Benzodiazepine derivatives, compositions and methods for treating cognitive disorders

Abstract

The present invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of the derivatives, and methods of using the derivatives or compositions in treating cognitive disorders associated with CNS disorders. The present invention also relates to the use of α5-containing GABA receptor antagonists in the treatment of cognitive disorders associated with CNS disorders in subjects in need of or at risk for such treatment, including age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI, age-associated memory impairment, age-related cognitive decline, dementia, Alzheimer's disease (AD), prodromal AD, PTSD, schizophrenia, bipolar disorder, ALS, cognitive disorders associated with cancer treatment, mental retardation, Parkinson's disease, autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction. A The present invention also relates to the use of α5-containing GABA receptor agonists in the treatment of brain cancer (including brain tumors, e.g., medulloblastoma) and cognitive impairment associated with brain cancer. A The present invention relates to the use of receptor agonists.

Description

[Technical Field]

[0001] Statement of government support This invention was made with government support under Grant No. U01 AG041140, Grant No. UH2NS101856 and Grant No. UH3NS101856 awarded by the National Institutes of Health (NIH), an agency of the United States Government, and specifically by its National Institute on Aging (NIA) Division. The United States Government has certain rights in this invention.

[0002] Related Applications This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 950,886, filed December 19, 2019, which is incorporated herein by reference in its entirety.

[0003] FIELD OF THE INVENTION The present invention relates to compounds, compositions and methods for treating cognitive disorders associated with central nervous system (CNS) disorders, cognitive disorders associated with brain cancer and brain cancer in subjects in need of such treatment. [Background technology]

[0004] Background of the Invention Cognitive ability can decline as a normal result of aging or as a result of central nervous system disorders.

[0005] For example, a significant proportion of elderly people experience a decline in cognitive abilities that exceeds that typical of normal aging. Such age-related loss of cognitive function is clinically characterized by a progressive loss of memory, cognition, reasoning, and judgment. Mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), or similar clinical 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 MCI (Plassman et al., 2008).

[0006] Cognitive impairment is also associated with other central nervous system (CNS) disorders, such as dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (especially mania), 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.

[0007] Thus, there is a need for effective treatments for cognitive impairment associated with central nervous system (CNS) disorders and for improving cognitive function in patients diagnosed with, or at risk of developing, age-related cognitive impairment, MCI, amnesic-MCI, AAMI, ARCD, dementia, AD, prodromal AD, PTSD, schizophrenia or bipolar disorder (particularly mania), 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, and similar central nervous system (CNS) disorders associated with cognitive impairment.

[0008] GABA A Receptor (GABA AR) 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 is associated with various CNS disorders related to cognitive impairment. In particular, α5-containing GABA receptors, 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 expression of the α5 subunit of the GABA receptor is reduced in the hippocampus (see International Patent Publication WO 2007 / 019312). A These results suggest that upregulation of R function may be effective in treating cognitive impairment associated with said CNS disorders. Therefore, α5-containing GABA receptors useful in therapeutic preparations for treating cognitive impairment associated with said CNS disorders are A Positive allosteric modulators of R are needed. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2007 / 019312 Summary of the Invention [Means for solving the problem]

[0011] Summary of the Invention The present invention relates to a compound of formula Va: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein U and the two carbon atoms designated by α and β together form a 5- or 6-membered aromatic ring having 0 to 2 nitrogen atoms; A, C, CR 6 or N, B and F are C, CR 6 and N, wherein B and F cannot both be N; D, N, NR 7 , O, C.R. 6 or C(R 6 )2, E, N, NR 7 , C.R. 6 or C(R 6 )2, W, N, NR 7 , C.R. 6 or C(R 6 )2, X is N, NR 7 , O, C.R. 6 or C(R 6 )2, Y and Z are C, CR 6 and N, wherein Y and Z cannot both be N; V is C or CR 6 That is, Or Z is C or CR 6 If V is C, CR 6 or N, The ring formed by X, Y, Z, V and W is [ka] If R 2 -OR 8 , -SR 8 , -(CH2) n OR 8 , -(CH2) n O(CH2) n R 8, -(CH2) p R 8 and -(CH2) n N(R”)R 10 and R 2 is independently substituted with 0 to 5 R'; m and n are independently an integer selected from 0 to 4; p is an integer selected from 2 to 4, Combine ' [ka] " each occurrence is either a single bond or a double bond, R 1 , R 2 , R 4 and R 5 For each occurrence, Halogen, -R, -OR, -NO2, -NCS, -CN, -CF2H, -CF3, -OCF2H -OCF3, -SiR3, -N(R)2, -SR, -SOR, -SO2R, -SO2N(R)2, -SO3R, -(CR2) 1~3 R, -(CR2) 1~3 -OR, -(CR2) 1~3 -O(CR2) 1~3 -R, -(CR2) 0~3 -C(O)NR(CR2) 0~3 R, -(CR2) 0~3 -C(O)NR(CR2) 0~3 OR, -C(O)R, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)R, -C(S)OR, -C(O)OR, -C(O)C(O )OR, -C(O)C(O)N(R)2, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -C(S)N(R)2, -(CR2) 0~3NHC(O)R, -N(R)N(R)COR, -N(R)N(R)C(O)OR, -N(R)N(R)CON(R)2, -N(R)SO2R, -N(R)SO2N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(S)R, -N(R)C(O)N( R)2, -N(R)C(S)N(R)2, -N(COR)COR, -N(OR)R, -C(=NH)N(R)2, -C(O)N(OR)R, -C(=NOR)R, -OP(O)(OR)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(H)(OR), C≡CR 8 , CH2CF3, and CHF3 are each independently selected from R 8 each occurrence is -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 membered heteroaryl or -(C1-C6)alkyl-5-10 membered heteroaryl; R 8 are each independently substituted with 0-5 of -halogen, -(C1-C6)alkyl, -CF3, -OCF3 or O-(C1-C6)alkyl, excluding -H and -(C1-C6)alkyl; R 3 is not present or is: Halogen, -R, -OR, -NO2, -NCS, -CN, -CF3, -OCF3, -SiR3, -N(R)2, -SR, -SOR, -SO2R, -SO2N(R)2, -SO3R, -(CR2) 1~3 R, -(CR2) 1~3 -OR, -(CR2) 0~3 -C(O)NR(CR2) 0~3 R, -(CR2) 0~3 -C(O)NR(CR2) 0~3OR, -C(O)R, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)R, -C(S)OR, -C(O)OR, -C(O)C(O )OR, -C(O)C(O)N(R)2, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -C(S)N(R)2, -(CR2) 0~3 NHC(O)R, -N(R)N(R)COR, -N(R)N(R)C(O)OR, -N(R)N(R)CON(R)2, -N(R)SO2R, -N(R)SO2N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(S)R, -N(R)C(O)N( R)2, -N(R)C(S)N(R)2, -N(COR)COR, -N(OR)R, -C(=NH)N(R)2, -C(O)N(OR)R, -C(=NOR)R, -OP(O)(OR)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(H)(OR), C≡CR 9 , COOMe, COOEt, -(C1-C6) alkyl-C≡CR 10 , CH2-OR 10 , and CH2-O-CH2-R 10 is selected from R 9 are respectively -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl, -(C3-C6)cycloalkyl-(C6-C10)aryl, [ka] is selected from R 9 are 0 to 5 R 11 and are independently substituted by R 11is independently selected at each occurrence from -halogen, -CF3, -OH, -OCF3, OCHF2, -O-(C1-C6)alkyl, -O-CH2-(C3-C6)cycloalkyl, -CN, -SCH3-(C6-C10)aryl, -(C1-C6)alkyl, and -5-10 membered heteroaryl; R 10 is selected from -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5-10 membered heteroaryl; R 10 are each independently substituted with 0 to 5 R'; R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl; R 7 are each independently substituted with 0 to 5 R'; R 6 are each independently -H or -(C1-C6)alkyl; R 7 are each independently -H or -(C1-C6)alkyl; R 8 are each independently -(C1-C6) alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl or 5-10 membered heteroaryl, and R 8 is independently substituted at each occurrence with 0 to 5 R'; R 10 are each independently -(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl or 5- to 10-membered heteroaryl, and R 10 is independently substituted at each occurrence with 0 to 5 R'; R is: H, (C1~C12)-aliphatic-, (C3-C10)-cycloalkyl-, (C3-C10)-cycloalkenyl-, [(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-, [(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic-, [(C3-C10)-cycloalkyl]-O-(C1-C12)-aliphatic-, [(C3-C10)-cycloalkenyl]-O-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6~C10)-aryl-(C1~C12)aliphatic-, (C6~C10)-aryl-O-(C1~C12)aliphatic-, (C6~C10)-aryl-N(R”)-(C1~C12)aliphatic-, 3- to 10-membered heterocyclyl-, (3 to 10-membered heterocyclyl)-(C1-C12)aliphatic-, (3 to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-N(R")-(C1-C12)aliphatic-, 5-10 membered heteroaryl-, (5-10 membered heteroaryl)-(C1-C12)-aliphatic-, (5-10 membered heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 membered heteroaryl)-N(R")-(C1-C12)-aliphatic- are independently selected from the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO2, and the heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, and S; Each occurrence of R is independently substituted with 0 to 5 R'; or when two R groups are attached to the same atom, the two R groups, together with the atom to which they are attached, may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, and SO, said ring being optionally substituted with 0-5 R', said ring being optionally fused to a (C-C)aryl, a 5-10 membered heteroaryl, a (C-C)cycloalkyl, or a 3-10 membered heterocyclyl; R' at each occurrence is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, and -N(R"); R" at each occurrence is independently selected from H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-; R" at each occurrence is independently selected from 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 and -N(R o )2 is independently substituted with 0 to 3 substituents selected from R o each occurrence is independently selected from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl- The present invention addresses the above-mentioned needs by providing:

[0012] In another aspect, the present invention provides a compound of formula A: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein Y and Z are each independently selected from C and N, provided that Y and Z cannot both be N; Combine ' [ka] " each occurrence is either a single bond or a double bond, R 1 are each independently halogen, —OH, or —O(C1-C6)alkyl; R 2 are -H and -OR, respectively. 8 , -SR 8 , -(CH2) n OR 8 , -(CH2) n SR 8 and R 9 are each —H, (C6-C12)aryl, or 5-10 membered heteroaryl, and R 9 are 0 to 5 R 11 is replaced by R 11 is independently selected at each occurrence from -halogen, -CF3, -OH, -OCF3, OCHF2, -O-(C1-C6)alkyl, -CN, -SCH3, -(C6-C10)aryl, and -(C1-C6)alkyl; m and n are independently an integer selected from 0 to 4. to provide.

[0013] In another aspect, the present invention provides a compound of formula B: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (wherein R 1 , R 2 , R 9 and m is as defined in Formula A). to provide.

[0014] In another aspect, the present invention provides a compound of formula C: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (wherein R 1 , R 2 , R 9 and m is as defined in Formula A). to provide.

[0015] The present invention also provides pharmaceutical compositions comprising a compound of Formula Va, A, B or C, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0016] In some embodiments, the compound of formula Va is GABA A In some embodiments, the compound of formula A is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of Formula B is a GABA receptor positive allosteric modulator. A In some embodiments, the compound of formula C is a GABA receptor positive allosteric modulator. A The compounds of formulas Va, A, B, and C are α5 receptor positive allosteric modulators. A It can be used to treat such conditions through its activity as an α5 receptor positive allosteric modulator.

[0017] 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 invention, 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 invention or its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its isomer, or a combination thereof.In certain embodiments of the present invention, the compound of the present invention 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.

[0018] In another aspect of the present invention, there is provided a method for treating brain cancer (including brain tumors such as medulloblastoma), 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 another aspect of the present invention, there is provided a method for protecting or improving cognitive function in a subject suffering from brain cancer (including brain tumors such as medulloblastoma), 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 invention, 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 24 hours.

[0019] In another aspect of the present invention, there is provided a method for treating Parkinson's disease psychosis, comprising administering to said 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. In certain embodiments of the present invention, the 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 is administered every 12 hours or every 24 hours.

[0020] In some embodiments, the compounds and compositions of the present invention are for use as pharmaceuticals. In some embodiments, the compounds and compositions of the present invention are for use in treating cognitive impairment 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 impairment 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 compounds and compositions of the present invention are for use as pharmaceuticals in the treatment of brain cancer (including brain tumors, e.g., medulloblastoma). In some embodiments, the compounds and compositions of the present invention are for use as pharmaceuticals in the treatment of cognitive impairment associated with brain cancer (including brain tumors, e.g., medulloblastoma). In some embodiments, the compounds and compositions of the present invention are for use as pharmaceuticals in the treatment of Parkinson's disease psychosis.

[0021] In some embodiments, the present application 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 for 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 compounds and compositions of the present invention are for use in the preparation of a medicament for treating brain cancer (including brain tumors, e.g., medulloblastoma). In some embodiments, the compounds and compositions of the present invention are for use in the preparation of a medicament for treating cognitive impairment associated with brain cancer (including brain tumors, e.g., medulloblastoma). In some embodiments, the compounds and compositions of the present invention are for use in the preparation of a medicament for treating Parkinson's disease psychosis. The present invention provides, for example, the following items. (Item 1) Compound of Formula A: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein: Y and Z are each independently selected from C and N, provided that Y and Z cannot both be N; Combine ' [ka] " each occurrence is either a single bond or a double bond, R 1 are each independently halogen, —OH, or —O(C1-C6)alkyl; R 2 are -H and -OR, respectively.8 , -SR 8 , -(CH 2 ) n OR 8 , -(CH 2 ) n SR 8 and R 8 each occurrence is -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 membered heteroaryl or -(C1-C6)alkyl-5-10 membered heteroaryl; R 8 are -halogen, -(C1-C6)alkyl, -CF, excluding -H and -(C1-C6)alkyl, respectively. 3 , -OCF 3 or O—(C1-C6)alkyl; R 9 are each —H, (C6-C12)aryl, or 5-10 membered heteroaryl, and R 9 are 0 to 5 R 11 is replaced by R 11 -halogen, -CF 3 , -OH, -OCF 3 , O.C.H.F. 2 , -O-(C1-C6) alkyl, -CN, -SCH 3 , independently selected from -(C6-C10)aryl and -(C1-C6)alkyl; m and n are independently integers selected from 0 to 4; The compound, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. (Item 2) R 1 are each a halogen or -OMe, R 2 are -H or -CH 2 OMe, R 9 are respectively,

change

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Table 9-1

Table 9-2

Table 9-3

[0022] [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.

[0023] [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.

[0024] [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.

[0025] [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.

[0026] [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.

[0027] [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.

[0028] [Figure 7]Figure 7 is a graph showing dose-dependent occupancy of GABAA α5 receptors 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 GABAA α5 receptor density) to RO15-4513 exposure in the cerebellum (an area with low GABAA α5 receptor density).

[0029] [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

[0030] Detailed Description of the Invention definition Unless otherwise defined herein, scientific and technical terms used in this application 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.

[0031] The methods and techniques of the present invention are generally 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, unless otherwise indicated.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).

[0032] 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).

[0033] 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.

[0034] 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).

[0035] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0036] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0037] The term "drug" is used herein to refer to a chemical compound (such as an organic or inorganic compound (including the compounds of the present invention), a mixture of chemical compounds, etc.), a biological macromolecule (such as a nucleic acid, an antibody (including a portion thereof, as well as humanized, chimeric, and human antibodies, and monoclonal antibodies), a protein or a portion thereof, e.g., a peptide, lipid, carbohydrate), or an extract made from a biological material (such as a cell or tissue of a bacterium, plant, fungus, or animal (especially mammal)). Drugs include, for example, drugs whose structure is known and drugs whose structure is unknown. The α5-containing GABA of such drugs can be used in various applications. A Receptor agonist activity may make them suitable as "therapeutic agents" in the methods and compositions of the present invention.

[0038] "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).

[0039] "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.

[0040] 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'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.

[0041] In animal model systems, cognitive function can be measured by a variety of conventional methods known in the art, including using Morris water maze (MWM), Barnes circular maze, elevated radial arm maze, T-maze, or any other maze that animals use spatial information.Cognitive function can be evaluated by assessing reversal learning, extradimensional set shifting, conditioned discrimination learning, and reward expectation.Other tests known in the art can also be used to evaluate cognitive function, such as novel object recognition task and odor recognition task.

[0042] 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 by electrophysiological techniques.

[0043] "Facilitation" of cognitive function refers to affecting the impaired cognitive function so that it closely resembles the function of an intact, normal subject. Cognitive function can be promoted to any detectable degree, but in humans, it is preferably promoted sufficiently so that the impaired subject can perform the daily activities of normal life at a level of proficiency as close as possible to that of an intact, normal subject or an intact, normal, age-matched subject.

[0044] In some cases, "promotion" of cognitive function in a subject affected by age-related cognition refers to affecting the impaired cognitive function so that the impaired cognitive function closely resembles the function of an intact normal age-matched subject or the function of a young adult subject.The cognitive function of the subject can be promoted to any detectable degree, but in humans, preferably promoted sufficiently so that the impaired subject can perform the daily activities of normal life at a level of proficiency as close as possible to that of an intact normal subject or a young adult subject or an intact normal age-matched subject.

[0045] "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 such decline is delayed.

[0046] "Improving" cognitive function includes promoting and / or preserving cognitive function in a subject.

[0047] " Cognitive impairment " refers to the cognitive function in a subject that is not as robust as expected in a normal, unimpaired subject.In some cases, cognitive function is reduced by about 5%, about 10%, about 30% or more compared to the cognitive function expected in a normal, unimpaired subject.In some cases, " cognitive impairment " in a subject affected by age-related cognitive impairment refers to the cognitive function in a subject that is not as robust as expected in a normal, unimpaired subject of the same age or as the function of a young adult subject (i.e., a subject who has an average score for a given age in cognitive tests).

[0048] "Age-related cognitive impairment" refers to cognitive impairment in elderly subjects, wherein the cognitive function of these subjects is not as robust as expected in normal age-matched subjects or expected in young adult subjects.In some cases, cognitive function is reduced by about 5%, about 10%, about 30% or more compared to 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 expected in young adult subjects.Age-related cognitive impairment can be related to mild cognitive impairment (MCI) (including amnestic MCI and non-amnestic MCI), age-associated memory impairment (AAMI) and age-related cognitive decline (ARCD).

[0049] "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.

[0050] "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 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.

[0051] 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).

[0052] "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).

[0053] "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.

[0054] " 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.

[0055] 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.

[0056] Vascular dementia is caused by stroke. Symptoms overlap with those of AD, but are not focused on memory loss.

[0057] 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.

[0058] 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.

[0059] "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.

[0060] "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.

[0061] "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.

[0062] 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.

[0063] "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.

[0064] 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.

[0065] "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.

[0066] 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).

[0067] 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.

[0068] 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.

[0069] 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.

[0070] "Treating" a condition or patient refers to taking steps to achieve beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, preventing or slowing the progression of the aforementioned diseases or disorders, or reducing, ameliorating, or slowing the progression of one or more symptoms of cognitive impairment associated with a CNS disorder (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 a CNS disorder (such as those described herein). In certain embodiments, treatment comprises alleviating, improving, or slowing down the progression of one or more symptoms associated with CNS disorders.In certain embodiments, the symptom to be treated is cognitive impairment or agnosia.The treatment of age-related cognitive impairment further comprises slowing down the conversion of age-related cognitive impairment (including but not limited to MCI, ARCD and AAMI) to dementia (e.g., AD).

[0071] " Treating cognitive impairment " refers to taking steps to improve cognitive function in the subject with cognitive impairment, so that the performance of the subject in one or more cognitive tests improves to any detectable degree, or further decline is prevented.Preferably, the cognitive function of the subject closely resembles the function of an unimpaired normal subject after the treatment of cognitive impairment.The treatment of cognitive impairment in humans can improve cognitive function to any detectable degree, but preferably is improved enough to allow the impaired subject to carry out the daily activities of normal life at the same proficiency level as an unimpaired normal subject.In some cases, " treating cognitive impairment " refers to taking steps to improve cognitive function in the subject with cognitive impairment, so that the performance of the subject in one or more cognitive tests improves to any detectable degree, or further decline is prevented.Preferably, the cognitive function of the subject closely resembles the function of an unimpaired normal subject after the treatment of cognitive impairment. 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 so that the cognitive function of the subject closely resembles that of an unimpaired, normal, age-matched subject or a young adult subject after treatment of the cognitive impairment.

[0072] "Administering" a substance, compound, or agent to a subject or "administering of" a substance, compound, or agent to a subject can be done using one of a variety of methods known to those skilled in the art. For example, a 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, e.g., a patch and pump, or a formulation that provides sustained, slow, or controlled release of the compound or agent. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods. In some embodiments, administration 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.

[0073] 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.

[0074] As used herein, "α5-containing GABA A receptor 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 Receptor (GABA A R), i.e., compounds that enhance the function of GABAergic Cl - In some embodiments, the α5-containing GABA A As used herein, an R agonist refers to a positive allosteric modulator that activates the activity of GABA. A Receptor agonists include α5-containing GABA receptor agonists of all formulas described herein. A Receptor agonists and specific α5-containing GABA A Included are receptor 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.

[0075] "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).

[0076] "Typical antipsychotics," as used herein, refer to conventional antipsychotic drugs that produce antipsychotic effects and movement-related adverse effects related to disorders of the nigrostriatal 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.

[0077] "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.

[0078] 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 invention. 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 in the present invention includes memantine and its derivatives and analogs, as well as their hydrates, polymorphs, prodrugs, salts and solvates.Memantine as used herein also includes the composition comprising memantine or its derivatives or analogs, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs, where the composition optionally further comprises at least one additional therapeutic agent (such as a therapeutic agent useful for treating CNS disorders or cognitive impairments associated therewith).In some embodiments, the memantine composition suitable for use in the present invention comprises memantine and a second therapeutic agent that is donepezil (trade name Aricept).

[0079] "Acetylcholinesterase inhibitors" or "AChE-I," 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. AChE-I suitable for use in the present application can include, for example, the subclassifications of (i) reversible non-competitive inhibitors or reversible competitive inhibitors, (ii) irreversible inhibitors, and (iii) quasi-irreversible inhibitors.

[0080] The term "co-administration," as used herein, refers to administration of α5-containing GABA A Receptor agonists (e.g., α5-containing GABA A This means that the first therapeutic agent (e.g., an antipsychotic drug, memantine, or an AChE-I) or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a time interval not exceeding about 15 minutes, and in some embodiments not exceeding about 10 minutes. When administered simultaneously, the α5-containing GABA A Receptor agonists (e.g., α5-containing GABA A receptor positive allosteric modulator) and a second therapeutic agent (e.g., an antipsychotic, memantine, or AChE-I) or a salt, hydrate, solvate, or polymorph thereof, in the same dosage form (e.g., an α5-containing GABA A Receptor agonists (e.g., α5-containing GABA A The therapeutic agent may be contained in a unit dosage form containing both the α5-containing GABA receptor positive allosteric modulator and the second therapeutic agent (e.g., an antipsychotic, memantine, or an AChE-I), or may be contained in separate dosage forms (e.g., an α5-containing GABA receptor positive allosteric modulator). A Receptor agonists (e.g., α5-containing GABA Aa first therapeutic agent (e.g., a steroid receptor positive allosteric modulator) or a salt, hydrate, solvate or polymorph thereof is included in one dosage form, and a second therapeutic agent (e.g., an antipsychotic, memantine, or an AChE-I) or a salt, hydrate, solvate or polymorph thereof is included in another dosage form).

[0081] The term "sequential administration," as used herein, refers to administration of α5-containing GABA A Receptor agonists (e.g., α5-containing GABA A This means that the first therapeutic agent (e.g., an α5-containing GABA receptor positive allosteric modulator) and the second therapeutic agent (e.g., an antipsychotic, memantine, or AChE-I) 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 Receptor agonists (e.g., α5-containing GABA A Either the first therapeutic agent (e.g., an α5-containing GABA receptor positive allosteric modulator) or the second therapeutic agent (e.g., an antipsychotic, memantine, or an AChE-I) may be administered first. A Receptor agonists (e.g., α5-containing GABA A The first therapeutic agent (e.g., an antipsychotic, memantine, or AChE-I) or a salt, hydrate, solvent, or polymorph thereof may be contained in separate dosage forms, optionally in the same container or package.

[0082] A "therapeutically effective amount" of a drug or agent is an amount of drug or agent that, when administered to a subject, has the intended therapeutic effect, for example, improvement of cognitive function, in a subject, for example, 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 exact effective amount required for a subject depends, for example, on the subject's size, health, and age, the nature and severity of cognitive impairment or other symptoms of CNS disorder (such as 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), and the therapeutic agent or combination of therapeutic agents selected for administration, as well as the mode of administration. One of ordinary skill in the art can readily determine the effective amount for a given situation using routine experimentation.

[0083] 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 GABA 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 compounds that are converted to GABA R-positive allosteric modulators by enzymatic activity in the host animal. A Converted into an α5 receptor positive allosteric modulator.

[0084] "Analog" is used herein to refer to a compound that is functionally similar to another chemical entity but does not share the same chemical structure. For example, an analog is sufficiently similar to a base or parent compound that it can be substituted for the base compound in therapeutic applications, despite minor structural differences.

[0085] "Derivative" is used herein to refer to a chemical modification of a compound. Chemical modifications of a compound can include, for example, replacing a hydrogen with an alkyl, acyl, or amino group. Many other modifications are also possible.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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).

[0092] 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.

[0093] 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).

[0094] 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).

[0095] 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.

[0096] As used herein, carbon atom designations can have the indicated integer and any intervening integer. For example, the number of carbon atoms in a (C1-C4)-alkyl group can be 1, 2, 3, or 4. It should be understood that these designations refer to the total number of atoms in the appropriate group. For example, in a (C3-C10)-heterocyclyl, the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.

[0097] " 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] The present application contemplates all isomers of the compounds of formulas Va, A, B, and C. As used herein, "isomer" includes optical isomers (stereoisomers, e.g., enantiomers and diastereoisomers), Z (zusammen) or E (entgegen) isomers, and tautomers. Many of the compounds useful in the methods and compositions of the present invention 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 invention also relates to all stereoisomers, such as enantiomers and diastereoisomers of the present compounds, or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726. Furthermore, certain compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each case, the present invention 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 invention, 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.

[0103] The compounds of the present invention are α5-containing GABA A α5-containing GABA receptors enhance R function. A R agonists (e.g., α5-containing GABA A receptor positive allosteric modulator) and GABAergic Cl - The current can be increased.

[0104] The present invention further provides pharmaceutical compositions comprising one or more compounds of the present invention together with a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical compositions of the present application may further comprise a second therapeutic agent, such as an antipsychotic drug, memantine, or AChE-I.

[0105] The present invention relates to α5-containing GABA AFurther provided are methods for treating cognitive disorders associated with said CNS disorders that are responsive to positive allosteric modulators of the receptor, 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 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 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 includes prevention or slowing the progression of a CNS disorder (such as those described herein). In certain embodiments, treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with a CNS disorder. In certain embodiments, the symptom being treated is cognitive impairment or agnosia. In another aspect of the present invention, there is provided a method of protecting or improving cognitive function in a subject in need thereof, comprising the step of administering to said 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.

[0106] Various CNS disorders associated with cognitive impairment (e.g., 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) may have different etiologies. However, the symptoms of cognitive impairment in each of the above-mentioned disorders may have overlapping causes. Thus, a composition or treatment method that treats cognitive impairment in one CNS disorder can also treat cognitive impairment in another. benzodiazepine derivatives

[0107] The present disclosure provides a compound of formula Va: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein U and the two carbon atoms designated by α and β together form a 5- or 6-membered aromatic ring having 0 to 2 nitrogen atoms; A, C, CR 6 or N, B and F are C, CR 6 and N, wherein B and F cannot both be N; D, N, NR 7 , O, C.R. 6 or C(R 6 )2, E, N, NR 7 , C.R. 6 or C(R 6 )2, W, N, NR 7 , C.R. 6 or C(R 6 )2, X is N, NR 7 , O, C.R.6 or C(R 6 )2, Y and Z are C, CR 6 and N, wherein Y and Z cannot both be N; V is C or CR 6 That is, Or Z is C or CR 6 If V is C, CR 6 or N, The ring formed by X, Y, Z, V and W is [ka] If R 2 -OR 8 , -SR 8 , -(CH2) n OR 8 , -(CH2) n O(CH2) n R 8 , -(CH2) p R 8 and -(CH2) n N(R”)R 10 and R 2 is independently substituted with 0 to 5 R'; m and n are independently an integer selected from 0 to 4; p is an integer selected from 2 to 4, Combine ' [ka] " each occurrence is either a single bond or a double bond, R 1 , R 2 , R 4 and R 5 For each occurrence, Halogen, -R, -OR, -NO2, -NCS, -CN, -CF2H, -CF3, -OCF2H -OCF3, -SiR3, -N(R)2, -SR, -SOR, -SO2R, -SO2N(R)2, -SO3R, -(CR2) 1~3 R, -(CR2) 1~3-OR, -(CR2) 1~3 -O(CR2) 1~3 -R, -(CR2) 0~3 -C(O)NR(CR2) 0~3 R, -(CR2) 0~3 -C(O)NR(CR2) 0~3 OR, -C(O)R, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)R, -C(S)OR, -C(O)OR, -C(O)C(O )OR, -C(O)C(O)N(R)2, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -C(S)N(R)2, -(CR2) 0~3 NHC(O)R, -N(R)N(R)COR, -N(R)N(R)C(O)OR, -N(R)N(R)CON(R)2, -N(R)SO2R, -N(R)SO2N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(S)R, -N(R)C(O)N( R)2, -N(R)C(S)N(R)2, -N(COR)COR, -N(OR)R, -C(=NH)N(R)2, -C(O)N(OR)R, -C(=NOR)R, -OP(O)(OR)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(H)(OR), C≡CR 8 , CHCF, and CHF, and particularly in some embodiments of the present invention, R 1 , R 2 , R 4 and R 5 at least one of is -OCF2H, R 8 each occurrence is -H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C6-C10)aryl, -(C6-C10)aryl, -5-10 membered heteroaryl or -(C1-C6)alkyl-5-10 membered heteroaryl; R 8 are each independently substituted with 0-5 of -halogen, -(C1-C6)alkyl, -CF3, -OCF3 or O-(C1-C6)alkyl, excluding -H and -(C1-C6)alkyl; R 3is not present or is: Halogen, -R, -OR, -NO2, -NCS, -CN, -CF3, -OCF3, -SiR3, -N(R)2, -SR, -SOR, -SO2R, -SO2N(R)2, -SO3R, -(CR2) 1~3 R, -(CR2) 1~3 -OR, -(CR2) 0~3 -C(O)NR(CR2) 0~3 R, -(CR2) 0~3 -C(O)NR(CR2) 0~3 OR, -C(O)R, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)R, -C(S)OR, -C(O)OR, -C(O)C(O )OR, -C(O)C(O)N(R)2, -OC(O)R, -C(O)N(R)2, -OC(O)N(R)2, -C(S)N(R)2, -(CR2) 0~3 NHC(O)R, -N(R)N(R)COR, -N(R)N(R)C(O)OR, -N(R)N(R)CON(R)2, -N(R)SO2R, -N(R)SO2N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(S)R, -N(R)C(O)N( R)2, -N(R)C(S)N(R)2, -N(COR)COR, -N(OR)R, -C(=NH)N(R)2, -C(O)N(OR)R, -C(=NOR)R, -OP(O)(OR)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(H)(OR), C≡CR 9 , COOMe, COOEt, -(C1-C6) alkyl-C≡CR 10 , CH2-OR 10 , and CH2-O-CH2-R 10 is selected from R 9 are respectively -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C1-C6)alkyl-(C6-C10)aryl, -(C1-C6)alkyl-5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -(C1-C6)alkyl-(C3-C6)cycloalkyl, -C(O)-(C6-C10)aryl, -(C3-C6)cycloalkyl-(C6-C10)aryl, [ka] In particular, in some aspects of the invention, R 9 is -(C3-C6)cycloalkyl-(C6-C10)aryl, [ka] is selected from R 9 are 0 to 5 R 11 and are independently substituted by R 11 is independently selected at each occurrence from -halogen, -CF3, -OH, -OCF3, OCHF2, -O-(C1-C6)alkyl, -O-CH2-(C3-C6)cycloalkyl, -CN, -SCH3, -(C6-C10)aryl, -(C1-C6)alkyl, and -5-10 membered heteroaryl, and particularly in some embodiments of the invention, R 11 are independently selected from -halogen, -OH, -OCHF, -O-(C1-C6)alkyl, -O-CH2-(C3-C6)cycloalkyl, -CN, and -SCH3; R 10 is selected from -H, -(C1-C6)alkyl, -(C6-C10)aryl, -5-10 membered heteroaryl, -(C3-C6)cycloalkyl, -CH2-(C3-C6)cycloalkyl, -CH2-(C6-C10)aryl and -CH2-5-10 membered heteroaryl; R 10 are each independently substituted with 0 to 5 R'; R7 is selected from -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -5-10 membered heteroaryl, -(C6-C10)aryl, -(C6-C10)aryl-(C1-C6)alkyl and -5-10 membered heteroaryl-(C1-C6)alkyl and -5-10 membered heteroaryl; each R7 is independently substituted with 0 to 5 R'; R 6 are each independently -H or -(C1-C6)alkyl; R7 are each independently -H or -(C1-C6)alkyl; R 8 are each independently -(C1-C6) alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl or 5-10 membered heteroaryl, and R 8 is independently substituted at each occurrence with 0 to 5 R'; R 10 are each independently -(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl or 5- to 10-membered heteroaryl, and R 10 is independently substituted at each occurrence with 0 to 5 R'; R is: H, (C1~C12)-aliphatic-, (C3-C10)-cycloalkyl-, (C3-C10)-cycloalkenyl-, [(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-, [(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic-, [(C3-C10)-cycloalkyl]-O-(C1-C12)-aliphatic-, [(C3-C10)-cycloalkenyl]-O-(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6~C10)-aryl-(C1~C12)aliphatic-, (C6~C10)-aryl-O-(C1~C12)aliphatic-, (C6~C10)-aryl-N(R”)-(C1~C12)aliphatic-, 3- to 10-membered heterocyclyl-, (3 to 10-membered heterocyclyl)-(C1-C12)aliphatic-, (3 to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-, (3-10 membered heterocyclyl)-N(R")-(C1-C12)aliphatic-, 5-10 membered heteroaryl-, (5-10 membered heteroaryl)-(C1-C12)-aliphatic-, (5-10 membered heteroaryl)-O-(C1-C12)-aliphatic-, and (5-10 membered heteroaryl)-N(R")-(C1-C12)-aliphatic- are independently selected from the heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO2, and the heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, and S; Each occurrence of R is independently substituted with 0 to 5 R'; or when two R groups are attached to the same atom, the two R groups, together with the atom to which they are attached, may form a 3-10 membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, and SO, said ring being optionally substituted with 0-5 R', said ring being optionally fused to a (C-C)aryl, a 5-10 membered heteroaryl, a (C-C)cycloalkyl, or a 3-10 membered heterocyclyl; R' at each occurrence is independently selected from halogen, -R", -OR", oxo, -CHOR", -CHNR", -C(O)N(R"), -C(O)OR", -NO, -NCS, -CN, -CF, -OCF, and -N(R"); R" at each occurrence is independently selected from H, -(C1-C6)-alkyl, -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O-(C1-C6)-alkyl- and (C6-C10)-aryl-O-(C1-C6)-alkyl-; R" at each occurrence is independently selected from halogen, -R o , -OR o , oxo, -CH2OR o , -CHN(Ro )2, -C(O)N(R o )2, -C(O)OR o , -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R o )2 is independently substituted with 0 to 3 substituents selected from R o each occurrence is independently selected from -(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl- and (C6-C10)-aryl- to provide.

[0108] In some embodiments, the compound of formula Va has formula A: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein Y and Z are each independently selected from C and N, provided that Y and Z cannot both be N; Combine ' [ka] " each occurrence is either a single bond or a double bond, R 1 are each independently halogen, —OH, or —O(C1-C6)alkyl; R 2 are -H and -OR, respectively. 8 , -SR 8 , -(CH2) n OR 8 , -(CH2) n SR 8 and R 9 are each —H, (C6-C12)aryl, or 5-10 membered heteroaryl, and R 9 are 0 to 5 R 11 is replaced by R 11is independently selected at each occurrence from -halogen, -CF3, -OH, -OCF3, OCHF2, -O-(C1-C6)alkyl, -CN, -SCH3, -(C6-C10)aryl, and -(C1-C6)alkyl; m and n are independently an integer selected from 0 to 4. It has a structure as follows.

[0109] In some embodiments, the present disclosure is directed to a compound having a structure according to Formula A, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein: R 1 are each a halogen or -OMe, R 2 are -H or -CH2OMe, R 9 are respectively, [ka] and R 9 are 0 to 5 R 11 is replaced by R 11 is independently selected at each occurrence from -halogen, -CF3, -OH, -OCF3, OCHF2, or -OMe).

[0110] In some embodiments, the compound of formula A has a structure according to formula B: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (wherein R 1 , R 2 , R 9 , m and n are as defined for compounds having a structure according to Formula A. It has.

[0111] In some embodiments, the compound of formula A has a structure according to formula C: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof (wherein R 1 , R 2 , R 9 , m and n are as defined for compounds having a structure according to Formula A. It has.

[0112] Examples of specific compounds of the present application include the following: [Table 7-1] [Table 7-2] [Table 7-3] and pharmaceutically suitable salts thereof, hydrates thereof, solvates thereof, polymorphs thereof, isomers thereof or combinations thereof.

[0113] Any embodiment described herein is also intended to correspond to 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, 125The 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.

[0114] Any of the individual embodiments listed herein can be used individually to define Formula Va, A, B or C or in combination to provide preferred embodiments of the present invention. General synthesis method

[0115] The compounds of the present invention can generally be prepared by methods known to those skilled in the art. Schemes 1-9 below present general synthetic routes for the preparation of compounds of formulas Va, A, B, and C. Other equivalent schemes will be readily apparent to a skilled organic chemist and can alternatively be used to synthesize various portions of the molecules, as exemplified by the following general schemes. Scheme 1. General synthesis of compounds of formula Va, or precursors to compounds of formula A or B, or compounds of formula B (X, Y, Z, V and W form a 1,2,3-triazole ring). [ka] Scheme 2. General synthesis of compounds of formula Va, or precursors to compounds of formula A or B, or compounds of formula B, where X, Y, Z, V, and W form a phenoxy-substituted 1,2,3-triazole ring. [ka] Scheme 3. General synthesis of compounds of formula Va allowing for divergent functionalization on the triazolo ring formed by X, Y, Z, V, and W [ka] Scheme 4. General synthesis of compounds of formula Va, where X, Y, Z, V and W form an aminomethyl-substituted 1,2,3-triazole ring. [ka] Scheme 5. General synthesis of compounds of formula Va, where X, Y, Z, V and W form an aralkyl- or heteroaralkyl-substituted 1,2,3-triazole ring. [ka] Scheme 6. General synthesis of compounds of formula Va or precursors to compounds of formula A or C, where X, Y, Z, V and W form a substituted 1,2,4-triazole ring. [ka] Scheme 7. General synthesis of compounds of formula Va, where X, Y, Z, V and W form a methyl-substituted 1,2,3-triazole ring. [ka] Scheme 8. General synthesis of compounds of formula Va, where X, Y, Z, V and W form a benzyl-substituted 1,2,3-triazole ring. [ka] Scheme 9. General synthesis of compounds of formula Va, A, B or C (R of compounds of formula Va) 3 is an optionally substituted alkynyl group) is exemplified in Scheme 9. [ka]

[0116] As will be recognized by one of ordinary skill in the art, compounds of Formula Va, A, B, and C having variables other than those illustrated above can be prepared by varying the chemical reagents or synthetic routes. Pharmaceutical Compositions and Modes of Administration

[0117] The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of Formulas Va, A, B, and C, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0118] The basic nitrogen-containing groups present in the compounds of the present invention can be quaternized with agents such as lower alkyl halides (such as 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 (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate); long-chain halides (such as 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 (such as benzyl bromide and phenethyl bromide). This can result in water-soluble or oil-soluble or water- or oil-dispersible products.

[0119] It is recognized that the compounds and drugs used in the compositions of the present invention should preferably easily cross the blood-brain barrier when administered peripherally. However, compounds that cannot cross the blood-brain barrier can still be effectively administered directly to the central nervous system, for example, by intraventricular or other neurocompatible routes.

[0120] In some embodiments of the present invention, α5-containing GABA A The R positive allosteric modulator is formulated with a pharmaceutically acceptable carrier.The pharmaceutically acceptable carrier that can be used in these compositions includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphate, 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 polymer, 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 The α5-containing GABA receptor 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 Receptor positive allosteric modulators) can be formulated for use in human medicine for administration in any convenient way.

[0121] In some embodiments, the therapeutic methods of the present invention include administering a compound or drug composition locally, systemically, or locally. For example, the compound or drug therapeutic compositions of the present invention may be formulated for administration by, for example, injection (e.g., intravenous, subcutaneous, or intramuscular), inhalation or insufflation (either through the mouth or nose), or oral, buccal, sublingual, transdermal, nasal, or parenteral administration. The compound or drug compositions described herein may be formulated as part of an implant or device and may also be formulated for slow or sustained release. When administered parenterally, the compound or drug therapeutic compositions for use in the present invention are preferably in a pyrogen-free, physiologically acceptable form. Techniques and formulations generally can be found in Remington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA.

[0122] 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.

[0123] α5-containing GABA AThe composition containing the R-positive allosteric modulator may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0124] In certain embodiments of the present invention, 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.

[0125] 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.

[0126] 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).

[0127] 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.

[0128] As described herein, compounds, drugs and their compositions can be administered in a slow, controlled 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 over an extended period of time, for example, over or equal to one hour (throughout or during an extended period of time).A sustained release dosage form releases drug at a substantially constant rate over an extended period of time, or a substantially constant amount of drug 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.

[0129] Those skilled in the art, such as physicians, can easily identify and use α5-containing GABA receptor antagonists to treat subjects using the compositions and methods of the present invention. A The required amount of R-positive allosteric modulator can be readily determined. The dosage regimen can be determined by, for example, the α5-containing GABA A It will be 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.

[0130] It is well known in the art that normalization to body surface area is a suitable method for extrapolating doses between species.To calculate the human equivalent dose (HED) from the dose used in treating age-dependent cognitive impairment in rats, the formula HED (mg / kg) = rat dose (mg / kg) × 0.16 can be used (see Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers, December 2002, Center for Biologics Evaluation and Research).For example, using this formula, a dose of 10 mg / kg in rats is equivalent to 1.6 mg / kg in humans.This conversion can be performed using the more general formula HED = animal dose (mg / kg) × (animal body weight (kg) / human body weight (kg)). 0.33 Based on.

[0131] In certain embodiments of the present invention, α5-containing GABA A The dose of the R-positive allosteric modulator is 0.0001-100 mg / kg / day (which, considering a typical human subject of 70 kg, is between 0.007-7000 mg / day).

[0132] In certain embodiments of the invention, the interval between doses is once every 12 or 24 hours. Less frequent intervals, such as once every 6 hours, may also be used.

[0133] 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.

[0134] 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.

[0135] The composition of the present invention contains α5-containing GABA A In addition to the R-positive allosteric modulator, other therapeutically useful agents may also be included. These other therapeutically useful agents may be combined with α5-containing GABA receptor antagonists in a single formulation according to the methods of the present invention. A It can be administered simultaneously or sequentially with the R-positive allosteric modulator.

[0136] It is understood by those skilled in the art that the compositions described herein can be adapted and modified to suit the intended use, and that the compositions described herein can be used in other suitable uses.For example, the compositions of the present application may further comprise a second therapeutic agent.Such other additions and modifications do not depart from the scope of the present invention. Pharmaceutical compositions containing antipsychotic drugs

[0137] The compounds or compositions of the present application 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, hydrates, solvates, or polymorphs thereof useful in the methods and compositions of the present invention include both typical and atypical antipsychotic drugs. In some embodiments, the compounds or compositions of the present invention can be used to treat one or more positive and / or negative symptoms and cognitive impairment associated with schizophrenia. In some embodiments, the compounds or compositions of the present invention can be used to treat one or more symptoms and cognitive impairment associated with bipolar disorder (particularly mania). In some embodiments of the present invention, the compounds or compositions of the present invention prevent or slow the progression of cognitive impairment in schizophrenia or bipolar disorder (particularly mania) in the subject.

[0138] In some embodiments, the antipsychotic suitable for use in the present invention is selected from atypical antipsychotic drugs.Such atypical antipsychotic drugs include but are not limited to those disclosed in 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.

[0139] In some embodiments, atypical antipsychotics suitable for use in the present invention 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.

[0140] In some embodiments, antipsychotic drugs suitable for use in the present invention 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, Typical antipsychotics include oxyprothepin, penfluridol, perazine, pericyazine, perphenazine, pimozide, pipamperon, 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.

[0141] In some embodiments of the present invention, 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.

[0142] In some embodiments, the α5-containing GABA A In other embodiments, the α5-containing GABA receptor positive allosteric modulator and the antipsychotic drug described herein, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, are administered simultaneously or sequentially, or in a single formulation or in separate co-packaged formulations. A The receptor positive allosteric modulator and the antipsychotic drug, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, are administered via various routes. As used herein, "combination" includes administration via any of these formulations or administration routes. Pharmaceutical compositions containing memantine

[0143] The compounds or compositions of the present application 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 a subject 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).

[0144] 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 up to 28 mg / day. Some of the memantine and its derivatives and analogs useful in the present invention are disclosed in United States Patent No. 3,391,142; United States Patent No. 4,122,193; United States Patent No. 4,273,774; and United States Patent No. 5,061,703, all of which are incorporated herein by reference.Other memantine derivatives or memantine analogs useful in the present invention include but are not limited to the compounds disclosed in United States Patent Application Publication No. US20040087658, US20050113458, US20060205822, US20090081259, US20090124659 and US20100227852; European Patent Application Publication No. EP2260839A2; European Patent No. EP1682109B1; and PCT Application Publication No. WO2005079779, all of which are incorporated herein by reference. As used in the present invention, 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 its derivatives or analogs, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof, where the composition optionally further comprises at least one additional therapeutic agent (such as a therapeutic agent useful for treating CNS disorders or cognitive disorders 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).

[0145] In another embodiment of the present invention, α5-containing GABA A In other embodiments, the α5-containing GABA receptor positive allosteric modulator and memantine (or a memantine derivative / analog) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof are administered simultaneously or sequentially, or in a single formulation or in separate co-packaged formulations. A The receptor positive allosteric modulator and memantine (or a memantine derivative / analog) or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug thereof are administered via various routes. As used herein, "combination" includes administration via any of these formulations or administration routes. Pharmaceutical compositions containing acetylcholinesterase inhibitors (AChE-I)

[0146] The compounds or compositions of the present application may be used in combination with an acetylcholinesterase inhibitor in treating cognitive impairment associated with central nervous system (CNS) disorders 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).

[0147] AChE-I 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.

[0148] In certain embodiments, AChE-I useful in the present invention 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.

[0149] In certain embodiments, exemplary AChE-Is that can be used in accordance with the present invention 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, and the like. AChE-Is include icopezil, neostigmine (Prostigmine, Vagostigmine), 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 fused quinoline derivatives, and cyclic amide derivatives. Other typical AChE-Is include carbamates and organophosphonate compounds (such as metrifonate (trichlorfo)). Benzazepinols such as galantamine are also useful AChE-Is. In some embodiments, AChE-Is suitable for use in combination with the compounds and compositions of the present application include donepezil (aricept), galantamine (razadyne), or rivastigmine (exelon).

[0150] In another embodiment of the present invention, α5-containing GABA A The receptor positive allosteric modulator and AChE-I, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs thereof, are administered simultaneously or sequentially, or in a single formulation or in separate co-packaged formulations. A The receptor positive allosteric modulator and AChE-I, or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs, are administered via various routes. As used herein, "combination" includes administration via any of these formulations or administration routes.

[0151] In some embodiments, the compounds and compositions described herein are for use as pharmaceuticals. In some embodiments, the compounds and compositions of the present invention are for use in treating cognitive impairment associated with CNS disorders in subjects in need of or at risk of such treatment. In some embodiments, CNS disorders associated with cognitive impairment 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.

[0152] In some embodiments, the present application 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, 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. How to assess cognitive impairment

[0153] Animal model serves as an important resource for developing and evaluating the treatment for cognitive impairment related to CNS disorders.The characteristics that characterize cognitive impairment in animal model usually extend to cognitive impairment in humans.Therefore, the effectiveness in such animal model is expected to predict 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.

[0154] 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, subjects' spatial memory can be tested in the RAM under control or test compound treatment conditions. As part of the test, subjects are pretreated with a vehicle control or a test compound at a dose range prior to the trial. At the beginning of each trial, a subset of the rungs in the eight-run maze are blocked off. Subjects can access food in the unblocked rungs that are accessible during this initial "information phase" of the trial. The subject 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 subject 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 subject makes during the retention test phase is tracked. An error occurs in that trial if the subject enters a lane where food was already found in the previous component of the delay period of that trial, or if the subject revisits a lane that was already visited in the post-delay session. Fewer errors indicate better spatial memory. The number of errors made by the test subject under various test compound treatment regimens can then be compared for the effectiveness of the test compound in treating cognitive impairment associated with a CNS disorder.

[0155] 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). Subjects are trained to locate a submerged escape platform hidden beneath the surface of the pool. During training trials, subjects 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 subject does not locate the escape platform within a set time, the experimenter guides the subject to the platform and places it on it to "teach" 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, when measured by the time that mouse spends at the location of escape platform (not present now) or the number of times that mouse crosses this location, the preference level of subject to this location indicates better spatial memory, that is, the treatment of cognitive impairment.Then, the preference to the location of escape platform under different treatment conditions can be compared to the effectiveness of test compound in treating the cognitive impairment associated with CNS damage.

[0156] 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.

[0157] In addition to assessing cognitive ability, the progression of age-related cognitive impairment and dementia, as well as the transition from age-related cognitive impairment 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 as seen by resting-state fMRI (R-fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). 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). 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). Age-related cognitive impairment

[0158] The present invention relates to 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 age-related cognitive impairment or the risk thereof using a receptor positive allosteric modulator (i.e., a compound of the present invention). In certain embodiments, treatment includes preventing age-related cognitive impairment or slowing its progression. In certain embodiments, treatment includes reducing, ameliorating, 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 methods and compositions can be used in clinical applications for treating age-related cognitive impairment in conditions such as MCI, ARCD, and AAMI, or the risk thereof, in human patients. The doses of the compositions and the administration intervals for the methods are safe and effective for these applications, as described herein. In some embodiments of the present invention, there is provided a method of protecting or improving cognitive function in a subject having age-related cognitive impairment, comprising the step of administering to said 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.

[0159] In some embodiments, the subject treated by the methods and compositions of the present invention exhibits or is at risk of age-related cognitive impairment. In some embodiments, age-related cognitive impairment includes, but is not limited to, age-associated memory impairment (AAMI), mild cognitive impairment (MCI) and age-related cognitive decline (ARCD).

[0160] 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 the age-related cognitive impairment in humans.Therefore, the effectiveness in such animal model is expected to predict the effectiveness in humans.

[0161] 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.

[0162] 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. Dementia

[0163] 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 for treating dementia using receptor positive allosteric modulators are provided. In certain embodiments, the treatment includes preventing dementia or slowing its progression. In certain embodiments, the 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 invention 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 invention 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), vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. The methods and compositions can be used in clinical applications in treating dementia 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.

[0164] Animal models serve as an important resource for developing and evaluating treatments for dementia. The characteristics that characterize dementia in animal models usually extend to dementia in humans. Therefore, efficacy in such animal models is expected to predict efficacy in humans. 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 can be used to test the effectiveness of the methods and compositions of the present invention in treating dementia.

[0165] The effectiveness of the methods and compositions of the invention in treating dementia or dementia-related cognitive impairment 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

[0166] 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. A Methods and compositions are provided for treating post-traumatic stress disorder (PTSD) using a receptor positive allosteric modulator. In certain embodiments, treatment includes preventing or slowing the progression of 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 invention 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 invention 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 human patients in clinical applications to treat PTSD. The doses of the compositions and the administration intervals for the methods are those that are safe and effective for their intended use, as described herein.

[0167] 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).

[0168] Animal models serve as an important resource for developing and evaluating treatments for PTSD.The characteristics that characterize PTSD in animal models usually extend to PTSD in humans.Therefore, the effectiveness in such animal models is expected to predict the effectiveness in humans.Various animal models of PTSD are known in the art.

[0169] 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 results in an enhanced acoustic startle response (ASR) in rats, comparable to the exaggerated acoustic startle that is a prominent 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.

[0170] The effectiveness of the methods and compositions of the invention in treating PTSD or 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

[0171] The present invention relates to 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 schizophrenia or bipolar disorder (particularly mania) using receptor positive allosteric modulators.In certain embodiments, treatment includes preventing or slowing the progression of 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. In addition, 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. In some embodiments, treatment involves alleviating, improving, or slowing the progression of one or more symptoms associated with bipolar disorder (particularly mania) and cognitive impairment. Some embodiments of the present invention 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 invention 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 schizophrenia or bipolar disorder (particularly mania) in human patients. The dose of the composition and the administration interval for the method are those that are safe and effective for their use, as described herein.

[0172] 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.

[0173] Animal models serve as an important resource for developing and evaluating treatments for schizophrenia.The characteristics that characterize schizophrenia in animal models usually extend to schizophrenia in humans.Therefore, the effectiveness in such animal models is expected to predict the effectiveness in humans.Various animal models of schizophrenia are known in the art.

[0174] One animal model of schizophrenia is chronic treatment with methionine. Methionine-treated mice exhibit insufficient expression of GAD67 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 treatment with methylaoxymethanol acetate (MAM) in rats. Pregnant female rats are administered MAM (20 mg / kg, intraperitoneally) on day 17 of gestation. MAM treatment recapitulates the pathogenesis process (pathogenesis) that leads to a schizophrenia-like phenotype in their offspring, 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 any 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 assay the effectiveness of the methods and compositions of the present invention in treating schizophrenia or bipolar disorder (particularly mania).

[0175] 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 can be suitable for use in assessing the effectiveness of the methods and compositions of the present invention in treating schizophrenia or bipolar disorder (particularly mania).For example, the methods and compositions of the present invention can be evaluated using MAM-treated animals for their effects on the regulation of the central hippocampus (vHipp), the increase in DA neuron population activity, and the hyperlocomotion response to amphetamine in MAM-treated animals.

[0176] 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 the receptor, 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 hyperlocomotion response to amphetamine in MAM-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 α5GABA 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 α5GABA 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 invention to assess the effectiveness of the methods and compositions of the present invention in treating schizophrenia or bipolar disorder (particularly mania). 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.

[0177] 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 test the effectiveness of the methods and compositions of the present invention in treating schizophrenia or bipolar disorder (especially mania).

[0178] Apomorphine-induced climbing behavior (AIC) and apomorphine stereotypy (AIS) in mice are another animal model useful in the present invention. A drug is administered to the 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, 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 that receive 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 schizophrenia or bipolar disorder (especially mania).

[0179] 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.

[0180] The effectiveness of the methods and compositions of the invention in treating schizophrenia or 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)

[0181] The present invention relates to 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 ALS using receptor positive allosteric modulators. In certain embodiments, treatment includes preventing ALS or slowing its progression. In certain embodiments, treatment includes alleviating, ameliorating, 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 invention 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 invention 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 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.

[0182] 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.

[0183] The effectiveness of the methods and compositions of the invention in treating ALS or ALS-associated cognitive impairment 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

[0184] The present invention relates to 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 a receptor positive allosteric modulator. In certain embodiments, treatment includes preventing or slowing the progression of cognitive impairment associated with cancer therapy. In certain embodiments, treatment includes alleviating, improving, or slowing the progression of one or more symptoms associated with cognitive impairment associated with cancer therapy. 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 invention or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. The method and composition can be used in human patients in clinical applications to treat cognitive impairment associated with cancer therapy. The dose of the composition and the administration interval for the method are as described herein, and are safe and effective for these applications.

[0185] 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).

[0186] 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.

[0187] Animal model serves as an important resource for developing and evaluating treatment for the cognitive impairment associated with cancer treatment.The characteristics that characterize the cognitive impairment associated with cancer treatment in animal model usually extend to the cognitive impairment associated with cancer treatment in humans.Therefore, the effectiveness in such animal model is expected to predict the effectiveness in humans.A variety of animal models of the cognitive impairment associated with cancer treatment are known in the art.

[0188] 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 cancer therapy-associated cognitive impairment can then be examined using cognitive tests to assess the effectiveness of the methods and compositions of the present invention in treating cancer therapy-associated cognitive impairment. As discussed herein, various cognitive tests known in the art can be used to assess the effectiveness of the methods and compositions of the present invention in treating cancer therapy-associated cognitive impairment, as well as human subjects with cancer therapy-associated cognitive impairment. Parkinson's disease (PD)

[0189] 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.

[0190] Parkinson's disease psychosis is experienced by approximately one-third of PD patients and significantly impacts their quality of life. Psychosis is characterized by hallucinations, delusions, and other sensory disturbances, including the "sense of being" illusion and hallucination. The underlying causes of psychosis in PD patients are not fully understood. However, the occurrence of cognitive impairment in PD patients has been identified as a risk factor associated with the development of psychosis (Laura B. Zahodne and Hubert H. Fernandez, Drugs Aging. 2008, 25(8), 665-682).

[0191] 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 genetic, drug use, the aging process, viral infection, or various 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).

[0192] 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 increase 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.

[0193] The present invention relates to 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 for treating PD using receptor positive allosteric modulators are provided. In certain embodiments, treatment includes preventing PD or slowing its progression. In certain embodiments, treatment includes reducing, ameliorating, or slowing the progression of one or more symptoms associated with PD. In certain embodiments, the symptom treated is cognitive impairment. For example, the methods and compositions of the present disclosure can be used to improve motor / cognitive impairments 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 invention, 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 invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. In another embodiment of the present invention, there is provided a method of treating Parkinson's disease psychosis, comprising the step of administering to said 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.

[0194] There are several animal models of PD. 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 Ranjita B. et al. for a review of these models (Ranjita B. et al. BioEssays 2002, 24, 308-318). Additional information regarding these animal models is readily available from Jackson Laboratories (see also http: / / research.jax.org / grs / parkinsons.html), as well as numerous publications disclosing the use of these validated models.

[0195] The effectiveness of the methods and compositions of the invention 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

[0196] 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 is a disabling neurological disorder affecting thousands of Americans. It encompasses several subtypes, has 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).

[0197] 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 autism using receptor positive allosteric modulators. In certain embodiments, treatment includes preventing autism or slowing its progression. In certain embodiments, treatment includes reducing, ameliorating, 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 / agnosia symptoms that are symptomatic of autism. In some embodiments of the present invention, 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.

[0198] 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, which is an established model with a robust behavioral phenotype related to 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 invention in treating autism or autism-related 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

[0199] 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).

[0200] 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.

[0201] The present invention contemplates the treatment of mild mental retardation, moderate mental retardation, severe mental retardation, profound mental retardation, and mental retardation of unspecified severity. Such mental retardation may, but need not, be related to chromosomal changes (e.g., Down's syndrome due to trisomy 21), genetic, pregnancy and perinatal problems, and other severe mental disorders. The present invention provides α5-containing GABA AMethods and compositions are provided for treating mental retardation using a receptor 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 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 impairments symptomatic of mental retardation. In some embodiments of the present invention, a method of protecting or improving cognitive function in a subject with mental retardation 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.

[0202] 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)

[0203] 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.

[0204] 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.

[0205] 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). Research suggests that OCD may be related to abnormal levels of a neurotransmitter called serotonin. First-line treatment for OCD consists of behavioral therapy, cognitive therapy, and medication. 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 experience complete remission of their symptoms.

[0206] The present invention relates to 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 Receptor agonists (e.g., α5-containing GABA AThe present invention provides methods and compositions for treating OCD using a compound of the present invention (a compound of the present invention or 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. In certain embodiments, the treatment includes preventing OCD or slowing its progression. In certain embodiments, the 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 invention, a method for 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 invention or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof.

[0207] A quinpirole-sensitized rat model has been developed for OCD.The compulsive checking behavior of this quinpirole-sensitized rat, which is a characteristic feature of OCD compulsive behavior, tends to be interrupted.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 invention 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

[0208] 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.

[0209] 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.

[0210] The present invention relates to α5-containing GABA AMethods and compositions are provided for treating substance addiction using a receptor 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. 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 invention, 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.

[0211] 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

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] Medulloblastoma is a highly malignant primitive tumor that primarily occurs in the posterior fossa of the brain in children. It is the most common malignant brain tumor in children. The most lethal medulloblastoma subtype is GABAergic. A It exhibits high expression of the receptor α5 subunit gene and MYC amplification. See, for example, J Biomed Nanotechnol. 2016 Jun;12(6):1297-302.

[0218] 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.

[0219] The present invention relates to α5-containing GABA AMethods and compositions are provided for treating brain cancer (e.g., a brain tumor described herein) using a receptor 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 brain cancer. 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 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 invention, a method of 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 invention 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)

[0220] The present invention relates to the α5-containing GABA A Further provided are methods and compositions for treating the dysfunction of neurological disorders and neuropathological conditions by 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 related to such dysfunction.In another aspect of the present invention, provided are methods and compositions for protecting or improving cognitive function in subjects in need thereof by using the compound of the present invention, or its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, its isomer, or combinations thereof.

[0221] The Research Domain Criteria (RDoC) is expected to enhance clinical criteria such as the DSM and ICD for diagnosing diseases and disorders affecting the nervous system (see, e.g., Am. J. Psychiatry 167:7 (2010)). 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 receptor expression may be a therapeutic target for dysfunctional neuronal circuits identified under RDoC. GABA A Assays for α5 subunit binding and receptor positive allosteric modulator activity

[0222] GABA A GABA containing the α5 subunit A The affinity of the test compound for the receptor can be determined using receptor binding assays known in the art, see, e.g., U.S. Patent No. 7,642,267 and U.S. Patent No. 6,743,789, which are incorporated herein by reference.

[0223] α5-containing GABA A The 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 AThe test can be performed by assaying the GABA-induced chloride conductance of the receptor. Cells expressing such receptors can be exposed to an effective amount of the compound of the present invention. Such cells can be contacted in vivo with the compound of the present invention by contacting them with a body fluid containing the compound of the present invention, for example, with cerebrospinal fluid. In vitro testing can be performed by contacting the cells with the compound of the present invention in the presence of GABA. GABA A GABA containing the α5 subunit A An increase in GABA-induced chloride conductance in the presence of a test compound in cells expressing the receptor indicates that the compound has positive allosteric modulator activity. Such a change in conductance can be, for example, a GABA receptor. A Receptor subunit mRNA (GABA A Xenopus oocytes injected with GABA A This can be detected by using voltage clamp assays performed on HEK293 cells transfected with plasmids encoding the receptor subunits, or on in vivo, ex vivo or cultured neurons.

[0224] 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.

[0225] The compounds of the present disclosure can be synthesized using methods similar to those described in WO2018 / 130868. However, one of skill in the art will readily recognize that the specific methods and results discussed are merely illustrative of the invention, which is more fully described in the embodiments that follow.

[0226] Compounds 731 and 736 were prepared by subjecting compound 328 of WO2018 / 130868 to Sonogashira reaction conditions using appropriate starting materials. For exemplary reaction conditions, see Scheme 29 and compound 285 of WO2018 / 130868.

[0227] Compounds 733-734 were prepared by subjecting compound 356 (Scheme 41) of WO2018 / 130868 to Sonogashira reaction conditions using appropriate starting materials. For exemplary reaction conditions, see Scheme 29 and compound 285 of WO2018 / 130868.

[0228] Compounds 732 and 735 were prepared by subjecting compound 403 of WO2018 / 130868 to Sonogashira reaction conditions using appropriate starting materials. For exemplary reaction conditions, see Scheme 29 and compound 285 of WO2018 / 130868.

[0229] Compound 737 was prepared by subjecting compound 256 (Scheme 29) of WO2018 / 130868 to Sonogashira reaction conditions using appropriate starting materials. For exemplary reaction conditions, see Scheme 29 and compound 285 of WO2018 / 130868.

[0230] Synthesis of Compound 633 [ka] Scheme 11 [ka]

[0231] Compound 17' (see Scheme 11 of WO2018 / 130868, 17:R) in anhydrous CHCl (25 mL) and anhydrous DMF (25 mL) 1 =OMe;17':R 1To a stirred solution of (═Cl) (2.96 g, 11.2 mmol), imidazole (1.91 g, 28.1 mmol), DMAP (274 mg, 2.24 mmol), and EtN (4.7 mL, 33.7 mmol) was added TBSCl (3.37 g, 22.4 mmol). The reaction mixture was stirred overnight at room temperature under N. After this time, the resulting reaction mixture was diluted with EtOAc (300 mL), washed with 10% aqueous LiCl (3 × 50 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 5% EtOAc / CHCl to give compound 633-1 as a white solid (3.67 g, 87%): MS [M+Na] = 401.

[0232] To a stirred solution of compound 633-1 (3.67 g, 9.69 mmol) in anhydrous DMF (50 mL) under N2 at -20 °C was added NaH (60% in mineral oil, 426 mg, 10.7 mmol).

[0233] The resulting mixture was stirred at −20° C. for 10 minutes. After this time, PMBCl (2.0 mL, 14.8 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The resulting mixture was quenched with 10% aqueous LiCl (100 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with 10% aqueous LiCl (3×30 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 10% to 30% EtOAc / hexane to give compound 633-2 as a pale yellow solid (4.59 g, 95%): MS [M+1]=499.

[0234] To a stirred solution of compound 633-2 (4.59 g, 9.20 mmol) in anhydrous THF (100 mL) at 0 °C under N was added TBAF (1 M solution in THF, 18.4 mL, 18.4 mmol). The reaction mixture was stirred at 0 °C for 2 h. After this time, the reaction was quenched with saturated aqueous NH Cl (100 mL) and extracted with CHCl (3 × 100 ml). The combined extracts were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 50% to 100% EtOAc / hexane to give compound 633-3 as a white foam (2.92 g, 83%): MS [M+1] = 385.

[0235] To a stirred solution of compound 633-3 (2.92 g, 7.59 mmol) in anhydrous CHCl (150 mL) at room temperature under N was added PPh (3.98 g, 15.2 mmol) followed by CBr (3.02 g, 9.11 mmol). The reaction mixture was stirred at room temperature for 4 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 30%-60% EtOAc / hexane to give compound 633-4 as a white foam (2.59 g, 76%): MS [M+1] = 447.

[0236] To a stirred solution of compound 633-4 (576 mg, 1.29 mmol) in anhydrous THF (10 mL) and anhydrous MeOH (45 mL) was added NaH (60% in mineral oil, 515 mg, 12.9 mmol) portionwise over 40 min at 0 °C under N. The reaction mixture was stirred at 0 °C for 1.5 h. After this time, the reaction was quenched with saturated aqueous NH Cl (100 mL) and neutralized to pH 7 with 6 N aqueous HCl. The resulting mixture was extracted with CHCl (3 × 100 mL). The combined extracts were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 50% to 100% EtOAc / hexane to give compound 633-5 as a white foam (436 mg, 85%): MS [M+1] = 399.

[0237] A solution of compound 633-5 (1.66 g, 4.16 mmol) in TFA (15 mL) was heated to reflux (85 °C, oil bath) for 2 days. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CHCl (100 mL), washed with saturated NaHCO (3 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 50% to 100% EtOAc / hexane to give compound 633-6 as an off-white solid (810 mg, 70%): MS [M+1] = 279.

[0238] To a stirred solution of 1,2,4-triazole (506 mg, 7.33 mmol) in anhydrous CH3CN (30 mL) at 0 °C under N2, DIPEA (1.3 mL, 7.46 mmol) was added, followed by POCl3 (0.2 mL, 2.15 mmol). The reaction mixture was stirred at 0 °C for 2 h. After this time, a solution of compound 633-6 (1.02 g, 3.66 mmol) in anhydrous CH3CN (50 mL) was added. The reaction mixture was allowed to warm to room temperature and then heated to reflux (oil bath at 100 °C) overnight. The reaction mixture was cooled to room temperature and quenched with ice-cold water (50 mL). The resulting mixture was extracted with CHCl2 (3 × 100 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 50% to 100% EtOAc / CH2Cl2 to give compound 633-7 as a yellow solid (950 mg, 79%): MS [M+1] = 330.

[0239] To a stirred solution of KOT-Bu (485 mg, 4.32 mmol) in anhydrous DMF (10 mL) was added CNCHClEt (0.47 mL, 4.30 mmol) at −50° C. under N. The reaction mixture was stirred at −50° C. for 1 h. After this time, a solution of compound 633-7 (950 mg, 2.88 mmol) in anhydrous DMF (15 mL) was added. The reaction mixture was allowed to warm slowly to room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO (50 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined extracts were washed with 10% aqueous LiCl (3×30 mL) and brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 8% MeOH / EtOAc to give compound 633-8 as a yellow solid (815 mg, 76%): MS [M+1] = 374.

[0240] To a stirred solution of compound 633-8 (150 mg, 0.401 mmol) in THF (15 mL) and water (7 mL) was added LiOH·HO (84 mg, 2.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After this time, the reaction mixture was concentrated under reduced pressure. The resulting mixture was acidified to a pH of about 2 using 2N aqueous HCl. The solid was collected by filtration. The filter cake was washed with water (10 mL) and dried under high vacuum to give compound 633-9 as a white solid (125 mg, 90%): MS [M+1] = 346.

[0241] A suspension of compound 633-9 (122 mg, 0.353 mmol), I (269 mg, 1.06 mmol), and KPO (75 mg, 0.353 mmol) in anhydrous DMF (9 mL) was sealed and placed in a microwave reactor at 170 °C for 30 min. After this time, the reaction mixture was cooled to room temperature and diluted with 10% aqueous LiCl (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined extracts were washed with 10% aqueous LiCl (3 × 30 mL) and brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 1% to 4% MeOH / CHCl to give compound 633-10 as a white solid (35 mg, 23%): MS [M+1] = 428.

[0242] Argon was bubbled through a suspension of compound 633-10 (32 mg, 0.0748 mmol), compound 633-11 (37 μL, 0.303 mmol), and CuI (4 mg, 0.0210 mmol) in anhydrous DMF (4 mL) for 5 min. After this time, EtN (52 μL, 0.373 mmol) was added, followed by Pd(dppf)Cl·CHCl (12 mg, 0.0147 mmol). The resulting mixture was heated at 40 °C under argon for 2 h. The reaction mixture was then cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (3 × 30 mL). The combined extracts were washed with 10% aqueous LiCl (3 × 20 mL) and brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0% to 4% MeOH / CH2Cl2 to give compound 633 as an off-white solid (13 mg, 41%): 1 H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J = 1.8 Hz, 1H), 8.27 (s, 1H), 8.13 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 8.7, 2.3 Hz, 1H), 7.92 (dd, J = 8.6, 2.3 Hz, 1H), 7.86 (dd, J = 8.7, 2.3 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 4.64 (s, 2H), 4.43 (br s, 2H), 3.91 (s, 3H), 3.26 (s, 3H); ESI MS, m / z = 433 [M+H] + .

[0243] Compounds 738-740 were prepared by subjecting compound 633-10 of Scheme 11 to Sonogashira reaction conditions using the appropriate starting materials under the conditions described for compound 633 in Scheme 11.

[0244] Compounds 731-740 were analyzed by MS and 1 Identification by H NMR. Identification by MS is summarized in Table 5 below. Table 5. MS characterization of compounds 731–740: [Table 5-1] [Table 5-2] [Table 5-3] Example 105 α5-containing GABA A Receptor (GABA A R) Evaluation of positive allosteric modulator activity

[0245] Process 1: GABA A Establishment of clones of R subunits (α5, β3, γ2, α1, α2, and α3) and preparation of corresponding cRNA:GABA A Human clones of the -Rα5, β3, γ2, α1, α2, and α3 subunits are obtained from commercial sources (e.g., OriGene, http: / / www.origene.com and Genescript, http: / / www.genescript.com). These clones are engineered into pRC, pCDM, pcDNA, and pBluescript KSM vectors (for expression in oocytes) or other equivalent expression vectors. Host cells are transiently transfected using conventional transfection agents (e.g., FuGene, Lipofectamine 2000, or others).

[0246] Step 2 - Functional GABAergic receptors of α5β3γ2, α1β3γ2, α2β3γ2, and α3β3γ2 subtypes in a Xenopus oocyte expression system AAssay: cRNA encoding the α5, β3, γ2, α1, α2, and α3 subunits was in vitro transcribed using the T3 mMESSAGE mMACHINE Kit (Ambion) and injected into freshly prepared Xenopus oocytes (at a 2:2:1 ratio of α:β:γ or other optimized conditions). After 2 days of culture, GABAergic Cl- currents were measured from the oocytes using a TEVC setup (Warner Instruments, Inc., Foster City, CA). To validate this system, GABA, benzodiazepines, and diazepam were used as reference compounds.

[0247] Step 3 - Evaluating the positive allosteric modulator activity of test compounds for the α5β3γ2 subtype and for off-target activity for the α1-α3-linked β3γ2 subtype if an EC50 = 5 μM selectivity cutoff is reached: GABAergic Cl- currents from oocytes are measured in a TEVC setting in the presence of test compounds. The positive allosteric modulator activity of each test compound is tested in a five-point dose-response assay. Test compounds include several reference compounds (literature EC50 values ​​for the α5β3γ2 subtype are in the range of 3-10 μM). The EC50 for each compound at the α5β3γ2 subtype is obtained. If the EC50 at α5β3γ2 is ≤ 5 μM, the EC50s for the other three subtypes (α1β2γ2, α2β3γ2, and α3β3γ2) are further determined individually to test the selectivity of the compound for the α5β3γ2 subtype over the other subtypes.

[0248] Step 4 - Evaluate further test compounds against the α5β3γ2 subtype and test for off-target activity if an EC50 = 0.5 μM selectivity cutoff is reached: A second batch of test compounds is tested using the same strategy but with a lower EC50 cutoff (0.5 μM). Again, determine the EC50 for the α5β3γ2 subtype for each compound. Only if the EC50 for the α5-containing receptor is <0.5 μM will the α1-α3-bound β3γ2 subtype be tested. Example 106 GABA A Evaluation of compounds for binding activity and positive allosteric modulator activity at the α5 receptor (A)GABA A Binding activity of test compounds to R

[0249] Tissue culture and membrane preparation: GABA A Binding was performed on Ltk cells (provided by Merck Co., NJ, USA) stably expressing the following receptors: α1β1γ2, α2β3γ2, α3β3γ2, and α5β3γ2. Cells were seeded in 100 mm culture plates in DMEM / F12 medium containing 10% serum and antibiotics at 5% CO2 and grown for 1–2 days. GABA receptors were then upregulated by dexamethasone as follows: A Induced the expression of R:α5-containing GABA A For R, 0.5 μM for 1 day, and α1-, α2-, and α3-containing GABA A For R, 2 μM was used for 3 days. After induction, cells were harvested by scraping into Dulbecco's phosphate-buffered saline (DPBS, pH 7.4, Invitrogen, Carlsbad, CA, USA) and centrifuged at 150 × g for 10 min. The pellet was washed twice by resuspension and centrifugation. Cell pellets from at least five different preps were combined and suspended in binding assay buffer (50 mM KH2PO4; 1 mM EDTA; 0.2 M KCl, pH 7.4), and membranes were prepared by sonication (3–5 times, 30 s) using a Branson Sonifier 150 (G. Heinmann, Germany). Protein content was determined using the BCA assay (Bio-Rad Labs, Reinach, Switzerland) using bovine serum albumin (Sigma-Aldrich, St. Louis, MO, USA) as the standard. Aliquots were prepared and stored at -20°C for further use in binding assays.

[0250] Ligand binding: 3Saturation binding curves were obtained by incubating membranes with increasing concentrations (0.01–8 nM) of [H]Rol5-1788 (Flumazepil, 75–85 Ci / mmol, PerkinElmer, MA, USA), and nonspecific binding was measured in the presence of 10 μM diazepam. The α1-, α2-, α3-, and α5-containing GABA binding curves were calculated from the saturation curves. A K against R d value or lower K d At the radioligand concentration at the value, the [ 3 H] inhibition of Rol5-1788 binding was performed.

[0251] All binding assays were performed in assay buffer for 1 hour at 4°C. The total assay volume was 1000kJ / mL for α5-containing GABA. A For R membranes, 0.5 ml containing 0.2 mg / ml protein and α1-, α2-, and α3-containing GABA A For R membranes, the volume was 0.5 ml containing 0.4 mg / ml. The incubation was terminated by filtration through GF / B filters using a 24-Cell Harvestor (Brandel, Gaithersburg, MD, USA) followed by three washes with ice-cold assay buffer. The filters were transferred to scintillation vials, 5 ml of scintillation fluid was added, vortexed to mix, and kept in the dark. Radioactivity was measured the next day using a scintillation counter (Beckman Coulter, Brea, CA, USA). All assays were performed in triplicate.

[0252] Data analysis: Saturation and inhibition curves were obtained using GraphPad Prism software (GraphPad Software, Inc., CA, USA). The equilibrium dissociation constant (K i value) is calculated using the Cheng-Prusoff formula K i =IC 50 / (1+S / K d ) (where IC 50 teeth,[ 3is the concentration of unlabeled ligand that inhibits 50% of [H] ligand binding, S is the concentration of radioactive ligand, and K d is the equilibrium dissociation constant of the radioactive ligand). K is expressed as the mean ± SD from triplicate assays using the log range of compounds (1 nM to 10 μM). i value was determined. (B) α5β2γ2 subtype GABA A Positive allosteric modulator activity of test compounds against R

[0253] First, using a protocol substantially similar to that presented above, the compounds of the present invention are induced to react with GABA A EC of GABA in oocytes containing receptors (α5β2γ2) 20 Concentrations were screened at 100 nM for their ability to stimulate ATP production.

[0254] On day 1, 1ng / 32nL of GABA A One oocyte was injected with α5β2γ2 cDNA. Testing began on day 2. The cDNA injected into the oocyte was a mixture of alpha, beta, and gamma subunits, with a ratio of 1:1:10 (by weight). The total weight of the mixed three subunits injected into one oocyte was 1 ng in a volume of 32 nl. Injected oocytes can also be tested on day 3. In such cases, the amount of cDNA injected into the oocyte should be reduced by 20%.

[0255] The compounds of the present invention were tested using the following procedure.

[0256] GABA dose-response 1) Eight oocytes were placed in eight chambers of the OpusXpress and superfused with modified Barth's saline (MBS) at 3 mL / min. Glass electrodes (0.5–3 megaohms) back-filled with 3 M KCl were used. The membrane potential of the oocytes was voltage-clamped at -60 mV. 2) To stabilize the oocytes, the average EC obtained from the previous test was used. 20GABA was applied 5–6 times. Between each GABA application, wash the oocytes with MBS for 5–10 min. 3) GABA dose-response analysis was performed to determine the EC 20 Obtain GABA values.

[0257] Controlled trials (diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate) 1) New tests were performed using new oocytes. 2) To stabilize the oocytes, EC 20 GABA was applied 5-6 times, and between each GABA application, the oocytes were washed with MBS for 5-10 minutes. 3).EC 20 GABA was applied to induce a current (I GABA The oocytes were washed with MBS for 5 to 10 minutes. 4) Pre-apply 1 μM diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate for 40 seconds, followed by 1 μM diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate and EC 20 GABA and I were simultaneously applied. test I got test I GABA % activation was obtained by dividing by .

[0258] Test compound at multiple doses 1) In the control test, repeat steps 1), 2) and 3) above. 2) A first concentration of test compound was pre-applied for 40 seconds, followed by the same concentration of test compound and EC 20 By simultaneously applying GABA, I test I got test I GABA Divide by to get % activation. 3) All tested oocytes were discarded, and new oocytes were used to repeat steps 1) and 2) above, testing the same compound at a second concentration. Each oocyte was used for only one test concentration of a single test compound. These steps were repeated for the other test compounds.

[0259] In some embodiments, the compounds of the present application have an α5-containing GABA concentration of less than 200 nM, less than 180 nM, less than 150 nM, or less than 100 nM. A The binding affinity of R (K i In some embodiments, the compounds of the present application have an α5-containing GABA A The binding affinity of R (K i In some embodiments, the compounds of the present application have an α5-containing GABA A The binding affinity of R (K i )

[0260] In some embodiments, the compounds of the present application are α1-containing GABA A α5-containing GABA A In some embodiments, the compounds of the present application are selective for α1-containing GABA A α5-containing GABA A It is more than 50-fold, more than 100-fold, more than 500-fold, or more than 1000-fold selective for R.

[0261] In some embodiments, the compounds of the present application have a α5-containing GABA concentration of less than 500 nM, less than 100 nM, or less than 50 nM. A R's EC 50 In some embodiments, the compounds of the present application have an α5-containing GABA A R's EC 50 It has.

[0262] In some embodiments, the compounds of the present application at 100 nM inhibit the activity of α5-containing GABA A In some embodiments, the compounds of the present application activate α5-containing GABA R by more than 10%, more than 25%, more than 50%, or more than 75% at 1000 nM. A Activate R by more than 10%, more than 25%, more than 50%, or more than 75%.

[0263] The screening results of the binding activity test and the PAM functional activity test are summarized in Tables 1 and 2 below.

[0264] Table 1 below illustrates the range of GABAα5 binding Ki associated with compounds of the present disclosure: Table 1 [Table 1]

[0265] Table 2 below illustrates the range of functional activation of GABAα5 associated with compounds of the present disclosure: Table 2 [Table 2]

[0266] Selected compounds of the invention exhibit >10-fold binding selectivity for GABAα5 relative to GABAα1, GABAα2, or GABAα3. Some compounds of the present application demonstrate greater than 20-fold, 50-fold, or 100-fold binding selectivity for GABAα5 relative to GABAα1, GABAα2, or GABAα3.

[0267] Table 6 below illustrates the range of binding selectivity of compounds of the present disclosure for GABAα5 versus GABAα1, GABAα2, or GABAα3. Table 6 [Table 6] Example 107 Effect of methyl 3,5-diphenylpyridazine-4-carboxylate in aged impaired (AI) rats

[0268] Methyl 3,5-diphenylpyridazine-4-carboxylate, corresponding to compound number 6 in van Niel et al. J. Med. Chem. 48:6004-6011 (2005), is a selective α5-containing GABA receptor antagonist. A It is an R agonist. 20The effects of 3,5-diphenylpyridazine-4-carboxylate methyl ester on aged impaired rats were investigated using the RAM task. Furthermore, the effects of α5-containing GABA A Receptor occupancy by methyl 3,5-diphenylpyridazine-4-carboxylate at the receptor was also examined. (A) Effects of methyl 3,5-diphenylpyridazine-4-carboxylate in aged impaired rats using the radial maze (RAM) behavioral task.

[0269] The effects of methyl 3,5-diphenylpyridazine-4-carboxylate on in vivo spatial memory retention in aged impaired (AI) rats were assessed in a radial arm maze (RAM) behavioral task using vehicle control and four different dose levels of methyl 3,5-diphenylpyridazine-4-carboxylate (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, and 3 mg / kg, i.p.). The RAM behavioral task was performed on eight AI rats. All five treatment conditions (vehicle and four dose levels) were tested on all eight rats.

[0270] The RAM apparatus used consisted of eight equidistantly spaced rungs. Elevated maze rungs (7 cm wide x 75 cm long) protruded from each side of an octagonal central platform (30 cm diameter, 51.5 cm high). Transparent side walls above the rungs were 10 cm high and bent at a 65° angle to form a depression. A food well (4 cm diameter, 2 cm deep) was located at the distal end of each rung. Froot Loops™ (Kellogg Company) were used as rewards. Blocks (30 cm high x 12 cm wide) constructed from Plexiglas™ could be placed to prevent entry into any rung. Numerous additional maze cues were provided around the perimeter of the apparatus.

[0271] AI rats were first subjected to a pretraining trial (Chappell et al. Neuropharmacology 37: 481-487, 1998) consisting of a 4-day acclimation period, an 18-day training period on a standard win-shift task, and another 14-day training period in which a short delay was imposed between the presentation of an experimenter-specified subset of lanes (e.g., five lanes accessible, three lanes blocked), as well as the completion of an 8-lane win-shift task (i.e., all eight lanes accessible).

[0272] During the acclimation phase, rats were accustomed to the maze for four consecutive 8-minute sessions. During each session, food rewards were scattered on the RAM, first on the central platform and along the runways, and then gradually confined to the runways. After this acclimation phase, a standard training protocol was used, in which food pellets were placed at the end of each runway. Rats underwent one trial per day for 18 days. Each daily trial ended after obtaining all eight food pellets, 16 choices, or 15 minutes had elapsed. After this training phase was completed, a second training phase was conducted, in which memory demands were increased by imposing a short delay between trials. At the beginning of each trial, three runs of the eight-run maze were blocked off. Rats were able to access food on the five runs that were accessible during this initial "information phase" of the trial. The rat was then removed from the maze for 60 seconds, during which time the maze barriers were removed, allowing access to all eight lanes. The rat was then returned to the center platform and allowed to obtain the remaining food rewards during the "retention" phase of the trial. The identity and location of the blocked lanes was varied from trial to trial.

[0273] The number of "errors" made by AI rats during the retention test phase was tracked: an error occurred in a trial if they entered a lane from which food had already been retrieved during the pre-delay portion of that trial, or if they revisited a lane they had already visited during the post-delay session.

[0274] After the pretraining test was completed, rats were subjected to a trial with an extended delay interval between the information phase (presentation of some blocked runways) and the retention test (presentation of all runways), i.e., a 2-hour delay. During the delay interval, rats were kept on a cart in their individual home cages near the maze in the testing room. 30–40 min before each daily trial, AI rats were pretreated intraperitoneally (ip) with one injection of one of the following five conditions: 1) vehicle control (5% dimethyl sulfoxide, 25% polyethylene glycol 300, and 70% distilled water); 2) 0.1 mg / kg methyl 3,5-diphenylpyridazine-4-carboxylate; 3) 0.3 mg / kg methyl 3,5-diphenylpyridazine-4-carboxylate; 4) 1 mg / kg methyl 3,5-diphenylpyridazine-4-carboxylate; and 5) 3 mg / kg methyl 3,5-diphenylpyridazine-4-carboxylate. Injections were administered every other day, with a washout day between. Each AI rat was treated with all five conditions within the study period. To counteract any potential bias, an ascending-descending dose series was used to assess the drug effects; that is, a series of doses was administered first in ascending order, then in descending order. Thus, each dose was administered twice.

[0275] Parametric statistics (paired t-test) were used to compare the performance of AI rats on a 2-hour delayed version of the RAM task in the presence of various doses of methyl 3,5-diphenylpyridazine-4-carboxylate and vehicle control (see Figure 1). The mean number of errors made per trial was significantly lower with 3 mg / kg methyl 3,5-diphenylpyridazine-4-carboxylate treatment (mean number of errors ± standard error = 1.31 ± 0.40) than with vehicle control (mean number of errors ± standard error = 3.13 ± 0.62). Compared with vehicle control treatment, methyl 3,5-diphenylpyridazine-4-carboxylate significantly improved memory performance at 3 mg / kg (t(7) = 4.233, p = 0.004).

[0276] AI rats were treated with 0.3 mg / kg of α5-containing GABA A Concurrent treatment with the R inverse agonist TB21007 rendered the 3 mg / kg therapeutic dose ineffective. The mean number of errors made by rats treated with the TB21007 / methyl 3,5-diphenylpyridazine-4-carboxylate combination (0.3 mg / kg TB21007 and 3 mg / kg methyl 3,5-diphenylpyridazine-4-carboxylate) was 2.88 ± 1.32, which was not different from the mean number of errors made by rats treated with the vehicle control (3.13 ± 1.17). Thus, the effect of methyl 3,5-diphenylpyridazine-4-carboxylate on spatial memory was not related to the GABAergic pathway. A This is an α5 receptor-dependent effect (see Figure 1). (B) α5-containing GABA A Effect of methyl 3,5-diphenylpyridazine-4-carboxylate on receptor occupancy animal

[0277] Adult male Long Evans rats (265–295 g, Charles River, Portage, MI, n = 4 / group) were administered GABA A α5 receptor occupancy studies were used. Rats were housed individually in ventilated stainless steel racks on a 12:12 light / dark cycle. Food and water were available ad libitum. For further studies evaluating compound exposure at behaviorally active doses, young or aged Long Evan rats (n = 2-4 / group) were used for these studies. compound

[0278] Ro15-4513 inhibits GABA receptors in the hippocampus and cerebellum A It was used as a receptor occupancy (RO) tracer for the α5 receptor site. Other alpha subunit-containing GABA A GABA compared to receptors A Based on the selectivity of Ro15-4513 for the α5 receptor and its potential to inhibit GABA receptor agonism in animals and humans, ARo15-4513 was chosen as the tracer because it has been successfully used in α5 RO studies (see, e.g., Lingford-Hughes et al., J. Cereb. Blood Flow Metab. 22:878-89 (2002); Pym et al., Br. J. Pharmacol. 146: 817-825 (2005); and Maeda et al., Synapse 47: 200-208 (2003)). Ro15-4513 (1 μg / kg) was dissolved in 25% hydroxyl-propyl beta-cyclodextrin and administered intravenously 20 minutes before RO assessment. Methyl 3,5-diphenylpyridazine-4-carboxylate (0.1–10 mg / kg) was synthesized by Nox Pharmaceuticals (India), dissolved in 25% hydroxyl-propyl beta-cyclodextrin, and administered intravenously 15 min before tracer injection. Compounds were administered in a volume of 0.5 ml / kg, except for the highest dose of methyl 3,5-diphenylpyridazine-4-carboxylate (10 mg / kg), which was administered in a volume of 1 ml / kg due to solubility limitations. Tissue preparation and analysis

[0279] Twenty minutes after tracer injection, rats were sacrificed by cervical dislocation. The whole brain was quickly removed and gently rinsed with sterile water. Trunk blood was collected in EDTA-coated Eppendorf tubes and stored on wet ice until the study was completed. The hippocampus and cerebellum were excised, stored in 1.5 ml Eppendorf tubes, and kept on wet ice until tissue extraction. Six cortical brain tissue samples were collected from drug-naive rats for use in preparing blanks and standard curve samples.

[0280] A volume of acetonitrile containing 0.1% formic acid was added to each sample, four times the weight of the tissue sample. For standard curve (0.1–30 ng / g) samples, the calculated volume of standard was reduced by the volume of acetonitrile. The samples were homogenized (FastPrep-24, Lysing Matrix D; 5.5 m / s, 60 s, or 7–8 watts using a sonic probe dismembrator; Fisher Scientific) and centrifuged at 14,000 rpm for 16 min. The resulting supernatant (100 μl) was diluted with 300 μl of sterile water (pH 6.5). The solution was then thoroughly mixed and analyzed for Ro15-4513 (tracer) and methyl 3,5-diphenylpyridazine-4-carboxylate by LC / MS / MS.

[0281] For plasma exposure, blood samples were centrifuged at 14,000 rpm for 16 minutes. After centrifugation, 50 μl of supernatant (plasma) from each sample was added to 200 μl of acetonitrile + 0.1% formic acid. For standard curve (1-1,000 ng / ml) samples, the calculated volume of standard was reduced by the volume of acetonitrile. The samples were sonicated in an ultrasonic water bath for 5 minutes and then centrifuged at 16,000 rpm for 30 minutes. 100 μl of supernatant was withdrawn from each sample vial and placed into a new glass autosampler vial, followed by the addition of 300 μl of sterile water (pH 6.5). The solution was then thoroughly mixed and analyzed for methyl 3,5-diphenylpyridazine-4-carboxylate by LC / MS / MS.

[0282] Hippocampus (GABA A α5 receptor density areas) and the cerebellum (GABA A By a ratio method comparing occupancy in the α5 receptor-low density region with that in the α5 receptor-low density region, and further by using a high dose of GABA to define full occupancy. A Receptor occupancy was measured by the α5 negative allosteric modulator L-655,708 (10 mg / kg, iv).

[0283] Vehicle administration followed by 1 μg / kg iv tracer administration of Ro15-4513 resulted in >5-fold higher levels of Ro15-4513 in the hippocampus (1.93 ± 0.05 ng / g) compared with the cerebellum (0.36 ± 0.02 ng / g). Methyl 3,5-diphenylpyridazine-4-carboxylate (0.01–10 mg / kg iv) did not affect cerebellar levels of Ro15-4513 (Figure 2) but dose-dependently reduced Ro15-4513 binding in the hippocampus, with the 10 mg / kg iv dose demonstrating >90% occupancy (Figure 3). Both methods of calculating the RO gave very similar results, with the ED50 value for methyl 3,5-diphenylpyridazine-4-carboxylate being 1.8 mg / kg based on the ratio method, or 1.1 mg / kg when L-755,608 was used to define occupancy.

[0284] Methyl 3,5-diphenylpyridazine-4-carboxylate exposure was below the limit of quantification (BQL) at 0.01 mg / kg iv in both plasma and hippocampus, but was detectable at low levels in the hippocampus at 0.1 mg / kg iv (see Table 3). Hippocampal exposure was linear with a 10-fold increase in dose from 0.1 to 1 mg / kg iv, resulting in a 12-fold increase in exposure. Increasing the dose from 1 to 10 mg / kg iv alone improved exposure approximately 5-fold. Plasma exposure improved 12-fold with increasing dose from 1 to 10 mg / kg iv. Table 3: % GABA induced by methyl 3,5-diphenylpyridazine-4-carboxylate (0.01-10 mg / kg, iv) A α5 receptor occupancy. Hippocampal and plasma exposure to methyl 3,5-diphenylpyridazine-4-carboxylate by treatment group in young Long Evans rats. [Table 3]

[0285] Further studies were conducted in aged Long-Evans rats to determine behaviorally relevant dose exposures in cognitive studies. To bridge the receptor occupancy studies performed in young Long-Evans rats, exposures in young Long-Evans rats were also determined. Exposures in young and aged Long-Evans rats were relatively similar (Table 4, Figure 4). A three-fold increase in dose from 1 to 3 mg / kg i.p. resulted in a greater than dose-proportional increase in exposure in both the hippocampus and plasma in young and aged rats, with increases of 4.5- to 6.6-fold. Table 4: Hippocampal and plasma exposure of methyl 3,5-diphenylpyridazine-4-carboxylate by treatment group in young Long Evans rats. [Table 4]

[0286] In this RO study, a 180 ng / g exposure (1 mg / kg, iv) in the hippocampus demonstrated 32–39% receptor occupancy depending on the method used to determine RO. This exposure is comparable to that observed in aged rats at 3 mg / kg, ip, suggesting that a 30–40% RO is required for cognitive efficacy in this model.

[0287] These studies demonstrated that methyl 3,5-diphenylpyridazine-4-carboxylate inhibits GABA A demonstrated that 3,5-diphenylpyridazine-4-carboxylate increased α5 receptor occupancy in a dose-dependent manner. It also demonstrated favorable brain exposure with a brain / plasma ratio of >1. These studies suggest that 3,5-diphenylpyridazine-4-carboxylate increases GABA receptor occupancy. A It was further demonstrated that its cognitive enhancing effects were mediated by positive allosteric modulation at the a5 subtype receptor. Example 108 Effects 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 in aged impaired (AI) rats

[0288] Ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate, corresponding to compound number 49 in Achermann et al. Bioorg. Med. Chem. Lett., 19:5746-5752 (2009), selectively inhibits α5-containing GABA receptors. A It is an R agonist.

[0289] The effects 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 in vivo spatial memory retention in aged impaired (AI) rats were assessed in a radial arm maze (RAM) behavioral task substantially similar to the task described in Example 107(A) using vehicle control (25% cyclodextrin, which was tested three times: at the beginning, middle, and end of an ascending / descending series) and six different dose levels 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 (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, and 30 mg / kg, each dose tested twice). The same experiment was repeated using the same vehicle control and the same 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, where the vehicle control was tested five times, the 3 mg / kg dose 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 was tested four times, and the other 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.

[0290] Parametric statistics (paired t-tests) were used to compare the retention performance of AI rats in a 4-h delayed version of the RAM task in the context of 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 and vehicle control (see Figure 5). Compared to vehicle control treatment, ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate significantly improved memory performance at 3 mg / kg (t(7) = 4.13, p = 0.004 or t(7) = 3.08, p = 0.018) and 10 mg / kg (t(7) = 2.82, p = 0.026).

[0291] α5-containing GABA A 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 receptor occupancy was also investigated following a procedure substantially similar to that described in Example 107(B) (see above). This study demonstrated that ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate (0.01-10 mg / kg iv) reduced Ro15-4513 binding in the hippocampus without affecting Ro15-4513 levels in the cerebellum (Figure 6), with the 10 mg / kg iv dose demonstrating >90% occupancy (Figure 7). Example 109 Effects of 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one in aged impaired rats using the Morris water maze behavioral task

[0292] 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one, corresponding to compound 44 in J. Med. Chem. 46:2227-2240 (2003), selectively inhibits the α5-containing GABA receptor. A It is an R agonist.

[0293] The effects of 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one on in vivo spatial memory retention in aged impaired (AI) rats were assessed using the Morris water maze behavioral task. The water maze is a pool surrounded by a series of novel patterns. Training protocols for the water maze can be based on a modified water maze task shown to be hippocampal-dependent (de Hoz et al., Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus, 9:118-36, 1999).

[0294] Cognitively impaired aged rats were unilaterally cannulated into the lateral ventricle. The stereotaxic coordinates were 1.0 mm posterior to bregma, 1.5 mm lateral to the midline, and 3.5 mm ventral to the skull surface. After approximately 1 week of recovery, rats were pretrained in a water maze for 2 days (6 trials per day) to locate a submerged escape platform hidden below the surface of the pool; the location of the escape platform was changed daily. No intracerebroventricular (ICV) injections were performed during pretraining.

[0295] After pretraining, rats were injected intravenously with either 100 μg of 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (n = 6) in 5 μl of DMSO or vehicle DMSO (n = 5) 40 min before water maze training and testing. Training consisted of eight trials per day over two days, with the hidden escape platform remaining in the same location. Rats were given 60 s to locate the platform, with a 60 s interval between trials. 24 h after the end of training, rats were given a probe test (120 s) in which the escape platform was removed. There were four blocks during training, with each block containing four training trials.

[0296] Vehicle- and 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one-treated rats found the escape platform almost simultaneously at the beginning of training (Block 1). In this training block, both vehicle- and 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one-treated rats took approximately 24 seconds to find the platform. However, 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one-treated rats were able to find the platform better (i.e., faster) than vehicle-treated rats at the end of training (Block 4). In block 4, rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one took approximately 9.6 seconds to find the escape platform, while vehicle-treated rats took approximately 19.69 seconds. These results suggest that 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one improved learning of the water maze task in rats (see Figure 8(A)).

[0297] In the test trial 24 hours after training, the escape platform was removed. To test the rats' long-term memory, their exploration / swimming patterns were used to measure whether they remembered the location of the escape platform during pre-training. In this trial, the "target ring" was a designated area 1.5 times the size of the escape platform surrounding the area where the platform was located during pre-training. The "opposite ring" was a control area of ​​the same size as the target ring, located opposite the target ring in the pool. If rats had good long-term memory, they tended to explore the area surrounding the location of the platform during pre-training (i.e., the "target" ring, not the "opposite" ring). "Time in ring" was the amount of time, in seconds, that the rat spent in the target or opposite ring area. "Number of crossings" in the ring was the number of times the rat swam across the target or opposite ring area.

[0298] Vehicle-treated rats spent the same amount of time in the target and contralateral rings, indicating that they did not seem to remember the location of the platform during pretrial training. In contrast, rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one spent significantly more time in the target ring and crossed the "target ring" more frequently than the time spent in the "contralateral ring" or the number of crossings of the "contralateral ring." These results suggest that 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one improved rats' long-term memory in the water maze task (see Figures 8(B) and 8(C)).

[0299] The compounds of the present invention are AThese compounds have demonstrated a positive allosteric modulatory effect on the α5 receptor (see, e.g., Example 106). A The compounds of the present invention enhance the effects of GABA at the α5 receptor. Therefore, the compounds of the present invention are effective in preventing the effects of other GABA receptors in aged, impaired animals (such as rats). A This should produce cognitive-enhancing effects similar to those produced by alpha5 receptor selective agonists (such as methyl 3,5-diphenylpyridazine-4-carboxylate, ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate and 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one) (see, e.g., Examples 28-30). (Item 1) Compound of Formula A: [ka] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, wherein: Y and Z are each independently selected from C and N, provided that Y and Z cannot both be N; Combine ' [ka] " each occurrence is either a single bond or a double bond, R 1 are each independently halogen, —OH, or —O(C1-C6)alkyl; R 2 are -H and -OR, respectively. 8 , -SR 8 , -(CH2) n OR 8 , -(CH2) n SR 8 and R 9are each —H, (C6-C12)aryl, or 5-10 membered heteroaryl, and R 9 are 0 to 5 R 11 is replaced by R 11 is independently selected at each occurrence from -halogen, -CF3, -OH, -OCF3, OCHF2, -O-(C1-C6)alkyl, -CN, -SCH3, -(C6-C10)aryl, and -(C1-C6)alkyl; m and n are independently integers selected from 0 to 4; The compound, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. (Item 2) R 1 are each a halogen or -OMe, R 2 are -H or -CH2OMe, R 9 are respectively, [ka] and R 9 Each has 0 to 5 R 11 is replaced by R 11 is independently selected from -halogen, -CF3, -OH, -OCF3, OCHF2, or -OMe, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. (Item 3) The compound has a structure according to Formula B: [ka] 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, having the formula: (Item 4) The compound has a structure according to Formula C: [ka] 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, having the formula: (Item 5) below: [Table 8-1] [Table 8-2] or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof. (Item 6) A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an isomer thereof, or a combination thereof, and an acceptable carrier, adjuvant, or vehicle. (Item 7) 7. The pharmaceutical composition of claim 6, wherein the composition further comprises a second therapeutic agent. (Item 8) 8. The pharmaceutical composition according to item 7, wherein the second therapeutic agent is selected from antipsychotic drugs, memantine and acetylcholinesterase inhibitors (AChE-I). (Item 9) 8. The pharmaceutical composition according to item 7, wherein the second therapeutic agent is an antipsychotic selected from aripiprazole, olanzapine and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof. (Item 10) 8. The pharmaceutical composition of item 7, wherein the second therapeutic agent is memantine, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof. (Item 11) 9. The pharmaceutical composition according to item 8, wherein the second therapeutic agent is an AChE-I selected from donepezil, galantamine and rivastigmine, and pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof and polymorphs thereof. (Item 12) A method for treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising administering a compound according to any one of items 1 to 5 or a pharmaceutical composition according to any one of items 6 to 11. (Item 13) 13. The method of item 12, wherein the CNS disorder is age-related cognitive impairment. (Item 14) 13. The method of item 12, wherein the cognitive disorder is mild cognitive impairment (MCI). (Item 15) Item 15. The method of item 14, wherein the mild cognitive impairment is amnesic mild cognitive impairment (AMCI). (Item 16) 13. The method of claim 12, wherein the CNS disorder is dementia. (Item 17) Item 17. The method of item 16, wherein the dementia is Alzheimer's disease. (Item 18) 13. The method of item 12, wherein the CNS disorder is schizophrenia, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), mental retardation, Parkinson's disease (PD), autism, obsessive-compulsive behavior, substance addiction, bipolar disorder, or a disorder related to cancer treatment. (Item 19) A method for treating brain cancer in a subject in need thereof, comprising administering a compound according to any one of items 1 to 5, or a pharmaceutical composition according to any one of items 6 to 11. (Item 20) A method for treating cognitive impairment associated with brain cancer in a subject in need thereof, comprising administering a compound according to any one of items 1 to 5 or a pharmaceutical composition according to any one of items 6 to 11. (Item 21) 21. The method of item 19 or 20, wherein the brain cancer is medulloblastoma. (Item 22) A method for treating Parkinson's disease psychosis in a subject in need thereof, comprising administering a compound according to any one of items 1 to 5 or a pharmaceutical composition according to any one of items 6 to 11.

Claims

1. below: 【Table 9-1】 【Table 9-2】 【Table 9-3】 or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an enantiomer thereof, a diastereoisomer thereof, a Z (zusammen) isomer, an E (entgegen) isomer thereof, a tautomer thereof, or a combination thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an enantiomer thereof, a diastereoisomer thereof, a Z (zusammen) isomer thereof, an E (entgegen) isomer thereof, a tautomer thereof, or a combination thereof, and an acceptable carrier, adjuvant, or vehicle.

3. The pharmaceutical composition of claim 2 , wherein the composition further comprises a second therapeutic agent.

4. 4. The pharmaceutical composition of claim 3, wherein the second therapeutic agent is selected from an antipsychotic, memantine, and an acetylcholinesterase inhibitor (AChE-I).

5. 4. The pharmaceutical composition of claim 3, wherein the second therapeutic agent is an antipsychotic selected from aripiprazole, olanzapine, and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

6. 4. The pharmaceutical composition of claim 3, wherein the second therapeutic agent is memantine, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof.

7. 5. The pharmaceutical composition of claim 4, wherein the second therapeutic agent is an AChE-I selected from donepezil, galantamine, and rivastigmine, and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

8. 8. A composition or pharmaceutical composition for treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an enantiomer thereof, a diastereoisomer thereof, a Z (zusammen) isomer thereof, an E (entgegen) isomer thereof, a tautomer thereof, or a combination thereof, or the pharmaceutical composition of any one of claims 2 to 7.

9. The composition of claim 8, wherein the CNS disorder is age-related cognitive impairment.

10. The composition of claim 8, wherein the cognitive disorder is mild cognitive impairment (MCI).

11. The composition of claim 10, wherein the mild cognitive impairment is amnesic mild cognitive impairment (AMCI).

12. The composition of claim 8, wherein the CNS disorder is dementia.

13. The composition of claim 12, wherein the dementia is Alzheimer's disease.

14. 9. The composition of claim 8, wherein the CNS disorder is schizophrenia, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), mental retardation, Parkinson's disease (PD), autism, obsessive-compulsive behavior, substance addiction, bipolar disorder, or a disorder related to cancer treatment.

15. 8. A composition or pharmaceutical composition for treating brain cancer in a subject in need thereof, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an enantiomer thereof, a diastereoisomer thereof, a Z (zusammen) isomer, an E (entgegen) isomer thereof, a tautomer thereof, or a combination thereof, or the pharmaceutical composition of any one of claims 2-7.

16. 8. A composition or pharmaceutical composition for treating cognitive impairment associated with brain cancer in a subject in need thereof, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an enantiomer thereof, a diastereoisomer thereof, a Z (zusammen) isomer, an E (entgegen) isomer thereof, a tautomer thereof, or a combination thereof, or the pharmaceutical composition of any one of claims 2 to 7.

17. The composition of claim 15 or 16, wherein the brain cancer is medulloblastoma.

18. 8. A composition or pharmaceutical composition for treating Parkinson's disease psychosis in a patient in need thereof, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, an enantiomer thereof, a diastereoisomer thereof, a Z (zusammen) isomer thereof, an E (entgegen) isomer thereof, a tautomer thereof, or a combination thereof, or the pharmaceutical composition of any one of claims 2 to 7.

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