), galantamine (Reminyl, Razadyne). , rivastigmine (Exelon, SZD-ENA-713), huperzine A, icopezil, neostigmine (Prostigmin, Vagostigmin), Aricept (donepezil, E2020), lactucopicrin, monoamine acridines and their derivatives, piperidine and piperazine derivatives, N-benzyl-piperidine derivatives, piperidinyl-alkanoyl heterocyclic compounds, 4-(1-benzyl:piperidyl)-substituted condensed quinoline derivatives, and cyclic amide derivatives. Other typical AChEIs include carbamates and organophosphonate compounds, such as metrifonate (trichlorfon). Benzazepinols, such as galantamine, are also useful AChEIs. In some embodiments, suitable AChEIs for use in combination with the compounds and compositions of the present application include donepezil (aricept), galantamine (razadyne), or rivastigmine (exelon).

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

[0183] The compounds, compositions or combinations of the present disclosure may be used in combination with an SV2A inhibitor in treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need of or at risk of such treatment (including, but not limited to, subjects with or at risk of age-related cognitive impairment, mild cognitive impairment (MCI), amnesic 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 Publication Nos. 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 and U.S. Patent Application No. 2008 / 0081832. In certain embodiments, SV2A inhibitors useful in the present disclosure include those described in British Patent Nos. 1,039,113 and 1,309,692, all of which are incorporated herein by reference.

[0185] In some embodiments of the present disclosure, the SV2A inhibitor or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam, 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 its pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer is levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer thereof. In some embodiments of the present disclosure, the SV2A inhibitor or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer 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 its pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer thereof is seletracetam or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, or isomer thereof. Seletracetam refers to the compound (2S)-2-[(4S)-4-(2,2-difluoroethenyl)-2-oxopyrrolidin-1-yl]butanamide (IUPAC name). In certain embodiments of the present invention, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam or a pharmaceutically acceptable salt thereof.

[0186] In certain embodiments, levetiracetam, brivaracetam, or seletracetam, or a pharmaceutically acceptable salt thereof, can be administered in a dosage as disclosed in, for example, U.S. Patent Application No. 12 / 580,464 (Publication No. US-2010-0099735), U.S. Patent Application No. 13 / 287,531 (Publication No. US-2012-0046336), U.S. Patent Application No. 13 / 370,253 (Publication No. US-2012-0214859), 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 seletracetam) or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, 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 seletracetam) or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof is about 0.1 to 500 mg / day. Daily doses that may be used are 0.0015mg / kg, 0.002mg / kg, 0.0025mg / kg, 0.005mg / kg, 0.01mg / kg, 0.02mg / kg, 0.03mg / kg, 0.04mg / kg, 0.05mg / kg, 0.06mg / kg, 0.07mg / kg, 0.08mg / kg, 0.09mg / kg, 0.1mg / kg, 0.2mg / kg, 0.3mg / 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, 1.8 mg / 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 g, 45 mg, 50 mg, 55 mg, 60 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 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, or 500 mg.

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

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

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

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

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

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

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

[0195] In another embodiment of the present disclosure, α5-containing GABA A The R-positive allosteric modulator and the SV2A inhibitor or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a prodrug thereof are administered simultaneously or sequentially, or in a single formulation, or in separate formulations packaged together or separately. A The R-positive allosteric modulator and the SV2A inhibitor or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof are administered by different routes. As used herein, "combination" includes packaging or administration by any of these formulations or administration routes. Evaluation of cognitive impairment and its treatment

[0196] Animal model serves as an important resource for developing and evaluating the treatment for cognitive impairment associated with CNS disorders.The characteristics that characterize cognitive impairment in animal model usually extend to cognitive impairment in humans.Therefore, those skilled in the art understand that the effectiveness in such animal model is a reasonable prediction of the effectiveness in humans.The degree of cognitive impairment in animal model for CNS disorders and the effectiveness of the treatment method for said CNS disorders can be tested and confirmed using various cognitive tests.

[0197] The radial arm maze (RAM) behavioral task is an example of a cognitive test that specifically examines spatial memory (Chappell et al. Neuropharmacology 37: 481-487, 1998). The RAM apparatus, for example, consists of eight equidistantly spaced rungs. The maze rungs extend from each side of a central platform. A food pit is located at the distal end of each rung. Food is used as a reward. Blocks can be placed to prevent entry into any rung. Numerous additional maze cues may be provided around the periphery of the apparatus. After acclimation and training periods, the spatial memory of model animals can be tested in the RAM under control or test compound treatment conditions. As part of the test, animals are pretreated with a vehicle control or a test compound at a range of doses prior to the trial. At the beginning of each trial, a subset of the rungs in the eight-run maze are blocked off. Animals can access food in the unblocked rungs during this initial "information phase" of the trial. The animal is then removed from the maze for a delay (e.g., 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 delay) between the information phase and a subsequent "retention test" in which the barriers on the maze are removed, thus allowing access to all eight lanes. After the delay, the animal is returned to the center platform (with the barriers to the previously blocked lanes removed) and is able to access the remaining food rewards during the retention test phase of this trial. The identity and location of the blocked lanes changes from trial to trial. The number of "errors" the animal makes during the retention test phase is tracked. An error occurs in that trial if the animal enters a lane where food was already found in the previous component of the delay period of that trial, or if the animal revisits a lane that it had already visited in the post-delay session. Fewer errors indicate better spatial memory. The number of errors made by the test animals in the various test compound treatment regimens can then be compared to assess the effectiveness of the test compound in treating cognitive deficits associated with CNS damage in the model.

[0198] Another cognitive test that can be used to evaluate the effects of test compounds on cognitive impairment in CNS disorder model animals is the Morris water maze. The water maze is a pool surrounded by a series of novel patterns. Training protocols for the water maze can be based on modified water maze tasks that have been shown to be hippocampal-dependent (de Hoz et al., Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999). Test animals are trained to locate a submerged escape platform hidden beneath the surface of the pool. During training trials, animals are released into the maze (pool) from random starting positions on the periphery of the pool. The starting position is changed for each trial. If the animal does not locate the escape platform within a set time, the experimenter guides the animal to the platform and places it on it to "teach" it the platform location. After a delay time after the last training trial, carry out the recording test in the absence of escape platform to evaluate spatial memory.For example, the preference level of animal to escape platform (not present now) measured by the time that animal spends at this position or the number of times that animal crosses this position indicates better spatial memory, that is, the treatment of cognitive impairment.Then, the preference to escape platform position under different treatment conditions can be compared to evaluate the effectiveness of test compound in treating the cognitive impairment associated with CNS damage in model.

[0199] There are various tests known in the art for assessing cognitive function in humans, including, but not limited to, the Clinical Global Impression of Change Scale (CIBIC-plus scale); the Mini-Mental State Examination (MMSE); the Neuropsychiatric Index (NPI); the Clinical Dementia Scale (CDR); the Cambridge Neuropsychological Test Battery (CANTAB); the Sandoz Clinical Assessment of the Geriatrics (SCAG), the Buschke Multiple Choice Recall Test (Buschke and Fuld, 1974); the Verbal Paired Associations 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 Test Battery, which includes tests of working memory, processing speed, attention, verbal learning, visual learning, reasoning and problem solving, and social cognition. Folstein et al., J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); See Marquis et al., 2002 and Masur et al., 1994. See also Buchanan, RW, Keefe, RSE, Umbricht, D., Green, MF, Laughren, T., and Marder, SR (2011) The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209-1217. Another example of a cognitive test in humans is the explicit three-way forced-choice task. In this test, subjects are presented with color photographs of common objects consisting of three types of image pairs: similar pairs, identical pairs, and a mixture of unrelated foils.The second of the pair of similar objects is called the "decoy." These image pairs are completely randomized and presented individually as a series of images. Subjects are instructed to judge whether the object they see is new, old, or similar. A "similar" response to the presentation of the decoy stimulus indicates successful memory retrieval by the subject. In contrast, recalling the decoy stimulus as "old" or "new" indicates that correct memory retrieval did not occur.

[0200] In addition to assessing cognitive ability, the progression of age-related and other cognitive disorders and dementia, as well as the transition from age-related and other cognitive disorders to dementia, can be monitored by assessing surrogate changes in the subject's brain. Proxy changes include, but are not limited to, changes in regional brain volume, perforant path degradation, and changes in brain function observed by resting-state fMRI (R-fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). Examples of regional brain volumes useful for monitoring the progression of cognitive disorders and dementia include a decrease in hippocampal volume and a decrease in the volume or thickness of the entorhinal cortex. These volumes can be measured in subjects, for example, by MRI. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010). Perforant path degradation has been shown to be associated with age and cognitive decline. For example, elderly people with more perforant path degradation tend to perform worse on hippocampus-dependent memory tests. Perforant path degradation can be monitored in subjects by ultra-high-resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting-state fMRI (R-fMRI) involves imaging the brain while at rest and recording large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated between functionally related regions. Seed-based functional connectivity, signal independent component analysis, and / or frequency-domain analysis are used to reveal functional connectivity between brain regions, particularly those whose connectivity increases or decreases with age, as well as the degree of cognitive impairment and / or dementia. FDG-PET uses FDG uptake as a measure of regional metabolic activity in the brain. Decreased FDG uptake in areas such as the posterior cingulated cortex, temporoparietal cortex, and frontal association cortex has been shown to correlate with cognitive decline and the degree of dementia. Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002). Risk factors for developing cognitive impairment

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

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

[0203] In some embodiments, a subject treated in the methods and uses of the present disclosure (a subject who exhibits or displays cognitive ability within the normal range for the subject's age) is at risk of developing cognitive decline or cognitive impairment, the risk being a genetic risk associated with the presence of one or more genomic variants, mutations, or polymorphisms in the subject's genome associated with altered expression of a gene selected from the group consisting of ABCA7, CLU, CR1, PICALM, PLD3, TREM2, and SORL1. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, the risk being associated with the presence of one or more genomic variants, mutations, or polymorphisms associated with ABCA7 in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, the risk being associated with the presence of one or more genomic variants, mutations, or polymorphisms associated with CLU in the subject's genome. In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, the risk being associated with the presence of one or more genomic variants, mutations, or polymorphisms associated with CR1 in the subject's genome. In some embodiments, a subject is at risk of developing cognitive decline or cognitive impairment, and 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, a subject is at risk of developing cognitive decline or cognitive impairment, and 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, a subject is at risk of developing cognitive decline or cognitive impairment, and 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, a subject is at risk of developing cognitive decline or cognitive impairment, and 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, and the risk is associated with the presence of at least one allele of APOE4 gene in the subject's genome.In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, and the risk is associated with the presence of one allele of APOE4 gene in the subject's genome.In some embodiments, the subject is at risk of developing cognitive decline or cognitive impairment, and the risk is associated with the presence of both APOE4 alleles in the subject's genome.

[0205] In some embodiments, the subject is at risk of developing cognitive decline or impairment, and the risk is associated with the presence of one or more biofluid biomarkers selected from the group consisting of p-tau, t-tau, and amyloid beta in the subject. In some embodiments, the subject is at risk of developing cognitive decline or impairment, and 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 impairment, and 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 impairment, and 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 for use in treating cognitive disorders associated with CNS disorders in a subject in need thereof. In some embodiments, CNS disorders associated with cognitive disorders include, but are not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction.

[0207] In some embodiments, the disclosed compounds, compositions, or combinations are for use in treating a cognitive disorder in a subject at risk for a cognitive disorder associated with a risk factor for said cognitive disorder. In some embodiments, the cognitive disorder associated with the risk factor includes, but is not limited to, age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, mental retardation, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction.

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

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

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

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

[0212] The present disclosure provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. AMethods and compositions are provided for treating age-related cognitive impairment or the risk thereof using R-positive allosteric modulators (i.e., compounds of the present disclosure). In certain embodiments, treatment includes preventing age-related cognitive impairment or slowing its progression. In certain embodiments, treatment includes reducing, improving, or slowing the progression of one or more symptoms associated with age-related cognitive impairment. In certain embodiments, treatment of age-related cognitive impairment includes slowing the transition from age-related cognitive impairment (including, but not limited to, MCI, ARCD, and AAMI) to dementia (e.g., AD). The present methods and compositions can be used in clinical applications for treating age-related cognitive impairment or the risk thereof in conditions such as age-related MCI, ARCD, and AAMI in human patients. The dose of the present compositions and the administration interval for the present methods are safe and effective for these applications, as described herein. In some embodiments of the present disclosure, there is provided a method of protecting or improving cognitive function in a subject having age-related cognitive impairment, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[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 impairment.In some embodiments, age-related cognitive impairment includes but is not limited to age-associated memory impairment (AAMI), age-related mild cognitive impairment (MCI) and age-related cognitive decline (ARCD).

[0214] Animal model serves as an important resource for developing and evaluating the treatment for such age-related cognitive impairment.The characteristics that characterize age-related cognitive impairment in animal model usually extend to age-related cognitive impairment in humans.Therefore, the effectiveness in such animal model can reasonably predict the effectiveness 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 aged Long-Evans rats (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107:618-626, (1993)). In behavioral assessment using the Morris Water Maze (MWM), rats learn and remember the location of an escape platform, guided by the placement of spatial cues surrounding the maze. The cognitive basis of this ability is tested in probe trials using a measure of the animal's spatial bias when searching for the escape platform location. Although aged rats in the study population have no difficulty swimming to the visible platform, camouflaging the platform detects age-dependent impairments and requires the use of spatial information. The performance of individual aged rats in outbred Long-Evans strains varies greatly. For example, a proportion of such rats perform comparable to young adults; however, approximately 40-50% fall outside the range of young performance. This variability among aged rats reflects reliable individual differences. Thus, within the aged population, some animals are cognitively impaired and designated as aged impaired (AI), while others are unimpaired and designated as aged unimpaired (AU).For example, Colombo et al., Proc. Natl. Acad. Sci. 94: 14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10: 691-708, (1989); Gallagher et al. Behav. Neurosci. 107:618-626, (1993); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93: 9926-9930, (1996); Nicolle et al., Neuroscience 74: 741-756, (1996); Nicolle et al., J. Neurosci. 19: 9604-9610, (1999); International Patent Publication No. WO 2007 / 019312 and International Patent Publication No. WO 2004 / 048551. Such animal models of age-related cognitive impairment can be used to assay the effectiveness of the methods and compositions of the invention in treating age-related cognitive impairment.

[0216] The effectiveness 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 radial arm maze, as discussed herein. Mild cognitive impairment

[0217] In some embodiments, the subject treated with the disclosed method, use, combination, pharmaceutical composition, combination for use, or pharmaceutical composition for use exhibits non-age-related MCI or is at risk of such a disorder. The method, use, combination, pharmaceutical composition, combination for use, or pharmaceutical composition for use may be useful in clinical applications in human patients for the treatment of non-age-related MCI (including amnesic MCI and non-amnesic MCI).

[0218] The present disclosure provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. AProvided are methods, uses, combinations, pharmaceutical compositions, combinations for use, or pharmaceutical compositions for use that are useful for treating mild cognitive impairment or the risk thereof using R-positive allosteric modulators (i.e., compounds of the present disclosure). In certain embodiments, treatment involves improving cognitive function in patients with mild cognitive impairment. In certain embodiments, treatment involves slowing or delaying the progression of mild cognitive impairment. In certain embodiments, treatment involves reducing the rate of cognitive decline associated with mild cognitive impairment. In certain embodiments, treatment involves preventing mild cognitive impairment or slowing its progression. In certain embodiments, treatment involves alleviating, ameliorating, or slowing the progression of one or more symptoms associated with mild cognitive impairment. Dementia

[0219] The present disclosure also provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. AMethods and compositions are provided for treating cognitive impairment associated with dementia using R-positive allosteric modulators. In certain embodiments, treatment includes preventing or slowing the progression of cognitive impairment associated with dementia. In certain embodiments, treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with dementia. In certain embodiments, the symptom being treated is cognitive impairment. Some embodiments of the present disclosure provide a method for protecting or improving cognitive function in a subject with dementia, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In certain embodiments, the dementia is Alzheimer's disease (AD), prodromal AD, vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. The methods and compositions can be used in clinical applications in treating cognitive impairment associated with dementia and its embodiments in human patients. The doses of the compositions and the administration intervals for the methods are safe and effective for their use, as described herein.

[0220] Animal models serve as an important resource for developing and evaluating treatments for dementia and dementia-related cognitive impairment.The characteristics that characterize dementia and dementia-related cognitive impairment in animal models usually extend to dementia and dementia-related cognitive impairment in humans.Therefore, the effectiveness in such animal models can reasonably predict the effectiveness 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 dementia-associated cognitive impairment can be used to assay the effectiveness of the inventive methods and compositions of the present disclosure in treating dementia-associated cognitive impairment.

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

[0222] The present invention also provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. AMethods and compositions are provided for treating cognitive impairment associated with post-traumatic stress disorder (PTSD) using R-positive allosteric modulators. In certain embodiments, treatment includes preventing or slowing the progression of cognitive impairment associated with PTSD. In certain embodiments, treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with PTSD. In certain embodiments, the symptom being treated is cognitive impairment. Some embodiments of the present disclosure provide a method for protecting or improving cognitive function in a subject with PTSD, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. The methods and compositions can be used in clinical applications in treating cognitive impairment associated with PTSD in human patients. The doses of the compositions and the administration intervals for the methods are safe and effective for their use, as described herein.

[0223] Patients with PTSD (and, to a lesser extent, trauma-exposed patients without 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 abilities. Older individuals with PTSD have greater cognitive decline than control patients (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 model serves as an important source for developing and evaluating treatment for PTSD and cognitive impairment related to PTSD.The characteristics that characterize PTSD in animal model usually extend to PTSD in humans.Therefore, the effectiveness in such animal model can reasonably predict the effectiveness in humans.Various animal models of PTSD are known in the art.

[0225] One rat model of PTSD is time-dependent sensitization (TDS). TDS involves exposing animals to a severe stressful event, followed by recall of the situation of this previous stress. The following is an example of TDS: Rats are restrained and then placed in a swimming tank, and allowed to swim for a period of time, for example, 20 minutes. After this, each rat is immediately exposed to a gas anesthetic until it loses consciousness, and then finally dried off. The animals are left undisturbed for several days, for example, one week. Next, the rats are exposed to a "restoration" session consisting of the original stressor, for example, a swimming session in a swimming tank (Liberzon et al., Psychoneuroendocrinology 22: 443-453, 1997; Harvery et al., Psychopharmacology 175:494-502, 2004). TDS induces an enhanced acoustic startle response (ASR) in rats, comparable to the exaggerated acoustic startle, a hallmark symptom of PTSD (Khan and Liberzon, Psychopharmacology 172: 225-229, 2004). Such animal models of PTSD can be used to assess the effectiveness of the methods and compositions of the present invention in treating PTSD and PTSD-related cognitive impairment.

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

[0227] The present disclosure provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. AFurther provided are methods and compositions for treating cognitive impairment associated with schizophrenia or bipolar disorder (particularly mania) using R positive allosteric modulators.In certain embodiments, treatment includes preventing or slowing the progression of cognitive impairment associated with schizophrenia or bipolar disorder (particularly mania).Schizophrenia is characterized by a wide range of psychopathologies, including positive symptoms such as abnormal or distorted mental representations (e.g., hallucinations, delusions), or symptoms related to dopamine dysregulation (e.g., high dopaminergic response, high dopaminergic behavioral response, dopaminergic hyperactivity or excessive locomotor activity or psychosis), negative symptoms characterized by decreased motivation and reduced adaptive goal-directed behavior (e.g., anhedonia, flat affect, loss of motivation), and cognitive impairment.In certain embodiments, treatment includes alleviating, improving, or slowing the progression of one or more positive and / or negative symptoms and cognitive impairment associated with schizophrenia. Additionally, there are several other psychiatric disorders, such as schizotypical disorder and schizoaffective disorder, other acute and chronic mental illnesses, and bipolar disorder (particularly mania), which share symptomology with schizophrenia, including cognitive impairment. In some embodiments, treatment involves alleviating, improving, or slowing the progression of one or more symptoms associated with bipolar disorder (particularly mania), such as cognitive impairment. Some embodiments of the present disclosure provide a method for protecting or improving cognitive function in a subject with schizophrenia or bipolar disorder, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. The present methods and compositions can be used in clinical applications in treating cognitive impairment associated with schizophrenia or bipolar disorder (particularly mania) in human patients. The dose of the composition and the administration interval for the method are safe and effective for these applications, as described herein.

[0228] Cognitive impairment is associated with schizophrenia. It precedes the onset of psychosis and is present in unaffected relatives. Schizophrenia-associated cognitive impairment constitutes a good predictor of functional outcomes and is a central feature of the disorder. The cognitive features of schizophrenia reflect dysfunction of frontal cortical and hippocampal circuits. Patients with schizophrenia also exhibit hippocampal pathology, reduced hippocampal volume, and hyperactivity due to reduced neuronal size and dysfunction. An imbalance between excitation and inhibition in these brain regions has also been documented in patients with schizophrenia, suggesting that drugs targeting inhibitory mechanisms may be therapeutic. See, e.g., 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 cognitive impairment associated with schizophrenia.The characteristics that characterize schizophrenia in animal models usually extend to schizophrenia in humans.Therefore, the effectiveness in such animal models can reasonably predict the effectiveness in humans.Various animal models of schizophrenia are known in the art.

[0230] One animal model of schizophrenia is chronic treatment with methionine. Methionine-treated mice exhibit insufficient GAD67 expression in the frontal cortex and hippocampus, similar to that reported in postmortem brains of schizophrenic patients. These mice also exhibit deficits in startle prepulse inhibition and social interaction (Tremonlizzo et al., PNAS, 99: 17095-17100, 2002). Another animal model of schizophrenia is methylaoxymethanol acetate (MAM) treatment in rats. Pregnant female rats are administered MAM (20 mg / kg, intraperitoneally) on day 17 of gestation. MAM treatment recapitulates the pathogenesis of the offspring, leading to a schizophrenia-like phenotype, including anatomical changes, behavioral deficits, and altered neuronal information processing. More specifically, MAM-treated rats exhibit a low density of parvalbumin-positive GABAergic interneurons in parts of the prefrontal cortex and hippocampus. In behavioral tests, MAM-treated rats exhibit a decrease in latent inhibition. Latent inhibition is a behavioral phenomenon in which learning about previously exposed stimuli with certain consequences is impaired. This tendency to ignore previous benign stimuli and weaken the formation of associations with such stimuli is thought to prevent sensory overload. Low latent inhibition suggests psychiatric disorders. Latent inhibition can be tested in rats in the following manner: Rats are divided into two groups. One group is pre-exposed to a type of sound over multiple trials. The other group is not exposed to the sound. Then, both groups are subjected to an auditory fear conditioning procedure, in which the same sound is presented simultaneously with a noxious stimulus, such as an electric foot shock. Then, the sound is presented to both groups, and changes in the rats' locomotor activity during the sound presentation are monitored. After fear conditioning, rats respond to the tone presentation by strongly reducing locomotor activity. However, the group exposed to the tone before the conditioning period shows strong latent inhibition: reduced inhibition of locomotor activity in response to tone presentation. In contrast, MAM-treated rats show impaired latent inhibition.That is, exposure to the sound prior to the fear conditioning procedure does not significantly affect the inhibition of fear conditioning (see Lodge et al., J. Neurosci., 29:2344-2354, 2009). Such animal models of schizophrenia can be used to assess the effectiveness of the methods and compositions of the present invention in treating cognitive impairment associated with schizophrenia or bipolar disorder (particularly mania).

[0231] MAM-treated rats exhibit significantly enhanced locomotor responses (or abnormal locomotor activity) to low-dose D-amphetamine administration. They also exhibit a significant increase in the number of spontaneously firing ventral tegmental area dopamine (DA) neurons. These results are thought to be the result of excessive hippocampal activity, because inactivating the ventral hippocampus (vHipp) in MAM-treated rats (e.g., by intravHipp administration of the sodium channel blocker tetrodotoxin (TTX) to MAM rats) completely reversed the increased activity of the DA neuron population and normalized the increased amphetamine-induced locomotor activity. The correlation between hippocampal dysfunction and hypersensitivity of the DA system is thought to underlie the enhanced response to amphetamine in MAM-treated animals and in schizophrenic patients. See Lodge DJ et al. Neurobiology of Disease (2007), 27(42), 11424-11430. The use of MAM-treated rats in the above study may be suitable for use in assessing the effectiveness of the methods and compositions of the present disclosure in treating schizophrenia or bipolar disorder (particularly mania) and their associated cognitive disorders.For example, the methods and compositions of the present invention can be evaluated using MAM-treated animals for their effects on the regulation of central hippocampus (vHipp), the increase in DA neuron population activity and the hyperlocomotion response to amphetamine in MAM-treated animals.

[0232] In MAM-treated rats, dysfunction of the hippocampus (HPC) leads to overactivity of the dopamine system. AA benzodiazepine-positive allosteric modulator (PAM) selective for the α5 subunit of GABA R, SH-053-2'FR-CH3, will be tested for its effects on hippocampal (HPC) output. The effect of SH-053-2'FR-CH3 on the hyperlocomotor response to amphetamine in PAM-treated animals will also be examined. A R-PAM, both when administered systemically and when injected directly into the ventral HPC, reduces the number of spontaneously active DA neurons in the ventral tegmental area (VTA) of MAM rats to levels observed in saline-treated rats (control group). Furthermore, HPC neurons in both saline- and MAM-treated animals express α5-GABA receptors. A R shows a decrease in cortically evoked responses after PAM treatment. Furthermore, the increased locomotor response to amphetamine observed in MAM-treated rats is due to the α5-GABA A R decreases after PAM treatment. See Gill K. M et al. Neuropsychopharmacology (2011), 1-9. The use of MAM-treated rats in the above study can be suitable for use in the present disclosure to assess the effectiveness of the methods and compositions of the present invention in treating schizophrenia or bipolar disorder (particularly mania) and their associated cognitive disorders. For example, the methods and compositions of the present invention can be evaluated using MAM-treated animals for their effects on hippocampal (HPC) output and the hyperlocomotion response to amphetamine in MAM-treated animals.

[0233] Administration of MAM to pregnant rats on embryonic day 15 (E15) severely impaired the offspring's spatial memory or the ability to learn the spatial location of four objects on an eight-lane radial arm maze. Furthermore, MAM-treated rats on embryonic day 17 (E17) were able to reach the performance level of control rats during the early stages of training, but after a 30-minute delay, they were unable to process and retrieve spatial information, indicating significant impairment of working memory. See Gourevitch R. et al. (2004). Behav. Pharmacol, 15, 287-292. Such animal models of schizophrenia can be used to assess the effectiveness of the methods and compositions of the present invention in treating cognitive impairments associated with schizophrenia or bipolar disorder (especially mania).

[0234] Apomorphine-induced climbing behavior (AIC) and apomorphine stereotypy (AIS) in mice are another animal model useful in the present disclosure. A drug is administered to mice at a desired dose level (e.g., intraperitoneally). Subsequently, for example, 30 minutes later, the experimental mice are challenged with apomorphine (e.g., 1 mg / kg sc). Five minutes after apomorphine injection, apomorphine-induced sniff-lick-bite syndrome (stereotypy) and climbing behavior are scored and recorded for each animal. Readings can be repeated every 5 minutes during the 30-minute test session. For each syndrome (stereotypy and climbing behavior), the scores for each animal over the 30-minute test session are summed. If the effect reaches at least 50% inhibition, the ID is calculated using nonlinear least-squares calculations with inverse prediction. 50Calculate the value (95% confidence interval). The average climbing behavior score and stereotypy behavior score can be expressed as a percentage of the control value observed in vehicle-treated (e.g., saline-treated) mice administered apomorphine. See Grauer SM et al. Psychopharmacology (2009) 204, 37-48. This mouse model can be used to test the effectiveness of the methods and compositions of the present invention in treating cognitive impairment associated with schizophrenia or bipolar disorder (especially mania).

[0235] In another well-established preclinical model of schizophrenia, rats chronically exposed to the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine develop positive and negative symptoms of psychosis as well as cognitive impairment. Male Long-Evans rats are intraperitoneally injected with ketamine (30 mg / kg, twice daily) for two weeks during adolescence (2 months of age). Once the rats reach adulthood (approximately 4-5 months of age), behavioral testing is performed to assess behavioral symptoms in response to ketamine exposure and the efficacy of treatments to alleviate those symptoms. See, for example, Enomoto et al., Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 668-675.

[0236] The effectiveness of the methods and compositions of the present disclosure in treating schizophrenia and its associated cognitive disorders can also be assessed in animal models of schizophrenia or bipolar disorder (particularly mania), as well as in human subjects with schizophrenia, using a variety of cognitive tests known in the art, as discussed herein. Amyotrophic lateral sclerosis (ALS)

[0237] The present disclosure provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. AFurther provided are methods and compositions for treating cognitive impairment associated with ALS using R-positive allosteric modulators. In certain embodiments, treatment includes preventing or slowing the progression of cognitive impairment associated with ALS. In certain embodiments, treatment includes reducing, improving, or slowing the progression of one or more symptoms associated with ALS. In certain embodiments, the symptom being treated is cognitive impairment. Some embodiments of the present disclosure provide a method for protecting or improving cognitive function in a subject with ALS, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. The present methods and compositions can be used in clinical applications in treating cognitive impairment associated with ALS in human patients. The dose of the composition and the administration interval for the method are safe and effective for these applications, as described herein.

[0238] In addition to degeneration of motor neurons, ALS is characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory impairment, and neuronal hyperexcitability in various brain regions such as the cortex.

[0239] The effectiveness 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 and human subjects with ALS using a variety of cognitive tests known in the art, as discussed herein. Cognitive impairment associated with cancer treatment

[0240] The present disclosure provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. AFurther provided are methods and compositions for treating cognitive impairment associated with cancer therapy using R-positive allosteric modulators. In certain embodiments, treatment includes preventing or slowing the progression of cognitive impairment associated with cancer therapy. In certain embodiments, treatment includes reducing, improving, or slowing the progression of one or more symptoms associated with cognitive impairment associated with cancer therapy. In some embodiments, the symptom is cognitive impairment. Some embodiments of the present invention provide a method for protecting or improving cognitive function in a subject with cognitive impairment associated with cancer therapy, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. The method and composition can be used in clinical applications in treating cognitive impairment associated with cancer therapy in human patients. The dose of the composition and the administration interval for the method are safe and effective for these applications, as described herein.

[0241] Therapies used in cancer treatment, including chemotherapy, radiation, or a combination thereof, can cause cognitive impairment in patients, such as memory, learning, and attention.The cytotoxicity and other harmful side effects of cancer treatment on the brain are the basis for this form of cognitive impairment, which can last 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 the dysfunction of the prefrontal cortical and hippocampal circuits, which are essential for normal cognition. In animal models, exposure to either chemotherapy or radiation has a negative effect on performance on cognitive tests that specifically depend on these brain systems, particularly the hippocampus (Kim et al., J. Radiat. Res. 49:517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93:487-494, 2010). Therefore, drugs that target these cortical and hippocampal systems may be neuroprotective in patients undergoing cancer treatment and may be effective in treating symptoms of cognitive impairment that may persist beyond the intervention used as cancer treatment.

[0243] Animal models serve as an important resource for developing and evaluating treatments for cognitive impairment associated with cancer therapy. Characterizing cognitive impairment associated with cancer therapy in animal models The characteristics generally extend to cognitive impairment associated with cancer therapy in humans. Therefore, efficacy in such animal models reasonably predicts 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 those that involve the administration of antineoplastic agents such as cyclophosphamide (CYP) or radiation, e.g. 60 Examples include treating animals 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). The cognitive function of animal models of cognitive impairment associated with cancer therapy can then be examined using cognitive tests to assess the effectiveness of the methods and compositions of the present disclosure in treating cognitive impairment associated with cancer therapy. As discussed herein, the effectiveness of the methods and compositions of the present disclosure in treating cognitive impairment associated with cancer therapy, as well as human subjects with cognitive impairment associated with cancer therapy, can be assessed using various cognitive tests known in the art. Parkinson's disease (PD)

[0245] Parkinson's disease (PD) is a neurological disorder characterized by decreased voluntary movement. Affected patients have reduced motor activity and slower voluntary movements compared to normal individuals. Patients have a characteristic "mask-like" facial appearance, a tendency to hurry while walking, a hunched posture, and generalized muscle weakness. There is a typical "lead-pipe" rigidity of passive movements. Another important feature of the disease is tremor in the limbs, which occurs at rest and decreases during movement.

[0246] Parkinson's disease, whose etiology is unknown, is one of the most common movement disorders known as parkinsonism, affecting approximately 1 in 1,000 people. These other disorders, also classified as parkinsonism, can be caused by viral infections, syphilis, arteriosclerosis, trauma, and exposure to toxic chemicals and narcotics. It is believed that an inappropriate loss of synaptic stability can lead to the destruction of neuronal circuits and brain disease. Whether the cause is hereditary, drug use, the aging process, viral infection, or a variety of other factors, dysfunction of neuronal connections is believed to be the underlying cause of many neurological disorders, including PD (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

[0247] Regardless of the cause of this disease, the main pathological feature is the degeneration of dopaminergic cells in the basal ganglia, particularly in the substantia nigra. Due to the premature death of dopamine-containing neurons in the substantia nigra, the largest structure of the basal ganglia, the striatum reduces input from the substantia nigra, resulting in reduced dopamine release. Understanding the underlying pathology led to the introduction of the first successful treatments that could alleviate Parkinson's disease. Virtually all approaches to treating this disease are based on dopamine replacement. Drugs currently used in this treatment can be converted to dopamine after crossing the blood-brain barrier or can enhance dopamine synthesis and reduce its degradation. Unfortunately, the primary pathological event, cellular degeneration in the substantia nigra, cannot be rescued. The disease continues to progress, and after a certain period of time, dopamine replacement treatments often lose their effectiveness.

[0248] The present disclosure provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. A Methods and compositions are provided for treating cognitive impairment associated with PD using R-positive allosteric modulators. In certain embodiments, treatment includes preventing or slowing the progression of cognitive impairment associated with PD. In certain embodiments, treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with PD. In certain embodiments, the symptom being treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to improve motor / cognitive impairment symptomatic of Parkinson's disease. Furthermore, the methods and compositions of the present disclosure can be useful for treating memory impairment symptomatic of Parkinson's disease. In some embodiments of the present disclosure, a method for protecting or improving cognitive function in a subject with PD is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0249] Several animal models of PD exist. Exemplary animal models of PD include the reserpine model, methamphetamine model, 6-hydroxydopamine (6-OHDA) model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model, paraquat (PQ)-maneb model, rotenone model, 3-nitrotyrosine model, and genetic models using transgenic mice. Transgenic models include mice that overexpress α-synuclein, express human mutants of α-synuclein, or express LRKK2 mutations. See a review of these models by Ranjita B. et al. (Ranjita B. et al. BioEssays 2002, 24, 308-318). Additional information on these animal models can be found at Jackson Laboratories (see also http: / / research.jax.org / grs / parkinsons.html), and Numerous publications disclosing the use of these validated models are readily available.

[0250] The effectiveness of the methods and compositions of the present disclosure in treating PD or PD-related cognitive impairment can be assessed in any of the above animal models of PD and in human subjects with PD using a variety of cognitive tests known in the art, as discussed herein. autism

[0251] Autism is a neurodevelopmental disorder characterized by dysfunction in three core behavioral dimensions: repetitive behaviors, social deficits, and agnosia. The repetitive behavior domain includes obsessive-compulsive behaviors, unusual attachments to objects, strict adherence to routines or rituals, and repetitive motor habits such as stereotypic and self-stimulatory behaviors. The social deficit dimension includes deficits in reciprocal social interactions, failure to maintain eye contact, poor ability to maintain conversation, and impaired everyday interaction skills. Agnosia can also include language abnormalities. Autism and related autism spectrum disorders are disabling neurological disorders that affect thousands of Americans. They encompass several subtypes, have a variety of putative causes, and few reported ameliorative treatments. Autism spectrum disorders can be present at birth or develop later, for example, at age 2 or 3. There are no clear biological markers for autism. The diagnosis of this disorder is made by considering the degree to which a child fits a behavioral syndrome characterized by poor communication, social, and cognitive abilities, as well as maladaptive behavioral patterns. Dysfunction of neuronal connections is thought to be one of the underlying causes of autism (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214). Recent studies have suggested that GABAergic neurotransmitters may be involved in autism spectrum disorders (ASD). A These findings indicate the presence of α5 defects and support further investigation of the GABAergic system in this disorder (Mendez MA, et al. Neuropharmacology. 2013, 68:195-201).

[0252] The present disclosure also provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. AMethods and compositions are provided for treating cognitive impairment associated with autism using R-positive allosteric modulators. In certain embodiments, treatment includes preventing or slowing the progression of autism or autism-related cognitive impairment. In certain embodiments, treatment includes reducing, improving, or slowing the progression of one or more symptoms associated with autism. In certain embodiments, the symptom being treated is cognitive impairment or agnosia. For example, the methods and compositions of the present disclosure can be used to improve motor deficits / agnosia symptomatic of autism. In some embodiments of the present disclosure, a method for protecting or improving cognitive function in a subject with autism is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0253] The valproic acid (VPA) rat model of autism using in vitro electrophysiological techniques established by Rodier et al. (Rodier, PM et al. Reprod. Toxicol. 1997, 11, 417-422) is one of the most comprehensively established lesion-based animal models of autism. It was based on the observation in the 1960s that pregnant women treated with VPA had a higher risk of giving birth to autistic children than normal populations within a limited embryonic timeframe. Offspring from pregnant rats exposed to VPA exhibit several anatomical and behavioral symptoms typical of autism, including a reduced 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 explored using another mouse model, the BTBR T+tf / J (BTBR) mouse, an established model with a robust behavioral phenotype associated with three diagnostic behavioral symptoms of autism: abnormal social interaction, impaired communication, and repetitive behaviors. See, for example, Silverman JL et al. Sci Transl. Med. 2012, 4, 131. The efficacy of the methods and compositions of the present disclosure in treating autism or autism-associated agnosia can be evaluated in VPA-treated rat models of autism or the BTBR T+tf / J (BTBR) mouse model, and in human subjects with autism, using various cognitive tests known in the art, as discussed herein. Mental retardation

[0254] Mental retardation is a global disability characterized by significantly impaired cognitive function and deficits in adaptive behavior. Mental retardation is often defined as an intelligence quotient (IQ) score below 70. Congenital causes are the primary cause of many cases of mental retardation. Dysfunction in neuronal connections is also thought to be one of the primary causes of mental retardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

[0255] In some instances, mental retardation includes, but is not limited to, Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, fragile X syndrome, Klinefelter syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat-Wilson syndrome, ciliopathies, Lowe syndrome, and siderium-type X-linked mental retardation. Down syndrome is a disorder involving some degree of mental retardation, distinctive facial features, and a combination of birth defects, often including heart defects, numerous infections, vision and hearing problems, and other health issues. Fragile X syndrome is a common form of inherited mental retardation, occurring in 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 contemplates the treatment of cognitive impairments associated with mild mental retardation, moderate mental retardation, severe mental retardation, profound mental retardation, and unspecified mental retardation.Such mental retardation may, but need not, be related to chromosomal changes (e.g., Down's syndrome due to trisomy 21), genetics, pregnancy and perinatal issues, and other severe mental disorders.The present disclosure provides a method for treating cognitive impairments associated with mild mental retardation, moderate mental retardation, severe mental retardation, profound mental retardation, and unspecified mental retardation.Such mental retardation may, but need not, be related to chromosomal changes (e.g., Down's syndrome due to trisomy 21), genetics, pregnancy and perinatal issues, and other severe mental disorders. AMethods and compositions are provided for treating cognitive impairment associated with mental retardation using an R-positive allosteric modulator (e.g., selected from a compound as described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof). In certain embodiments, treatment includes preventing or slowing the progression of cognitive impairment associated with mental retardation. In certain embodiments, treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with mental retardation. In certain embodiments, the symptom treated is agnosia / functional impairment. For example, the methods and compositions of the present disclosure can be used to improve motor / cognitive impairment symptomatic of mental retardation. In some embodiments of the present disclosure, a method is provided for protecting or improving cognitive function in a subject with mental retardation, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0257] Several animal models have been developed for mental retardation. For example, knockout mouse models have been developed for fragile X syndrome. Fragile X syndrome is a common form of mental retardation caused by the absence of the FMR1 protein, FMRP. Two FMRP homologs, FXR1P and FXR2P, have been identified. Like FMRP, FXR2P is highly expressed in the brain and testis. Both Fxr2 knockout mice and Fmr1 knockout mice, as well as Fmr1 / Fxr2 double knockout mice, are considered useful models for mental retardation, such as fragile X syndrome. See Bontekoe CJM et al. Hum. Mol. Genet. 2002, 11 (5): 487-498. The effectiveness of the methods and compositions of the invention in treating mental retardation or agnosia / impairment 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 a variety of cognitive tests known in the art, as discussed herein. Obsessive-compulsive behavior (obsessive-compulsive disorder)

[0258] Obsessive-compulsive disorder ("OCD") is a mental condition characterized most commonly by intrusive, repetitive, and unwanted thoughts (obsessions) that individuals feel compelled to act on (compulsions), leading to compulsive behaviors and mental acts. Current epidemiological data indicate that OCD is the fourth most common mental disorder in the United States. Some studies suggest that the prevalence of OCD is between 1 and 3 percent, but the prevalence of clinically recognized OCD is lower, suggesting that many individuals with the disorder may be undiagnosed. Patients with OCD are often diagnosed by psychologists, psychiatrists, or psychoanalysts according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) (2000), which includes features of obsessions and compulsions. Obsessions are characterized by (1) recurrent 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 merely excessive preoccupations with real-life problems; and (3) the person attempts to ignore or suppress the thoughts, urges, or images or to neutralize them with some other thought or behavior. The person recognizes that the obsessive thoughts, urges, or images are products of their own mind and not based in reality. Characteristics of compulsions include (1) repetitive behaviors or mental acts that the person feels compelled to perform in response to a compulsion or according to rules that must be strictly applied; and (2) the behaviors or mental acts are intended to prevent or reduce distress or to prevent some frightening event or situation; but the behaviors or mental acts are not actually related to the problem or are excessive.

[0259] Individuals with OCD typically perform tasks (or compulsions) to seek relief from obsession-related anxiety. They often perform repetitive behaviors (such as hand washing, counting, checking, or cleaning) in the hope of thwarting or erasing obsessive thoughts. However, performing these "rituals" only provides temporary relief. People with OCD may also be diagnosed with a range of other mental disorders, such as generalized anxiety disorder, anorexia nervosa, panic attacks, or schizophrenia.

[0260] Dysfunction in neuronal connections is thought to be one of the underlying 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 is caused by abnormalities in the neurotransmitter serotonin. It has been suggested that OCD may be related to normal levels of anxiety. First-line treatment for OCD consists of behavioral therapy, cognitive therapy, and pharmacotherapy. Medications for treatment include serotonin reuptake inhibitors (SRIs), such as paroxetine (Seroxat™, Paxil®, Xetanor™, ParoMerck™, Rexetin™), sertraline (Zoloft®, Stimuloton™), fluoxetine (Prozac®, Bioxetin™), escitalopram (Lexapro®), and fluvoxamine (Luvox®), as well as tricyclic antidepressants, particularly clomipramine (Anafranil®). Benzodiazepines are also used for treatment. However, as many as 40-60% of patients do not respond adequately to SRI treatment, and an even larger proportion do not achieve complete remission of their symptoms.

[0261] The present disclosure provides an α5-containing GABA receptor antagonist, such as one selected from the compounds described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. AR agonists (e.g., α5-containing GABA A Methods and compositions are provided for treating OCD and cognitive impairment associated with OCD using R positive allosteric modulators (R positive allosteric modulators). In certain embodiments, treatment includes preventing or slowing the progression of OCD and cognitive impairment associated with OCD. In certain embodiments, treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with OCD. In certain embodiments, the symptom treated is cognitive impairment or agnosia. For example, the methods and compositions of the present disclosure can be used to treat agnosia in OCD and / or improve cognitive function in patients with OCD. In some embodiments of the present disclosure, a method of protecting or improving cognitive function in a subject with OCD is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0262] A quinpirole-sensitized rat model has been developed for OCD.The compulsive checking behavior of this quinpirole-sensitized rat is likely to be interrupted, which is a characteristic feature of OCD compulsive behavior.In addition, the effect of the new 5-HT2C receptor agonist WAY-163909 has been evaluated using the schedule-induced excessive drinking (SIP) rodent model of obsessive-compulsive disorder.See, for example, Rosenzweig-Lipson S. et al. Psychopharmacology (Berl) 2007, 192, 159-70.The effectiveness of the methods and compositions of the present disclosure in treating OCD or OCD-related cognitive impairment or agnosia can be evaluated in the above-mentioned animal models and other animal models developed for OCD, as well as in 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 instantly upon exposure to a substance of abuse. Rather, it requires multiple, complex neuronal adaptations that occur over a period of time ranging from hours to days to months (Kauer JA Nat. Rev. Neurosci. 2007, 8, 844-858). The path to substance addiction generally begins with the voluntary use of one or more controlled substances (such as narcotics, barbiturates, methamphetamine, alcohol, nicotine, and various other such controlled substances). Over time, persistent use of these controlled substances impairs the voluntary ability to abstain from them due to the effects of long-term use on brain function and therefore behavior. Therefore, substance addiction is generally characterized by compulsive substance craving, seeking, and use that persist despite negative consequences. The cravings may represent changes in the patient's underlying neurobiology, which must likely be addressed in a meaningful way if recovery is to be achieved. Substance addiction is also often characterized by life-threatening withdrawal symptoms for some substances (e.g., alcohol, barbiturates), and in other cases, substantial morbidity (which can include nausea, vomiting, fever, dizziness, and profuse sweating), distress, and a diminished ability to recover. For example, alcoholism, also known as alcohol dependence, is one such substance addiction. Alcoholism is primarily characterized by four symptoms: craving, loss of control, physical dependence, and tolerance. These symptoms can also characterize substance addiction to other controlled substances. Cravings for alcohol and other controlled substances are often as strong as cravings for food or water. Thus, alcoholics may continue to drink despite significant family, health, and / or legal consequences.

[0264] Recent studies exploring the effects of alcohol, central stimulants, and opiates on the central nervous system (CNS) have demonstrated a variety of adverse mental health effects, including substance-induced cognitive impairment. See Nyberg F. Cognitive Impairments in Drug Addicts, Chapter 9. Substantial impairment of brain function has been observed in several laboratories and clinics due to these drugs. The adverse effects of drugs of abuse on the brain contribute to accelerated degeneration. An observation that has received particular attention in recent years is that chronic drug users exhibit pronounced damage to brain regions associated with executive and memory functions. Recognized neuroadaptations caused by addictive drugs, such as alcohol, central stimulants, and opiates, include reduced neurogenesis in the subgranular zone (SGZ) of the hippocampus. Indeed, it has been proposed that reduced adult neurogenesis in the SGZ may alter hippocampal function in a way that contributes to the relapse and maintenance of addictive behaviors. It also raises the possibility that reduced neural activity may contribute to the agnosia induced by these drugs of abuse.

[0265] The present disclosure provides α5-containing GABA AMethods and compositions are provided for treating cognitive impairment associated with substance addiction using an R-positive allosteric modulator (selected from a compound as described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof). In certain embodiments, treatment includes preventing or slowing the progression of substance addiction and cognitive impairment associated with substance addiction. In certain embodiments, treatment includes preventing or slowing the progression of substance addiction. In certain embodiments, treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with substance addiction. In certain embodiments, the symptom 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 of protecting or improving cognitive function in a subject with substance addiction is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0266] Several animal models have been developed to study substance addiction.For example, genetically selected Marchigian Sardinian alcohol-preference (msP) rat model has been developed to study the neurobiology of alcoholism.See Ciccocioppo R. et al.Substance addiction Biology 2006, 11, 339-355.The effectiveness of the methods and compositions of the present invention in treating substance addiction or cognitive impairment associated with substance addiction can also be evaluated in animal models of substance addiction and 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, usually associated with the growth of malignant brain tumors. As brain tumors grow, they can press on adjacent areas of the brain, causing that part of the brain to stop working as it should. Brain cancer rarely spreads to other tissues outside the brain. Tumor grades, based on how abnormal the cancer cells appear under a microscope, can be used to distinguish between slow-growing and fast-growing tumors. Brain tumors are classified according to the type of cell from which they appear to arise. Diffuse fibrous astrocytoma is 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 astrocytoma, WHO grade III anaplastic astrocytoma, and WHO grade IV glioblastoma multiforme (GBM). WHO grade II astrocytoma is the slowest-growing of the diffuse astrocytoma spectrum. Astrocytomas exhibit a marked tendency to infiltrate the surrounding brain and complicate therapeutic attempts at local control. These aggressive capabilities are often evident in both low-grade and high-grade tumors.

[0268] Glioblastoma multiforme is the most malignant stage of astrocytoma, with a survival time of less than two years for most patients. Histologically, these tumors are characterized by 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. A host of angiogenic growth factors and their receptors are found in GBM.

[0269] Biological subsets of astrocytomas exist, which may reflect the clinical heterogeneity observed in these tumors. These subsets include brainstem gliomas, which are a form of pediatric diffuse fibrillary astrocytoma that often follows a malignant course. Brainstem GBM shares genetic characteristics with adult GBM, which affects younger patients. Pleomorphic xanthoastrocytoma (PXA) is a superficial, low-grade astrocytic tumor that primarily affects young adults. Although these tumors have a bizarre histologic appearance, they are usually slow-growing tumors that may be amenable to surgical treatment. However, some PXA tumors may recur as GBM. Pilocytic astrocytoma is the most common astrocytic tumor of childhood and is clinically and histopathologically distinct from the diffuse fibrillary astrocytoma that affects adults. Pilocytic astrocytoma does not share the same genomic alterations as diffuse fibrillary astrocytoma. Subependymal giant cell astrocytomas (SEGAs) are periventricular, low-grade astrocytic tumors usually associated with tuberculous sclerosis (TS) and are histologically identical to the so-called "candle-guttering" tumors lining the ventricles of patients with TS. Like other neoplastic lesions in TS, they grow slowly and may resemble hamartomas rather than true neoplasms. Desmoplastic cerebral astrocytomas of infants (DCAIs) and desmoplastic infantile gangliogliomas (DIGGs) are large, superficial, usually cystic, benign astrocytomas affecting children in the first 1 to 2 years of life.

[0270] Oligodendrogliomas and oligoastrocytomas (mixed gliomas) are diffuse, usually brain tumors that are clinically and biologically most closely related 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 either WHO grade III anaplastic oligodendrogliomas or anaplastic oligoastrocytomas or WHO grade IV GBM. Thus, genetic alterations leading to oligodendroglial tumors constitute yet another pathway to GBM.

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

[0272] Medulloblastoma is a highly malignant primitive tumor that primarily occurs in the posterior fossa in children. It is the most common malignant brain tumor in children. It can spread throughout the CNS and often metastasizes to various 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, although some "atypical" meningiomas may recur locally, and some meningiomas are frankly malignant and may invade or metastasize to the brain. Atypical and malignant meningiomas are less common than benign meningiomas. Schwannomas are benign tumors that arise in peripheral nerves. Schwannomas can arise in the cranial nerves, particularly the vestibular portion of the eighth cranial nerve (vestibular schwannoma, acoustic schwannoma), presenting as a cerebellopontine angle mass. Hemangioblastomas are tumors of unknown origin composed of endothelial cells, pericytes, and so-called interstitial cells. These benign tumors most frequently occur in the cerebellum and spinal cord of young adults. Multiple hemangioblastomas are a hallmark of von Hippel-Lindau disease (VHL). Hemangiopericytomas (HPCs) are dural tumors that can exhibit locally invasive behavior and can metastasize. The histogenesis of dural-based hemangiopericytomas (HPCs) has long been debated, with some authors classifying them as a separate entity and others as a subtype of meningioma.

[0274] Group 3 tumors were α5-containing GABA A They share high expression of R. α5-containing GABA A R is present in patient-derived Group 3 cells and tumor tissues and expresses functional α5-containing GABAA The most lethal medulloblastoma subtype is GABAergic. A High expression of the Rα5 subunit gene and MYC amplification are shown. See, e.g., J. Biomed. Nanotechnol. 2016 Jun;12(6):1297-302.

[0275] The present invention relates to α5-containing GABA A R-positive allosteric modulators (such as those selected from a compound as described herein or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof) are used to inhibit the activity of α5-containing GABA receptors. A Methods and compositions are provided for treating brain cancers (e.g., brain tumors described herein) that express R and their associated cognitive impairments. In certain embodiments, treatment includes preventing or slowing the progression of brain cancer and brain cancer-associated cognitive impairment. In certain embodiments, treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with brain cancer. In certain embodiments, the symptom being treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to treat cognitive impairment and / or improve cognitive function in patients with brain cancer. In some embodiments of the present disclosure, a method for protecting or improving cognitive function in a subject with brain cancer is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In some embodiments, the brain tumor is a medulloblastoma. Research area standards (RdoC)

[0276] The present disclosure provides the α5-containing GABA AFurther provided are methods and compositions for treating cognitive impairment associated with neurological disorders and neuropsychiatric conditions using R positive allosteric modulator, or its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its isomer, or combinations thereof.In certain embodiments, treatment comprises alleviating, improving, or slowing down the progression of one or more symptoms associated with such disorders.In another aspect of the present disclosure, provided are methods and compositions for protecting or improving cognitive function in subjects who need to protect or improve cognitive function using the compound of the present disclosure or its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its isomer, or combinations thereof.

[0277] The Research Domain Criteria (RdoC) are used to enhance clinical criteria, such as those in the DSM and ICD, for diagnosing diseases and disorders affecting the nervous system (see, e.g., Am. J. Psychiatry 167:7 (2010)). The RdoC aims to provide a classification based on discoveries in genomics and neuroscience, as well as clinical observations. α5-containing GABA receptors in specialized neuronal circuits of the nervous system. A High expression levels of R are therapeutic targets for dysfunctional neuronal circuits identified under RdoC. GABA A Assays for α5 subunit binding and receptor positive allosteric modulator activity

[0278] GABA A GABA containing the α5 subunit A The affinity of the test compound for R can be determined using any receptor binding assay known in the art, see, e.g., U.S. Pat. No. 7,642,267 and U.S. Pat. No. 6,743,789, which are incorporated herein by reference.

[0279] α5-containing GABA AThe activity of a test compound as a positive allosteric modulator can be tested by electrophysiological methods known in the art.See, for example, U.S. Patent No. 7,642,267 and Guidotti et al., Psychopharmacology 180: 191-205, 2005.Positive allosteric modulator activity can be measured by, for example, GABA A GABA containing the α5 subunit A The activity of R can be tested by assaying the GABA-induced chloride ion conductance of R. Cells expressing such receptors can be exposed to an effective amount of a compound of the present disclosure. Such cells can be contacted in vivo with a compound of the present disclosure by contacting the cells with a body fluid containing the compound of the present disclosure, for example, by contacting the cells with cerebrospinal fluid. In vitro testing can be performed by contacting the cells with a compound of the present disclosure in the presence of GABA. GABA A GABA containing the α5 subunit A An increase in GABA-induced chloride conductance in cells expressing R in the presence of a test compound indicates that the compound has positive allosteric modulator activity. Such a change in conductance can be, for example, a signal from GABA receptors. A R subunit mRNA (GABA A Xenopus oocytes injected with GABA A This can be detected by using voltage clamp assays performed on HEK 293 cells transfected with a plasmid encoding the R subunit, or on in vivo, ex vivo or cultured neurons.

[0280] It will be understood by those skilled in the art that the methods described herein may be adapted and modified as appropriate for the application being addressed, and that the methods described herein may be used in other suitable applications, and that such other additions and modifications do not depart from the scope of the present invention.

[0281] The present disclosure will be better understood from the examples that follow. However, those skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the present disclosure, which is more fully described in the embodiments that follow. Example 1 Synthesis of compound 18 [ka] Scheme 4 [ka]

[0282] 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) at 0 °C was added acid chloride 4.2 (21.4 g, 130 mmol) dropwise. Upon completion of the addition, the ice bath was removed and the reaction was continued 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 product 4.3 (21.4 g) as a pinkish solid.

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

[0284] Ester 4.4 (2.54 g) from above was treated with DMSO (50 ml) and water (1 ml) at 160° C. for approximately 5 hours, cooled to room temperature, and an ice-water mixture (approximately 200 g) was added with stirring. The precipitate was collected by filtration and washed with water. The filtrate was repeatedly extracted with EtO, and the combined ether solution was washed with water, brine, dried over MgSO, filtered, and the solvent removed to give excess crude product. This was combined with the above precipitate and purified by column chromatography (0 to 100% EtOAc gradient in hexanes) to give 4.5 (1.4 g).

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

[0286] A solution of 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 minutes and then heated to 80° C. for 16 hours. Upon cooling, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO, brine, and dried over MgSO. Filtration, concentration, and subsequent silica gel column chromatography using a gradient of 0 to 8% MeOH in DCM as eluent afforded a brownish foamy solid, which was dissolved in DCM (30 mL) and treated with TFA (20 mL) at room temperature for 16 hours. The mixture was concentrated, diluted with EtOAc, washed with saturated NaHCO, and the aqueous layer was back-extracted with EtOAc (2×), combined with the organic layer, washed with brine, and dried over MgSO. Filtration and concentration followed by silica gel column chromatography using a gradient of 0 to 100% EtOAc in hexanes gave 218.0 mg of N11-methyl lactam (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 was added t-BuOK powder (192 mg) at −20° C. After stirring for 20 min at −20° C., diethyl chlorophosphate (329.5 mg, 1.91 mmol) was added dropwise and the reaction was allowed to slowly warm to approximately +5° C. with stirring over 2 h.

[0288] The reaction mixture was cooled back to -20 °C, and isocyanoacetic acid ethyl ester (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 warm 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 biphasic solution was collected by filtration, washed with water, and dried to give the desired product 4.7 (141.2 mg). The aqueous layer of the filtrate was separated, extracted with EtOAc, combined with the organic layer, washed with water (2x), brine (1x), and dried over MgSO. An additional 121.1 mg of product was obtained by silica gel column chromatography using a 0 to 100% EtOAc gradient in hexanes. The total product weight of 4.7 is 262.3 mg (73%).

[0289] Acetamide oxime (R = Me) was azeotroped three times in toluene prior to use. To a suspension of acetamide oxime (43.3 mg, 0.58 mmol) in THF (0.5 mL) was added 60% NaH dispersion in oil (11.7 mg, 0.293 mmol) at 0 °C. The suspension was stirred for 10 minutes. Ester 4.7 (16.5 mg, 0.049 mmol) from above was added. The ice bath was removed, and the resulting suspension was stirred at ambient temperature for 30 minutes, then heated at 70 °C for 40 minutes. The reaction mixture was quenched with saturated NaHCO and extracted with EtOAc, which was then washed with brine and dried over MgSO. Preparative TLC using 80% EtOAc in hexanes afforded the desired product, Example 1, Compound 18 (11.7 mg), as a yellowish solid. MS: [M+1] = 349. 1NMR (CDCl3) δ 7.76 (1H, s), 7.51 (1H,br d, J= 8 Hz), 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 [ka]

[0290] Example 2 was prepared similarly to Example 1, using N'-hydroxypivalimidamide in the final oxadiazole ring formation 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 [ka] Example 2a was prepared similarly to Example 1, using N'-hydroxy-2-(4-morpholinyl)ethanimidamide in the final oxadiazole ring formation step. MS: [M+1]=434. Example 3 Synthesis of Compound 03 [ka]

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

[0292] Example 4 was prepared similarly to Example 1, starting with methyl 2-amino-5-chlorobenzoate in the first step and using isobutylamide oxime in the final oxadiazole-forming step. MS: [M+1]=381. Scheme 5 [ka] Example 5 Synthesis of Compound 07 [ka]

[0293] A solution of intermediate A (R1 = OMe; 827 mg, 3.18 mmol) and benzylhydrazine diHCl (2.48 g, 12.7 mmol) in isopropanol (20 ml) was stirred at room temperature for 30 minutes and then heated to 90 °C for 5 hours. Upon cooling, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, brine, and dried over MgSO4. Filtration and concentration, followed by silica gel column chromatography using a 0 to 100% EtOAc gradient in hexane as the eluent, afforded benzylpyrazololactam 5.1 (523 mg) as a yellowish solid. 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) under nitrogen at −20°C, tBuOK powder (284 mg) was added. 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 approximately +50°C over 2 h with stirring. The reaction mixture was recooled to −20°C, and isocyanoacetic acid ethyl ester (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 warm to room temperature overnight. After quenching with saturated NaHCO3, ...

Claims

1. A compound having the structure of Formula I: 【Chemistry 471】 or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein: X is O, N, or -NR ３ or -C(R ４ ) １～２ are independently selected from W is O, N or NR ３ and V is O, NR ３ or -C(R ４ ) １～２ and When X is O, W is N and V is —C(R ４ ) １～２ and When X is N, W is O or —NR ３ and V is -C(R ４ ) １～２ and X is -NR ３ When W is N and V is -C(R ４ ) １～２ and X is -C(R ４ ) １～２ When W is N and V is O or —NR ３ and join 【Chemistry 472】 is either a single bond or a double bond at each occurrence, m is an integer selected from 0 to 4; Each R １ is -halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -NCS, -NO ２ , -CHF ２ , -CF ３ , -OCF ３ , -OCHF ２ , -CO(O)R7, -CH ２ -OR ８ , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R ２ is -CO(O)R7, -C≡C-R ９ , —(C1-C6) alkyl-C≡C—R ９ , -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, or -(C3-C10)cycloalkenyl, wherein each (5-6 membered)heteroaryl and (3-10 membered)heterocycle is substituted with 0-4 R7; Each R7 is —H, —CF ３ , -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl-(C1-C6)alkyl, or -(3-10 membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, said two R7 groups together with the atoms to which they are attached form N, NH, O, S, SO or SO ２ and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from Each R ８ is —H, —(C1-C6)alkyl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C3-C10)cycloalkenyl, —(C6-C10)aryl, —(C3-C6)cycloalkyl, —CH ２ -(C3-C6)cycloalkyl, -CH ２ -(C6-C10)aryl or -CH ２ -(5- to 10-membered) heteroaryl; R ８ each occurrence of is independently substituted with 0-5 R'; Each R ９ is selected from —H, —(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, (C3-C10)cycloalkenyl, —(C6-C10)aryl, —(C3-C6)cycloalkyl, —(C1-C6)alkyl-(C6-C10)aryl, —(C1-C6)alkyl-(5-10 membered)heteroaryl, —(C1-C6)alkyl-(C3-C6)cycloalkyl or —C(O)—(C6-C10)aryl; R ９ Each occurrence of １１ and are independently substituted by R １１ Each occurrence of is selected from -(C1-C6) alkyl, -O-(C1-C6) alkyl, -halogen, -CF ３ , -OCF ３ , -OMe, -(C6-C10)aryl or -(5-10 membered)heteroaryl, wherein said heterocyclyl is N, NH, O, S, SO or SO ２ wherein said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O or S; R ３ is —H, —(C1-C6)alkyl, —(C1-C6)alkyl-(C3-C6)cycloalkyl, —(C1-C6)alkyl-OR １２ , -(C1-C6) alkyl-N(R １２ ) ２ , -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, -(5-10 membered)heteroaryl, -C(O)-(C6-C10)aryl, -C(O)-(C1-C6)alkyl, or -C(O)-(C3-C6); R ３ is 0 to 5 R １２ are independently substituted with Each R １２ is -H, -halogen, -OR ｏ , R ｏ , oxo, -CH ２ OR ｏ , -CH ２ N (R ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ or -N(R ｏ ) ２ and R ｏ each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, or -(C6-C10)aryl, wherein said heterocyclyl is N, NH, O, S, SO, or SO ２ wherein said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O or S; R ４ is selected from —H or —(C1-C6)alkyl; R ６ is selected from —H or —(C1-C6)alkyl; Each R １３ and R １４ is independently selected from —H, —(C1-C3)aliphatic, or —(C3-C6)cycloalkyl; Each occurrence of R' is selected from halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR'' ２ , -C(O)N(R'') ２ , -C(O)OR'', -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ or -N(R'') ２ are independently selected from Each occurrence of R″ is independently selected from —H, —(C1-C6)aliphatic, —(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, —(C6-C10)aryl, —(C1-C6)alkyl-(5-10 membered)heteroaryl, —(C1-C6)alkyl-(C6-C10)aryl, —(C1-C6)alkyl-O-(5-10 membered)heteroaryl, or —(C1-C6)alkyl-O-(C6-C10)aryl, and each occurrence of R″ is independently substituted with 0-3 substituents; particularly, in some aspects of the present disclosure, R″ is independently substituted with 1-3 substituents, said substituents being halogen, —R ｏ , -OR ｏ , oxo, -CH ２ OR ｏ , -CH ２ N (R ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ or -N(R ｏ ) ２ is selected from R ｏ each occurrence is independently selected from -(C1-C6)aliphatic, -O(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-6 membered)heterocyclyl, -(5-10 membered)heteroaryl, or -(C6-C10)aryl, wherein said heterocyclyl is N, NH, O, S, SO, or SO ２ wherein said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O or S.

2. Structure of Formula IA: 【Chemistry 473】 [In the formula, m, R １ , R ２ , R ３ , R ４ , R ６ , R １３ and R １４ or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein:

3. Structure of Formula Ia: 【Chemistry 474】 [In the formula, m is an integer selected from 0 to 4; Each R １ is -halogen, -(C6-C10)aryl, -O(C1-C6)alkyl, -CN, -CHF ２ , -CF ３ , -OCF ３ , -OCHF ２ , -CO(O)R7, -CH ２ -OR ８ , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R ８ is independently selected from —H or —(C1-C6)alkyl; Each R ２ is -CO(O)R7, -C≡C-R ９ , —(C1-C6) alkyl-C≡C—R ９ , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, 【Chemistry 475】 is selected from each 5-6 membered heteroaryl and 3-10 membered heterocycle is substituted with 0-4 R7; Each R ９ is —H, —(C1-C6)alkyl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C6-C10)aryl, —(C1-C6)alkyl-(C6-C10)aryl, 【Chemistry 476】 is selected from R ９ Each occurrence of １１ and are independently substituted by R １１ Each occurrence of is selected from -(C1-C6) alkyl, -O-(C1-C6) alkyl, -halogen, -CF ３ , -OCF ３ , -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R ３ is independently selected from —H, —(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, —(C1-C6)alkyl-(C3-C6)cycloalkyl, or —(C1-C6)alkyl-(C6-C10)aryl; R ３ is 0 to 5 R １２ are independently substituted with Each R １２ is -H, -halogen, -OR ｏ , R ｏ , oxo, -CH ２ OR ｏ , -CH ２ N (R ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -CF ３ , -OCF ３ or -N(R ｏ ) ２ and R ｏ each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-10 membered)heterocyclyl, or -(C6-C10)aryl; Each R7 is —H, —CF ３ , -(C1-C6) alkyl, -(C3-C6) cycloalkyl, -(5-10 membered) heteroaryl, -(C6-C10) aryl, -CH ２ -(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 attached to the same atom, said two R7 groups together with the atoms to which they are attached form N, NH, O, S, SO or SO ２ and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from Each occurrence of R' is selected from halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR'' ２ , -C(O)N(R'') ２ , -C(O)OR'', -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ or -N(R'') ２ and R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, or —(C6-C10)aryl; R″ is independently substituted with 1 to 3 substituents, said substituents being halogen, —CF ３ , -OCF ３ , —O—(C1-C6)aliphatic or —(C1-C6)aliphatic; Each R ４ is selected from —H or —(C1-C6)alkyl; Each R ６ is selected from —H or —(C1-C6)alkyl; Each R １３ and R １４ are independently selected from —H, —(C1-C3)aliphatic, or —(C3-C6)cycloalkyl. or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, of the compound of claim 2,

4. Structure of Formula I-aa: 【Chemistry 477】 [In the formula, m is an integer selected from 0 to 4; Each R １ is halogen, —(C6-C10)aryl, —O(C1-C6)alkyl, —CN, —CHF ２ , -CF ３ , -OCF ３ , -OCHF ２ , CO(O)R7, CH ２ -OR ８ , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R ８ is independently selected from —H or —(C1-C6 alkyl); Each R ２ is CO(O)R7, C≡CR ９ , —(C1-C6) alkyl-C≡C—R ９ , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, -(C3-C10)cycloalkenyl, 【Chemistry 478】 is selected from each 5-6 membered heteroaryl and 3-10 membered heterocycle is substituted with 0-4 R7; Each R ９ is —H, —(C1-C6)alkyl, (5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, —(C6-C10)aryl, —(C1-C6)alkyl-(C6-C10)aryl, 【Chemistry 479】 is selected from R ９ Each occurrence of １１ and are independently substituted by R １１ Each occurrence of is selected from -(C1-C6) alkyl, -O-(C1-C6) alkyl, -halogen, -CF ３ , -OCF ３ , -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R ３ is independently selected from —H, —(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, —(C1-C6)alkyl-(C3-C6)cycloalkyl, or —(C1-C6)alkyl-(C6-C10)aryl; R ３ is 0 to 5 R １２ are independently substituted with Each R １２ is -H, -halogen, -OR ｏ , R ｏ , oxo, -CH ２ OR ｏ , -CH ２ N (R ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -CF ３ , -OCF ３ or -N(R ｏ ) ２ and R ｏ each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3-10 membered)heterocyclyl, or -(C6-C10)aryl; Each R7 is —H, —CF ３ , -(C1-C6) alkyl, -(C3-C6) cycloalkyl, -(5-10 membered) heteroaryl, -(C6-C10) aryl, -CH ２ -(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 attached to the same atom, said two R7 groups together with the atoms to which they are attached form N, NH, O, S, SO or SO ２ and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from Each occurrence of R' is selected from halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR'' ２ , -C(O)N(R'') ２ , -C(O)OR'', -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ or -N(R'') ２ are independently selected from 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 to 3 substituents, the substituents being halogen, —CF ３ , -OCF ３ , —O—(C1-C6)aliphatic or —(C1-C6)aliphatic; Each R ４ is selected from —H or —(C1-C6)alkyl; Each R ６ is selected from —H or —(C1-C6)alkyl; Each R １３ and R １４ are independently selected from —H, —(C1-C3)aliphatic, or —(C3-C6)cycloalkyl. or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, of the compound of claim 2,

5. m is 0, 1 or 2; However, when m is 1 or 2, R １ at least one occurrence of is -halogen or -O-(C1-C6)alkyl; Each R １ is independently selected from -halogen and -O-(C1-C6)alkyl; R ２ But -C≡C-R ９ , -(C3-C10)cycloalkenyl, 【Chemical 480】 is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R ９ is -(C1-C6) alkyl, 【Chemistry 481】 is selected from R ９ Each occurrence of １１ and are independently substituted by R １１ each occurrence of is independently selected from —(C1-C6)alkyl and —O—(C1-C6)alkyl; R ３ is 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; R ３ But 0 to 5 R １２ are independently substituted with R7 is -CF ３ , -(C1-C6) alkyl, -(C6-C10) aryl or -CH ２ -(C6-C10)aryl, wherein each R7 is independently substituted with 0-5 R'; R ４ and R ６ each occurrence of is -H, R １１ , R １２ , R １３ and R １４ 5. The compound of claim 4, wherein R′ and R″ are as defined in formula I-aa, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

6. Structure of Formula IB: 【Chemistry 482】 [In the formula, m, R １ , R ２ , R ３ , R ４ , R ６ , R １３ and R １４ or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein:

7. Structure of Formula Ib: 【Chemistry 483】 [In the formula, m is an integer selected from 0 to 4; Each R １ represents -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF ２ , -CF ３ , -OCF ３ , -OCHF ２ , -CO(O)R7, -CH ２ -OR ８ , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R ８ is independently selected from —H or —(C1-C6)alkyl; Each R ２ is -CO(O)R7, -C≡C-R ９ , —(C1-C6) alkyl-C≡C—R ９ , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, 【Chem.484】 is selected from each 5-6 membered heteroaryl or 3-10 membered heterocycle is substituted with 0-4 R7; Each R ９ is —H, —(C1-C6)alkyl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C6-C10)aryl, —(C1-C6)alkyl-(C6-C10)aryl, 【Chemistry 485】 is selected from R ９ Each occurrence of １１ and are independently substituted by R １１ Each occurrence of is selected from -(C1-C6) alkyl, -O-(C1-C6) alkyl, -halogen, -CF ３ , -OCF ３ , -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R ３ is —H, —(C1-C6)alkyl, —(C1-C6)alkyl-(C3-C6)cycloalkyl, —(C1-C6)alkyl-OR １２ , -(C1-C6) alkyl-N(R １２ ) ２ , -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, or -(5-10 membered)heteroaryl; R ３ is 0 to 5 R １２ are independently substituted with Each R １２ is -H, -halogen, -OR ｏ , R ｏ , oxo, -CH ２ OR ｏ , -CH ２ N (R ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ or -N(R ｏ ) ２ and R ｏ each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl, or -(C6-C10)aryl; Each R7 is —H, —CF ３ , -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(5-10 membered)heteroaryl, -(C6-C10)aryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(3-10 membered)heterocyclyl, wherein each R7 is independently substituted with 0-5 R'; or when two R7 groups are attached to the same atom, said two R7 groups together with the atoms to which they are attached form N, NH, O, S, SO or SO ２ and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from Each occurrence of R' is selected from -halogen, -R'', -OR'', oxo, -CH ２ OR'', -CH ２ NR'' ２ , -C(O)N(R'') ２ , -C(O)OR'', -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ or -N(R'') ２ are independently selected from R″ is selected from —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5-10 membered)heteroaryl, —(5-10 membered)heteroaryl, —(3-10 membered)heterocyclyl, —(C3-C6)cycloalkyl, or —(C6-C10)aryl; R″ is independently substituted with 1 to 3 substituents, the substituents being halogen, —CF ３ , -OCF ３ , —O(C1-C6)aliphatic, —(C1-C6)aliphatic, or —(5-10 membered)heteroaryl; Each R ４ and R ６ is independently selected from —H or —(C1-C6)alkyl; Each R １３ and R １４ are independently selected from H—, —(C1-C3)aliphatic, or —(C3-C6)cycloalkyl. or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, of the compound of claim 6 .

8. Structure of formula I-ba: 【Chemical 486】 [In the formula, m is an integer selected from 0 to 4; Each R １ represents -halogen, -(C6-C10)aryl, -OMe, -CN, -CHF ２ , -CF ３ , -OCF ３ , -OCHF ２ , -CO(O)R7, -CH ２ -OR ８ , -(C1-C6)alkyl-(C6-C10)aryl, -(5-10 membered)heteroaryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, or -(C3-C6)cycloalkyl; Each R ８ is independently selected from —H or —(C1-C6 alkyl); Each R ２ is -CO(O)R7, -C≡C-R ９ , —(C1-C6) alkyl-C≡C—R ９ , -(5- to 10-membered)heteroaryl, -(3- to 10-membered)heterocyclyl, 【Chemistry 487】 is selected from each 5-6 membered heteroaryl or 3-10 membered heterocycle is substituted with 0-4 R7; Each R ９ is —H, —(C1-C6)alkyl, —(5- to 10-membered)heteroaryl, —(3- to 10-membered)heterocyclyl, —(C6-C10)aryl, —(C1-C6)alkyl-(C6-C10)aryl, 【Chemical 488】 is selected from R ９ Each occurrence of １１ and are independently substituted by R １１ Each occurrence of is selected from -(C1-C6) alkyl, -O-(C1-C6) alkyl, -halogen, -CF ３ , -OCF ３ , -OMe, -(C6-C10)aryl, or -(5-10 membered)heteroaryl; R ３ is —H, —(C1-C6)alkyl, —(C1-C6)alkyl-(C3-C6)cycloalkyl, —(C1-C6)alkyl-OR １２ , -(C1-C6) alkyl-N(R １２ ) ２ , -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-(5-10 membered)heteroaryl, -(3-10 membered)heterocyclyl, or -(5-10 membered)heteroaryl; R ３ is 0 to 5 R １２ are independently substituted with Each R １２ is -H, -halogen, -OR ｏ , R ｏ , oxo, -CH ２ OR ｏ , -CH ２ N (R ｏ ) ２ , -C(O)N(R ｏ ) ２ , -C(O)OR ｏ , -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ or -N(R ｏ ) ２ and R ｏ each occurrence is independently selected from -(C1-C6)aliphatic, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocyclyl, -(5- to 10-membered)heteroaryl, or -(C6-C10)-aryl; Each R7 is —H, —CF ３ , -(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 attached to the same atom, said two R7 groups together with the atoms to which they are attached form N, NH, O, S, SO or SO ２ and optionally forming a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from Each occurrence of R' is selected from halogen, -R'', -OR'', oxo, CH ２ OR'', -CH ２ NR'' ２ , -C(O)N(R'') ２ , -C(O)OR'', -NO ２ , -NCS, -CN, -CF ３ , -OCF ３ or -N(R'') ２ are independently selected from R″ is —Cl, —F, —(C1-C6)alkyl, —OMe, —(C1-C6)alkyl-(5-10 membered)heteroaryl, —(5-10 membered)heteroaryl, —(3-10 membered)heterocyclyl, —(C3-C6)cycloalkyl, —(C6-C10)aryl, —H, or —C(O)CH ３ is selected from R″ is independently substituted with 1 to 3 substituents, the substituents being halogen, —CF ３ , -OCF ３ , —O(C1-C6)aliphatic, —(C1-C6)aliphatic, -(5-10 membered)heteroaryl or oxo; Each R ４ and R ６ is independently selected from —H or —(C1-C6)alkyl; Each R １３ and R １４ are independently selected from —H, —(C1-C3)aliphatic, or —(C3-C6)cycloalkyl. or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, of the compound of claim 6 .

9. m is 0, 1 or 2; However, when m is 1 or 2, R １ at least one occurrence of is -halogen or -O-(C1-C6)alkyl; Each R １ is independently selected from -halogen and -O-(C1-C6)alkyl; R ２ But -C≡C-R ９ , 【Chemistry 489】 is selected from each 5-membered heterocycle or heteroaryl is substituted with 0-4 R7; Each R ９ is selected from -(C1-C6) alkyl, and R ９ Each occurrence of １１ and are independently substituted by R １１ each occurrence of is selected from -(C1-C6)alkyl; R ３ is —H, —(C1-C6) alkyl, or —CH ２ -(C6-C10)aryl and -(3- to 10-membered)heterocyclyl; R ３ But 0 to 5 R １２ are independently substituted with R7 is -(C1-C6) alkyl, -CH ２ -(C6-C10)aryl, -(C3-C6)cycloalkyl, and -(3- to 10-membered)heterocyclyl; each R7 is independently substituted with 0-5 R'; R ４ and R ６ each occurrence of is -H, R １１ , R １２ , R １３ , R １４ and R' is as defined in formula I-ba, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

10. Structure of Formula IC: 【Chemistry 490】 [In the formula, m, R １ , R ２ , R ３ , R ４ , R ６ , R １３ and R １４ or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, of the compound of claim 1, wherein:

11. Structure of Formula ID: 【Chemical 495】 [In the formula, m, R １ , R ２ , R ４ , R ６ , R １３ and R １４ or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, of the compound of claim 1, wherein:

12. Structure of Formula IE: [500] [In the formula, m, R １ , R ２ , R ４ , R ６ , R １３ and R １４ or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, of the compound of claim 1, wherein:

13. Structure of Formula IF: 【Chemical 505】 [In the formula, m, R １ , R ２ , R ４ , R ６ , R １３ and R １４ or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein:

14. below: Table 9-1 Table 9-2 Table 9-3 Table 9-4 Table 9-5 Table 9-6 Table 9-7 Table 9-8 Table 9-9 Table 9-10 Table 9-11 Table 9-12 Table 9-13 Table 9-14 Table 9-15 Table 9-16 Table 9-17 Table 9-18 Table 9-19 Table 9-20 Table 9-21 Table 9-22 Table 9-23 Table 9-24 Table 9-25 Table 9-26 Table 9-27 Table 9-28 Table 9-29 Table 9-30 Table 9-31 Table 9-32 Table 9-33 Table 9-34 Table 9-35 Table 9-36 or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

15. below: Table 10-1 Table 10-2 Table 10-3 Table 10-4 Table 10-5 Table 10-6 Table 10-7 Table 10-8 Table 10-9 Table 10-10 Table 10-11 Table 10-12 Table 10-13 Table 10-14 Table 10-15 Table 10-16 Table 10-17 Table 10-18 or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

16. 16. A pharmaceutical composition comprising one or more of the compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or an isomer thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the compound or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or an isomer thereof is present in the composition in a therapeutically effective amount.

17. A composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof, or a pharmaceutical composition comprising one or more of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, for treating or preventing cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof.

18. 18. The composition of claim 17, wherein the CNS disorder is age-related cognitive impairment, mild cognitive impairment (MCI), amnesic mild cognitive impairment (aMCI), dementia, Alzheimer's disease, schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), mental retardation, Parkinson's disease (PD), autism, obsessive-compulsive behavior, substance addiction, prodromal AD, or a CNS disorder associated with cancer treatment.

19. A composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof, or a pharmaceutical composition comprising one or more of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, for treating or preventing brain cancer in a subject in need thereof.

20. A composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof, or a pharmaceutical composition comprising one or more of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, for treating or preventing cognitive impairment associated with brain cancer in a subject in need thereof.

21. 20. The composition of claim 19, wherein the brain cancer is medulloblastoma.

22. 21. The composition of claim 20, wherein the brain cancer is medulloblastoma.

23. A composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof, or a pharmaceutical composition comprising one or more of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, or isomer thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, for treating or preventing cognitive impairment associated with a risk factor for said cognitive impairment in a subject at risk of said cognitive impairment, wherein said risk factor for said cognitive impairment is age-related or a decrease in hippocampal function. a genetic risk associated with the presence of one or more genomic variants, mutations or polymorphisms 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 said subject; associated with the presence of at least one allele of the APOE4 gene in the genome of said subject; or associated with the presence of one or more biofluid biomarkers selected from the group consisting of p-tau, t-tau and amyloid beta in said subject.

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