METHODS AND COMPOSITIONS FOR TREATING SCHIZOPHRENIA

Field of the Invention

[0001] The invention relates to methods and compositions for treating

schizophrenia or bipolar disorder (in particular, mania). In particular, it relates to the use of a combination of a a5 -containing GABAA receptor agonist and an antipsychotic in treating a subject having or at risk for schizophrenia or bipolar disorder (in particular, mania).

Background of the Invention

[0002] Schizophrenia is a chronic psychiatric disorder, characterized by a wide spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and cognitive impairment. While abnormalities in the brain are proposed to underlie the full spectrum of psychopathology in schizophrenia, currently available antipsychotics are largely ineffective in treating cognitive impairments in schizophrenia patients.

[0003] Cognitive impairments in schizophrenia involve both frontal and temporal lobe functions that include memory, attention, processing speed, and executive control. Recent observations, drawn from preclinical animal models and human neuroimaging studies, indicate that altered brain activity/excitability in the medial temporal lobe memory system may contribute to cognitive impairment and may also play a role in augmenting psychotic symptoms due to disinhibition of dopaminergic neurons.

[0004] Cognitive deficits are increasingly recognized as a key clinical feature that can be detected in a prodromal phase and in remission, as well as during full expression of the illness but are not effectively treated by available antipsychotics. Because untreated features of schizophrenia, especially impaired cognition, predict long-term disability in patients (Green et al, Schizophr. Res. 2004, 72, 41-45), it is critical to develop effective therapies for the spectrum of this illness.

Summary of the Invention

[0005] In accordance with a first aspect of the present invention, there is provided a method for treating a subject suffering from schizophrenia or bipolar disorder (in particular, mania), or at risk thereof, the method comprising the step of administering to said subject a therapeutically effective amount of a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof in combination with a therapeutically effective amount of an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments, the methods of the present invention treat one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia. In some embodiments, the methods of the present invention treat one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania). In some embodiments of this invention, the methods of this invention prevent or slow the progression of cognitive impairment of schizophrenia or bipolar disorder (in particular, mania) in said subject.

[0006] In some embodiments of the invention, the antipsychotic is administered at a dose that is subtherapeutic as compared to the dose at which it is

therapeutically effective when administered in the absence of the a5-containing GABAA receptor agonist.

[0007] The a5 -containing GABAA receptor agonist useful in this invention may be any a5 -containing GABAA receptor agonist. In some embodiments of the methods and compositions of this invention, the a5 -containing GABAA receptor agonist is selected from the compounds disclosed in, e.g., U.S. Patent Application 61/413,971 and PCT publication WO2012068161, which are incorporated herein by reference. [0008] In some embodiments, the a5 -containing GABAA receptor agonist useful in the present invention is a compound of Formula I:

I or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein:

R' is -COOH, -C(0)NR ¹ R ² , or a 5-membered heterocyclic or heteroaryl ring having 1-3 heteroatoms selected from N, NH, O, SO, and S0 ₂ ; wherein the 5- membered heterocyclic or heteroaryl ring has 0-3 substituents selected

independently from J;

R ¹ and R ² are independently selected from:

H-,

(Cl-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

(C6-C10)-aryl-,

(C5-C10)-heteroaryl-, and (C3-C10)-heterocyclo-;

or R ¹ and R ² may be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered aromatic or non-aromatic ring having 0- 3 substituents independently selected from J, and having 0-3 additional heteroatoms independently selected from N, O, S, SO, or S0 ₂ ;

wherein each of R ¹ and R ² is independently substituted at each substitutable position with 0-3 substituents independently selected from J;

R is H, halogen or (Cl-C12)-aliphatic-, wherein said (Cl-C12)-aliphatic group is substituted with 0-3 substituents independently selected from J;

A and B are each independently selected from:

(C6-C10)-aryl-,

(C5-C10)-heteroaryl-, and

(C3-C10)-heterocyclo-; wherein A and B are each independently substituted with 0-5 substituents independently selected from J;

each J is independently selected from:

halogen, -OR ³ , -N0 ₂ , -CN, -CF ³ , -OCF ₃ , -R ³ , oxo, thioxo, 1 ,2-methylenedioxy, 1,2-ethylenedioxy, =N(R ³ ), =N(OR ³ ), -N(R ³ ) ₂ , -SR ³ , -SOR ³ , -S0 ₂

R ³ , -S0 ₂ N(R ³ ) ₂ , -S0 ₃ R ³ , -C(0)R ³ , -C(0)C(0)R ³ , -C(0)CH ₂ C(0)R ³ , -C(S)R ³ , - C(S)OR ³ , -C(0)OR ³ , -C(0)C(0)OR ³ , -C(0)C(0)N(R ³ ) ₂ , -OC(0)R ³ , -C(0)N(R 3) ₂ , -OC(0)N(R ³ ) ₂ , -C(S)N(R ³ ) ₂ , -(CH ₂ )o_

₂ NHC(0)R ³ , -N(R ³ )N(R ³ )COR ³ , -N(R ³ )N(R ³ )C(0)OR ³ , -N(R ³ )N(R ³ )CON(R ³ ) 2, -N(R ³ )S0 ₂ R ³ , -N(R ³ )S0 ₂ N(R ³ ) ₂ , -N(R ³ )C(0)OR ³ , -N(R ³ )C(0)R ³ , -N(R ³ )C(S )R ³ , -N(R ³ )C(0)N(R ³ ) ₂ , -N(R ³ )C(S)N(R ³ ) ₂ , -N(COR ³ )COR ³ , -N(OR ³ )R ³ , -C(= NH)N(R ³ ) ₂ , -C(0)N(OR ³ )R ³ , -C(=NOR ³ )R ³ , -OP(0)(OR ³ ) ₂ , -P(0)(R ³ ) ₂ , -P(0)( OR ³ ) ₂ , and -P(0)(H)(OR ³ );

each R ³ is independently selected from:

H-,

(Cl-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

[(C3-C 10)-cycloalkyl]-(C 1 -C 12)-aliphatic-,

[(C3-C 10)- cycloalkenyl]-(C 1 -C 12)-aliphatic-,

(C6-C10)-aryl-,

(C6-C 10)-aryl-(C 1 -C 12)aliphatic-,

(C3-C10)-heterocyclyl-,

(C6-C 10)-heterocyclyl-(C 1 -C 12)aliphatic-,

(C5-C10)-heteroaryl-, and

(C5-C 10)-heteroaryl-(C 1 -C 12)-aliphatic-;

or two R ³ groups bound to the same atom may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 1-3 heteroatoms independently selected from N, O, S, SO, and S0 ₂ , wherein said ring is optionally fused to a (C6-C10)aryl, (C5- C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl. In some embodiments, the compound of formula I is not:

[0009] The antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof that is useful in the methods and compositions of this invention include both typical and atypical antipsychotics. [0010] In some embodiments, the antipsychotics suitable for use in the present invention are selected from atypical antipsychotics, including, but not limited to, those disclosed in, for example, U.S. Patents 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573; 5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and 5,312,925, and EP Patents EP402644 and EP368388, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[0011] 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 the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. In some embodiments, the antipsychotic of this invention is selected from aripiprazole (Bristol-Myers Squibb), olanzapine (Lilly) and ziprasidone (Pfizer), and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[0012] In some embodiments, the antipsychotics suitable for use in the present invention are typical antipsychotics, including, but not limited to, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine, trihexyphenidyl, and zuclopenthixol, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

[0013] In some embodiments of the present invention, the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be selected from compounds that are dopaminergic agents (such as dopamine Dl receptor antagonists or agonists, dopamine D ₂ receptor antagonists or partial agonists, dopamine D3 receptor antagonists or partial agonists, dopamine D4 receptor antagonists), glutamatergic agents, N-methyl-D-aspartate (NMD A) receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid

(AMPA)/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents (such as alpha-2 adrenergic receptor agonists or antagonists and catechol-O-methyl transferase (COMT) inhibitors), serotonin receptor modulators (such as 5-HT ₂ A receptor antagonists, 5-HT _I A receptor partial agonists, 5-HT ₂ c agonists, and 5-HT6 antagonists), cholinergic agents (such as alpha-7 nicotinic receptor agonists, alpha4-beta2 nicotinic receptor agonists, allosteric modulators of nicotinic receptors and acetylcholinesterase inhibitors, muscarinic receptor agonists and antagonists), cannabinoid CB 1 antagonists, neurokinin 3 antagonists, neurotensin agonists, monoamine oxidase (MAO) B inhibitors, PDE10 inhibitors, neuronal nitric oxide synthase (nNOS) inhibitors, neurosteroids, and neurotrophic factors.

[0014] In some embodiments, the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof that is useful in the methods and compositions of this invention include compounds that may be used to treat at least one sign or symptom of schizophrenia or bipolar disorder (in particular, mania).

[0015] In some embodiments of the invention, the a5 -containing GABAA receptor agonist and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs are administered simultaneously, or sequentially, or in a single formulation, or in separate formulations packaged together. In other embodiments, the a5-containing GABAA receptor agonist and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs are administered via different routes. As used herein, "combination" includes administration by any of these formulations or routes of administration.

[0016] In some embodiments of the invention, the combined treatment has a longer or improved therapeutic effect in the subject than is attained by

administering the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in the absence of the a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof by at least about 1.5x, or 2. Ox, or 2.5x, or 3. Ox, or 3.5x, or 4. Ox, or 4.5x, or 5. Ox, or 5.5x, or 6. Ox, or 6.5x, or 7. Ox, or 7.5x, or 8. Ox, or 8.5x, or 9. Ox, or 9.5x, or lOx, or greater than about lOx.

[0017] In some embodiments of the invention, the combined treatment has a longer or improved therapeutic effect in the subject than is attained by

administering the a5-containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in the absence of the antipsychotic or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof by at least about 1.5x, or 2. Ox, or 2.5x, or 3. Ox, or 3.5x, or 4. Ox, or 4.5x, or 5. Ox, or 5.5x, or 6. Ox, or 6.5x, or 7. Ox, or 7.5x, or 8. Ox, or 8.5x, or 9. Ox, or 9.5x, or lOx, or greater than about lOx.

[0018] In accordance with another aspect of the present invention, there is provided a method of increasing the therapeutic index of an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in a method of treating schizophrenia or bipolar disorder (in particular, mania) in a subject in need or at risk thereof, comprising administering a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in combination with the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof to said subject. [0019] In some embodiments, the increase in the therapeutic index of the antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is greater than the therapeutic index of the antipsychotic or a

pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof when administered in the absence of the a5-containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof by at least about 1.5x, or 2. Ox, or 2.5x, or 3. Ox, or 3.5x, or 4. Ox, or 4.5x, or 5. Ox, or 5.5x, or 6. Ox, or 6.5x, or 7. Ox, or 7.5x, or 8. Ox, or 8.5x, or 9. Ox, or 9.5x, or lOx, or greater than about lOx.

[0020] In accordance with another aspect of this invention, there is provided a pharmaceutical composition for treating a subject suffering from schizophrenia or bipolar disorder (in particular, mania), or at risk thereof, the composition comprising a a5-containing GABAA receptor agonist and an antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof. In some embodiments, the composition of this invention is for treating one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia. In some embodiments, the composition of this invention is for treating one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania). In some embodiments, the composition is in a liquid form. In some embodiments, the composition is in an aqueous solution. In some embodiments, the composition is in a suspension form. In some embodiments, the composition is in a sustained release form, or a controlled release form, or a delayed release form, or an extended release form. In some embodiments, the composition is in a unit dosage form. In other embodiments, the two components of the compositions are in separate delivery forms packaged together. Brief Description of the Drawings

[0021] Figures 1(A)-(D) are graphs showing functional selectivity data, as demonstrated by the potentiation of GAB A EC50 concentration in Xenopus oocytes containing GABAA 5 receptors (α5β3γ2) vs. l receptors ( 1β2γ2), in the presence of test compounds. Figure 1(A) shows the functional selectivity data for compound 4; Figure 1(B) shows the functional selectivity data for compound 27; Figure 1(C) shows the functional selectivity data for compound 26; and Figure 1(D) shows the functional selectivity data for compound 29.

[0022] Figure 2 is a graph depicting the effects of administering methyl 3,5- diphenylpyridazine-4-carboxylate on the spatial memory retention of ten aged- impaired (Al) rats in an eight-arm Radial Arm Maze (RAM) test. The black bars refer to rats treated with vehicle alone; open bars refer to rats treated with methyl 3,5-diphenylpyridazine-4-carboxylate at different doses; hatched bar refers to rats treated with the combination of TB21007 and methyl 3,5-diphenylpyridazine-4- carboxylate.

[0023] Figure 3 is a graph showing the effect of methyl 3,5-diphenylpyridazine- 4-carboxylate (administered intravenously) on the binding of Ro 154513 in the hippocampus and cerebellum. Methyl 3,5-diphenylpyridazine-4-carboxylate blocked the binding of Ro 154513 in the hippocampus but did not affect binding of Ro 15413 in the cerebellum.

[0024] Figure 4 is a graph showing dose-dependent GABAA a5 receptor occupancy by methyl 3,5-diphenylpyridazine-4-carboxylate administered intravenously, with receptor occupancy determined either by the ratio between hippocampus (a region of high GABAA(X5 receptor density) exposure of RO 15- 4513 and cerebellum (a region with low GABAA(X5 receptor density) exposure of RO 15-4513, or by using the GABA _A a5 selective compound L-655,708 (10 mg/kg, i.v.) to define full occupancy.

[0025] Figure 5 is a graph showing exposure occupancy relationships for methyl 3,5-diphenylpyridazine-4-carboxylate in hippocampus. Methyl 3,5- diphenylpyridazine-4-carboxylate occupies about 32% of GABAA 5 receptors at exposures which are behaviorally active in aged-impaired rats.

[0026] Figure 6 is a graph depicting the effect of ethyl 3-methoxy-7-methyl-9H- benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine-1 0-carboxylate on the spatial memory retention of ten aged-impaired (AI) rats in an eight-arm Radial Arm Maze (RAM) test. Figure 6 shows the effect of ethyl 3-methoxy-7-methyl- 9H-benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepin e-10-carboxylate on the spatial memory retention of ten aged-impaired (AI) rats in the RAM test, where the vehicle control was tested 3 times, and the different doses of ethyl 3-methoxy- 7-methyl-9H-benzo[fJimidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4 ]diazepine-10- carboxylate were tested twice. In Figure 6, black bars refer to rats treated with vehicle alone and open bars refer to rats treated with ethyl 3-methoxy-7-methyl- 9H-benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepin e-10-carboxylate at different doses. [0027] Figure 7 is a graph showing the effect of ethyl 3-methoxy-7-methyl-9H- benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine-1 0-carboxylate (administered intravenously) on the binding of Ro 154513 in the hippocampus and cerebellum. Ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5- a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate blocked the binding of Ro 154513 in the hippocampus but did not affect binding of Ro 15413 in the cerebellum.

[0028] Figure 8 is a graph showing dose-dependent GABAA 5 receptor occupancy by ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5- a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate administered intravenously, as calculated by the ratio between hippocampus (a region of high GABAA(X5 receptor density) exposure of RO 15-4513 and cerebellum (a region with low GABA _A a5 receptor density) exposure of RO 15-4513 to define full occupancy. .

[0029] Figure 9(A)-(C) are graphs showing the effect of 6,6 dimethyl-3-(3- hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one, as compared to vehicle dimethyl sulfoxide (DMSO), in aged-impaired rats using a

Morris water maze behavioral task. Figure 9(A) shows the escape latency (i.e., the average time in seconds rats took to find the hidden platform in the water pool) during training in rats received 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2- yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats received vehicle DMSO; Figure 9(B) shows the amount of time spent in target annulus and opposite annulus by rats received 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)-6,7- dihydro-2-benzothiophen-4(5H)-one and rats received vehicle DMSO; Figure 9(C) shows number of crossing in target annulus and opposite annulus by rats received 6,6 dimethyl-3-(3-hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7-dihydro-2- benzothiophen-4(5H)-one and rats received vehicle DMSO.

Detailed Description of the Invention Definitions

[0030] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology,

pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art. [0031] The methods and techniques of the present invention are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. "Principles of Neural Science", McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al, "Molecular Cell Biology, 4th ed.", W. H. Freeman & Co., New York (2000); Griffiths et al, "Introduction to Genetic Analysis, 7th ed.", W. H. Freeman & Co., N.Y. (1999); Gilbert et al, "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000). [0032] Chemistry terms used herein are used according to conventional usage in the art, as exemplified by "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0033] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. 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 stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or

components).

[0035] The singular forms "a," "an," and "the" include the plurals 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 "agent" is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents which are known with respect to structure, and those which are not known with respect to structure.

[0038] A "patient", "subject", or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). [0039] "Cognitive function" or "cognitive status" refers to any higher order intellectual brain process or brain state, respectively, involved in learning and/or memory including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discrimination learning, decision-making, inhibitory response control, attentional set-shifting, delayed reinforcement learning, reversal learning, the temporal integration of voluntary behavior, expressing an interest in one's surroundings and self-care, speed of processing, reasoning and problem solving and social cognition. [0040] In humans, cognitive function may be measured, for example and without limitation, by the clinical global impression of change scale (CIBIC-plus scale); the Mini Mental State Exam (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric (SC AG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the Visual

Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R)

(Wechsler, 1997); the Benton Visual Retention Test, or the explicit 3-alternative forced choice task, or MATRICS consensus neuropsychological test battery. See Folstein et al, J Psychiatric Res 12: 189-98, (1975); Robbins et al, Dementia 5: 266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al, J Geriatr Psychiatry Neurol 12: 168-79, (1999); Marquis et al, 2002 and Masur et al, 1994. Also see Buchanan, R.W., Keefe, R.S.E., Umbricht, D., Green, M.F., Laughren, T., and Marder, S.R. (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 may be measured in various conventional ways known in the art, including using a Morris Water Maze

(MWM), Barnes circular maze, elevated radial arm maze, T maze or any other mazes in which the animals use spatial information. Cognitive function can be assessed by reversal learning, extradimensional set shifting, conditional discrimination learning and assessments of reward expectancy. Other tests known in the art may also be used to assess cognitive function, such as novel object recognition and odor recognition tasks.

[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 one to measure brain function. In animals, cognitive function may also be measured with electrophysiological techniques.

[0043] "Promoting" cognitive function refers to affecting impaired cognitive function so that it more closely resembles the function of a normal, unimpaired subject. Cognitive function may be promoted to any detectable degree, but in humans preferably is promoted sufficiently to allow an impaired subject to carry out daily activities of normal life at the same level of proficiency as a normal, unimpaired subject. [0044] "Preserving" cognitive function refers to affecting normal or impaired cognitive function such that it does not decline or does not fall below that observed in the subject upon first presentation or diagnosis, or delays such decline.

[0045] "Improving" cognitive function includes promoting cognitive function and/or preserving cognitive function in a subject. [0046] "Cognitive impairment" refers to cognitive function in subjects that is not as robust as that expected in a normal, unimpaired subject. In some cases, cognitive function is reduced by about 5%, about 10%, about 30%, or more, compared to cognitive function expected in a normal, unimpaired subject. In other cases, "cognitive impairment" in subjects affected by schizophrenia or bipolar disorder (in particular, mania) refers to cognitive function in subjects that is not as robust as that expected in normal, unimpaired subject.

[0047] "Schizophrenia" refers to a chronic debilitating disorder, characterized by a spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and cognitive impairment. While abnormalities in the brain are proposed to underlie the full spectrum of psychopathology in schizophrenia, currently available antipsychotics are largely ineffective in treating cognitive impairments in patients.

[0048] "Bipolar disorder" or "BP" or "manic depressive disorder" or "manic depressive illness" refers to a chronic psychological/mood disorder which can be characterized by significant mood changes including periods of depression and euphoric manic periods. BP may be diagnosed by a skilled physician based on personal and medical history , interview consultation and physical examinations. The term "mania" or "manic periods" or other variants refers to periods where an individual exhibits some or all of the following characteristics: racing thoughts, rapid speech, elevated levels of activity and agitation as well as an inflated sense of self-esteem, euphoria, poor judgment, insomnia, impaired concentration and aggression.

[0049] "Treating" a condition or patient refers to taking steps to obtain 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 disease or disorder, or alleviation, amelioration, or slowing the progression, of one or more symptoms associated with CNS disorders with cognitive impairment, such as schizophrenia or bipolar disorder (in particular, mania).

[0050] "Treating cognitive impairment" refers to taking steps to improve cognitive function in a subject with cognitive impairment so that the subject's performance in one or more cognitive tests is improved to any detectable degree, or is prevented from further decline. Preferably, that subject's cognitive function, after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired subject. Treatment of cognitive impairment in humans may improve cognitive function to any detectable degree, but is preferably improved sufficiently to allow the impaired subject to carry out daily activities of normal life at the same level of proficiency as a normal, unimpaired subject. In some cases, "treating cognitive impairment" refers to taking steps to improve cognitive function in a subject with cognitive impairment so that the subject's performance in one or more cognitive tests is improved to any detectable degree, or is prevented from further decline. Preferably, that subject's cognitive function, after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired subject. In some cases, "treating cognitive impairment" in a subject affecting by schizophrenia or bipolar disorder (in particular, mania) refers to takings steps to improve cognitive function in the subject so that the subject's cognitive function, after treatment of cognitive impairment, more closely resembles the function of normal, unimpaired subject.

[0051] "Administering" or "administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitonealy, intravenously, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow, or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. In some aspects, the 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 the drug administered by another and/or who provides a patient with a prescription for a drug is

administering the drug to the patient.

[0052] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administering, whether the subject is cognitively impaired at the time of administering, the extent of the impairment, and the chemical and biological properties of the compound or agent (e.g. solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion, or intravenously, e.g., to a subject by injection. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0053] As used herein, a "a5-containing GABAA receptor agonist", "a5- containing GABAA R agonist" or a "GABAA 5 receptor agonist" and other variations as used herein refer to a compound that up-regulates the function of a5- containing GABAA receptor (GABAA R), i.e., a compound that increase GABA- gated CI ^" currents. In some embodiments, a5 -containing GABAA R agonist as used herein refers to a positive allosteric modulator, which potentiates the activity of GAB A.

[0054] "Antipsychotic", "antipsychotic agent", "antipsychotic drug", or

"antipsychotic compound" refers to (1) a typical or an atypical antipsychotic; (2) an agent that is selected from dopaminergic agents, glutamatergic agents, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptor modulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors, nNOS inhibits, neurosteroids, and neurotrophic factors; and/or (3) an agent that is useful in treating one or more signs or symptoms of schizophrenia or bipolar disorder (in particular, mania).

[0055] "Typical antipsychotics", as used herein, refer to conventional antipsychotics, which produce antipsychotic effects as well as movement related adverse effects related to disturbances in the mgrostriatal dopamine system. These extrapyramidal side effects (EPS) include Parkinsonism, akathisia, tardive

dyskinesia and dystonia. See Baldessarini and Tarazi in Goodman & Oilman's The Pharmacological Basis of Therapeutics 10 Edition, 2001, pp. 485-520.

[0056] "Atypical antipsychotics", as used herein, refer to antipsychotic drugs that produce antipsychotic effects with little or no EPS and include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone,

paliperidone, quetiapine, risperidone and ziprasidone. " Atypical" antipsychotics differ from conventional antipsychotics in their pharmacological profiles. While conve tional antipsychotics are characterized principally by D ₂ dopamine receptor blockade, atypical antipsychotics show antagonist effects on multiple receptors including the 5HT _a and 5HT _C serotonin receptors and varying degrees of receptor affinities. Atypical antipsychotic drugs are commonly referred to as

serotonin/doparnine antagonists, reflecting the influential hypothesis that greater affinity for the 5HT ₂ receptor than for the D ₂ receptor underlies "atypical"

antipsychotic drug action or "second generation" antipsychotic drags. However, the atypical antipsychotics often display side effects, including, but not limited to, weight gain, diabetes (e.g., type ΪΪ diabetes mellitus), hyperlipidemia, QTc interval prolongation, myocarditis, sexual side effects, extrapyramidal side effects and cataract. Thus, atypical antipsychotics do not represent a homogeneous class, given their differences in the context of both alleviation of clinical symptoms and their potential for inducing side effects such as the ones listed above. Further, the common side effects of the atypical antipsychotics as described above often limit the antipsychotic doses that can be used for these agents.

[0057] The term "simultaneous administration," as used herein, means that the a5- containing GABAA receptor agonist and the antipsychotic, or their pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, are administered with a time separation of no more than about 15 minutes, and in some embodiments no more than about 10 minutes. When the drugs are administered simultaneously, the a5 -containing GABAA receptor agonist and the antipsychotic, or their salts, hydrates, solvates, or polymorphs, may be contained in the same dosage (e.g., a unit dosage form comprising both the a5-containing GABAA receptor agonist and the antipsychotic) or in discrete dosages (e.g., the a5-containing GABAA receptor agonist or its salt, hydrate, solvate, or polymorph is contained in one dosage form and the antipsychotic or its salt, hydrate, solvate, or polymorph is contained in another dosage form).

[0058] The term "sequential administration" as used herein means that the a5- containing GABAA receptor agonist and the antipsychotic, or their

pharmaceutically acceptable salts, hydrates, solvates, polymorphs, are administered with a time separation of more than about 15 minutes, and in some embodiments more than about one hour, or up to 12-24 hours. Either the a5-containing GABAA receptor agonist or the antipsychotic may be administered first. The a5 -containing GABAA receptor agonist and the antipsychotic, or their salts, hydrates, solvents, or polymorphs, for sequential administration may be contained in discrete dosage forms, optionally contained in the same container or package.

[0059] A "therapeutically effective amount" of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended

therapeutic effect, e.g. improving cognitive function in a subject suffering from a disease or disorder (e.g., schizophrenia or bipolar disorder (in particular, mania)), preventing or slowing the progression of a disease or disorder (e.g., schizophrenia or bipolar disorder (in particular, mania)), and/or alleviating, ameliorating, or slowing the progression of one or more symptoms associated with the disease or disorder (e.g., schizophrenia). The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, the nature and extent of the cognitive impairment, and the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine

experimentation.

[0060] "Subtherapeutic amount" refers to an amount administered of an agent or compound of the invention that is less than the therapeutic amount, that is, less than the amount normally used when said agent or compound is administered alone (i.e., individually and in the absence of other therapeutic agents or compounds) to treat disorders, such as schizophrenia or bipolar disorder (in particular, mania).

[0061] "Analog" is used herein to refer to a compound which functionally resembles another chemical entity, but does not share the identical chemical structure. For example, an analog is sufficiently similar to a base or parent compound such that it can substitute for the base compound in therapeutic applications, despite minor structural differences.

[0062] "Derivative" is used herein to refer to the chemical modification of a compound. Chemical modifications of a compound can include, for example, replacement of hydrogen by an alkyl, acyl, or amino group. Many other

modifications are also possible.

[0063] The term "prodrug" is art-recognized and is intended to encompass compounds or agents which, under physiological conditions, are converted into a a5-containing GABAA receptor agonist or an antipsychotic. A common method for making a prodrug is to select moieties which are hydrolyzed or metabolized under physiological conditions to provide the desired compound or agent. In other embodiments, the prodrug is converted by, for example, an enzymatic activity of the host animal to a a5 -containing GABAA receptor agonist or an antipsychotic.

[0064] The term "aliphatic" as used herein means a straight chained or branched alkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynyl embodiments need at least two carbon atoms in the aliphatic chain. Aliphatic groups typically contains from 1 (or 2) to 12 carbons, such as from 1 (or 2) to 4 carbons.

[0065] The term "aryl" as used herein means a monocyclic or bicyclic

carbocyclic aromatic ring system. For example, aryl as used herein can be a C5- CIO monocyclic or C8-C12 bicyclic carbocyclic aromatic ring system. Phenyl is an example of a monocyclic aromatic ring system. Bicyclic aromatic ring systems include systems wherein both rings are aromatic, e.g., naphthyl, and systems wherein only one of the two rings is aromatic, e.g., tetralin. [0066] The term "heterocyclic" as used herein means a monocyclic or bicyclic non-aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH, S, SO, or S0 ₂ in a chemically stable arrangement. For example, heterocyclic as used herein can be a C5-C10 monocyclic or C8-C12 bicyclic non-aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH, S, SO, or S0 ₂ in a chemically stable arrangement. In a bicyclic non-aromatic ring system embodiment of

"heterocyclyl", one or both rings may contain said heteroatom or heteroatom groups. In another bicyclic "heterocyclyl" embodiment, one of the two rings may be aromatic. In yet another heterocyclic ring system embodiment, a non-aromatic heterocyclic ring may optionally be fused to an aromatic carbocycle.

[0067] Examples of heterocyclic rings include 3-lH-benzimidazol-2-one, 3-(l- 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, 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 l,3-dihydro-imidazol-2-one.

[0068] The term "heteroaryl" as used herein means a monocyclic or bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement. For example, heteroaryl as used herein can be a C5-C10 monocyclic or C8-C12 bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement. In such a bicyclic aromatic ring system embodiment of "heteroaryl": - both rings are aromatic; and

- one or both rings may contain said heteroatom or heteroatom groups. [0069] Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, 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).

[0070] The term "cycloalkyl or cycloalkenyl" refers to a monocyclic or fused or bridged bicyclic carbocyclic ring system that is not aromatic. For example, cycloalkyl or cycloalkenyl as used herein can be a C5-C10 monocyclic or fused or bridged C8-C12 bicyclic carbocyclic ring system that is not aromatic.

Cycloalkenyl rings have one or more units of unsaturation. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl and decalinyl. [0071] As used herein, the carbon atom designations may have the indicated integer and any intervening integer. For example, the number of carbon atoms in a (Cl-C4)-alkyl group is 1, 2, 3, or 4. It should be understood that these designation 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.

[0072] "Pharmaceutically acceptable salt" is used herein to refer to an agent or a compound according to the invention that is a therapeutically active, non-toxic base and acid salt form of the compounds. The acid addition salt form of a compound that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p- aminosalicylic, pamoic and the like. See, e.g., WO 01/062726.

[0073] Compounds containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt form, e. g. metal or amine salts, by treatment with appropriate organic and inorganic bases. Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e. g., lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e. g. N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, said salt forms can be converted into the free forms by treatment with an appropriate base or acid. Compounds and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like. See, e.g., WO 01/062726. [0074] As used herein, the term "hydrate" refers to a combination of water with a compound wherein the water retains its molecular state as water and is either absorbed, adsorbed or contained within a crystal lattice of the substrate compound.

[0075] As used herein, the term "polymorph" refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo- polymorphs, 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 a different packing of the molecules in the lattice. This results in a different crystal symmetry and/or unit cell parameters which directly influences its physical properties such the X-ray diffraction characteristics of crystals or powders. A different polymorph, for example, will in general diffract at a different set of angles and will give different values for the intensities. Therefore X-ray powder diffraction can be used to identify different polymorphs, or a solid form that comprises more than one polymorph, in a reproducible and reliable way.

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 held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since Impurities present may produce undesired toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain

polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.

[0076] Many of the compounds useful in the methods and compositions of this invention have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45,11-30. The invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726. [0077] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the invention includes both mixture and separate individual isomers. Multiple substituents on a piperidinyl or the azepanyl ring can also stand in either cis or trans relationship to each other with respect to the plane of the piperidinyl or the azepanyl ring. Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present invention. With respect to the methods and compositions of the present invention, reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.

See, e.g., WO 01/062726. Description of Methods of the Invention

[0078] The methods of this invention comprise administration of a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt thereof in combination with administration of an antipsychotic or a pharmaceutically acceptable salt thereof. The agents or compounds of the a5 -containing GABAA receptor agonist or the antipsychotic and their pharmaceutically acceptable salts also include hydrates, solvates, polymorphs, and prodrugs of those agents, compounds, and salts.

Methods of Assessing Cognitive Impairment [0079] Animal models serve as an important resource for developing and evaluating treatments for CNS disorders with cognitive impairment. Features that characterize cognitive impairment in animal models typically extend to cognitive impairment in humans. Efficacy in such animal models is, thus, expected to be predictive of efficacy in humans. The extent of cognitive impairment in an animal model for a CNS disorder, and the efficacy of a method of treatment for said CNS disorder may be tested and confirmed with the use of a variety of cognitive tests.

[0080] A Radial Arm Maze (RAM) behavioral task is one example of a cognitive test, specifically testing spacial memory (Chappell et al. Neuropharmacology 37: 481-487, 1998). The RAM apparatus consists of, e.g., eight equidistantly spaced arms. A maze arm projects from each facet of a center platform. A food well is located at the distal end of each arm. Food is used as a reward. Blocks can be positioned to prevent entry to any arm. Numerous extra maze cues surrounding the apparatus may also be provided. After habituation and training phases, spatial memory of the subjects may be tested in the RAM under control or test compound- treated conditions. As a part of the test, subjects are pretreated before trials with a vehicle control or one of a range of dosages of the test compound. At the beginning of each trial, a subset of the arms of the eight-arm maze is blocked. Subjects are allowed to obtain food on the unblocked arms to which access is permitted during this initial "information phase" of the trial. Subjects are then removed from the maze for a delay period, e.g., a 60 second delay, a 15 minute delay, a one-hour delay, a two-hour delay, a six hour delay, a 24 hour delay, or longer) between the information phase and the subsequent "retention test," during which the barriers on the maze are removed, thus allowing access to all eight arms. After the delay period, subjects are placed back onto the center platform (with the barriers to the previously blocked arms removed) and allowed to obtain the remaining food rewards during this retention test phase of the trial. The identity and configuration of the blocked arms vary across trials. The number of "errors" the subjects make during the retention test phase is tracked. An error occurs in the trial if the subjects entered an arm from which food had already been retrieved in the pre-delay component of the trial, or if it re-visits an arm in the post-delay session that had already been visited. A fewer number of errors would indicate better spatial memory. The number of errors made by the test subject, under various test compound treatment regimes, can then be compared for efficacy of the test compound in treating CNS disorders with cognitive impairment. [0081] Another cognitive test that may be used to assess the effects of a test compound on the cognitive impairment of a CNS disorder model animal is the Morris water maze. A water maze is a pool surrounded with a novel set of patterns relative to the maze. The training protocol for the water maze may be based on a modified water maze task that has 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). The subject is trained to locate a submerged escape platform hidden underneath the surface of the pool. During the training trial, a subject is released in the maze (pool) from random starting positions around the perimeter of the pool. The starting position varies from trial to trial. If the subject does not locate the escape platform within a set time, the experimenter guides and places the subject on the platform to "teach" the location of the platform. After a delay period following the last training trial, a retention test in the absence of the escape platform is given to assess spatial memory. The subject's level of preference for the location of the (now absent) escape platform, as measured by, e.g., the time spent in that location or the number of crossings of that location made by the mouse, indicates better spatial memory, i.e., treatment of cognitive impairment. The preference for the location of the escape platform under different treatment conditions, can then be compared for efficacy of the test compound in treating CNS disorders with cognitive impairment.

[0082] There are various tests known in the art for assessing cognitive function in humans, for example and without limitation, the clinical global impression of change scale (CIBIC-plus scale); the Mini Mental State Exam (MMSE); the

Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric (SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the Visual Reproduction subtest of the Wechsler Memory Scale- Revised (WMS-R) (Wechsler, 1997); the Benton Visual Retention Test, or MATRICS consensus neuropsychological test battery which includes tests of working memory, speed of processing, attention, verbal learning, visual learning, reasoning and problem solving and social cognition. See Folstein et al., J

Psychiatric Res 12: 189-98, (1975); Robbins et al, Dementia 5: 266-81, (1994);

Rey, L'examen clinique en psycho logie, (1964); Kluger et al, J Geriatr Psychiatry Neurol 12: 168-79, (1999); Marquis et al, 2002 and Masur et al, 1994. Also see Buchanan, R.W., Keefe, R.S.E., Umbricht, D., Green, M.F., Laughren, T., and Marder, S.R. (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 3 -alternative forced choice task. In this test, subjects are presented with color photographs of common objects consisting of a mix of three types of image pairs: similar pairs, identical pairs and unrelated foils. The second of the pair of similar objects is referred to as the "lure". These image pairs are fully randomized and presented individually as a series of images. Subjects are instructed to make a judgment as to whether the objects seen are new, old or similar. A "similar" response to the presentation of a lure stimulus indicates successful memory retrieval by the subject. By contrast, calling the lure stimulus "old" or "new" indicates that correct memory retrieval did not occur. Schizophrenia

[0083] This invention provides methods and compositions for treating

schizophrenia or bipolar disorder (in particular, mania) using a a5 -containing GABAA receptor agonist or a pharmaceutically acceptable salt thereof in combination with an antipsychotic or a pharmaceutically acceptable salt thereof. In certain embodiments, treatment comprises preventing or slowing the

progression of schizophrenia or bipolar disorder (in particular, mania).

Schizophrenia is characterized by a wide spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonia, affective flattening, avolition), and cognitive impairment. In certain embodiments, treatment comprises alleviation, amelioration or slowing the progression, of one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia. Further, there are a number of other psychiatric diseases such as schizotypical and schizoaffective disorder, other acute- and chronic psychoses and bipolar disorder (in particular, mania), which have an overlapping

symptomatology with schizophrenia. In some embodiments, treatment comprises alleviation, amelioration or slowing the progression of one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania). The methods and compositions may be used for human patients in clinical applications in treating schizophrenia or bipolar disorder (in particular, mania). The dose of the composition and dosage interval for the method is, as described herein, one that is safe and efficacious in those applications. [0084] Cognitive impairments are associated with schizophrenia. They precede the onset of psychosis and are present in non-affected relatives. The cognitive impairments associated with schizophrenia constitute a good predictor for functional outcome and are a core feature of the disorder. Cognitive features in schizophrenia reflect dysfunction in frontal cortical and hippocampal circuits. Patients with schizophrenia also present hippocampal pathologies such as reductions in hippocampal volume, reductions in neuronal size and dysfunctional hyperactivity. An imbalance in excitation and inhibition in these brain regions has also been documented in schizophrenic patients suggesting that drugs targeting inhibitory mechanisms could be therapeutic. See, e.g., Guidotti et al.,

Psychopharmacology 180: 191-205, 2005; Zierhut, Psych. Res. Neuroimag.

183: 187-194, 2010; Wood et al, Neurolmage 52:62-63, 2010; Vinkers et al,

Expert Opin. Investig. Drugs 19: 1217-1233, 2009; Young et al., Pharmacol. Ther. 122: 150-202, 2009.

[0085] Animal models serve as an important resource for developing and evaluating treatments for schizophrenia. Features that characterize schizophrenia in animal models typically extend to schizophrenia in humans. Thus, efficacy in such animal models is expected to be predictive of efficacy in humans. Various animal models of schizophrenia are known in the art.

[0086] One animal model of schizophrenia is protracted treatment with methionine. Methionine-treated mice exhibit deficient expression of GAD67 in frontal cortex and hippocampus, similar to those reported in the brain of postmortem schizophrenia patients. They also exhibit prepulse inhibition of startle and social interaction deficits (Tremonlizzo et al, PNAS, 99: 17095-17100, 2002). Another animal model of schizophrenia is methylaoxymethanol acetate (MAM)-treatment in rats. Pregnant female rats are administered MAM (20 mg/kg, intraperitoneal) on gestational day 17. MAM -treatment recapitulate a

pathodevelopmental process to schizophrenia-like phenotypes in the offspring, including anatomical changes, behavioral deficits and altered neuronal information processing. More specifically, MAM-treated rats display a decreased density of parvalbumin-positive GABAergic interneurons in portions of the prefrontal cortex and hippocampus. In behavioral tests, MAM-treated rats display reduced latent inhibition. Latent inhibition is a behavioral phenomenon where there is reduced learning about a stimulus to which there has been prior exposure with any consequence. This tendency to disregard previously benign stimuli, and reduce the formation of association with such stimuli is believed to prevent sensory overload. Low latent inhibition is indicative of psychosis. Latent inhibition may be tested in rats in the following manner. Rats are divided into two groups. One group is pre- exposed to a tone over multiple trials. The other group has no tone presentation. Both groups are then exposed to an auditory fear conditioning procedure, in which the same tone is presented concurrently with a noxious stimulus, e.g. an electric shock to the foot. Subsequently, both groups are presented with the tone, and the rats' change in locomotor activity during tone presentation is monitored. After the fear conditioning the rats respond to the tone presentation by strongly reducing locomotor activity. However, the group that has been exposed to the tone before the conditioning period displays robust latent inhibition: the suppression of locomotor activity in response to tone presentation is reduced. MAM-treated rats, by contrast show impaired latent inhibition. That is, exposure to the tone previous to the fear conditioning procedure has no significant effect in suppressing the fear conditioning, {see Lodge et ah, J. Neurosci., 29:2344-2354, 2009) Such animal models of schizophrenia may be used to assay the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).

[0087] MAM-treated rats display a significantly enhanced locomotor response (or aberrant locomotor activity) to low dose D-amphetamine administration. The MAM-treated rats also display a significantly greater number of spontaneously firing ventral tegmental dopamine (DA) neurons. The above results are believed to be a consequence of excessive hippocampal activity because in MAM-treated rats, the ventral hippocampus (vHipp) inactivation (e.g., by intra vHipp administration of a sodium channel blocker, tetrodotoxin (TTX) to MAM rats) completely reversed the elevated DA neuron population activity and also normalized the augmented amphetamine-induced locomotor behavior. The correlation of hippocampal dysfunction and the hyper-responsivity of the DA system is believed to underlie the augmented response to amphetamine in MAM-treated animals and psychosis in schizophrenia patients. See Lodge D. J. et al. Neurobiology of Disease (2007), 27(42), 11424-11430. The use of MAM-treated rats in the above study may be suitable for use to assay the effectiveness of the methods and compositions of the present invention in treating schizophrenia or bipolar disorder

(in particular, mania). For example, the methods and compositions of this invention maybe evaluated, using MAM-treated animals, for their effects on the central hippocampus (vHipp) regulation, on the elevated DA neuron population activity and on the hyperactive locomotor response to amphetamine in the MAM- treated animals.

[0088] In MAM-treated rats, hippocampal (HPC) dysfunction leads to dopamine system hyperactivity. A benzodiazepine-positive allosteric modulator (PAM), selective for the a5 subunit of the GABAA receptor, SH-053-2'F-R-CH ₃ is tested for its effects on the output of the hippocampal (HPC). The effect of SH-053-2 - Pv-CH ₃ on the hyperactive locomotor response to amphetamine in MAM-treated animals is also examined. The a5GABAAR PAM 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), both when

administered systemically and when directly infused into the ventral HPC.

Moreover, HPC neurons in both saline-treated and MAM-treated animals show diminished cortical-evoked responses following the a5GABAAR PAM treatment. In addition, the increased locomotor response to amphetamine observed in MAM- treated rats is reduced following the (X5GABAAR PAM treatment. See Gill K. M et al. Neuropsychopharmacology (2011), 1-9. The use of MAM-treated rats in the above study may be suitable for use in the present invention to assay the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania). For example, the methods and compositions of this invention maybe evaluated, using MAM-treated animals, for their effects on the output of the hippocampal (HPC) and on the hyperactive locomotor response to amphetamine in the MAM-treated animals.

[0089] Administration of MAM to pregnant rats on embryonic day 15 (El 5) severely impairs spatial memory or the ability to learn the spatial location of four items on an eight-arm radial maze in the offspring. In addition, embryonic day 17 (El 7) MAM-treated rats are able to reach the level of performance of control rats at the initial stages of training, but are unable to process and retrieve spatial information when a 30-min delay is interposed, indicating a significant impairment in working memory. See Gourevitch R. et al. (2004). Behav. Pharmacol, 15, 287-292.

Such animal models of schizophrenia may be used to assay the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).

[0090] Apomorphine-induced climbing (AIC) and stereotype (AIS) in mice is another animal model useful in this invention. Agents are administered to mice at a desired dose level (e.g., via intraperitoneal administration). Thirty minutes later, experimental mice are challenges with apomorphine (e.g., with 1 mg/kg sc). Five minutes after the apomorphine injection, the sniffing-licking-gnawing syndrome (stereotyped behavior) and climbing behavior induced by apomorphine are scored and recorded for each animal. Readings can be repeated every 5 min during a 30- min test session. Scores for each animal are totaled over the 30-min test session for each syndrome (stereotyped behavior and climbing). If an effect reached at least of 50% inhibition, and ID ₅₀ value (95% confidence interval) is calculated using a nonlinear least squares calculation with inverse prediction. Mean climbing and sterotype scores can be expressed as a percent of control values observed in vehible treated (e.g., saline-treated) mice that receive apomorphine. See Grauer S. M. Psychopharmacology (2009) 204, 37-48. This mice model may be used to assay the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).

[0091] The efficacy of the methods and compositions of this invention in treating schizophrenia or bipolar disorder (in particular, mania) may also be assessed in animal models of schizophrenia, as well as human subjects with schizophrenia, using a variety of cognitive tests known in the art, as discussed above. a5-containing GABA _A Receptor Agonists

[0092] The a5 -containing GABAA receptor agonist useful in the present invention may be any a5 -containing GABAA receptor agonist. In some

embodiments, the a5-containing GABAA receptor agonist suitable for use in the methods and compositions of the present invention is selected from the compounds disclosed in, e.g., U.S. Patent Application 61/413,971 and PCT publication WO2012068161, which are incorporated herein by reference. [0093] In some embodiments, the a5-containing GABAA receptor agonist useful in the present invention is a compound of Formula I:

I or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein:

R' is -COOH, -C(0)NR ¹ R ² , or a 5-membered heterocyclic or heteroaryl ring having 1-3 heteroatoms selected from N, NH, O, SO, and S0 ₂ ; wherein the 5- membered heterocyclic or heteroaryl ring has 0-3 substituents selected

independently from J;

R ¹ and R ² are independently selected from:

H-,

(CI- -C12)- ^■ aliphatic-,

(C3- -C10)- ■cycloalkyl-,

(C3- -C10)- ■cycloalkenyl-,

(C6- -C10)- ■aryl-,

(C5- -C10)- ■heteroaryl-, and

(C3- -C10)- ^■ heterocyclo-; or R ¹ and R ² may be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered aromatic or non-aromatic ring having 0-

3 substituents independently selected from J, and having 0-3 additional heteroatoms independently selected from N, O, S, SO, or S0 ₂ ; wherein each of R ¹ and R ² is independently substituted at each substitutable position with 0-3 substituents independently selected from J; R is H, halogen or (Cl-C12)-aliphatic-, wherein said (CI -CI 2)- aliphatic is substituted with 0-3 substituents independently selected from J;

A and B are independently selected from:

(C6-C10)-aryl-,

(C5-C10)-heteroaryl-, and

(C3-C10)-heterocyclo-;

wherein A and B are independently substituted with 0-5 substituents independently selected from J;

each J is independently selected from:

halogen, -OR ³ , -N0 ₂ , -CN, -CF ³ , -OCF ₃ , -R ³ , oxo, thioxo, 1 ,2-methylenedioxy, 1,2-ethylenedioxy, =N(R ³ ), =N(OR ³ ), -N(R ³ ) ₂ , -SR ³ , -SOR ³ , -S0 ₂

R ³ , -S0 ₂ N(R ³ ) ₂ , -S0 ₃ R ³ , -C(0)R ³ , -C(0)C(0)R ³ , -C(0)CH ₂ C(0)R ³ , -C(S)R ³ , - C(S)OR ³ , -C(0)OR ³ , -C(0)C(0)OR ³ , -C(0)C(0)N(R ³ ) ₂ , -OC(0)R ³ , -C(0)N(R 3) ₂ , -OC(0)N(R ³ ) ₂ , -C(S)N(R ³ ) ₂ , -(CH ₂ )o_

₂ NHC(0)R ³ , -N(R ³ )N(R ³ )COR ³ , -N(R ³ )N(R ³ )C(0)OR ³ , -N(R ³ )N(R ³ )CON(R ³ ) 2, -N(R ³ )S0 ₂ R ³ , -N(R ³ )S0 ₂ N(R ³ ) ₂ , -N(R ³ )C(0)OR ³ , -N(R ³ )C(0)R ³ , -N(R ³ )C(S )R ³ , -N(R ³ )C(0)N(R ³ ) ₂ , -N(R ³ )C(S)N(R ³ ) ₂ , -N(COR ³ )COR ³ , -N(OR ³ )R ³ , -C(= NH)N(R ³ ) ₂ , -C(0)N(OR ³ )R ³ , -C(=NOR ³ )R ³ , -OP(0)(OR ³ ) ₂ , -P(0)(R ³ ) ₂ , -P(0)( OR ³ ) ₂ , and -P(0)(H)(OR ³ );

each R ³ is independently selected from:

H-,

(Cl-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

[(C3-C 10)-cycloalkyl]-(C 1 -C 12)-aliphatic-,

[(C3-C 10)- cycloalkenyl]-(C 1 -C 12)-aliphatic-,

(C6-C10)-aryl-,

(C6-C 10)-aryl-(C 1 -C 12)aliphatic-, (C3-C10)-heterocyclyl-,

(C6-C 10)-heterocyclyl-(C 1 -C 12)aliphatic-,

(C5-C10)-heteroaryl-, and

(C5-C 10)-heteroaryl-(C 1 -C 12)-aliphatic-; or two R ³ groups bound to the same atom may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 1-3 heteroatoms independently selected from N, O, S, SO, and S0 ₂ , wherein said ring is optionally fused to a (C6-C10)aryl, (C5- C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl.

[0094] In some embodiments, the a5 -containing GABAA receptor agonist of present invention is a compound of Formula I:

I or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein:

R is -C(0)NR ¹ R ² wherein

R ¹ and R ² are independently selected from:

H-,

(Cl-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

(C6-C10)-aryl-,

(C5-C10)-heteroaryl-, and (C3-C10)-heterocyclo-;

or R ¹ and R ² may be taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered aromatic or non-aromatic ring having 0- 3 additional heteroatoms independently selected from N, O, S, SO, and S0 ₂ ; wherein each of R ¹ and R ² is independently substituted at each substitutable position with 0-3 substituents independently selected from J;

or R is a 5-membered heteroaryl ring having 1-3 heteroatoms selected from N, NH, O, SO, and S0 ₂ ; wherein the 5-membered heteroaryl ring has 0-2 substituents selected independently from J;

R is H, halogen or (Cl-C12)-aliphatic-, wherein said CI -CI 2 aliphatic group is substituted with 0-3 substituents independently selected from J;

A and B are independently selected from:

(C6-C10)-aryl-,

(C5-C10)-heteroaryl-, and

(C3-C10)-heterocyclo-;

wherein A and B are independently substituted with 0- 5 substituents

independently selected from J;

each J is independently selected from:

halogen, -OR ³ , -N0 ₂ , -CN, -CF ³ , -OCF ₃ , -R ³ , oxo, thioxo, 1 ,2-methylenedioxy, 1,2-ethylenedioxy, =N(R ³ ), =N(OR ³ ), -N(R ³ ) ₂ , -SR ³ , -SOR ³ , -S0 ₂

R ³ , -S0 ₂ N(R ³ ) ₂ , -S0 ₃ R ³ , -C(0)R ³ , -C(0)C(0)R ³ , -C(0)CH ₂ C(0)R ³ , -C(S)R ³ , - C(S)OR ³ , -C(0)OR ³ , -C(0)C(0)OR ³ , -C(0)C(0)N(R ³ ) ₂ , -OC(0)R ³ , -C(0)N(R 3) ₂ , -OC(0)N(R ³ ) ₂ , -C(S)N(R ³ ) ₂ , -(CH ₂ )o_

₂ NHC(0)R ³ , -N(R ³ )N(R ³ )COR ³ , -N(R ³ )N(R ³ )C(0)OR ³ , -N(R ³ )N(R ³ )CON(R ³ ) 2, -N(R ³ )S0 ₂ R ³ , -N(R ³ )S0 ₂ N(R ³ ) ₂ , -N(R ³ )C(0)OR ³ , -N(R ³ )C(0)R ³ , -N(R ³ )C(S )R ³ , -N(R ³ )C(0)N(R ³ ) ₂ , -N(R ³ )C(S)N(R ³ ) ₂ , -N(COR ³ )COR ³ , -N(OR ³ )R ³ , -C(= NH)N(R ³ ) ₂ , -C(0)N(OR ³ )R ³ , -C(=NOR ³ )R ³ , -OP(0)(OR ³ ) ₂ , -P(0)(R ³ ) ₂ , -P(0)( OR ³ ) ₂ , and -P(0)(H)(OR ³ );

each R ³ is independently selected from:

H-,

(Cl-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

[(C3-C 10)-cycloalkyl]-(C 1 -C 12)-aliphatic-,

[(C3-C 10)-cycloalkenyl]-(C 1 -C 12)-aliphatic-, (C6-C10)-aryl-,

(C6-C 10)-aryl-(C 1 -C 12)aliphatic-,

(C3-C10)-heterocyclyl-,

(C6-C 10)-heterocyclyl-(C 1 -C 12)aliphatic-,

(C5-C10)-heteroaryl-, and

(C5-C 10)-heteroaryl-(C 1 -C 12)-aliphatic-;

or two R ³ groups bound to the same atom may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 1- 3 heteroatoms independently selected from N, O, S, SO, and S0 ₂ , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-

C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl.

[0095] In certain embodiments, the compound of Formula I is not:

[0096] In a more specific embodiment, the a5 -containing GABAA receptor agonist useful in the present invention is a com ound that has the Formula I-A:

I-A or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in any of the embodiments herein. [0097] In certain embodiments for a compound of Formula I-A, at least one of R ¹ and R ² is hydrogen. For example, R ¹ and R ² are each independently hydrogen. [0098] In some embodiments for a compound of Formula I-A, at least one of R ¹ and R ² is (Cl-C12)-aliphatic- substituted at each substitutable position with 0-3 substituents independently selected from J. For example, R ¹ and R ² are each independently (Cl-C12)-aliphatic- substituted at each substitutable position with 0- 3 substituents independently selected from J. In one embodiment, R ¹ and R ² are each independently unsubstituted (Cl-C4)-aliphatic groups, such as methyl, ethyl or allyl. In another embodiment, R ¹ and R ² are each independently (Cl-C4)-alkyl, and wherein at least one of R ¹ and R ² is substituted with at least one (C6-C10)- aryl, such as phenyl. In yet another embodiment, R ¹ and R ² are each independently (Cl-C4)-alkyl, and R ¹ and R ² are each independently substituted with at least one (C6-C10)-aryl, such as phenyl.

[0099] In other embodiments for a compound of Formula I-A, R ¹ is H- and R ² is (Cl-C12)-aliphatic- substituted at each substitutable position with 0-3 substituents independently selected from J. For example, R ¹ is H- and R ² is unsubstituted (Cl- C4)-alkyl, such as methyl or isopropyl. In another embodiment, R ¹ is H- and R ² is (Cl-C12)-aliphatic- that is substituted with at least one (C6-C10)-aryl group, such as where R ² is a phenyl-(Cl-C4)-alkyl- group.

[0100] In another embodiment for a compound of Formula I-A, R ¹ and R ² taken together with the atom to which they are attached form a C5-C10 aromatic or non- aromatic ring. Examples of these rings include a 5-membered aromatic or non- aromatic ring. For example, R ¹ and R ² taken together with the atom to which they are attached form a pyrrolidine ring.

[0101] In another embodiment, the a5 -containing GABAA receptor agonist useful in the present invention is a compound that has the Formula I-B:

I-B or pharmaceutically acceptable salt thereof; wherein X, Y and Z are each independently selected from -CR ⁴ -, -N(R ⁴ )-, -N=, -O- and -S-,

R ⁴ and R ⁵ are each independently selected from:

halogen, -OR ³ , -N0 ₂ , -CN, -CF ³ , -OCF ₃ , -R ³ , oxo, thioxo, 1 ,2-methylenedioxy,

1,2-ethylenedioxy, =N(R ³ ), =N(OR ³ ), -N(R ³ ) ₂ , -SR ³ , -SOR ³ , -S0 ₂

R ³ , -S0 ₂ N(R ³ ) ₂ , -S0 ₃ R ³ , -C(0)R ³ , -C(0)C(0)R ³ , -C(0)CH ₂ C(0)R ³ , -C(S)R ³ , - C(S)OR ³ , -C(0)OR ³ , -C(0)C(0)OR ³ , -C(0)C(0)N(R ³ ) ₂ , -OC(0)R ³ , -C(0)N(R 3) ₂ , -OC(0)N(R ³ ) ₂ , -C(S)N(R ³ ) ₂ , -(CH ₂ )o_

2NHC(0)R ³ , -N(R ³ )N(R ³ )COR ³ , -N(R ³ )N(R ³ )C(0)OR ³ , -N(R ³ )N(R ³ )CON(R ³ )

₂ , -N(R ³ )S0 ₂ R ³ , -N(R ³ )S0 ₂ N(R ³ ) ₂ , -N(R ³ )C(0)OR ³ , -N(R ³ )C(0)R ³ , -N(R ³ )C(S )R ³ , -N(R ³ )C(0)N(R ³ ) ₂ , -N(R ³ )C(S)N(R ³ ) ₂ , -N(COR ³ )COR ³ , -N(OR ³ )R ³ , -C(= NH)N(R ³ ) ₂ , -C(0)N(OR ³ )R ³ , -C(=NOR ³ )R ³ , -OP(0)(OR ³ ) ₂ , -P(0)(R ³ ) ₂ , -P(0)( OR ³ ) ₂ , and -P(0)(H)(OR ³ ); and the other variables in the Formula are as defined in any of the embodiments herein.

[0102] In certain embodiments for a compound of Formula I-B, X is-O-.

[0103] In other embodiments for a compound of Formula I-B, Z is -N=. In yet another embodiment for a compound of Formula I-B, X is-O- and Z is -N=.

[0104] In yet other embodiments for a compound of Formula I-B, Y is -CR ⁴ - or - N=. In certain embodiments for a compound of Formula I-B, Y is -CR ⁴ - and R ⁴ is H or (Cl-C12)-aliphatic. In one embodiment, Y is -CR ⁴ - and R ⁴ is H. In another embodiment, Y is -CR ⁴ - and R ⁴ is (Cl-C4)-alkyl.

[0105] In some embodiments for a compound of Formula I-B, X, Y and Z are defined herein and R ⁵ is (Cl-C12)-aliphatic- or -C(0)OR ³ . For example, R ⁵ is (Cl-C4)-alkyl, such as methyl or ethyl. In other embodiments for a compound of Formula I-B, R ⁵ is -C(0)OR ³ , wherein R ³ is (Cl-C12)aliphatic, such as (C1-C4)- alkyl-. In some embodiments, R ⁵ is -C(0)OMe. In certain embodiments for a compound of Formula I-B, X is -0-, Z is -N=, Y is -CR ⁴ - or -N=, and R ⁵ is (Cl- C12)-aliphatic- or -C(0)OR ³ . [0106] In another embodiment, the a5 -containing GABAA receptor agonist useful in the present invention is a compound that has the Formula I-C:

I C, or a pharmaceutically acceptable salt thereof, wherein A, B and R are as defined any of the embodiments herein.

[0107] In another embodiment, the a5 -containing GABAA receptor agonist useful in the present invention is a compound that has the Formula I-D:

I-D or a pharmaceutically acceptable salt thereof; wherein:

X, Y and Z are each independently selected from -C(R ⁴ ) ₂ -, N(R ⁴ ), N, O, and S; and each of R ⁴ and R ⁵ are independently selected from:

halogen, -OR ³ , -N0 ₂ , -CN, -CF ³ , -OCF ₃ , -R ³ , oxo, thioxo, 1 ,2-methylenedioxy, 1 ,2-ethylenedioxy, =N(R ³ ), =N(OR ³ ), -N(R ³ ) ₂ , -SR ³ , -SOR ³ , -S0 ₂

R ³ , -S0 ₂ N(R ³ ) ₂ , -S0 ₃ R ³ , -C(0)R ³ , -C(0)C(0)R ³ , -C(0)CH ₂ C(0)R ³ , -C(S)R ³ , -C(S )OR ³ , -C(0)OR ³ , -C(0)C(0)OR ³ , -C(0)C(0)N(R ³ ) ₂ , -OC(0)R ³ , -C(0)N(R ³ ) ₂ , -O C(0)N(R ³ ) ₂ , -C(S)N(R ³ ) ₂ , -(CH ₂ )o_

₂ NHC(0)R ³ , -N(R ³ )N(R ³ )COR ³ , -N(R ³ )N(R ³ )C(0)OR ³ , -N(R ³ )N(R ³ )CON(R ³ ) ₂ , - N(R ³ )S0 ₂ R ³ , -N(R ³ )S0 ₂ N(R ³ ) ₂ , -N(R ³ )C(0)OR ³ , -N(R ³ )C(0)R ³ , -N(R ³ )C(S)R ³ , - N(R ³ )C(0)N(R ³ ) ₂ , -N(R ³ )C(S)N(R ³ ) ₂ , -N(COR ³ )COR ³ , -N(OR ³ )R ³ , -C(=NH)N(R ³ ) ₂ , -C(0)N(OR ³ )R ³ , -C(=NOR ³ )R ³ , -OP(0)(OR ³ ) ₂ , -P(0)(R ³ ) ₂ , -P(0)(OR ³ ) ₂ , and -P(0)(H)(OR ³ ); and A, B and R are as defined in any of the embodiments herein.

[0108] In certain embodiments for a compound of Formula I-D, X is-O-.

[0109] In some embodiments for a compound of Formula I-D, Z is -N=. In other embodiments for a compound of Formula I-D, X is-O- and Z is -N=.

[0110] In yet other embodiments for a compound of Formula I-D, Y is -C(R ⁴ ) ₂ . For example, Y is -C(R ⁴ ) ₂ and at least one R ⁴ is H or (Cl-C12)-aliphatic. In other embodiments, Y is -C(R ⁴ ) ₂ and each R ⁴ is independently H. In another

embodiment Y is -C(R ⁴ ) ₂ , where at least one R ⁴ is (Cl-C4)-alkyl-.

[0111] In some embodiments for a compound of Formula I-D, X, Y and Z are as defined herein, and R ⁵ is (Cl-C12)-aliphatic- or -C(0)OR ³ . For example, R ⁵ is (Cl-C4)-alkyl, such as methyl or ethyl. In some embodiments for a compound of Formula I-D, R ⁵ is -C(0)OR ³ , where R ³ is (Cl-C12)aliphatic, such as (C1-C4)- alkyl-. In some embodiments, R ⁵ is -C(0)OMe. In certain embodiments for a compound of Formula I-D, X is -0-, Z is -N=, Y is -C(R ⁴ ) ₂ , and R ⁵ is (CI -CI 2)- aliphatic- or -C(0)OR ³ . [0112] The following description applies to any of the embodiments of Formulae I, I-A, I-B, I-C and I-D described above.

[0113] In one aspect, the a5-containing GABAA receptor agonist of the present invention is a compound, wherein A is (C6-C10)-aryl- or (C5-C10)-heteroaryl-, each of said aryl or heteroaryl being independently substituted with 0-5

substituents independently selected from J. In certain aspects, A is phenyl, substituted with 0-5 substituents independently selected from J. For example, A can be phenyl that is unsubstituted or substituted with at least one halogen or - OR ³ . In one embodiment, A is phenyl that is substituted with at least one F, CI, or -OCH ₃ . [0114] In another embodiment, A is a 5-membered or 6-membered heteroaryl substituted with 0-5 substituents independently selected from J, such as where A is pyrazolyl or pyridyl. Examples of these 5-membered or 6-membered heteroaryl groups are ones that are unsubstituted or substituted with at least one (CI -CI 2)- aliphatic, such as -CH ₃ .

[0115] In another aspect, the a5 -containing GABAA receptor agonist of the present invention is a compound, wherein B is (C6-C10)-aryl- or (C5-C10)- heteroaryl-, each of said aryl or heteroaryl being independently substituted with 0- 5 substituents independently selected from J. In certain aspects, B is phenyl substituted with 0-5 substituents independently selected from J.

[0116] The invention also includes combinations of A and B as described above. In some embodiments, B is phenyl substituted with 0-5 substituents independently selected from J, and A is phenyl, pyrazolyl or pyridyl, substituted with 0- 3 substituents independently selected from J. These combinations can in turn be combined with any or all of the values of X, Y, Z, R, R ¹ , R ² , R ³ , R4 and R ⁵ described above.

[0117] In certain embodiments, the a5 -containing GABAA receptor agonist of the present invention is a compound of formula I, wherein B is phenyl; A is phenyl, pyrazolyl or pyridyl, substituted with 0-2 substituents independently selected from -OR ³ where R ³ is (Cl-C4)alkyl- (such as -OMe), halogen (such as - CI and -F), and (Cl-C4)alkyl- (such as -Me); R is hydrogen; R' is selected from the group consisting of:

(1) -COOH;

(2) -C(0)NR ¹ R ² , wherein

R ¹ and R ² are each independently (Cl-C4)-aliphatic- (such as methyl, ethyl and allyl),

or R ¹ and R ² are each independently (Cl-C4)-alkyl (such as methyl), wherein at least one of R ¹ and R ² is substituted with at least one phenyl,

or R ¹ is H, and R ² is (Cl-C4)-alkyl (such as methyl and isopropyl), or R ¹ and R ² taken together with the nitrogen atom to which they are bound form a 5-membered non-aromatic ring (such as a pyrrolidine ring); and (3) a 5-membered heterocyclic or heteroaryl ring having one nitrogen atom and one oxygen atom (such as oxazole or dihydrooxazole); wherein the 5-membered heterocyclic or heteroaryl ring has 0-2 substituents selected independently from (Cl-C4)-alkyl- (such as methyl, ethyl and isopropyl) and -C(0)OR ³ where R ³ is (C 1 -C4)alkyl- (such as -COOMe).

[0118] In some embodiments, the a5-containing GABAA receptor agonist of the present invention is a compound of formula I, wherein B is phenyl; A is phenyl substituted with 0 or 1 substituent selected from

-OR ³ where R ³ is (Cl-C4)alkyl- (such as -OMe) and halogen (such as -CI); R is hydrogen; R' is selected from the group consisting of:

(1) -COOH;

(2) -C(0)NR ¹ R ² , wherein

R ¹ and R ² are each independently (Cl-C4)-alkyl- (such as methyl),

or R ¹ and R ² are each independently (Cl-C4)-alkyl (such as methyl), wherein at least one of R ¹ and R ² is substituted with one phenyl,

or R ¹ is H, and R ² is (Cl-C4)-alkyl (such as methyl and isopropyl); and

(3) a 5-membered heterocyclic or heteroaryl ring having one nitrogen atom and one oxygen atom (such as oxazole or dihydrooxazole), wherein the 5-membered heterocyclic or heteroaryl ring has 1 substituent selected from (Cl-C4)-alkyl- (such as methyl and ethyl) and -C(0)OR ³ where R ³ (C 1 -C4)alkyl- (such as -COOMe).

[0119] Examples of particular a5-containing GABAA receptor agonist useful in the present invention include:

and pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof.

[0120] Those of skill in the art can readily recognize that the present invention allows for various combinations of moiety choices for variables in the generic structures. [0121] Any embodiment given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, unless otherwise indicated. Isotopically labeled compounds have structures depicted by the

Formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ² H, ³ H, ^U C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ C1, ¹²⁵ I, respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as ³ H, ¹³ C, and ¹⁴ C, are present. Such isotopically labeled compounds are useful in metabolic studies (preferably with ¹⁴ C), reaction kinetic studies (with, for example 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 in radioactive treatment of patients. In particular, an ¹⁸ F or labeled compound may be particularly preferred for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. [0122] Any of the individual embodiments recited above, including those embodiments defining compounds 1-37, may define Formula I individually or be combined to produce a preferred embodiment of this invention.

[0123] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formulas I, I- A, I-B, I-C or I-D or pharmaceutically acceptable salt form thereof and an antipsychotic or pharmaceutically acceptable salt form thereof.

[0124] Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. [0125] Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium

carboxymethylcellulose, polyacrylates, waxes,

polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. General Synthetic Methodology

[0126] The a5-containing GABAA receptor agonists of this invention may be prepared in general by methods known to those skilled in the art. Schemes 1-9 below illustrate synthetic routes to the compounds of the present invention. Other equivalent schemes, which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes below. Scheme 1

Scheme 1 above provides a general synthetic route for the preparation of compounds of Formula I-A and compounds of Formula I-C.

cheme 2

1

[0127] Scheme 2 above provides a synthetic route for the preparation of compounds of Formula I-A. As would be recognized by skilled practitioners, compounds of Formula I with A, B, R and R other than those depicted above may be prepared by varying chemical reagents or the synthetic route.

[0128] For example, compounds of Formula I-A wherein R is other than -C(0)NHMe may be prepared by reacting compound 40 with a compound of Formula R ^X R ² NH under appropriate basic conditions, as shown in Scheme 3. Scheme 3

[0129] Similarly, compounds of Formula I-A wherein A is other than phenyl and R' is other than -C(0)NHMe may be prepared by reacting compound 38 with a boron reagent of formula A-B(Y) _n , wherein Y _n is -(OH) ₂ , -(0-alkyl) ₂ ,

-F ₃ or -(alkyl) ₂ , under appropriate Suzuki coupling reactions, as shown in Schemes 4.

Scheme 4

[0130] Scheme 5 below provides a general synthetic route for the preparation of compounds of Formula I-B and compounds of Formula I-D. As would be recognized by skilled practitioners, compounds of Formula I-B or Formula I-D with X, Y and Z, other than those depicted in Scheme 5, may be prepared by varying chemical reagents or the synthetic route.

Scheme 5

I-D I-B [0131] Scheme 6 below provides a synthetic route for the preparation of

compounds of Formula I-D. As would be recognized by skilled practitioners, compounds of Formula I-D with R ⁵ other than those depicted above in Scheme 6 may be prepared by varying chemical reagents or the synthetic route.

Scheme 6

I-C VII _! _ _{£> (R IS H5} x _is _o_ _{5 z} is _ _N =

Y is -CH ₂ - and R ⁵ is Me-)

IX I-Bl Scheme 7 above provides a synthetic route for the preparation of compounds of

Formula I-Bl (e.g., compounds of Formula I-B, wherein R is H, X is -0-, Z is

-N=, Y is -CH=, and R ⁵ is methyl), using a compound of Formula I-B2 (e.g., a compound of Formula I-B, wherein R is H, X is -0-, Z is -N=, Y is -CH=, and R ⁵ is -COOMe) as the starting material. Scheme 8

XII I-B3

Scheme 8 above provides a synthetic route for the preparation of compounds of Formula I-B3 (e.g., compounds of Formula I-B, wherein R is H, X is -0-, Z is -N=, Y is -CH=, and R ⁵ is ethyl), using the compound of Formula I-B2 as the starting material.

Scheme 9

Scheme 9 above provides a synthetic route for the preparation of compounds of Formula I-B4 (e.g., compounds of Formula I-B, wherein R is H, X is -0-, Z is -N=, Y is -CH=, and R ⁵ is iso-propyl), using the compound of Formula I-B2 as the starting material. As would be recognized by skilled practitioners, compounds of Formula I-B with X, Y, Z and R ⁵ other than those depicted above in Schemes 7-9 may be prepared by varying chemical reagents or the synthetic route. Antipsychotics

[0132] The antipsychotics suitable for use in the present invention may be any antipsychotic drugs or agents or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof. (I) "Typical" and ' 'Atypical" Antipsychotics

[0133] Among the antipsychotics or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs thereof that are useful in the methods and compositions of this invention are atypical and typical antipsychotics.

[0134] In some embodiments, the antipsychotic is an atypical antipsychotic or pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof. Atypical antipsychotics offer several clinical benefits including, for example, superior side effect profiles, particularly with regard to extrapyramidal side effects (EPS). mAtypical antipsychotics typically differ from typical antipsychotics in their "limbic-specific" dopamine type 2 (D2)-receptor binding. Atypical antipsychotics, also display a high ratio of serotonin type 2 (5-HT2)- receptor binding to D2 binding. Atypical antipsychotics have high affinity for the 5 -HT2 -receptor and function as antagonists of serotonin for the 5 -HT2 -receptor.

[0135] Examples of atypical antipsychotics include, but are not limited to:

Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy]-3,4-di- hydrocarbostyril (commercially available from Bristol-Meyers Squibb Co.,

Princeton, NJ under the trade name Ability®) is disclosed in U.S. Patents No. 4,734,416 and 5,006,528, which are incorporated herein by reference. Exemplary formulations and dosages of aripiprazole suitable for use in treating schizophrenia and bipolar disorder are described in U.S. Patents 6,977,257; 7,115,587; and 7,550445, which are herein incorporated by reference in their entirety.

Asenapine, traiis-5- chloro-2-methyl-2,3,3a,12b-tetrahydro-l H- dibenz[2,3:6,7]oxepino[4,5-c]pyrro!e (under trade name Saphris® or Sycrest®) is disclosed in U.S. Patents 4,145,434 and 5,763,476, which are herein incorporated by reference in their entirety. An orthorhombic crystal form of asenapine is described in U.S. Patent 7,741,358, which is also incorporated herein by reference.

Clozapine, 8-chloro- 11 -(4-methyl-l-piperaziny l)-5H-dibenzo[b,e] [ 1 ,4]-diazepine (commercially available from Mylan Pharmaceuticals, Morgantown, WV under the trade name Mylan®) is disclosed in U.S. Patent No. 3,539,573, which is herein incorporated by reference. Clinical efficacy of Clozapine in the treatment of schizophrenia has previously been disclosed. Hanes, et al, Psychopharmacol. Bull, 24, 62 (1988).

Iloperidone, l-[4-[3-[4-(6-Fluoro-l,2-benzisoxazol-3-y[)-l-piperidmyl]pro poxy]-3- methoxypheiiyljethanone (under trade name Fanapt®) is disclosed in EP Patent EP402644, which is incorporated herein by reference. The use of iloperidone in treating psychotic symptom and exemplary dosages of iloperidone suitable for such treatment are disclosed in U.S. Patent USRE39198, which is incorporated herein by reference. Olanzapine, 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno [2,3- b][l,5]benzodiazepine, disclosed in U.S. Patent No. 5,229,382 (commercially available from Eli Lilly, Indianapolis, IN under the trade name Zyprexa®) which is hereby incorporated by reference, as being useful for the treatment of

schizophrenia, schizophreniform disorder, acute mania, mild anxiety states, and psychosis. The use of olanzapine in treating schizophrenia and exemplary dosages of olanzapine for such use are disclosed in U.S. Patents 5,625897, 5627178, 5,817655, 5,919485 and 6960577. Olanzapine polymorphs are disclosed in U.S. Patent 5,736,541, incorporated herein by reference. Olanzapine hydrate forms are disclosed in U.S. Patent 6,251,895, incorporated herein by reference. Lurasidone, (3aR,4S,7R,7aS)-2-{(lR,2R)-2-[4-(l,2-benzisotM

l-yl-methyl]cyclohexylmethyl}h^

(developed by Dainippon Sumitomo Pharma Co., Ltd. under trade name Latuda®) is disclosed in U.S. Patent 5,532,372, incorporated herein by reference.

Paliperidone, 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl ]-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4Hpyrido [l,2-a]pyrimidin-4-one (developed by Janssen Pharmaceutica under the trade name Invega® or Invega sustenna®), is disclosed in EP Patent 368388. The use of paliperidone in treating phychosis and exemplary formulations for such use are disclosed in U.S. Patents 5,158,952, 5,254,556, 5,352459, 6,077,843 and 6,555,544, all of which are incorporated herein by reference.

Quetiapine, 5-[2-(4-dibenzo[b,fJ [1,4] thiazepin-l l-yl-l-piperazinyl)- eth-oxy]ethanol (commercially available from Astra Zeneca, Wilmington, DE under the tradename Seroquel®) its activity in assays which demonstrate utility in the treatment of schizophrenia are disclosed in U.S. Patent No. 4,879,288, which is herein incorporated by reference. Exemplary formulations of quetiapine for use in treating schizophrenia and bipolar disorder are disclosed in U.S. Patent 5,948,437, incorporated herein by reference.

Risperidone, 3-[2-[4-(6-fluoro- 1 ,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl- 6,7,8,9-tetrahydro-4H-pyrido-[ 1 ,2-a]pyrimidin-4-one (commercially available from Janssen under the trade name Risperdal®) and its use in the treatment of psychotic diseases are disclosed in U.S. Patent No. 4,804,663, which is herein incorporated by reference.

Sertindole, l-[2-[4-[5-chloro-l-(4-fiuorophenyl)-lH-indol-3-yl]- 1- piperidinyl]ethyl]imidazolidin-2-one, is described in U.S. Patent No. 4,710,500.

Its use in the treatment of schizophrenia is described in U.S. Patent Nos. 5,112,838 and 5,238,945. U.S. Patents No. 4,710,500; 5,112,838; and 5,238,945 are herein incorporated by reference in their entirety.

Ziprasidone, 5- [2-[4-(l,2-benzoisothiazol-3-yl)-l-piperazinyl]ethyl]-6-chlo ro-l,3- dihydro-2H-indol-2-one, (commercially available from Pfizer Inc., New York, NY under the trade name Geodon®) is disclosed in U.S. Patents No. 4,831,031 and 5,312,925 and its activity in assays which demonstrate utility in the treatment of schizophrenia are described in U.S. Patent No. 4,831 ,031 , all of which are herein incorporated by reference. Surmontil (trimipramine maleate), 5-(3-dimethylamino-2-methylpropyl)-10,l 1- dihydro-5H-dibenz (b,f) azepine acid maleate (Commercially available from Odyssey Pharmaceuticals, Inc, North Hanover, NJ under the trade name

Surmotil®). [0136] In some embodiment, the antipsychotic for the methods and compositions of this invention is selected from aripiprazole, olanzapine and ziprasidone, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof.

[0137] In some embodiments of the invention, the antipsychotic is a typical antipsychotic. Such typical antipsychotics include, but are not limited to, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine, trihexyphenidyl, and zuclopenthixol, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs and polymorphs thereof.

(2) Antipsychotics Displaying Various Pharmacology /Mechanisms

[0138] Suitable antipsychotics or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof for the present invention may be selected from compounds/agents that are dopaminergic agents, glutamatergic agents, NMD A receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptor modulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors, nNOS inhibits, neurosteroids, and neurotrophic factors. [0139] In some embodiments, the antipsychotic is a dopaminergic agent selected from dopamine Dl receptor antagonists or agonists (for example, dihydrexidine, A77636 and SKF81297), dopamine D ₂ receptor antagonists or partial agonists (e.g., some typical and atypical antipsychotics), dopamine D3 receptor antagonists or agonists (for example, S33084, SB-277011-A, AVE5997 and (±)-PD 128907), dopamine D4 receptor antagonists (for examples, clozapine and sonepiprazole (U- 101387 or PNU-101387G)).

[0140] In some embodiments, the antipsychotic is a glutamatergic agent selected from NMDA receptor positive allosteric modulators (e.g., glycine, D-cycloserine and D-serine), glycine reuptake inhibitors (e.g., N-(3-(4'-fluorophenyl)-3-(4'- phenylphenoxy)propyl) sarcosine and glycyldodecylamide) , glutamate reuptake inhibitor (e.g., excitatory amino-acid transporters EAAT3 antagonists), metabotropic glutamate receptors agonists (e.g., LY-354740), AMPA/kainate receptor antagonists (e.g., LY-293558, GYKI52466 and LY-326325), ampakines (CX-516), and glutathione prodrugs. [0141] In some embodiments, the antipsychotic is a noradrenergic agent selected from alpha-2 adrenergic receptor agonists or antagonists (e.g., guanfacine, clozapine and risperidone) and COMT inhibitors (e.g., tolcapone).

[0142] In some embodiments, the antipsychotic is a serotonin receptor modulator selected from 5-HT ₂ A receptor antagonists, 5-HT _I A receptor partial agonists, 5- HT ₂ c agonists, and 5-HT6 antagonists (e.g., some atypical antipsychotics).

[0143] In some embodiments, the antipsychotic is a cholinergic agent selected from alpha-7 nicotinic receptor agonists (e.g., 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A or GTS-21)), alpha4-beta2 nicotinic receptor agonists (e.g., SIB- 1553 A), allosteric modulators of nicotinic receptors and acetylcholinesterase inhibitors, muscarinic receptor agonists and antagonists (e.g., N- desmethylclozapine, xanomeline, PTAC, and BuTAC).

[0144] In some embodiments, the antipsychotic is selected from cannabinoid CB1 antagonists (e.g., SR141716) , neurokinin 3 antagonists (e.g., osanetant (SR- 142801) and talnetant), neurotensin agonists (e.g., SR-48692), MAO B inhibitors (e.g., Selegiline (deprenyl) and rasagiline), PDE10 inhibitors (e.g., Papaverine), NNOS inhibits (e.g., methylene blue, LNOARG, L-NAME, and 7-nitroindazole), neurosteroids (e.g., dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), pregnenolone (PREG) and pregnenolone sulfate (PREGS)), and neurotrophic factors (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3/4/5)).

(3) Antipsychotics Useful for Treating Symptoms of Schizophrenia or Bipolar Disorder (in particular, mania)

[0145] In some embodiments, the antipsychotics or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs thereof that are useful in the methods and compositions of this invention include those that are useful in treating one or more signs or symptoms of schizophrenia or bipolar disorder (in particular, mania).

[0146] Schizophrenia is characterized by psychological symptoms such as perception (hallucinations), ideation, reality testing (delusions), thought processes (loose associations), feeling (flatness, inappropriate effect) , behavior (catatonia, disorganization), attention, concentration, motivation (avolition, impaired intentions and planning) and judgment (see for example Diagnostic and Statistical Manual of Mental Disorders IV, American Psychiatric Association). In general, the symptoms of schizophrenia are divided into positive and negative symptoms with hallucinations and delusions being positive features, and features such as flatness, poverty of speech and impaired executive functions representing negative symptoms. Clinical rating scales such as Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms provide criteria to

differentiate between, and rate, positive and negative symptoms. Frequently included in the description of negative symptoms are the cognitive deficits schizophrenic and schizotypical patients suffer from. These include impairment in attention, verbal fluency, executive functions such as planning, working memory and visual and verbal learning and memory. These types of cognitive dysfunction can be measured with a variety of tests, such as Visual Search, Verbal Fluency, Wisconsin Card Sorting, Trail Making - Part B, Symbol Digit, Hopkins Verbal Learning, Digit Span, Stroop-Color-Word and Attentional Capacity. MATRICS consensus neuropsychological test battery which includes tests of working memory, speed of processing, attention, verbal learning, visual learning, reasoning and problem solving and social cognition. Moreover, it has been found that cognitive measures predict work function and overall outcome as assessed by the Global Assessment Scale and Quality of Life Scale. Several studies have now

demonstrated that neuropsychological functions, reflecting several negative and cognitive symptoms of the disease, may be more impaired in male schizophrenic patients when compared to female patients. Further, there are a number of other psychiatric diseases such as schizotypical and schizoaffective disorder, other acute- and chronic psychoses and bipolar disorder which have an overlapping

symptomatology with schizophrenia. Any compounds or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs thereof that are useful in treating at least one of the signs or symptoms of schizophrenia or bipolar disorder (in particular, mania), including, for example, those recited above, are useful in the methods and compositions of this invention.

[0147] Among the antipsychotics or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs thereof that are useful in the methods and compositions of this invention are those disclosed, for example, in U.S. Patents

4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573; 5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and 5,312,925, and EP Patents EP402644 and EP368388, and the pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs thereof. [0148] In some embodiments, the antipsychotics useful in this invention include those compounds/agents disclosed, for example, in U.S. Patents or Patent Publications US20020052401A1; US20020091118A1; US20020091119A1;

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Method of Treating Schizophrenia or Bipolar Disorder (in particular, mania) with the Administration of a a5-containing GABA _A Receptor Agonist and an Antipsychotic or Pharmaceutically Acceptable Salts Thereof

[0149] In one aspect, the invention provides methods and compositions for treating a subject suffering from schizophrenia or bipolar disorder (in particular, mania), or the risk thereof by administering a a5-containing GABAA receptor agonist or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in combination with an antipsychotic or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. In some embodiments, the methods of this invention treat one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia. In some embodiments, the methods of this invention treat one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania).

[0150] The a5 -containing GABAA receptor agonist and the antipsychotic suitable for the method of this invention may be selected from any of those as described above. In some embodiments, the a5-containing GABAA receptor agonist is selected from any of the compounds of Formulas I, I-A, I-B, I-C and I-D, as described above, and in U.S. Patent Application 61/413,971 and PCT publication WO2012068161, including, for example, compounds of any of the embodiments of Formulas I, I-A, I-B, I-C and I-D and the specific compounds described herein and in U.S. Patent Application 61/413,971 and PCT publication WO2012068161; and the antipsychotic is selected from (1) atypical and typical antipsychotics (such as those described above); (2) agents that are dopaminergic agents (such as dopamine Dl receptor antagonists or agonists, dopamine D ₂ receptor antagonists or partial agonists, dopamine D3 receptor antagonists or partial agonists, dopamine D4 receptor antagonists), glutamatergic agents, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents (such as alpha-2 adrenergic receptor agonists or antagonists and COMT inhibitors), serotonin receptor modulators (such as 5-HT ₂ A receptor antagonists, 5- HT _I A receptor partial agonists, 5-HT ₂ c agonists, and 5-HT6 antagonists), cholinergic agents (such as alpha-7 nicotinic receptor agonists, 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, MAO B inhibitors, PDE10 inhibitors, nNOS inhibits, neurosteroids, and neurotrophic factors, including, e.g., those specific such agents as described above, and (3) any compounds that are useful in treating one or more sign or symptoms of schizophrenia or bipolar disorder (in particular, mania) (including, e.g., the agents disclosed in any of the above-listed patents or patent application publications), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof. In some of the above embodiments, the antipsychotic for the methods of this invention is an atyptical antipsychotic selected from, e.g., aripiprazole, olanzapine and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof.

[0151] In some embodiments, the subject that suffers schizophrenia or bipolar disorder (in particular, mania) is a human patient. The subject may be a human or other mammal such as a non-human primate, or rodent (e.g., rat). In some

embodiments, the subject is a human patient.

[0152] The use of the a5 -containing GABAA receptor agonists and

pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof in combination with antipsychotics and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs may reduce the amount of antipsychotics necessary for the treatment of schizophrenia or bipolar disorder (in particular, mania). In some embodiments, the subject that suffers schizophrenia or bipolar disorder (in particular, mania) is a human patient, and thus the use of the a5- containing GABA _A receptor agonists reduce the side effects caused by

antipsychotics without diminishing efficacy. Further, in some embodiments, the efficacy of a combination of the a5 -containing GABAA receptor agonists and antipsychotics and pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof exceeds the efficacy of either drug administered alone at its optimal dose and thus, is an improved treatment for schizophrenia or bipolar disorder (in particular, mania).

[0153] It will be appreciated that compounds and agents used in the compositions and methods of this invention preferably should readily penetrate the blood-brain barrier when peripherally administered. Compounds which cannot penetrate the blood-brain barrier, however, can still be effectively administered directly into the central nervous system, e.g., by an intraventricular or other neuro-compatible routes.

[0154] As used herein, administration of a5 -containing GABAA receptor agonist and an antipsychotic or pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof "in combination" includes simultaneous administration and/or administration at different times, such as sequential administration. Simultaneous administration of the a5 -containing GABAA receptor agonist and the antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates and polymorphs can optionally be combined with supplemental doses of the a5 -containing GABAA receptor agonist and/or the antipsychotic and their salts, hydrates, solvates and polymorphs. Simultaneous administration of drugs encompasses administration as co-formulation or, alternatively, as separate compositions.

[0155] In accordance with this invention, the a5 -containing GABAA receptor agonist and the psychotic, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs thereof, can be administered to a subject via any suitable route or routes. In some embodiments, the drugs are administered orally; however, administration intravenously, subcutaneously, intra-arterially, intramuscularly, intraspinally, rectally, intrathoracically, intraperitoneally, intracentricularly, or transdermally, topically, or by inhalation is also contemplated. The agents can be administered orally, for example, in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or the like, prepared by art recognized procedures. In certain embodiments, the a5-containing GABAA receptor agonist and the antipsychotic, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs thereof, can be administered to a subject via different routes. For example, the a5-containing GABAA receptor agonist or its salt, solvate, hydrate, or polymorph is administered intravenously and the antipsychotic or its salt, solvate, hydrate, or polymorph is administered orally.

[0156] In some embodiments, the administration is a slow or extended release. The term "extended release" is widely recognized in the art of pharmaceutical sciences and is used herein to refer to a controlled release of an active compound or agent from a dosage form to an environment over (throughout or during) an extended period of time, e.g. greater than or equal to one hour. An extended release dosage form will release drug at substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrementally over an extended period of time. The term "extended release" used herein includes the terms "controlled release," "prolonged release," "sustained release," "delayed release," or "slow release" as these terms are used in the pharmaceutical sciences. In some embodiments, the extended release dosage is administered in the form of a patch or a pump.

[0157] When a solid carrier is used for administration, the preparation may be in a tablet, placed in a hard gelatin capsule in powder or pellet form, or it may be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the forms of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

[0158] Dosage schedules of the agents and compositions according to the methods of the invention will vary according to the particular compound or compositions selected, the route of administration, the nature of the condition being treated, the age, and condition of the patient, the course, or stage of treatment, and will ultimately be at the discretion of the attending physician. It will be understood that the amount of the a5- containing GABAA receptor agonist and the antipsychotic and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof administered will be amounts effective to produce a desired biological effect, such as beneficial results, including clinical results. It will be understood that an effective amount can be administered in more than one dose and over a course of treatment.

[0159] Desired duration of administration of the a5 -containing GABAA receptor agonist and the antipsychotic and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof can be determined by routine experimentation by one skilled in the art. For example, the a5 -containing GABAA receptor agonist and the antipsychotic and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof may be administered for a period of 1-4 weeks, 1-3 months, 3-6 months, 6-12 months, 1-2 years, or more, up to the lifetime of the patient.

[0160] It is known in the art that normalization to body surface area is an

appropriate method for extrapolating doses between species. The human

equivalent dose (HED) for this dosage can be estimated using the following formula that accounts for differences in body surface area (see Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers, December 2002, Center for Biologies Evaluation and Research): HED = animal dose X (Km animal / Km human) where the Km factor is body weight divided by body surface area (Km rat has been determined as 6, and Km human is 37; see Reagan-Saw, Nihal, Ahmad, 2007). Thus, a dosage of 10 mg/kg in rats is equivalent to 1.6 mg/kg in humans (10 mg/kg X (6 / 37) = 1.6 mg/kg). For human subjects, to calculate a dose in mg from the dose in mg/kg, the dose in mg/kg is multiplied by a typical adult weight of 70 kg.

[0161] In certain embodiments of the invention, the dose of the a5 -containing GABAA R agonist is between 0.0001 and 100 mg/kg/day (which, given a typical human subject of 70 kg, is between 0.007 and 7000 mg/day). [0162] In some embodiments, the antipsychotic useful in the present invention is an atypical antipsychotic. Generally the amount of an atypical antipsychotic administered to a patient is an amount sufficient to have a therapeutic effect. In a preferred embodiment the amount of an atypical antipsychotic administered to a patient is an amount sufficient to treat at least one symptom or sign of

schizophrenia or bipolar disorder (in particular, mania), wherein the one sign or symptom may include, but are not limited to, any of those described above, including, for example, delusions, hallucinations, disorganized speech (e.g., frequent derailment or incoherence), grossly disorganized or catatonic behavior and negative symptoms (e.g., affective flattening, alogia, avolition). One skilled in the art will recognize that the amount of atypical antipsychotic will vary with many factors including the potency of the atypical antipsychotic, the age and weight of the patient, and the severity of the condition or disorder to be treated. The dosages of the drugs used in the present invention can, in the final analysis, be set by the physician in charge of the case, using knowledge of the drugs, the properties of the drugs in combination as detemlined in clinical trials, and the characteristics of the patient, including diseases other than that for which the physician is treating the patient.

[0163] Non-limiting daily dosage amounts for several atypical antipsychotics are provided herein: Aripiprazole, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, up to about 30 mg/day or about 10-15 mg/day; Asenapine, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some

embodiments, about 10 mg/day;

Clozapine, about 0.1-1000 mg/day, about 1-900 mg/day, about 5-900 mg/day, about 10-900 mg/day, about 100-900 mg/day, about 100-800 mg/day or about 100- 750 mg/day, and in some embodiments, about 150-450 mg/day or about 300-450 mg/day;

Iloperidone, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, about 12-24 mg/day;

Olanzapine, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, about 10-15 mg/day;

Lurasidone, about 0.1-500 mg/day, about 1-500 mg/day, about 1-250 mg/day, about 10-250 mg/day, about 10-100 mg/day, or about 20-100 mg/day, and in some embodiments, about 40-80 mg/day;

Paliperidone, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, about 6 mg/day; Quetiapine, about 0.1-1000 mg/day, about 1-900 mg/day, about 1-800 mg/day, about 50-800, about 100-800, or about 200-800 mg/day, and in some

embodiments, about 150-750 mg/day, about 300 mg/day or about 400-800 mg/day;

Risperidone, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in some embodiments, about 4-8 mg/day or 1-6 mg/day; Ziprasidone, about 0.1-250 mg/day, about 1-150 mg/day, about 1-100 mg/day, about 20-100, or about 20-80 mg/day, and in some embodiments, up to about 40 mg/day, or up to about 80 mg/day or about 40-80 mg/day.

[0164] For repeated administrations over several days or weeks or longer, depending on the condition, the treatment is sustained until a sufficient level of cognitive function is achieved.

[0165] The antipsychotic or a salt, hydrate, solvate or polymorph thereof may be administered at dosage levels distinct from conventional levels (e.g., at subtherapeutic doses) when provided in combination with a5 -containing GABAA receptor agonist, due to a a5-containing GABAA receptor agonist-dependent increase in the antipsychotic's therapeutic index. In some embodiments, the increase in the antipsychotic's therapeutic index due to the combination with a5 -containing GABAA receptor agonist is greater than the therapeutic index of the antipsychotic administered in the absence of a a5-containing GABAA receptor agonist by at least about 1.5x or 2. Ox or 2.5x or 3. Ox or 3.5x or 4. Ox or 4.5x or 5. Ox or 5.5x or 6. Ox or 6.5x or 7. Ox or 7.5x or 8. Ox or 8.5x or 9. Ox or 9.5x or lOx, or greater than about lOx. In some embodiments, combination of an antipsychotic with the a5 -containing GABAA receptor agonist reduces the dosage of the antipsychotic required for its therapeutic effect. In some embodiments, the antipsychotic is an atypical antipsychotic. When used in combination with a5- containing GABAA receptor agonist, such atypical antipsychotic is administered at a dose lower than required for its therapeutic effect when administered in the absence of a5 -containing GABAA receptor agonist.

[0166] The frequency of administration of the composition of this invention may be adjusted over the course of the treatment, based on the judgment of the administering physician. It will be clear that the a5 -containing GABAA receptor agonist and the antipsychotic and their salts, hydrates, solvates and polymorphs can be administered at different dosing frequencies or intervals. For example, a5-containing GABAA receptor agonist can be administered daily (including multiple doses per day) or less frequently. An antipsychotic can be administered daily (including multiple doses per day) or less frequently. In some embodiments, sustained continuous release formulations of a a5- containing GABAA receptor agonist and an antipsychotic may be desired. Various formulations and devices for achieving sustained release are known in the art.

[0167] In certain embodiments of the invention, the combined administration of a5- containing GABAA receptor agonist or a salt, hydrate, solvate and polymorph thereof and an antipsychotic or a salt, hydrate, solvate and polymorph thereof can attain a longer or improved therapeutic effect in the subject than that attained by administering only the a5-containing GABAA receptor agonist or only the antipsychotic, by at least about 1.5x, or 2. Ox, or 2.5x, or 3. Ox, or 3.5x, or 4. Ox, or 4.5x, or 5. Ox, or 5.5x, or 6. Ox, or 6.5x, or 7. Ox, or 7.5x, or 8. Ox, or 8.5x, or 9. Ox, or 9.5x, or lOx, or greater than about lOx.

Compositions of this Invention

[0168] In one aspect, the invention provides compositions comprising a a5- containing GABAA receptor agonist and at least one antipsychotic and their salts, hydrates, solvates and polymorphs. In some embodiments, the a5-containing GABAA receptor agonist and the antipsychotic may be present in a single dosage unit (e.g., combined together in one capsule, tablet, powder, or liquid, etc.).

[0169] The a5 -containing GABAA receptor agonist and the antipsychotic suitable for the compositions of this invention may be selected from any of those as described above. In some embodiments, the a5-containing GABAA receptor agonist is selected from any of the compounds of Formulas I, I- A, I-B, I-C and I-D, as described above, and in U.S. Patent Application 61/413,971 and PCT publication WO2012068161, including, for example, compounds of any of the embodiments of Formulas I, I- A, I-B, I-C and I-D and the specific compounds described herein and in U.S. Patent

Application 61/413,971 and PCT publication WO2012068161; and the antipsychotic is selected from (1) atypical and typical antipsychotics (such as those described above);

(2) agents that are dopaminergic agents (such as dopamine Dl receptor antagonists or agonists, dopamine D ₂ receptor antagonists or partial agonists, dopamine D3 receptor antagonists or partial agonists, dopamine D4 receptor antagonists), glutamatergic agents, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs), Ml muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents (such as alpha-2 adrenergic receptor agonists or antagonists and COMT inhibitors), serotonin receptor modulators (such as 5-HT ₂ A receptor antagonists, 5-HT _I A receptor partial agonists, 5-HT ₂ c agonists, and 5-HT6 antagonists), cholinergic agents (such as alpha-7 nicotinic receptor agonists, alpha4- beta2 nicotinic receptor agonists, allosteric modulators of nicotinic receptors and acetylcholinesterase inhibitors, muscarinic receptor agonists and antagonists), cannabinoid CBl antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors, nNOS inhibits, neurosteroids, and neurotrophic factors, including, e.g., those specific such agents described above, and (3) any compounds that are useful in treating one or more sign or symptoms of schizophrenia or bipolar disorder (in particular, mania) (including, e.g., the agents disclosed in any of the above- listed patents or patent application publications), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof. In some the above

embodiments, the antipsychotic for the methods of this invention is an atyptical antipsychotic selected from, e.g., aripiprazole, olanzapine and ziprasidone, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs or prodrugs thereof

[0170] The composition described herein can contain more than one a5 -containing GABAA receptor agonist and/or more than one antipsychotic. In some embodiments, the a5 -containing GABAA receptor agonist and the antipsychotic are in a single dosage form, in a unit dosage form, in separate dosage forms, or in separate dosage forms packaged together.

[0171] The compositions described herein can further contain pharmaceutically acceptable excipient(s) and may contain other agents that serve to enhance and/or complement the effectiveness of the a5-containing GABAA receptor agonist and/or the antipsychotic. The compositions may also contain additional agents known to be useful for treating cognitive function disorder.

[0172] The composition in the present invention may be in solid dosage forms such as capsules, tablets, dragrees, pills, lozenges, powders and granule. Where appropriate, they may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled releases of one or more active ingredient such as sustained or prolonged release according to methods well known in the art. In certain

embodiments, the composition is in form of a slow, controlled, or extended release. The term "extended release" is widely recognized in the art of pharmaceutical sciences and is used herein to refer to a controlled release of an active compound or agent from a dosage form to an environment over (throughout or during) an extended period of time, e.g. greater than or equal to one hour. An extended release dosage form will release drug at substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrementally over an extended period of time. The term "extended release" used herein includes the terms "controlled release", "prolonged release", "sustained release", or "slow release", as these terms are used in the pharmaceutical sciences. In some embodiments, the extended release dosage is administered in the form of a patch or a pump. The composition may also be in liquid dosage forms including solutions, emulsions, suspensions, syrups, and elixirs.

[0173] The compositions may be specifically formulated for administration by any suitable route as described herein and known in the art. Compositions for parental administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Compositions for intraoral and oral delivery (including sublingual and buccal administration, e.g. Danckwerts et al, and oral) include but are not limited to bioadhesive polymers, tablets, patches, liquids and semisolids (see e.g., Smart et al). Compositions for respiratory delivery (pulmonary and nasal delivery) include but are not limited to a variety of pressurized metered dose inhalers, dry powder inhalers, nebulizers, aqueous mist inhalers, drops, solutions, suspensions, sprays, powders, gels, ointments, and specialized systems such as liposomes and microspheres (see e.g. Owens et al, "Alternative Routes of Insulin Delivery" and Martini et al). Compositions for transdermal delivery include but are not limited to colloids, patches, and microemulsions. Other suitable administration forms for the above and other include depot injectable formulations, suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc. [0174] The compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[0175] Therapeutic formulations can be prepared by methods well known in the art of pharmacy, see, e.g., Goodman et al, 2001; Ansel, et al, 2004; Stoklosa et al, 2001; and Bustamante, et al., 1993.

[0176] It will be understood by one of ordinary skill in the art that the

compositions and methods described herein may be adapted and modified as is appropriate for the application being addressed and that the compositions and methods described herein may be employed in other suitable applications, and that such other additions and modifications will not depart from the scope hereof.

[0177] This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the embodiments which follow thereafter.

Examples

Example 1: Synthesis of compound 1

[0178] Compound 1 was prepared according to synthetic Scheme 1. The

syntheses of the intermediates and the final product are detailed as follows. (A) 3-oxo-5-phenyl-2, 3-dihydropyridazine-4-carbonitrile:

[0179] To a solution of phenyl glyoxal (1 g, 7.46 mmol) in ethanol (50 mL), cyanoacetohydrazide (738 mg, 7.46 mmol) was added under nitrogen atmosphere and stirred at room temperature ("rt") for 24 h. After complete consumption of starting materials (by TLC), the reaction mixture was filtered and washed with EtOAc (25 mL X 3). The solvent was evaporated under reduced pressure to obtain crude product as a brown solid which was taken forward for next step without further purification.

[0180] Sodium metal (342 mg, 14.86 mmol) was added to absolute ethanol (100 mL) at 0 °C under argon atmosphere. After complete consumption of sodium metal, a solution of product from the previous step (37.28 mmol) in ethanol (100 mL) was added drop wise to the alkoxide solution at 0 °C and then refluxed for 4 h.

The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was dissolved in 25 mL of water and pH was adjusted to 5 using 6N HC1 (25 mL). The precipitated solid was isolated by filtration. The crude product was purified by column chromatography (100-200 mesh silica gel, 5%

MeOH in CH ₂ CI ₂ ) to furnish 3-oxo-5-phenyl-2, 3-dihydropyridazine-4-carbonitrile

(380 mg, 26%) as an ash color solid.

TLC system: 50% EtOAc-hexane

Rf-value: 0.6

Visualization: UV

Mass (M-H) ⁺ : 196

1H-NMR (δ, DMSO-de, 400 MHz): 7.6 (m, 3H), 7.75 (m, 2H), 8.25 (s, 1H), 13.9 (bs, 1H).

(B) Methyl 3-oxo-5-phenyl-2, 3-dihydropyridazine-4-carboxylate:

[0181] The solution of 3-oxo-5-phenyl-2, 3-dihydropyridazine-4-carbonitrile (4.5 g, 22.84 mmol) in 60% aqueous H ₂ S0 ₄ (45 mL) was heated to 150 °C for 24 h. After the completion of the starting material, the reaction mixture was cooled to rt, quenched with ice cold water and extracted with CH ₂ C1 ₂ (250 mL x 5), washed with brine (50 mL x 1) and dried over anhydrous Na ₂ S0 ₄ . The combined organic extracts were evaporated under reduced pressure to furnish 3-oxo-5-phenyl-2,3- dihydropyridazine-4-carboxylic acid (2.5 g, 48%) as a pale yellow solid.

TLC system: 10 % MeOH- CH ₂ C1 ₂

Rf- value: 0.2

Visualization: UV

Mass (M+H) ⁺ : 217

[0182] A solution of 3-oxo-5-phenyl-2,3-dihydropyridazine-4-carboxylic acid (500 mg, 2.31 mmol) in methanol (25 mL) at 0 °C, thionyl chloride (5 mL, 40 mmol) was added drop wise and refluxed for 12 h at 80 °C. After completion of starting material, the volatiles were removed under reduced pressure to obtain crude product which was extracted with ethyl acetate (100 mL x 3), washed with brine (50 mL) and dried over anhydrous Na ₂ S0 ₄ to furnish 3-oxo-5-phenyl-2, 3- dihydropyridazine-4-carboxylate (450 mg) as a light yellow solid which was carried to the next step without further purification.

TLC system: 5 % MeOH-DCM

Rf-value: 0.7

Visualization: UV

Mass (M+H) ⁺ : 231

(C) Methyl 3-chloro-5-phenylpyridazine-4-carboxylate:

[0183] A solution of 3-oxo-5-phenyl-2, 3-dihydropyridazine-4-carboxylate (450 mg, 1.95 mmol) in POCl ₃ (5 mL, 60 mmol) was heated to 100 °C for 3 h. After the completion of starting material, the volatiles were removed under reduced pressure. The reaction mixture was quenched with ice cold water (10 mL), extracted with ethyl acetate (50 mL x 3), washed with water (10 mL x 1), NaHC0 ₃ (15 mL x 1), brine solution (25 mL x 1) and dried over anhydrous Na ₂ S0 ₄ . The combined organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, 15 % EtOAc in hexane) to furnish methyl 3-chloro-5-phenylpyridazine-4- carboxylate (300 mg, 62%) as a pale yellow solid.

TLC system: 30 % EtOAc-Hexane

Rf-value: 0.8

Visualization: UV

Mass (M+H) ⁺ : 249

1H-NMR (δ, CDC1 ₃ , 400 MHz): 3.82, (s, 3H), 7.45 (m, 2H), 7.55 (m, 3H), 9.25 (s, 1H).

(D) Methyl 3, 5-diphenylpyridazine-4-carboxylate:

[0184] A solution of methyl 3-chloro-5-phenylpyridazine-4-carboxylate (300 mg,

1.20 mmol) in 1,4-dioxane (15 mL), distilled water (5 mL), sodium carbonate (256 mg, 2.41 mmol) and phenyl boronic acid (1.91 g, 1.57 mmol) were added and the reaction mixture was degassed for 10 min, followed by addition of tetrakis (triphenylphosphine) palladium (139 mg, 0.12 mmol) and refluxed at 100 °C for 12 h under argon atmosphere. After the completion of starting materials, the reaction mixture was cooled to rt and filtered through a celite pad to remove the solid impurities. The filtrate was diluted with ethyl acetate (40 mL), washed with aq

NaHCC"3 (5 mL x 1), brine solution (5 mL x 1) and dried over anhydrous Na ₂ S0 ₄ .

The organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, 5 % EtOAc in hexane) to furnish methyl 3, 5-diphenylpyridazine-4-carboxylate (300 mg, 82 %) as a white solid.

TLC system: 30 % EtOAc-Hexane

Rf-value: 0.5

Visualization: UV

Mass (M+H) ⁺ : 291

HPLC: 93.7%

1H-NMR (δ, CDC1 ₃ , 400 MHz): 3.58, (s, 3H), 7.4-7.6 (m, 8H), 7.7 (m, 2H), 9.28 (s, 1H). (E) Methyl 3, 5-diphenylpyridazine-4-carboxylic acid (compound 6):

[0185] To a solution of methyl 3, 5-diphenylpyridazine-4-carboxylate (300 mg, 1.03 mmol) in 1 : 1 MeOH: H ₂ 0 (10 mL), KOH (576 mg, 10.28 mmol) was added and refluxed at 100 °C for 12 h. After the completion of starting material, the reaction mixture was diluted with water (5 mL x 1) and washed with ethyl acetate (5 mL x 1). The aqueous layer was acidified with 6N HC1 (5 mL) solution, solid precipitated out. The solid was filtered and dried to furnish methyl 3, 5- diphenylpyridazine-4-carboxylic acid (compound 6) (275 mg, 96%) as a white solid.

TLC system: 5% MeOH-DCM

Rf-value: 0.2

Visualization: UV

Mass (M+H) ⁺ : 277.2

HPLC: 98.09% (F) TV-methyl- 3, 5-diphenylpyridazine-4-carboxamide (compound 1):

[0186] To a solution of methyl 3, 5-diphenylpyridazine-4-carboxylic acid (compound 6) (200 mg, 0.72 mmol) in CH ₂ C1 ₂ (10 mL), oxalyl chloride (230 mg, 1.81 mmol), catalytical DMF were added and stirred at 0 °C for 1 h. After the complete consumption of the acid shown by TLC, the volatiles were removed under reduced pressure and the crude acid chloride obtained was taken up in dry CH ₂ C1 ₂ (5 mL). A solution of methyl amino hydrochloride (238 mg, 3.62 mmol) in CH ₂ C1 ₂ (5 mL) cooled to 0 °C, triethylamine (219 mg, 2.17 mmol) and acid chloride were added dropwise at 5 °C. After the completion of the starting material, the reaction mixture was diluted with CH ₂ CI ₂ (20 mL), washed with aq NaHC0 ₃ (5 mL x 1), brine (5 mL x 1) and dried over anhydrous Na ₂ S0 ₄ . The combined organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, 30 % EtOAc in hexane) to furnish N-methyl- 3, 5-diphenylpyridazine-4- carboxamide (compound 1) (100 mg, 47 %) as a light orange solid.

TLC system: 10 % EtOAc-hexane,

Rf-value: 0.6,

Visualization: UV

1H NMR (δ, CDC1 ₃ , 400 MHz): 9.24 (s, 1H), 7.83-7.80 (m, 2H), 7.56-7.49 (m, 7H), 5.43 (brs, 1H), 2.62 (d, J= 4.4 Hz, 3H), 2.17 (s, 1H).

Mass spec. Mass calculated for Ci ₈ Hi ₅ N ₃ 0: 289.12; Mass found 290.2 [M+H] ⁺ HPLC Purity Eluent a) 0.05% TFA in H ₂ 0 b) ACN (Gradient), ZORBAX Eclipse XDB C-18 150*4.6 mm, 5μ; Flow 1.0 mL/min: 97.24% (250 nm); RT = 5.33 min LCMS Purity Symmetry C-18 75*4.6 mm, 3.5μ; 97.95% (250 nm); RT = 4.19 min; Mass found 290.2 [M+H] ⁺

[0187] A variety of other compounds of Formula I- A have been prepared by methods substantially similar to those described in Example 1. The

characterization data for these compounds is summarized in Table 1 below.

Table 1: Characterization Data for Selected Compounds of Formula I-A

Example 2: Synthesis of compounds 25 and 26

[0188] Compounds 25 and 26 were prepared according to synthetic Scheme 5. The syntheses of the intermediates and the final products are detailed as follows. (A) Methyl 2-(3, 5-diphenylpyridazine-4-carboxamido)-3-hydroxypropanoate [0189] The solution of compound 6 (50 mg, 1.81 mmol) in DMF (0.5 mL), DIPEA (93 mg, 0.72 mmol), HATU (138 mg, 0.36 mmol) were sequentially added and stirred for 10 min at rt. Then methyl 2-amino-3-hydroxypropanoate (84 mg, 0.54 mmol) was added and stirred overnight at rt. Reaction was quenched by addition of ice cold water. The precipitated solid was filtered, washed with hexane, dried over anhydrous Na ₂ S0 ₄ and azeotroped with toluene to furnish methyl 2-(3, 5-diphenylpyridazine-4-carboxamido)-3-hydroxypropanoate (20 mg, 29%) as an off white solid.

TLC system: 50% EtOAc-Hexane

Rf- value: 0.2

Visualization: UV

1H NMR (δ, DMSO-D ₆ , 400 MHz): 9.33 (s, 1H), 9.18 (d, J = 8.4 Hz, 1H) 7.75- 7.73 (m, 2H), 7.63-7.61 (m, 2H), 7.51-7.48 (m, 6H), 4.90 (t, J= 5.6 Hz, 1H), 4.31- 4.26 (m, 1H), 3.52 (s, 3H), 3.41-3.35 (m, 1H), 3.18-3.14 (m, 1H)

Mass spec. Mass calculated for C ₂ iHi ₉ N ₃ 0 ₄ : 377.14; Mass found 378.0 [M+H] ⁺

(B) Methyl 2-(3,5-diphenylpyridazin-4-yl)-4,5-dihydrooxazole-4-carboxyl ate (compound 25):

[0190] To a solution of methyl 2-(3,5-diphenylpyridazine-4-carboxamido)-3- hydroxypropanoate (220 mg, 0.58 mmol) in DCM (15 mL), (diethylamino)sulfur trifluoride (188 mg, 1.16 mmol) was added at -76 °C and stirred at -76 °C for 2 h. Potassium carbonate (400 mg, 2.8 mmol) was added to the reaction mixture at -78 °C and the resulting reaction mixture was warmed to rt. Reaction was quenched by addition of saturated Na ₂ C0 ₃ , extracted with DCM (2 x 25 mL), washed with brine (1 x 10 mL) and dried over anhy. Na ₂ S0 ₄ . Evaporation of the solvent under reduced pressure gave crude product methyl 2-(3, 5-diphenylpyridazin-4-yl)-4, 5- dihydrooxazole-4-carboxylate (compound 25) (130 mg, 61 >) as an off white solid. TLC system: 60%> EtOAc-Hexane, Rf-value: 0.6, Visualization: UV

1H NMR (δ, DMSO-i 6, 400 MHz): 9.47 (s, 1H), 7.66-7.65 (m, 2H), 7.55-7.53 (m, 8H), 4.73 (t, J= 7.6 Hz, 1H), 4.35-4.30 (m, 2H), 3.57 (s, 3H)

Mass spec. Mass calculated for C ₂ iHi ₇ N ₃ 0 ₃ : 359.13; Mass found 359.9 [M+H] ⁺ HPLC Purity Eluent a) 0.05% HCOOH in H ₂ 0 b) ACN (Gradient), ZORBAX XDB C-18 150*4.6 mm, 5μ; Flow 0.8 mL/min: 98.73% (249 nm); RT = 4.49 min LCMS Purity ZORBAX XDB C-18 150*4.6 mm, 5μ; 98.69% (250 nm); RT = 4.5 min; Mass found 359.9 [M+H] ⁺

(C) Methyl 2-(3,5-diphenylpyridazin-4-yl)oxazole-4-carboxylate (compound 26):

[0191] To a solution of methyl 2-(3-(3-methoxyphenyl)-5-phenylpyridazin-4-yl)- 4,5-dihydrooxazole-4-carboxylate (compound 25) (60 mg, 0.16 mmol) in DCM (3 mL), DBU (76 mg, 0.5 mmol), bromotrichloromethane (83 mg, 0.41 mmol) was added at 0 °C, stirred for 3 h and then warmed to rt. Reaction was quenched by addition of sat. sodium bicarbonate solution, extracted with DCM (2 x 25 mL), washed with brine (1 x 5 mL) and dried over anhydrous Na ₂ S0 ₄ . Evaporation of solvent under reduced pressure gave the crude product that was purified by column chromatography (100-200 mesh silica gel, 35% EtOAc-Hexane) to furnish methyl 2-(3-(3-methoxyphenyl)-5-phenylpyridazin-4-yl) oxazole-4-carboxylate (compound 26) (35 mg, 59%>) as an off white solid.

TLC system: 50% EtOAc-Hexane, Rf-value: 0.5, Visualization: UV

1H NMR (δ, DMSO-d6, 400 MHz): 9.37 (s, 1H), 8.10 (s, 1H), 7.48-7.46 (m, 2H), 7.41-7.37 (m, 6H), 7.28-7.26 (m, 2H), 3.85 (s, 3H)

Mass spec. Mass calculated for C ₂ iHi ₅ N ₃ 0 ₃ : 357.11; Mass found 357.9 [M+H] ⁺ HPLC Purity Eluent a) 0.05% HCOOH in H ₂ 0 b) ACN (Gradient), ZORBAX XDB C-18 150*4.6 mm, 5μ; Flow 0.8 mL/min: 98.36% (253 nm); RT = 5.47 min LCMS Purity ZORBAX XDB C-18 150*4.6 mm, 5μ; 98.69% (250 nm); RT = 4.5 min; Mass found 359.9 [M+H] ⁺

[0192] A variety of other compounds of Formula I-B and Formula I-D have been prepared by methods substantially similar to those described in Example 2. The characterization data for these compounds is summarized in Table 2 below. Table 2: Characterization Data for Selected Compounds of Formula I-B and Formula I-D

Example 3: Synthesis of compound 21

[0193] Compound 21 was prepared according to synthetic Scheme 6. The syntheses of the intermediates and the final product are detailed as follows.

(A) N-(l-hydroxypropan-2-yl)-3,5-diphenylpyridazine-4-carboxamid e

[0194] To a solution of methyl 3, 5-diphenylpyrridazine-4-carboxylic acid (compound 6) (250 mg, 0.90 mmol) in DMF (3 mL), DIPEA (0.47 mL, 2.71 mmol), HATU (516 mg, 1.35 mmol) were sequentially added and stirred at rt. After 15 min. 2-amino-l-propanol (203 mg, 2.71 mmol) was added and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). Combined organic extract was washed with water (2 x 10 mL), brine (1 x 10 mL) and dried over anhydrous Na ₂ S0 ₄ and evaporated under reduced pressure to obtain the crude product N-(l -hydroxy propan-2-yl)-3, 5-diphenylpyridazine-4-carboxamide (160 mg) as an off white solid.

TLC system: 80% EtOAC-Hexane, Rf-value: 0.5, Visualization: UV

(B) 2-(3,5-diphenylpyridazin-4-yl)-4-methyl-4,5-dihydrooxazole (compound 21):

[0195] To a solution of N-(l -hydroxy propan-2-yl)-3, 5-diphenylpyridazine-4- carboxamide (150 mg, 0.45 mmol) in DCM (8 mL), DAST (145 mg, 0.90 mmol) was added at -78 °C and stirred for 2 h. After completion of starting materials, solid K ₂ C0 ₃ (248 mg, 1.80 mmol) was added to the reaction mixture at -78 °C and stirred at rt for 4 h. The reaction mixture was diluted with DCM (20 mL), washed with water (2 x 8 mL), saturated NaHC0 ₃ (1 x 5 mL), water (1 x 5 mL), brine (1 x 2 mL) and dried over anhy.Na ₂ S0 ₄ . Evaporation of the solvent under reduced pressure gave the crude product which was purified by column chromatography (100-200 mesh silica gel, 35% EtOAc-Hexane) to furnish 2-(3, 5- diphenylpyridazin-4-yl)-4-methyldihydrooxazole (compound 21) (90 mg, 63%>) as pale yellow solid.

TLC system: 60% EtOAc-Hexane

Rf-value: 0.5

Visualization: UV

LNB No: COS-10-A004-170 1H NMR (CDC1 ₃ , 400 MHz): δ 9.27 (s, 1H), 7.78-7.76 (m, 2H), 7.54-7.47 (m, 8H), 4.19 (t, J= 9.2 Hz, 1H), 4.09-4.08 (m, 1H), 3.65 (t, J= 7.2 Hz, 1H), 1.02 (d, J = 6.4 Hz, 3H)

Mass spec. Mass calculated for C20H17N3O: 315.14; Mass found 315.9 [M+H] ⁺ HPLC Purity Eluent a) 0.1 % HCOOH in H ₂ 0 b) ACN (Gradient), ZORBAX

XDB C-18 150*4.6 mm, 5μ; Flow 0.8 mL/min: 98.41% (250 nm); RT = 5.03 min LCMS Purity Eluent a) 0.1% HCOOH in H ₂ 0 b) ACN (Gradient), ZORBAX XDB C-18 150*4.6 mm, 5μ; Flow 0.8 mL/min: 97.31% (250 nm); RT = 5.01 min; Mass found 316.0 [M+H] ⁺ Example 4: Synthesis of compound 20

[0196] Compound 20 was prepared according to synthetic Scheme 7. The syntheses of the intermediates and the final product are detailed as follows.

(A) (2-(3, 5-diphenylpyridazin-4-yl) oxazol-4-yl) methanol:

[0197] To a solution of compound 26 (20 mg, 0.056 mmol) in THF (3 mL), LAH (5.0 mg, 0.14 mmol) was added at -30 °C and stirred for lh. The reaction mixture was quenched with saturated ammonium chloride solution at -30 °C. The reaction mixture was slowly warmed to rt and filtered through celite bed, washed with ethyl acetate. The organic layer was washed with brine, dried over anhy. Na ₂ S0 ₄ and concentrated under reduced pressure to obtain the crude product gave (2-(3, 5-diphenylpyridazin-4-yl) oxazol-4-yl) methanol (16 mg, 88%) as an yellow solid.

TLC system: 50% EtOAc-Hexane, Rf-value: 0.2, Visualization: UV

(B) 4-(bromomethyl)-2-(3, 5-diphenylpyridazin-4-yl) oxazole:

[0198] To a solution of (2-(3, 5-diphenylpyridazin-4-yl) oxazol-4-yl) methanol

(220 mg, 0.66 mmol) in DCM (8 mL), PBr ₃ (91 mg, 0.33 mmol) was added at 0 °C and the reaction mixture was warmed to rt and stirred for 12 h. After completion of starting material, reaction was quenched with saturated NaHC0 ₃ solution, extracted with ethyl acetate (2 x 25 mL), washed with brine (1 x 10 mL). Solvent was removed under reduced pressure to obtain the crude product 4-(bromomethyl)-

2-(3, 5-diphenylpyridazin-4-yl) oxazole (250 mg) which was carried to next step without further purification. TLC system: 50% EtOAc-Hexane, Rf-value: 0.6, Visualization: UV

(C) 2-(3,5-diphenylpyridazin-4-yl)-4-methyloxazole (compound 20):

[0199] To a solution of 4-(bromomethyl)-2-(3, 5-diphenylpyridazin-4-yl) oxazole (250 mg, 0.64 mmol) in methanol (8 mL), Pd/C (80 mg, wt/wt) was added and the resulting reaction mixture was stirred under hydrogen atmosphere for 1.5 h. The reaction mixture was filtered through a celite bed, washed with methanol and concentrated under reduced pressure to obtain the crude product which was purified by preparative TLC to furnish 2-(3, 5-diphenylpyridazin-4-yl)-4- methyloxazole (compound 20) (13.6 mg, 6.8%) as pale yellow gummy liquid. TLC system: 50% EtOAc-Hexane, Rf-value: 0.5, Visualization: UV

1H NMR (δ, CDC1 ₃ , 400 MHz): 9.33 (s, 1H), 7.47-7.37 (m, 9H), 7.26 (s, 2H), 2.05 (s, 3H).

Mass spec. Mass calculated for C ₂ oHi ₅ N ₃ 0: 313.12; Mass found 313.5 [M] ⁺

LCMS Purity at ZORBAX XDB C-18 150*4.6 mm, 5μ; 93.61% (250 nm); RT = 6.17 min; Mass found 314.0 [M+H] ⁺

[0200] Also prepared in similar fashion was compound 24:

TLC system: 40% EtOAc-Hexane, Rf-value: 0.4, Visualization: UV

1H NMR (δ, CDC1 ₃ , 400 MHz): 9.33 (s, 1H), 7.27-7.24 (m, 4H), 7.09 (s, 1H), 6.99-6.96 (m, 2H), 3.78 (m, 3H), 2.06 (s, 3H)

Mass spec. Mass calculated for C ₂ iHi ₇ N ₃ 0 ₂ : 343.13; Mass found 343.5 [M] ⁺

HPLC Purity Eluent a) 0.1% HCOOH in H ₂ 0 b) ACN (Gradient), ZORBAX XDB C-18 150*4.6 mm, 5μ; Flow 0.8 mL/min: 92.16% (260 nm); RT = 6.26 min Example 5: Synthesis of compound 22

[0201] Compound 22 was prepared according to synthetic Scheme 8. The syntheses of the intermediates and the final product are detailed as follows.

(A) l-(2-(3, 5-diphenylpyridazin-4-yl) oxazol-4-yl)ethanone

[0202] To a solution of compound 26 (50 mg, 0.14 mmol) in THF (4 mL), MeMgBr (0.7 mL, 0.70 mmol) was added at -40 °C and the reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate (25 mL), washed with brine (1 x 10 mL) and dried over Na ₂ S0 ₄ . Evaporation of the solvent under reduced pressure gave the crude product which was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-hexane) to furnish l-(2-(3, 5-diphenylpyridazin-4-yl) oxazol-4-yl)ethanone (20 mg, 42% ) as an off white solid.

TLC system: 50% EtOAc-Hexane, Rf-value: 0.2, Visualization: UV

1H NMR (δ, CDC1 ₃ , 400 MHz): 9.38 (s, 1H), 8.03 (s, 1H), 7.48-7.38 (m, 8H),

7.29-7.26 (m, 2H), 2.34 (s, 3H).

Mass spec. Mass calculated for C ₂ iHi ₅ N ₃ 0 ₂ : 341.12; Mass found 341.5 [M] ⁺

(B) l-(2-(3, 5-diphenylpyridazin-4-yl) oxazol-4-yl) ethanol

[0203] To a solution of l-(2-(3, 5-diphenylpyridazin-4-yl) oxazol-4-yl)ethanone (30 mg, 0.088 mmol) in methanol (4 mL), NaBH ₄ (8.4 mg, 0.176 mmol) was added at 0 °C and the reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was quenched in ice cold water, extracted with ethyl acetate (25 mL). The organic layer was washed with brine(l x 5 mL), dried over Na ₂ S0 ₄ and concentrated under reduced pressure to obtain the crude product which was carried further without any purification gave l-(2-(3, 5-diphenylpyridazin-4-yl) oxazol-4- yl) ethanol (30 mg)

TLC system: 50% EtOAc-Hexane, Rf-value: 0.2, Visualization: UV

Mass spec. Mass calculated for C ₂ iHi ₇ N ₃ 0 ₂ : 343.13; Mass found 343.5 [M] ⁺

(C) 2-(3, 5-diphenylpyridazin-4-yl)-4-vinyloxazole

[0204] To a solution of l-(2-(3, 5-diphenylpyridazin-4-yl) oxazol-4-yl) ethanol (30 mg, 0.08 mmol) in toluene (4 mL), p-tolenesulfonic acid (10 mg) was added and the reaction mixture was refluxed for 2 h. After complete consumption of starting materials, reaction was quenched by solid K ₂ C0 ₃ . Solvents were evaporated under reduced pressure to obtain the crude product that was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-Hexane) to furnish 2-(3, 5-diphenylpyridazin-4-yl)-4-vinyloxazole (25 mg, 89%>) as a gummy liquid.

TLC system: 50%> EtOAc-Hexane, Rf-value: 0.6, Visualization: UV

Mass spec. Mass calculated for C ₂ iHi ₅ N ₃ 0: 325.12; Mass found 325.4 [M] ⁺ (D) 2-(3,5-diphenylpyridazin-4-yl)-4-ethyloxazole (compound 22)

[0205] To a solution of 2-(3, 5-diphenylpyridazin-4-yl)-4-vinyloxazole (25 mg, 0.07 mmol) in methanol (4 mL), 10% Pd/C (20 mg, wt/wt) was added and the reaction mixture was stirred under hydrogen atmosphere for 2 h. The reaction mixture was filtered through a celite bed and washed with methanol. Solvent was evaporated under reduced pressure to obtain the crude product that was purified by column chromatography (100-200 mesh silica gel 25% EtOAc-Hexane) to furnish 2-(3, 5-diphenylpyridazin-4-yl)-4-ethyloxazole (compound 22) (5.7 mg, 22%>) as a pale yellow gummy liquid.

TLC system: 50% EtOAc-Hexane, Rf-value: 0.6, Visualization: UV

LCMS Purity at XBridge C-18 150*4.6 mm, 5μ: 82.73% (258 nm); RT = 5.96 min; Mass found 327.5 [M] ⁺

Example 5: Synthesis of compound 23 [0206] Compound 23 was prepared according to synthetic Scheme 9. The syntheses of the intermediates and the final product are detailed as follows.

(A) 2-(2-(3,5-diphenylpyridazin-4-yl)oxazol-4-yl)propan-2-ol

[0207] The solution of compound 26 (50 mg, 0.14 mmol) in THF (4 mL),

MeMgBr (0.7 mL, 0.7 mmol) was added at -40°C. The reaction mixture was warmed to rt and stirred for 1 hr. Saturated ammonium chloride solution was added, extracted with ethyl acetate (2 x 25 mL), washed with brine (1 x 5 mL), dried over anhydrous Na ₂ S0 ₄ and evaporation of solvent under reduced pressure gave the crude product which was purified by column chromatography (100-200 mesh silica gel, 20%EtOAc-Hexane) to furnish 2-(2-(3,5-diphenylpyridazin-4- yl)oxazol-4-yl)propan-2-ol (25 mg, 50%>) as an off white solid.

TLC system: 50% EtOAc-Hexane, Rf-value: 0.2, Visualization: UV

1H NMR (CDC1 ₃ , 400 MHz): δ 9.35 (s, 3H), 7.44-7.40 (m, 2H), 7.40-7.37 (m,

6H), 7.26-7.25 (m, 2H), 1.36 (s, 6H)

Mass spec. Mass calculated for C ₂₂ Hi ₉ N ₃ 0 ₂ : 357.15; Mass found 357.5 [M] ⁺ (B) 2-(3,5-diphenylpyridazin-4-yl)-4-(prop-l-en-2-yl)oxazole:

[0208] To a solution of 2-(2-(3, 5-diphenylpyridazin-4-yl) oxazol-4-yl) propan-2- ol (80 mg, 0.22 mmol) in toluene (4 mL), p-toluenesulfonic acid (20 mg) was added and the reaction mixture was refluxed for 2 h. After completion of starting material, reaction was quenched with solid K ₂ CO ₃ . Solvent was removed under reduced pressure to obtain the crude product that was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-Hexane) to furnish 2-(3, 5- diphenylpyridazin-4-yl)-4-vinyloxazole (70 mg, 92%) as a gummy liquid.

TLC system: 70% EtOAc-Hexane, Rf-value: 0.8, Visualization: UV

Mass spec. Mass calculated for C ₂₂ H ₁₇ N ₃ O: 339.14; Mass found 339.5 [M] ⁺

(C) 2-(3,5-diphenylpyridazin-4-yl)-4-isopropyloxazole (compound 23)

[0209] To a solution of 2-(3, 5-diphenylpyridazin-4-yl)-4-vinyloxazole (70 mg, 0.20 mmol) in methanol (5 mL), 10%> Pd/C (35 mg, wt/wt) was added and the resulting reaction mixture was stirred at rt under hydrogen atmosphere for 2 h. The reaction mixture was filtered through celite bed, washed with methanol and evaporation of solvent under reduced pressure gave the crude product which was purified by column chromatography to furnish 2-(3,5-diphenylpyridazin-4-yl)-4- isopropyloxazole (compound 23) (25 mg, 95%>) as pale yellow gummy liquid. TLC system: 50% EtOAc-Hexane

Rf-value: 0.6

Visualization: UV

1H NMR (δ, CDC1 ₃ , 400 MHz): 9.31 (s, 1H), 7.45-7.35 (m, 9H), 7.26-7.20 (m, 2H), 2.74-2.70 (m, 1H), 1.06 (d, J= 6.8 Hz, 6H)

Mass spec. Mass calculated for C22H19N3O: 341.15; Mass found 341.5 [M] ⁺

HPLC Purity Eluent a) 0.1% HCOOH in H ₂ 0 b) ACN (Gradient), ZORBAX XDB C-18 150*4.6 mm, 5μ; Flow 1.0 mL/min: 95.71% (258 nm); RT = 7.59 min LCMS Purity at XBridge C-18 150*4.6 mm, 5μ; 95.23% (258 nm); RT = 7.11 min; Mass found 341.5 [M] ⁺ [0210] Example 6: Assessing a5-containing GABA _A Receptor (GABA _A R) agonist activity

[0211] Step 1: Establish clones of GABAAR subunits(a5, β3, γ2, al, a2 and a3) and prepare the corresponding cRNAs: Human clones of GABAA-R 5, β3, γ2, al, a2 and a3 subunits are obtained from commercial resources {e.g., OriGene, http://www.origene.com and Genescript, http://www.genescript.com). These clones are engineered into pRC, pCDM, pcDNA, and pBluescript KSM vector (for oocyte expression) or other equivalent expression vectors. Conventional transfection agents {e.g., FuGene, Lipofectamine 2000, or others) are used to transiently trans feet host cells.

[0212] Step 2 - Functional GABAAR Assay of α5β3γ2, α1β3γ2, α2β3γ2, and α3β3γ2 subtypes in Xenopus oocyte expression system: cRNAs encoding α5, β3, γ2, al, a2 and a3 subunits are transcribed in vitro using T3 mMESSAGE mMACHINE Kit (Ambion) and injected (in a ratio of α:β:γ = 2:2: 1 or other optimized conditions) into oocytes freshly prepared from Xenopus laevis. After two days of culturing, GABA-gated CI- currents from oocytes are performed using TEVC setups (Warner Instruments, Inc., Foster City, CA). GABA,

benzodiazepine, and diazepam are used as reference compounds to validate the system.

[0213] Step 3 - Evaluate test compounds for agonist activity on the α5β3γ2 subtype and test off-target activity on the al to a3coupled β3γ2 subtypes when the EC50= 5 μΜ selectivity cut-off is reached: The GABA-gated CI- current from oocytes are measured in the TEVC setup in the presence of the test compounds. The agonist activity of each the test compounds is tested in a 5 -point dose-response assay. The test compounds include some reference compounds (literature EC50 values for the α5β3γ2subtype are in the range of 3-10 μΜ). EC50s in the α5β3γ2subtype are obtained for each compound. If the EC50 in α5β3γ2 is < 5μΜ, then the EC50 of the other three subtypes (α1β2γ2, α2β3γ2 and α3β3γ2) is further determined individually in order to test for selectivity of the compounds in the α5β3γ2subtype over other subtypes.

[0214] Step 4 - Evaluate further test compounds on the α5β3γ2 subtype and test off-target activities when the ΕΟ50=0.5μΜ selectivity cut-off is reached: The second batch of test compounds are tested using the same strategy, but with a lower EC50 cutoff (0.5 μΜ). Again, the EC50s of the α5β3γ2 subtype for each of the compounds is determined. The l to a3 coupled β3γ2 subtypes are tested only if the EC 50 for the a5 -containing receptor is < 0.5 μΜ.

Example 7: Evaluating Compounds for Agonist Activity on the GABA _A a5 Receptors

[0215] The agonist activity of the compounds of this invention was determined by measuring their effect on GABA-gated CI- current from Xenopus oocytes expressing GABAA α5β3γ2 subtype receptor in a two-electrode voltage clamp (TEVC) setup. Compounds demonstrating greater than 5% potentiation of the GAB A EC50 were indicative of compounds with positive allosteric modulation of the GABAA a5 receptor. That is, these compounds would enhance the effects of GABA at the GABA _A a5 receptor.

Materials

[0216] Adult female Xenopus laevis frogs were purchased from Nasco (Fort Atkinson, WI). Gentamicin, 3-aminobenzoic acid ethyl ester, GABA, Diazepam, Flumazenil, and collagenase were purchased from Sigma (St. Louis, MO). All chemicals used were of reagent grade. GABA stocks were prepared in the extracellular solution, i.e., Modified Barth's Saline (MBS) containing NaCl (88 mM), KC1 (2 mM), MgS0 ₄ (0.82 mM), Ca(N0 ₃ ) ₂ (0.33 mM), CaCl ₂ (0.41 mM), NaHC0 ₃ (2.4 mM) and HEPES (10 mM). Stock solutions of Diazepam,

Flumazenil and compounds of the present invention were prepared in dimethyl sulfoxide (DMSO) and then diluted to an appropriate concentration with the extracellular solution just before use. To avoid adverse effects from DMSO exposure, the final concentration of DMSO was not higher than 0.3% (v/v).

Experimental Procedures

(A) Expression of GABAA-R α5β3γ2 or α1β2γ2 subtype in Xenopus Oocytes

[0217] Xenopus oocytes were isolated according to previously published procedures (see, e.g., Goldin et al. Methods Enzymol. 207:266-279 (1992)). The isolated Xenopus oocytes were injected with GABAAR CDNAS (1 : 1 : 1 ratio for a total volume of 1 ng of α1β2γ2 or α5β3γ2) cloned into mammalian expression vectors. In particular, al, β2, γ2 were cloned into pcDNA3.1. and a5 and β3 were cloned into pcDNA3.1 myc-His. Vectors were verified by partial sequencing (DNA Core Facility, University of Southern California, USA). After injection, oocytes were stored in incubation medium (Modified Barth's Saline (MBS) supplemented with 2 mM sodium pyruvate, 0.5 mM theophylline and 50 mg/L gentamycin), in petri dishes (VWR, San Dimas, CA). All solutions were sterilized by passage through 0.22 μΜ filters. Oocytes, stored at 18°C, usually expressed GABAARS (e.g., α5β3γ2 or α1β2γ2 subtype), 1-2 days after injections. Oocytes were used in experiments for up to 5 days after injection. (B) GABA dose-response in Xenopus Oocyte expressing al and a5 GABA A RS

[0218] A high-throughput two-electrode voltage clamp (TEVC) system

(OpusXpress A6000; Molecular Devices, Union City, CA), which automates the impalement of oocytes, fluid delivery and current recording from 8 oocytes in parallel, was used to carry out all electrophysiological recordings.

[0219] Xenopus Oocytes expressing GABA _A -R α5β3γ2 or α1β2γ2 subtype, as prepared in section (A) above, were placed in 8 chambers of OpusXpress and perfused by MBS at 3mL/min. Glass electrodes back-filled with 3 M KC1 (0.5-3 megaohms) were used. Membrane potential of oocytes was voltage-clamped at - 60mV. Oocytes with holding current larger than 0.5 μΑ were discarded. [0220] Different concentrations of GAB A (3 μΜ - 10 mM for a 1 -containing

GABA _A Rs, or 0.3 μΜ - 1 mM for a5-containing GABA _A Rs) were applied once for 30 sec, with 5-15 min washes between the applications. Longer wash periods were allowed after the applications of higher GAB A concentrations. At the start of each week, a GABA dose-response experiment was conducted to determine an approximate GABA EC50 concentration for the batch of oocytes. EC50 ranged from

100-200 μΜ for al-containing GABAARS, and 10-20 μΜ a5-containing

GABAARS.

(C) Functional GABAAR assay o f α5β3γ2 or α!β2γ2 subtype in Xenopus oocyte expression system using Diazepam and Flumazenil as reference compounds

[0221] Diazepam and Flumazenil were used as reference compounds. In this study the GABA-gated CI ^" current from oocytes expressing α5β3γ2 GABA _A R was measured in the TEVC setup in the presence of Diazepam and Flumazenil. GABA EC20 was applied for 30 sec 4-5 times to establish a stable response. 1 μΜ

Diazepam was pre-applied for 60 sec, followed by co-application of 1 μΜ

Diazepam and GABA at EC ₂ o concentration for 30 sec. After a 15-20 min wash, a combination of 1 μΜ Diazepam and 10 μΜ Flumazenil was applied for 60 sec followed by co-application of the same combination with GABA at EC ₂ o concentrations for 30 sec. After a 15-20 min wash, co-application of 1 μΜ

Diazepam and EC ₂ o GABA was repeated to establish the recovery.

[0222] The effect of Diazepam was analyzed from the peak amplitude of Diazepam-(plus EC ₂ o GABA)-induced current (test 1) with the peak amplitude of GABA-induced current before the Diazepam application (reference). The effect of Flumazenil was determined from the peak amplitude of Diazepam-plus- Flumazenil-(plus EC ₂ o GABA)-induced current (test 2) normalized on the peak amplitude of Diazepam-induced current (control). Other compounds may also be used in this study as reference compounds. For example, methyl-6,7-dimethoxy-4- ethyl-beta-carboline-3-carboxylate (DMCM) and L655708 were tested at 1 μΜ, using the same protocol.

(C) Agonist activity of test compounds on a5B3y2 subtype GABAAR

[0223] Compounds of the present invention were initially screened at 1 μΜ for their ability to potentiate an EC ₅₀ concentration of GABA in oocytes containing GABAA receptors (α5β3γ2) using a protocol essentially similar to the one presented above for Diazepam and Flumazenil (see section (B)). In this study, the GABA-gated CI ^" current from oocytes expressing GABAA-R α5β3γ2 subtype was measured in the TEVC setup in the presence of the test compounds. Specifically, GABA EC ₅₀ was applied for 30 sec 4-5 times to establish stable response. Next, the test compounds (1 μΜ) were pre-applied for 60 sec, followed by coadministration of the test compounds (1 μΜ) and GABA at EC ₅₀ concentration for 30 sec. After a 15-20 min wash, EC ₅₀ GABA was tested once again. Upon conclusion of compound testing and successful washout, a 1.0 μΜ Diazepam was tested and used for comparative activity on the two GABA _A R subtypes. [0224] The effect of each test compound was determined from the peak amplitude of Diazepam-plus-compound-(plus EC50 GABA)-induced current normalized on the peak amplitude of Diazepam-(plus EC50 GABA)-induced current (control). Other concentrations of the test compound may also be tested following the same protocol.

[0225] A compound which demonstrates greater than 5% potentiation of the GABA EC50 is indicative that the compound has a positive allosteric modulatory effect on the GABAA 5 receptor. Such compound will enhance the effects of GABA at the GABAA 5 receptor. Exemplary compounds that demonstrated greater than 5% potentiation of the GABA EC50 are shown in Table 3 below.

Table 3: Exemplary compounds with >5% Potentiation of GABA EC50 Concentration in Oocytes containing GABAA receptors (α5β3γ2)

102

103

(D) Evaluate test compounds for o ff-target activity on the α!β2γ2 subtype

[0226] Compounds having a positive allosteric modulatory effect on GABA _A 5 receptors were next evaluated across a range of concentrations (i.e., at 0.01 , 0.1 , 1 , 10 and 100 μΜ) to determine the concentration response curve at GABAA 5 receptors (α5β3γ2) and selectivity vs. GABAA al receptors (α1 β2γ2). The results are shown in Figures 1(A)-(D). Compounds 4, 26, 27 and 29 demonstrated strong positive allosteric modulation of GABA at GABAA a5 receptors with markedly reduced positive allosteric modulation at GABAA l receptors. Compound 26 demonstrated positive allosteric modulation of GABA at the GABAA a5 receptor with no evidence of activity at the GABAA al receptor, indicating that this compound is a GABAA 5 receptor specific agonist, consistent with specificity of this compound for the GABAA 5 receptor relative to the GABAA l receptor. (E) Data analysis

[0227] Data for each experimental point were obtained from 4 or more Xenopus oocytes and from at least two different frogs. The n refers to the number of

Xenopus oocytes tested. Results are expressed as mean ± SEM. Where no error bars are shown, they are smaller than the symbols. Prism (GraphPAD Software, San Diego, CA) and Excel were used to perform curve fitting and statistical analyses. GABA concentration response curves were generated using non-linear regression analysis: [/ = 7 _max [A] " ^H / ([A] " ^H + EC ₅₀ " ^H )] where / is the peak current recorded following application of a range of agonist concentrations, [A]; 7 _max is the estimated maximum current; EC50 is the GABA concentration required for a half-maximal response and n _H is the Hill slope. Example 8: Effect of Methyl 3,5-diphenylpyridazine-4-carboxylate in Aged- Impaired (AI) Rats

[0228] 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 a5 -containing GABAA R agonist. It has an a5 in vitro efficacy of +27 (EC ₂₀ ). The effect of methyl 3,5-diphenylpyridazine-4-carboxylate in aged- impaired rats was studied using a RAM task. Moreover, receptor occupancy by methyl 3,5-diphenylpyridazine-4-carboxylate in a5-containing GABAA receptor was also studied.

(A) Effect of Methyl 3,5-diphenylpyridazine-4-carboxylate in Aged-Impaired Rats Using a Radial Arm Maze (RAM) Behavioral Task

[0229] The effects of methyl 3,5-diphenylpyridazine-4-carboxylate on the in vivo spatial memory retention of aged-impaired (AI) rats were assessed in a Radial Arm Maze (RAM) behavioral task using vehicle control and four different dosage levels of methyl 3,5-diphenylpyridazine-4-carboxylate (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg and 3 mg/kg, ip). RAM behavioral tasks were performed on eight AI rats. All five treatment conditions (vehicle and four dosage levels) were tested on all eight rats. [0230] The RAM apparatus used consisted of eight equidistantly-spaced arms. An elevated maze arm (7 cm width x 75 cm length) projected from each facet of an octagonal center platform (30 cm diameter, 51.5 cm height). Clear side walls on the arms were 10 cm high and were angled at 65° to form a trough. A food well (4 cm diameter, 2 cm deep) was located at the distal end of each arm. Froot Loops™ (Kellogg Company) were used as rewards. Blocks constructed of Plexiglas™ (30 cm height x 12 cm width) could be positioned to prevent entry to any arm.

Numerous extra maze cues surrounding the apparatus were also provided.

[0231] The AI rats were initially subjected to a pre-training test (Chappell et al. Neuropharmacology 37: 481-487, 1998). The pre-training test consisted of a habituation phase (4 days), a training phase on the standard win-shift task (18 days) and another training phase (14 days) in which a brief delay was imposed between presentation of a subset of arms designated by the experimenter (e.g. , 5 arms available and 3 arms blocked) and completion of the eight-arm win-shift task (i.e., with all eight arms available).

[0232] In the habituation phase, rats were familiarized to the maze for an 8- minute session on four consecutive days. In each of these sessions, food rewards were scattered on the RAM, initially on the center platform and arms and then progressively confined to the arms. After this habituation phase, a standard training protocol was used, in which a food pellet was located at the end of each arm. Rats received one trial each day for 18 days. Each daily trial terminated when all eight food pellets had been obtained or when either 16 choices were made or 15 minutes had elapsed. After completion of this training phase, a second training phase was carried out in which the memory demand was increased by imposing a brief delay during the trial. At the beginning of each trial, three arms of the eight-arm maze were blocked. Rats were allowed to obtain food on the five arms to which access was permitted during this initial "information phase" of the trial. Rats were then removed from the maze for 60 seconds, during which time the barriers on the maze were removed, thus allowing access to all eight arms. Rats were then placed back onto the center platform and allowed to obtain the remaining food rewards during this "retention test" phase of the trial. The identity and configuration of the blocked arms varied across trials. [0233] The number of "errors" the AI rats made during the retention test phase was tracked. An error occurred in the trial if the rats entered an arm from which food had already been retrieved in the pre-delay component of the trial, or if the rat re-visited an arm in the post-delay session that it had already visited.

[0234] After completion of the pre-training test, rats were subjected to trials with more extended delay intervals, i.e., a two-hour delay, between the information phase (presentation with some blocked arms) and the retention test (presentation of all arms). During the delay interval, rats remained off to the side of the maze in the testing room, on carts in their individual home cages. AI rats were pretreated 30 - 40 minutes before daily trials with a one-time shot of the following five conditions: 1) vehicle control - 5% dimethyl sulfoxide, 25% polyethylene glycol 300 and 70% distilled water; 2) methyl 3,5-diphenylpyridazine-4-carboxylate at 0.1 mg/kg; 3) methyl 3,5-diphenylpyridazine-4-carboxylate at 0.3 mg/kg; 4) methyl 3,5- diphenylpyridazine-4-carboxylate at 1 mg/kg); and 5) methyl 3,5- diphenylpyridazine-4-carboxylate at 3 mg/kg; through intraperitoneal (i.p.) injection. Injections were given every other day with intervening washout days. Each AI rat was treated with all five conditions within the testing period. To counterbalance any potential bias, drug effect was assessed using ascending- descending dose series, i.e., the dose series was given first in an ascending order and then repeated in a descending order. Therefore, each dose had two

determinations.

[0235] Parametric statistics (paired t-tests) was used to compare the retention test performance of the AI rats in the two-hour delay version of the RAM task in the context of different doses of methyl 3,5-diphenylpyridazine-4-carboxylate and vehicle control {see Figure 2). The average numbers of errors that occurred in the trials were significantly fewer with methyl 3,5-diphenylpyridazine-4-carboxylate treatment of 3 mg/kg/ (average no. of errors ± standard error of the mean (SEM) = 1.31 ± 0.40) than using vehicle control (average no. of errors ± SEM = 3.13 ± 0.62). Relative to vehicle control treatment, methyl 3,5-diphenylpyridazine-4- carboxylate significantly improved memory performance at 3 mg/kg (t(7) = 4.233, p = 0.004). [0236] The therapeutic dose of 3 mg/kg became ineffective when the AI rats were concurrently treated with 0.3 mg/kg of TB21007, a a5-containing GABAA R inverse agonist. The average numbers of errors made by rats with the combined TB21007/ methyl 3,5-diphenylpyridazine-4-carboxylate treatment (0.3 mg/kg TB21007 with 3 mg/kg methyl 3,5-diphenylpyridazine-4-carboxylate) was 2.88 ± 1.32, and was no different from rats treated with vehicle control (3.13 ± 1.17 average errors). Thus, the effect of methyl 3,5-diphenylpyridazine-4-carboxylate on spatial memory is a GABAA 5 receptor-dependent effect (see Figure 2). (B) Effect of Methyl 3,5-diphenylpyridazine-4-carboxylate on a5-containins GABAA Receptor Occupancy

Animals

[0237] Adult male Long Evans rats (265-295 g, Charles River, Portage, MI, n=4/group) were used for GABAA(X5 receptor occupancy studies. Rats were individually housed in ventilated stainless-steel racks on a 12: 12 light/dark cycle. Food and water were available ad libitum. In additional studies to evaluate compound exposures at behaviorally active doses, young or aged Long Evan rats (n= 2-4/group) were used for these studies.

Compounds

[0238] Ro 15-4513 was used as a receptor occupancy (RO) tracer for GABAA(X5 receptor sites in the hippocampus and cerebellum. Ro 15-4513 was chosen as the tracer based on its selectivity for GABAA(X5 receptors relative to other alpha subunit containing GABA _A receptors and because it has been successfully used for GABA _A a5 RO studies in animals and humans (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)). Ro 15-4513 (1 μg/kg), was dissolved in 25% hydroxyl-propyl beta-cyclodextrin and administered i.v. 20' prior to the RO evaluations. Methyl 3,5-diphenylpyridazine-4-carboxylate (0.1 - 10 mg/kg) was synthesized by Nox Pharmaceuticals (India) and was dissolved in 25%> hydroxyl-propyl beta-cyclodextrin and administered i.v. 15' prior to 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

[0239] The rats were sacrificed by cervical dislocation 20' post tracer injection. The whole brain was rapidly removed, and lightly rinsed with sterile water. Trunk blood was collected in EDTA coated eppendorf tubes and stored on wet ice until study completion. Hippocampus and cerebellum were dissected and stored in 1.5 ml eppendorf tubes, and placed on wet ice until tissue extraction. In a drug naive rat, six cortical brain tissues samples were collected for use in generating blank and standard curve samples.

[0240] Acetonitrile containing 0.1% formic acid was added to each sample at a volume of four times the weight of the tissue sample. For the standard curve (0.1- 30 ng/g) samples, a calculated volume of standard reduced the volume of acetonitrile. The sample was homogenized (FastPrep-24, Lysing Matrix D; 5.5 m/s, for 60 seconds or 7-8 watts power using sonic probe dismembrator; Fisher

Scientific) and centrifuged for 16-minutes at 14,000 rpm. The (100 μΐ) supernatant solution was diluted by 300 μΐ of sterile water (pH 6.5). This solution was then mixed thoroughly and analyzed via LC/MS/MS for Ro 15-4513 (tracer) and methyl 3 ,5 -diphenylpyridazine-4-carboxylate .

[0241] For plasma exposures, blood samples were centrifuged at 14000 rpm for 16 minutes. After centrifuging, 50ul of supernatant (plasma) from each sample was added to 200 μΐ of acetonitrile plus 0.1% formic acid. For standard curve (1-1000 ng/ml) samples, a calculated volume of standard reduced the volume of

acetonitrile. Samples were sonicated for 5 minutes in an ultrasonic water bath, followed by centrifugation for 30 minutes, at 16000 RPM. lOOul of supernatant was removed from each sample vial and placed in a new glass auto sample vial, followed by the addition of 300 μΐ of sterile water (pH 6.5). This solution was then mixed thoroughly and analyzed via LC/MS/MS for methyl 3,5-diphenylpyridazine- 4-carboxylate.

[0242] Receptor occupancy was determined by the ratio method which compared occupancy in the hippocampus (a region of high GABAA(X5 receptor density) with occupancy in the cerebellum (a region with low GABA _A a5 receptor density) and additionally by a high dose of the GABAA(X5 negative allosteric modulator L- 655,708 (10 mg/kg, i.v.) to define full occupancy.

[0243] Vehicle administration followed by tracer administration of 1 μg/kg, i.v., of Ro 15-4513 resulted in > 5-fold higher levels of Ro 15-4513 in hippocampus (1.93 ± 0.05 ng/g) compared with cerebellum (0.36 ± 0.02 ng/g). Methyl 3,5- diphenylpyridazine-4-carboxylate (0.01 - 10 mg/kg, i.v. ) dose-dependently reduced Ro 15-4513 binding in hippocampus, without affecting cerebellum levels of Ro 15-4513 (Figure 3) with a dose of 10 mg/kg, i.v., demonstrating >90% occupancy (Figure 4). Both methods of calculating RO yielding very similar results with ED50 values for methyl 3,5-diphenylpyridazine-4-carboxylate as 1.8 mg/kg or 1.1 mg/kg based on the ratio method or using L-755,608 to define occupancy .

[0244] Methyl 3,5-diphenylpyridazine-4-carboxylate exposure was below the quantification limits (BQL) at 0.01 mg/kg, i.v., in both plasma and hippocampus and but was detectable at low levels in hippocampus at 0.1 mg/kg, i.v. (see Table 4). Hippocampal exposure was linear as a 10-fold increase in dose from 0.1 to 1 mg/kg, i.v., resulted in a 12-fold increase in exposure. Increasing the dose from 1 to 10 mg/kg, i.v., only increased the exposure by ~5-fold. Plasma exposure increased 12-fold as the dose increased from 1 to 10 mg/kg, i.v. Table 4: % GABAA 5 Receptor Occupancy by methyl 3,5-diphenylpyridazine-4- carboxylate (0.01-10 mg/kg, i.v.). Hippocampus and Plasma Exposure of methyl 3,5-diphenylpyridazine-4-carboxylate by Treatment Group in young Long Evans rats.

[0245] Additional studies were conducted in aged Long-Evans rats in order to determine the exposures at the behaviorally relevant doses in the cognition studies. Exposure in young Long-Evans rats was also determined to bridge with the receptor occupancy studies that were conducted in young Long-Evans rats.

Exposures in young and aged Long-Evans rats were relatively similar (Table 5, Figure 5). Increasing the dose 3 -fold from 1 to 3 mg/kg, ip resulted in a greater than dose-proportional increase in exposure in young and aged rats in both hippocampus and plasma with increases ranging from 4.5 to 6.6-fold.

Table 5: Hippocampus and Plasma Exposure of methyl 3,5-diphenylpyridazine-4- carboxylate in Young Long Evans Rats by Treatment Group

[0246] In the RO studies, an exposure of 180 ng/g in hippocampus (1 mg/kg, i.v.) represented 32-39% receptor occupancy depending on method used to determine RO. This exposure is comparable to that observed in aged rats at 3 mg/kg, i.p., suggesting that 30-40% RO is required for cognitive efficacy in this model.

[0247] These studies demonstrated that methyl 3,5-diphenylpyridazine-4- carboxylate produced dose-dependent increase in GABAA a5 receptor occupancy. Methyl 3,5-diphenylpyridazine-4-carboxylate also demonstrated good brain exposure with brain/plasma ratios>l . The studies further demonstrated that methyl 3,5-diphenylpyridazine-4-carboxylate was producing its cognitive enhancing effects by positive allosteric modulation at the GABAA a5 subtype receptor.

Example 9: Effect of Ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5- a] [l,2,4]triazolo[4,3-d] [l,4]diazepine-10-carboxylate in Aged-Impaired (ΑΙ) Rats

[0248] Ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5-a][l,2,4]triazolo[ 4,3- d][l,4]diazepine-10-carboxylate, corresponding to compound number 49 in Achermann et al. Bioorg. Med. Chem. Lett., 19:5746-5752 (2009), is a selective a5 -containing GABAA R agonist.

[0249] The effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5- a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate on the in vivo spatial memory retention of aged-impaired (AI) rats was assessed in a Radial Arm Maze (RAM) behavioral task that is essentially similar to the task as described in Example 3 (A), using vehicle control (25% cyclodextrin, which was tested 3 times: at the beginning, middle and end of ascending/descending series) and six different doses levels (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg, each dose was tested twice) of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5- a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate. The same experiment was repeated using the same vehicle control and doses of ethyl 3-methoxy-7-methyl- 9H-benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepin e-10-carboxylate, where the vehicle control was tested 5 times, the 3 mg/kg dose of ethyl 3-methoxy- 7-methyl-9H-benzo[fJimidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4 ]diazepine-10- carboxylate was tested 4 times, and the other doses of ethyl 3-methoxy-7-methyl- 9H-benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepin e-10-carboxylate were tested twice.

[0250] Parametric statistics (paired t-tests) was used to compare the retention test performance of the AI rats in the four-hour delay version of the RAM task in the context of different doses of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5- a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate and vehicle control {see Figure 6). Relative to vehicle control treatment, ethyl 3-methoxy-7-methyl-9H- benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine-1 0-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 at 10 mg/kg (t(7) = 2.82, p=0.026).

[0251] The effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5- a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate on a5-containing GABAA receptor occupancy was also studied following a procedure that is essentially similar to the one as described in Example 8(B) {see above). This study demonstrated that ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[l,5- a][l,2,4]triazolo[4,3-d][l,4]diazepine-10-carboxylate (0.01 - 10 mg/kg, i.v. ) reduced Ro 15-4513 binding in hippocampus, without affecting cerebellum levels of Ro 15-4513 (Figure 7) with a dose of 10 mg/kg, i.v., demonstrating >90% occupancy (Figure 8).

Example 10: Effect of 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)- 6,7-dihydro-2-benzothiophen-4(5H)-one in Aged-Impaired Rats Using a Morris Water Maze Behavioral Task

[0252] 6,6 dimethyl-3-(3-hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7-dihydro-2- benzothiophen-4(5H)-one, corresponding to compound 44 in Chambers et al. J. Med. Chem. 46:2227-2240 (2003) is a selective a5-containing GABAA R agonist.

[0253] The effects of 6,6 dimethyl-3-(3-hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7- dihydro-2-benzothiophen-4(5H)-one on the in vivo spatial memory retention of aged-impaired (AI) rats were assessed in a Morris water maze behavioral task. A water maze is a pool surrounded with a novel set of patterns relative to the maze. The training protocol for the water maze may be based on a modified water maze task that has 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).

[0254] Cognitively impaired aged rats were implanted unilaterally with a cannula into the lateral ventricle. Stereotaxic coordinates were 1.0 mm posterior to bregma, 1.5 mm lateral to midline, and 3.5 mm ventral to the skull surface. After about a week of recovery, the rats were pre-trained in a water maze for 2 days (6 trials per day) to locate a submerged escape platform hidden underneath the surface of the pool, in which the escape platform location varied from day to day. No

intracerebroventricular (ICV) infusion was given during pre -training.

[0255] After pre-training, rats received ICV infusion of either 100 μg 6,6 dimethyl-3-(3-hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-

4(5H)-one (n = 6) in 5 μΐ DMSO or vehicle DMSO (n = 5) 40 min prior to water maze training and testing. Training consisted of 8 trials per day for 2 days where the hidden escape platform remained in the same location. Rats were given 60 seconds to locate the platform with a 60 seconds inter-trial interval. The rats were given a probe test (120 seconds) 24 hr after the end of training where the escape platform was removed. During the training, there were 4 blocks, where each block had 4 training trials.

[0256] Rats treated with vehicle and 6,6 dimethyl-3-(3-hydroxypropyl)thio-l- (thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one found the escape platform about the same time at the beginning of training (block 1). In this block of training, rats treated with vehicle and 6,6 dimethyl-3-(3-hydroxypropyl)thio-l- (thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one both spent about 24 seconds to find the escape platform. However, rats treated with 6,6 dimethyl-3-(3- hydroxypropyl)thio- 1 -(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one were able to find the platform more proficiently (i.e., quicker) at the end of training (block 4) than those treated with vehicle alone. In block 4, rats treated with 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)-6,7-dihydr o-2-benzothiophen- 4(5H)-one spent about 9.6 seconds to find the escape platform, while rats treated with vehicle spent about 19.69 seconds. These results suggest that 6,6 dimethyl-3- (3-hydroxypropyl)thio-l-(thiazol-2-yl)-6,7-dihydro-2-benzoth iophen-4(5H)-one improved the learning of the water maze task in rats (see Figure 9(A)).

[0257] During a test trial 24 hr after training, the escape platform was removed. The search/swim pattern of the rats was used to measure whether the rats remember where the escape platform was located during pre-trial training in order to test for the long-term memory of the rats. In this trial, "target annulus" is a designated area 1.5 times the size of the escape platform around the area where the platform was located during pre-trial training. "Opposite annulus" is a control area of the same size as the size of the target annulus, which is located opposite to the target annulus in the pool. If the rats had good long term memory, they would tend to search in the area surrounding the location where the platform was during the pre-trial training (i.e., the "target" annulus; and not the "opposite" annulus). "Time in annulus" is the amount of time in seconds that the rat spent in the target or opposite annulus area. "Number (#) of crossings" in annulus is the number of times the rat swam across the target or opposite annulus area. [0258] Rats received vehicle spent the same amount of time in the target annulus and opposite annulus, indicating that these rats did not seem to remember where the platform was during the pre-trial training. By contrast, rats treated with 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)-6,7-dihydr o-2-benzothiophen- 4(5H)-one spent significantly more time in the target annulus, and crossed the "target annulus" more often, as compared to the time they spent in, or the number of times they crossed the "opposite annulus". These results suggest that 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)-6,7-dihydr o-2-benzothiophen- 4(5H)-one improved the long-term memory of rats in the water maze task (see, Figures 9(B) and 9(C)).

[0259] Compounds of the present invention demonstrated positive allosteric modulatory effect on the GABAA 5 receptor {See, e.g., Example 7). These compounds will enhance the effects of GABA at the GABAA 5 receptor.

Therefore, compounds of the present invention should produce cognitive enhancing effects in aged-impaired animals (such as rats), similar to the effects produced by other GABA _A 5 receptor selective agonists, such as methyl 3,5- diphenylpyridazine-4-carboxylate, ethyl 3-methoxy-7-methyl-9H- benzo[f]imidazo[l,5-a][l,2,4]triazolo[4,3-d][l,4]diazepine- 10-carboxylate, and 6,6 dimethyl-3-(3-hydroxypropyl)thio-l-(thiazol-2-yl)-6,7-dihydr o-2-benzothiophen- 4(5H)-one {See, e.g., Examples 8-10).