Treatment of antidepressant resistant subjects

Abstract

The present disclosure generally relates to the surprising discovery that azabicyclo thienyl compounds can treat depression in subjects resistant to anti-depressive agent therapy and / or treat depression-related cognitive disorders in subjects resistant to anti-depressive agent therapy.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Australian Provisional Patent Application No. 2022901596 filed on June 10, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates generally to the field of pharmaceuticals for treating depression in a subject resistant to antidepressant therapy and / or treating depression-related cognitive impairment in a subject resistant to antidepressant therapy. Background Art

[0004] Major depressive disorder (MDD) involves a major depressive episode that is not part of any mental disorder or bipolar disorder. The symptoms of a major depressive episode include depressed mood; a significant decrease in interest or pleasure in all or almost all activities for most of the day; weight loss or weight gain when not on a diet, or a decrease or increase in appetite almost every day; insomnia or drowsiness almost every day; psychomotor agitation or retardation almost every day; fatigue or loss of energy almost every day; feeling worthless or excessive or inappropriate guilt almost every day; decreased ability to think or concentrate almost every day, or indecision; repeated consideration of death, repeated suicidal ideation without a specific plan, or attempted suicide or a specific plan for suicide. In addition, the symptoms cause clinically significant pain or damage in social, occupational or other important functional areas (Diagnostic and Statistical Manual of Mental Disorders, 5th edition, American Psychiatric Association, 2013).

[0005] Current treatment options for depression include monotherapy or combination therapy using various classes of drugs, including monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), serotonin-specific reuptake inhibitors (SSRIs), serotonin noradrenergic reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), "natural products" (e.g., Kava-Kava, St. John's Wort), dietary supplements (e.g., s-adenosylmethionine), and the like. More specifically, drugs used to treat depression include, but are not limited to, imipramine, amitriptyline, desipramine, desipramine, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, chlomipramine, fluoxetine, tine, citalopram, sertraline, paroxetine, tianeptine, nefazadone, venlafaxine, desvenlafaxine, duloxetine, reboxetine, mirtazapine, phenelzine, tranylcypromine, and / or moclobemide. Several of these agents are also used when depression and anxiety disorders coexist, such as in anxious depression, including, but not limited to, serotonin reuptake inhibitors.

[0006] Clinically, up to about 50% of patients with depression who initially adopt antidepressant therapy do not experience timely relief of depression symptoms. This group represents level 1 treatment-resistant depression, that is, failure to show an "adequate" response to an "adequate" treatment trial. About 30% of patients with depression still have partial or complete treatment resistance to at least two antidepressant treatments (including combination therapy). Increasingly, treatments for treatment-resistant depression include enhancement strategies, including treatment with pharmacological agents such as antipsychotics (such as quetiapine, aripiprazole, olanzapine, risperidone, etc.), lithium, carbamazepine, and triiodothyronine; adjunctive electroconvulsive therapy; adjunctive transcranial magnetic stimulation, etc.

[0007] Therefore, there remains a need for alternative and effective treatments for treating depression in subjects resistant to antidepressant therapy, including treating depression-related cognitive impairment. Summary of the invention

[0008] The present disclosure is based, in part, on the surprising discovery that azabicyclic thienyl compounds can treat depression in a subject resistant to antidepressant therapy and / or treat depression-related cognitive impairment in a subject resistant to antidepressant therapy.

[0009] Thus, in a first aspect, there is provided a method of treating or preventing depression in a subject resistant to antidepressant therapy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0010]

[0011] Where R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered carbocyclic group, 3-10 membered heterocyclic group, -CN, -CF3, -OR 3 、-SR 3 、-NR 3 R 4 、-COR 3 、-CO2R 3 、-CONR 3 R 4、-NR 3 COR 4 、-SO2R 3 、-SO2NR 3 R 4 and-NR 3 S02R 4 ; where R 3 and R 4 Each independently selected from the group consisting of: hydrogen, C 1-6 wherein each of the 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -CF3, -OR 5 、-SR 5 、-NR 5 R 6 、-COR 5 、-CO2R 5 、-CONR 5 R 6 、-NR 5 COR 6 、-SO2R 5 、-SO2NR 5 R 6 and-NR 5 S02R 6 ; and where R 5 and R 6 Each independently selected from hydrogen and C 1-6 Alkyl group.

[0012] In a second aspect, a method for treating or preventing depression-related cognitive impairment in a subject resistant to antidepressant treatment is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0013]

[0014] Where R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered carbocyclic group, 3-10 membered heterocyclic group, -CN, -CF3, -OR 3 、-SR 3 、-NR 3 R 4 、-COR 3 、-CO2R 3 、-CONR 3 R 4 、-NR 3 COR 4 、-SO2R 3 、-SO2NR 3 R 4 and-NR 3 S02R 4 ; where R 3 and R 4 Each independently selected from the group consisting of: hydrogen, C 1-6 wherein each of the 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -CF3, -OR 5 、-SR 5 、-NR 5 R 6 、-COR 5 、-CO2R 5 、-CONR 5 R 6 、-NR 5 COR 6 、-SO2R 5 、-SO2NR 5 R 6 and-NR 5 S02R 6 ; and where R 5 and R 6 Each independently selected from hydrogen and C 1-6 Alkyl group.

[0015] In one example, the treatment is for depression and depression-related cognitive impairment in the subject.

[0016] In one embodiment, the compound of formula Ia is:

[0017]

[0018] In another aspect, there is provided the use of a compound of Formula I or Formula Ia as described herein according to any example or embodiment thereof for treating depression in a subject resistant to antidepressant treatment and / or treating depression-related cognitive impairment in a subject resistant to antidepressant treatment.

[0019] In another aspect, there is provided a method for using a compound of Formula I or Formula Ia according to any example or embodiment thereof as described herein in the manufacture of a medicament for treating or preventing depression in a subject resistant to antidepressant treatment and / or treating depression-related cognitive disorders in a subject resistant to antidepressant treatment.

[0020] In another aspect, there is provided a compound of formula I or formula Ia as described herein according to any example or embodiment thereof for use in treating or preventing depression in a subject resistant to antidepressant treatment and / or treating depression-related cognitive impairment in a subject resistant to antidepressant treatment.

[0021] Unless explicitly stated otherwise, any embodiment herein should be considered applicable to any other embodiment mutatis mutandis.

[0022] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for purposes of illustration only. As described herein, functionally equivalent products, compositions and methods are clearly within the scope of the present invention.

[0023] Throughout this specification, references to individual steps, compositions of matter, groups of steps, or groups of compositions of matter shall be considered to cover both one and more (i.e., one or more) of such steps, compositions of matter, groups of steps, or groups of compositions of matter, unless expressly stated otherwise or the context requires otherwise. DETAILED DESCRIPTION

[0024] General Definition

[0025] Unless specifically defined otherwise, all technical and scientific terms used herein should be regarded as having the same meaning as commonly understood by one of ordinary skill in the art (eg, chemistry, biochemistry, medicinal chemistry, microbiology, etc.).

[0026] As used herein, the term "and / or" (e.g., "X and / or Y") should be understood to mean "X and Y" or "X or Y," and should be considered to provide explicit support for both meanings or for either meaning (e.g., A and / or B includes options i) A, ii) B, or iii) A and B).

[0027] As used herein, unless stated to the contrary, the term about means + / - 20%, typically + / - 10%, and often + / - 5% of a specified value.

[0028] As used herein, the terms "a", "an", and "the" include both singular and plural aspects unless the context clearly dictates otherwise.

[0029] It should be understood that, for the sake of clarity, certain features described herein in the context of separate embodiments may also be provided in a single embodiment in combination. Conversely, for the sake of brevity, various features described in the context of a single embodiment may also be provided individually or in any sub-combination.

[0030] Throughout this specification, various aspects and components of the present invention can be presented in range format. Range format is included for convenience, and should not be interpreted as an inflexible limitation to the scope of the present invention. Therefore, unless otherwise indicated, the description of the range should be considered to have clearly disclosed all possible sub-ranges and individual numerical values ​​within this range. For example, unless an integer or contextual implicit integer is required, the description of a range such as from 1 to 5 should be considered to have clearly disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5, etc., and individual and partial numbers within the stated range, such as 1, 2, 3, 4, 5, 5.5 and 6. Regardless of the disclosed range width, this applies. Where specific values ​​are required, these values ​​will be indicated in the specification.

[0031] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of stated elements, integers or steps or groups of elements, integers or steps but not the exclusion of any other elements, integers or steps or groups of elements, integers or steps.

[0032] It will be clearly understood that, although a number of prior art disclosures are referenced herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or any other country.

[0033] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. Although methods and materials similar to or equivalent to the methods and materials described herein can be used in the practice or test of the present invention, suitable methods and materials are described below. In the event of a conflict, this specification (including definitions) shall prevail. In addition, the materials, methods and examples are only illustrative and are not intended to be restrictive.

[0034] As used herein, the term "treating" (or "treat," "treatment," etc.) includes reducing, alleviating, and / or eliminating one or more symptoms associated with a particular disorder or condition. Such symptoms may be associated with depression and cognitive deterioration or disorders associated with depression in subjects who have shown at least some resistance to antidepressant treatment. For example, as used herein, the phrase "treating a cognitive disorder" includes improving, reducing, alleviating, and / or eliminating symptoms associated with a cognitive disorder relative to symptoms prior to treatment.

[0035] As used herein, the term "preventing" (or "prevention") includes the prevention and treatment of a particular disorder or condition. For example, as used herein, the phrase "preventing cognitive impairment" refers to preventing the onset or continuation of symptoms associated with cognitive impairment in a subject. In some embodiments, the phrase "preventing cognitive impairment" refers to slowing or stopping the progression of cognitive impairment. In some embodiments, the phrase "preventing cognitive impairment" refers to delaying or preventing the onset of symptoms of cognitive impairment. Prevention can be absolute (so that cognitive impairment does not occur), or can be effective only in some individuals to a certain extent or for a limited amount of time.

[0036] As used herein, the term "subject" can be used interchangeably with the terms "patient" and "individual." In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0037] As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0038] As used herein, the term "alkyl" encompasses both straight-chain (i.e., linear) and branched hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, and hexyl. In one example, an alkyl group has from one to six carbon atoms (i.e., C 1-6 alkyl).

[0039] As used herein, the term "alkoxy" refers to the group -O-alkyl, where "alkyl" is as described above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy. In one example, the alkoxy group has from one to six carbon atoms (i.e., -OC 1-6 alkyl).

[0040] As used herein, the term "alkenyl" refers to both straight-chain unsaturated hydrocarbon groups and branched unsaturated hydrocarbon groups having at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl. In one example, an alkenyl group has two to six carbon atoms (i.e., C 2-6 alkenyl).

[0041] As used herein, the term "alkynyl" refers to both straight-chain unsaturated hydrocarbon groups and branched unsaturated hydrocarbon groups having at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl. In one example, an alkynyl group has two to six carbon atoms (i.e., C 2-6 alkynyl).

[0042] As used herein, the term "haloalkyl" refers to an alkyl group having at least one halogen substituent, wherein "alkyl" and "halogen" are as described above. Similarly, the term "dihaloalkyl" means an alkyl group having two halogen substituents, and the term "trihaloalkyl" means an alkyl group having three halogen substituents. Examples of haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoropropyl and fluorobutyl. Examples of dihaloalkyl groups include difluoromethyl and difluoroethyl. Examples of trihaloalkyl groups include trifluoromethyl and trifluoroethyl. In one example, a haloalkyl group has one to six carbon atoms (i.e., C 1-6 haloalkyl).

[0043] As used herein, the term "oxyhaloalkyl" refers to the group -O-haloalkyl, where "haloalkyl" is as described above. Examples of -O-haloalkoxy include -O-fluoromethyl, -O-chloromethyl, -O-bromomethyl, -O-iodomethyl, -O-fluoropropyl, and -O-fluorobutyl. In one example, the oxyhaloalkyl has one to six carbon atoms (i.e., -OC 1-6 haloalkyl).

[0044] As used herein, the term "carbocyclyl" refers to an aromatic or non-aromatic cyclic group of carbon atoms. A carbocyclyl may, for example, be monocyclic or polycyclic (i.e., bicyclic, tricyclic). A polycyclic carbocyclyl may contain fused rings. In one example, a carbocyclyl has three to ten carbon atoms (i.e., C 3-10 In one example, a carbocyclic group has three to seven carbon atoms (i.e., C 3-7Examples of monocyclic non-aromatic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Aromatic carbocyclic groups include phenyl and naphthylenediyl.

[0045] As used herein, the term "heterocyclic group" refers to an aromatic or non-aromatic cyclic group similar to a carbocyclic group, but wherein one to three carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. Heterocyclic groups can be, for example, monocyclic or polycyclic (e.g., bicyclic). Polycyclic heterocyclic groups can, for example, contain condensed rings. In bicyclic heterocyclic groups, one or more heteroatoms can be present in each ring, or heteroatoms can be present only in one ring in the ring. The heteroatom can be N, O or S. Heterocyclic groups containing suitable nitrogen atoms include corresponding N-oxides. In one example, heterocyclic groups have three to ten atoms (i.e., 3-10 heterocyclic groups). In one example, heterocyclic groups have three to seven atoms (i.e., 3-7 heterocyclic groups). The example of monocyclic non-aromatic heterocyclic radical includes aziridine radical, azetidinyl radical, pyrrolidinyl radical, imidazolidinyl radical, pyrazolidinyl radical, piperidinyl radical, piperazinyl radical, tetrahydrofuranyl radical, tetrahydropyranyl radical, morpholinyl radical, thiomorpholinyl radical and azepanyl radical. The example of bicyclic heterocyclic radical that wherein one ring in the ring is non-aromatic radical includes dihydrobenzofuranyl radical, indanyl radical, indolinyl radical, isoindolinyl radical, tetrahydroisoquinolyl radical, tetrahydroquinolyl radical and benzazepanyl radical. The example of monocyclic aromatic heterocyclic radical (also referred to as monocyclic heteroaryl radical) includes furanyl radical, thienyl radical, pyrrolyl radical, oxazolyl radical, thiazolyl radical, imidazolyl radical, oxadiazolyl radical, thiadiazolyl radical, pyridyl radical, triazolyl radical, triazinyl radical, pyridazinyl radical, isothiazolyl radical, isoxazolyl radical, pyrazinyl radical, pyrazolyl radical and pyrimidinyl radical. Examples of bicyclic aromatic heterocyclic groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridinyl, pyridopyrimidinyl, isoquinolinyl, and benzohydrooxazole.

[0046] depression

[0047] The subject matter of the present disclosure is based in part on the surprising discovery that compounds of Formula I can be used to treat or prevent depression in subjects resistant to antidepressant therapy and / or to treat or prevent depression-related cognitive impairment in subjects resistant to antidepressant therapy. Thus, in one aspect, a method is provided for treating or preventing depression in subjects resistant to antidepressant therapy and / or to treat or prevent depression-related cognitive impairment in subjects resistant to antidepressant therapy.

[0048] Those skilled in the art will recognize that where the present disclosure relates to a method of prevention, a subject in need will include any subject or patient (e.g., human) who has experienced or exhibited at least one symptom of a disorder, disease, or condition to be prevented. In addition, a subject in need may additionally be a subject who has not yet exhibited any symptoms of a disorder, disease, or condition to be prevented, but has been considered by a physician, clinician, or other medical professional to be at risk of developing the disorder, disease, or condition. For example, a subject may be considered to be at risk of developing a disorder, disease, or condition (and therefore in need of prevention or preventive treatment) due to the subject's medical history, including but not limited to family history, pre-treatment, coexisting (comorbid) disorders or conditions, genetic testing, etc.

[0049] Antidepressant resistance

[0050] As used herein, the term "depression" includes major depressive disorder (MDD), unipolar depression, anxiety-disturbed depression, bipolar depression, and dysthymia. In one example, depression is MDD. Depression can be defined as treatment-resistant depression, such as treatment-resistant MDD.

[0051] As used herein, the term "treatment-resistant depression" or "resistant to antidepressant treatment" can be defined as a depression (e.g., MDD) that has not responded to an adequate course of adequate treatment with one or more antidepressants (e.g., at least two antidepressants). One skilled in the art will recognize that failure to respond to an adequate course of treatment with a given antidepressant can be readily determined retrospectively or prospectively.

[0052] As used herein, unless the context requires otherwise, the term "antidepressant" means any agent that can be used to treat depression. Suitable examples include, but are not limited to, monoamine oxidase inhibitors such as phenelzine, tranylcypromine, moclobemide, etc.; tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, etc.; tetracyclics such as maprotiline, etc.; acyclics such as nomifensine, etc.; triazolopyridines such as trazodone, etc.; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, citalopram, escitalopram, etc. pram), fluvoxamine, etc.; serotonin reuptake antagonists, such as nefazodone, etc.; serotonin noradrenergic reuptake inhibitors, such as venlafaxine, milnacipran, desvenlafaxine, duloxetine, etc.; noradrenergic and specific serotonergic agents, such as mirtazapine, etc.; noradrenalin reuptake inhibitors, such as reboxetine, edivoxetine, etc.; atypical antidepressants, such as bupropion, etc.; natural products, such as Kava-Kava, St. John's Wort, etc.; dietary supplements, such as s-adenosylmethionine, etc.; and neuropeptides, such as thyrotropin-releasing hormone, etc.; compounds targeting neuropeptide receptors, such as neurokinin receptor antagonists, etc.; and hormones, such as triiodothyronine, etc.

[0053] Therapeutically effective dosage levels and dosing regimens for antidepressants (e.g., monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic agents, noradrenergic reuptake inhibitors, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones, and other agents disclosed herein) can be readily determined by one of ordinary skill in the art. For example, therapeutic dosage amounts and regimens for approved marketed agents are publicly available, such as listed in package labels, standard dosage guidelines, standard dosage references (e.g., physician's desk references), or other sources.

[0054] In one example, the subject who is resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of: serotonin specific reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NARIs), norepinephrine and specific serotonin antidepressants (NaSSAs), melatonin agonists (MAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), reversible inhibitors of monoamine oxidase (RIMAs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and serotonin modulators (SMs).

[0055] In another example, the subject who is resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of imipramine, amitriptyline, dothiepin, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, citalopram, sertraline, paroxetine, tianeptine, nefazodone, venlafaxine, desvenlafaxine, duloxetine, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, reboxetine, mianserin, agomelatine, and vortioxetine.

[0056] In another example, the subject who is resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs). The SSRI can be selected from one or more of the following: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, indalpine, zimelidine, alapropate, centpropazine, ciprofloxacin, femoxetine, ifoxetine, omiloxetine, panuramine, pirandamine, and seproxetine. For example, the SSRI can be selected from one or more of the following: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline.

[0057] In another example, the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of norepinephrine reuptake inhibitors (NARIs). In one example, the NARI is reboxetine.

[0058] In another example, the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of norepinephrine and specific serotonergic antidepressants (NaSSA). In one example, the NaSSA is selected from mirtazapine and / or mianserin.

[0059] In another example, the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of melatonin agonists (MAs). In one example, the MA is agomelatine.

[0060] In another example, the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of serotonin and norepinephrine reuptake inhibitors (SNRIs). In one example, the SNRI is selected from one or more of the following: atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, and venlafaxine.

[0061] In another example, the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of reversible inhibitors of monoamine oxidase (RIMA). In one example, the RIMA is moclobemide.

[0062] In another example, the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of tricyclic antidepressants (TCAs). In one example, the TCA is selected from one or more of the following: amitriptyline, clomipramine, dosulpiride, imipramine, nortriptyline, and doxepin.

[0063] In another example, the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of monoamine oxidase inhibitors (MAOIs). In one example, the MAOI is selected from phenelzine and / or tranylcypromine.

[0064] In another example, the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of serotonin modulators (SMs). In one example, the SM is vortioxetine.

[0065] In another example, the subject resistant to antidepressant treatment is a subject resistant to treatment for major depressive disorder (MDD).

[0066] It will be understood that there is a well-known method for diagnosing the depression (for example, MDD) of a subject. In one example, by using Hamilton Depression Rating Scale (Hamilton Depression Rating Scale, HAM-D or HDRS) to identify a subject to diagnose depression or MDD. The HAM-D scale relates to 17 projects, wherein the highest rating is 54 points, which indicates severe depression. In some instances, the HAM-D rating can be at least 15 points, 16 points, 17 points, 18 points, 19 points, 20 points, 21 points, 22 points, 23 points, 24 points, 25 points, 26 points, 27 points, 28 points, 29 points or 30 points. In one example, HAM-D is at least 17 points. In another example, depression or MDD are diagnosed using Diagnostic Statistical Manual of Mental Disorders (DSM-5) standard (referring to the Diagnostic Statistical Manual of Mental Disorders of the American Psychiatric Association, the fifth edition). DSM-IV or DSM-V criteria can also be obtained using the Mini International Neuropyschiatric Interview (MINI) (Lecrubier et al., Eur Psychiatry, 1997, 12, pp. 224-231). Additional details can be found at

[0067] The present invention relates to a method for the detection of schizophrenia in patients with schizophrenia who were treated with schizophrenia in the presence of a schizophrenia virus. The method is available online at https: / / harmresearch.org / mini-international-neuropsychiatric-interview-mini / , which is incorporated herein by reference.

[0068] It will be appreciated that administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, can provide an improvement in depression in a treated subject relative to an untreated subject.

[0069] Improvement in depression in treated subjects can be determined using the Montgomery and Asberg Depression Rating Scale (MADRS), which involves a clinical interview that progresses from broad questions about symptoms to more detailed questions that allow for precise assessment of severity. The assessor decides whether the score is on a defined scale step (0, 2, 4, 6) or between (1, 3, 5). The questions are for obvious sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to sleep, pessimistic thoughts, and suicidal thoughts. Additional details can be obtained in Quilty et al., International Journal of Methods in Psychiatric Research, Int. J. Methods Psychiatr. Res. 22 (3): 175-184 (2013) (wileyonlinelibrary.com) DOI: 10.1002 / mpr.1388. MADRS produces an assessment of 0-60 points, wherein the higher the score, the higher the severity of depression. In some instances, MADRS is assessed as at least 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, 45 points or 50 points. In some instances, the method reduces the MADRS assessment of the treated subject by at least about 1 point, 2 points, 3 points, 4 points, 5 points, 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, 45 points or 50 points. In some examples, the methods improve the MADRS rating of the treated subject by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0070] Cognitive impairment

[0071] The subject matter of the present disclosure is based in part on the surprising discovery that compounds of Formula I can be used to treat or prevent depression in subjects resistant to antidepressant therapy and / or to treat or prevent depression-related cognitive impairment in subjects resistant to antidepressant therapy. Thus, in one aspect, a method of treating or preventing depression-related cognitive impairment in subjects resistant to antidepressant therapy is provided.

[0072] Can use Wechsler Adult Intelligence Scale (WAIS) scale (WAIS-IV that for example is published in 2008) to determine the depression-related cognitive impairment of the experimenter who is resistant to antidepressant treatment.WAIS-IV is made up of 10 core subtests and five supplementary subtests, and wherein 10 core subtests comprise full scale IQ.In the case of new WAIS-IV, the speech / performance subscale of previous version is removed, and is replaced by index score.General ability index (GAI) is included, and it is made up of similarity, vocabulary and information subtest in verbal comprehension index, and block design, matrix reasoning and visual puzzle subtest in perceptual reasoning index.GAI is useful clinically, because it can be used as the measure of cognitive ability to the less susceptible to obstacle influence. Wechsler, David (1939). "The measurement of adult intelligence". Baltimore: Williams & Wilkins. p. 229. "Wechsler Adult Intelligence Scale--Revised". http: / / www.cps.nova.edu / ~cpphelp / WAIS-R.html.

[0073] There are four index scores representing the main components of intelligence:

[0074] Verbal Comprehension Index (VCI)

[0075] ●Perceptual Reasoning Index (PRI)

[0076] Working Memory Index (WMI)

[0077] ●Processing Speed ​​Index (PSI)

[0078] In some instances, the subject has at least a 0.1, 0.5, 1, 2, or 5 SD handicap as measured by the WAIS coded test relative to age, education, and sex.

[0079] In other examples, the Cogstate Neuropyschological Testing Battery criteria, the Hopkins Verbal Learning Test or the Hopkins Verbal Learning Test Revised, the Controlled Word Association Test and the Trail Making A and B Test, the Category Fluency Test, the Letter Fluency Test, the Patient Global Impression of Severity (PGI-S) test, and the Patient Global Impression of Improvement (PGI-I) test can be used to determine depression-related cognitive impairment in subjects who are resistant to antidepressant treatment.

[0080] In other examples, the Cogstate Neuropsychological Test Battery, the Hopkins Verbal Learning Test (or the Hopkins Verbal Learning Test-Revised), the Controlled Word Association Test, and the A and B Trail Making Test can be used to identify depression-related cognitive impairment in subjects who are resistant to antidepressant treatment.

[0081] In some instances, the improvement is by showing the baseline change of executive function and / or episodic memory.The change of baseline executive function and / or episodic memory can be assessed by reference to any one test or standard in test or standard as described herein, or if test or standard is described herein, then the comprehensive situation as one or more tests or standards is assessed.In one example, the improvement of executive function is assessed according to the comprehensive situation of the performance of the treated subject in single review test (One Back Test), classification fluency test [CFT], letter fluency test [LFT] and international digit symbol substitution test-symbol (International Digit Symbol Substitution Test-Symbols).In another example, the improvement of executive function is assessed according to the comprehensive situation of the performance (only immediate recall) in single card learning (One Card Learning) and Hopkins Verbal Learning Test-Revised Edition [HVLT-R] of the treated subject.

[0082] In one example, the Hopkins Verbal Learning Test (HVLT) or the Hopkins Verbal Learning Test-Revised (HVLT-R) can be used to determine the depression-related cognitive impairment of a subject who is resistant to antidepressant treatment. HVLT-R is a measure of verbal episodic memory, which consists of 3 initial learning trials, a delayed recall test and a yes / no delayed recognition test. HVLT-R has 6 alternative forms and parallel forms, thus reducing the possibility of exercise effect. At some. In some instances, the method provides the improvement of the HVLT or HVLT-R assessment of the subject treated. In some instances, the method makes the HVLT or HVLT-R assessment of the subject treated improve at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

[0083] In one example, the A and B line test can be used to determine depression-related cognitive impairment in subjects who are resistant to antidepressant treatment. The A and B line test is a paper-based test for evaluating the performance of processing speed and executive function. Part A of the test assesses complex attention and requires participants to connect randomly positioned numbered circles as quickly as possible. Part B assesses executive function and requires connecting circled letters and numbers in alternating numbers and letters in order (i.e., 1-A-2-B, etc.) as quickly as possible, alternating between numbers and letters. In some instances, the method provides an improvement in the A and B line performance of the treated subject. In some instances, the method improves the A and B line performance of the treated subject by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

[0084] In one example, a classification fluency test (CFT) can be used to determine the depression-related cognitive impairment of a subject who is resistant to antidepressant treatment. In one example, a classification fluency test (CFT) can be used to determine the depression-related cognitive impairment of a subject who is resistant to antidepressant treatment. Letter Fluency Test (LFT). CFT and LFT measure the performance of language and executive function areas and are paper-based verbal fluency tests. CFT measures the spontaneous generation of words representing different classifications (such as animals, fruits and vegetables) within 1 minute. LFT measures the spontaneous generation of words starting with a specified letter within 1 minute (assessing 3 different letters, such as F, A and S in each applicable trial visit). In some examples, the method provides an improvement in the CFT score of a treated subject. In some examples, the method improves the CFT score of a treated subject by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some instances, the method provides an improvement in the LFT score of the treated subject. In some instances, the method improves the LFT score of the treated subject by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

[0085] In one example, the Patient Global Impression of Severity (PGI-S) and the Patient Global Impression of Improvement (PGI-I) can be used to determine depression-related cognitive impairment in subjects who are resistant to antidepressant treatment. PGI-S and PGI-I enable participants to provide their perception of the severity of their symptoms and an assessment of any improvements observed during the trial. Participants are prompted to describe their personal overall perception of their depression and cognitive impairment. For PGI-S, participants will rate the severity of their symptoms on a seven-point scale: 1, absent; 2, very mild; 3, mild; 4, moderate; 5, moderately severe; 6, severe; 7, very severe. The 7-point scale of PGI-I is rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worsened; 6, much worsened; or 7, very much worsened. In some examples, the method provides an improvement in the PGI-S score of the treated subject. In some instances, the method improves the PGI-S score of the treated subject by at least about 1 point, 2 points, 3 points, 4 points, 5 points, or 6 points. In some instances, the method provides an improvement in the PGI-I score of the treated subject. In some instances, the method improves the PGI-I score of the treated subject by at least about 1 point, 2 points, 3 points, 4 points, 5 points, or 6 points.

[0086] In one example, the Cogstate neuropsychological test battery can be used to identify depression-related cognitive impairment in subjects who are resistant to antidepressant treatment.

[0087] As used herein, "cognitive impairment" refers to a deterioration or loss of cognitive ability relative to a subject. Such deterioration or loss of cognitive ability may be evident in an otherwise cognitively healthy subject.

[0088] Other medical conditions that may be associated with cognitive impairment or deterioration include those that primarily affect the central nervous system (CNS) or are highly associated with it. In some embodiments, the subject does not suffer from another medical condition associated with the central nervous system (CNS), such as Alzheimer's disease (AD).

[0089] In some embodiments, the subject may not have a condition associated with significantly elevated levels of cortisol, such as dementia. Dementias include, but are not limited to, Alzheimer's disease, multi-infarct dementia, dementia with Lewy bodies, frontotemporal dementia (including Pick's disease), progressive supranuclear palsy, Korsakoff's syndrome, Biswanger's disease, HIV-associated dementia, Creutzfeldt-Jakob disease (CJD), multiple sclerosis, motor neuron disease, Parkinson's disease, Huntington's disease, Niemann-Pick disease type C, normal pressure hydrocephalus, and Down's syndrome.

[0090] The subject's Cortisol level (in nmol / L) may be less than about 450, 440, 430, 420, 410, 400, 390, 380, 370, 360, 250, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, or 200. The subject's Cortisol level (in nmol / L) may be at least about 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, or 350. The cortisol level of the experimenter (in nmol / L) can be in the range provided by any two levels of these upper and / or lower limits. For example, the cortisol level of the experimenter (in nmol / L) can be in the range between about 150 and 400, between 170 and 350, or between 200 and 330. The cortisol level can be measured from the plasma or serum of the experimenter. The cortisol level can represent the mean value of daily or weekly measurements.

[0091] Age and gender of the subjects

[0092] It should be understood that cognitive decline is different for different subjects. In some embodiments, the age of the subject (in years) is at least about 5, 10, 15, 18, 20, 30, 40, 50, 60, 70, 75, 80, 90, or 100. In some embodiments, the age of the subject (in years) is less than about 90, 80, 75, 70, 60, 50, 40, 30, 20, 18, or 10. The age of the subject can be in the range between any two values ​​of these upper and / or lower limits.

[0093] Subjects at increased risk for depression and related cognitive impairment

[0094] It will also be understood that the methods disclosed herein can be applied to prevent and / or reduce cognitive impairment in subjects at increased risk of antidepressant-resistant depression and related cognitive impairment. "Increased risk" is used herein to refer to a subject that may have a higher likelihood of experiencing antidepressant-resistant depression and related cognitive impairment. In some embodiments, the subject has an increased risk of antidepressant-resistant depression. In some embodiments, the subject has an increased risk of antidepressant-resistant cognitive impairment. In some embodiments, the subject has an increased risk of experiencing severe antidepressant-resistant depression and related cognitive impairment.

[0095] Those skilled in the art will appreciate that there are many factors that may cause a subject to have an increased risk of antidepressant-resistant depression and related cognitive impairment. Factors that may cause a subject to have an increased risk include, but are not limited to, the presence of specific genetic markers, a family history of antidepressant-resistant depression and related cognitive impairment, exposure to specific medical conditions associated with antidepressant-resistant depression and related cognitive impairment, and / or environmental factors associated with antidepressant-resistant depression and related cognitive impairment, and / or social factors associated with antidepressant-resistant depression and related cognitive impairment, and / or external factors associated with antidepressant-resistant depression and related cognitive impairment.

[0096] Enhanced cognitive abilities

[0097] It will also be understood that the methods disclosed herein can be beneficial to treat or prevent cognitive disorders in subjects with antidepressant resistant depression and / or related cognitive disorders. As used herein, "treatment" refers to the improvement of cognitive ability compared to the subject's previous ability (i.e., before applying a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof). In certain embodiments, the subject has experienced cognitive improvement. The enhancement of cognitive ability may be related to one or more aspects of cognition, including, for example, psychomotor function, visual attention, learning and memory, working memory and visual associative memory. Such cognitive abilities can be measured using various techniques known in the art, such as the techniques described below (e.g., Cogstate test suite). In certain embodiments, the subject has experienced psychomotor function enhancement. In certain embodiments, the subject has experienced visual attention enhancement. In certain embodiments, the subject has experienced learning and memory enhancement. In certain embodiments, the subject has experienced working memory enhancement. In certain embodiments, the subject has experienced visual associative memory enhancement.

[0098] Methods for assessing cognitive abilities

[0099] There are several tests by which the cognitive abilities of a subject can be assessed. Thus, based on the results of these tests, it is possible to assess the cognitive decline of a subject.

[0100] Those skilled in the art will appreciate that there are various tests that can be used to accurately assess the cognitive state of a subject and similar cognitive degradation. Such tests include, but are not limited to, Cogstate test batteries; Cambridge Neuropsychological Test Automated Battery (CANTAB); IQ (IQ) test; Kohs Block Design Test; Miller Analogies Test; Otis-Lennon School Ability Test (OLSAT); Raven's Progressive Matrices; Stanford-Binet Intelligence Scales; Wechsler Intelligence Scale for Children (WISC); Wonderlic Test; Porteus Maze Test; Pimsleur Language Aptitude Test (Pimsleur Language Aptitude Test); Battery); Knox Cubes; Draw a Man Test; Mini-Mental State Examination (MMSE); Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, ADCOM, Rey Auditory Visual Learning Test (RAVLT), NTB and NPI); and CDR computerized assessment system. The Cogstate battery of tests includes, for example, detection tests, identification tests, single card learning tests, single review working memory tests, continuous paired associative learning tests, and international digital symbol substitution tests-symbols. Each test is designed to assess various parameters that can be attributed to the cognitive abilities of the subject. Therefore, in some embodiments, administration of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof provides improvements in cognitive tests (Cogstate battery of tests) in treated subjects relative to untreated subjects. Improvement on cognitive tests (as determined by the Cogstate battery of tests) can also be considered based on the sum of each individual test result (e.g., Detection Test, Identification Test, Single Card Learning Test, Single Recall Working Memory Test, International Digit Symbol Substitution Test, and Serial Paired Associates Learning Test).

[0101] In some instances, any one or more cognitive tests measuring improvement in reaction time can provide an improvement of at least about (log10, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some instances, any one or more cognitive tests can provide a "p-value" probability measure of less than about 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or 0.001 from a treated group of subjects. In some instances, a cognitive test can provide a Cohen's "d-value" standardised difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8. In some examples, cognitive tests may provide "p-values" and "d-values" according to any combination of their individual embodiments as described herein.

[0102] In some embodiments, administration of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof provides an improvement in psychomotor function in a treated subject relative to an untreated subject. Psychomotor function is demonstrated by an improvement in simple reaction time and is measured as a function of performance speed (Log 10 Milliseconds). As will be appreciated by those skilled in the art, psychomotor function is essential for the ability of a subject to perform both gross motor skills and fine motor skills. Therefore, psychomotor function is an important component of physical skills, including, for example, movement, coordination, manipulation, dexterity, elegance, strength and speed. Therefore, it is foreseeable that the methods described herein may be particularly applied to improve the psychomotor function of cognitive healthy subjects. In some embodiments, administration of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof provides an improvement in the psychomotor function of cognitive healthy subjects. In some embodiments, administration of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof provides an improvement in the physical skills of cognitive healthy subjects. In some embodiments, administration of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof provides an improvement in the gross motor skills of cognitive healthy subjects. In some embodiments, administration of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof provides an improvement in the fine motor skills of cognitive healthy subjects.

[0103] It is foreseeable that the methods described herein may also be particularly useful in helping a subject recover psychomotor function. The loss of psychomotor function may be caused by any number of reasons, including but not limited to accidents and / or injuries, strokes or other medical conditions. The loss of such psychomotor skills may affect any one or more areas of the subject's body, including but not limited to the limbs. Therefore, administration of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof may help recover psychomotor function. The term "recovering psychomotor function" is used herein to mean recovering previous motor function to some extent.

[0104] In some embodiments, the use of Formula I compound or its pharmaceutically acceptable salt, solvate or prodrug provides performance improvement of psychomotor function speed. Relative to untreated subjects, the psychomotor function speed improvement between treated subjects can be measured. In some instances, less than about 2.60, 2.59, 2.58, 2.57, 2.56, 2.55, 2.54, 2.53, 2.52, 2.51 or 2.50 log10 reaction time (milliseconds) can provide psychomotor function speed improvement. In some instances, psychomotor function speed improvement can be at least about (log10, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.20. In some instances, the p-value probability measure for the psychomotor function test for the treated subject group is less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09. In some instances, the psychomotor function test can provide a Cohen's d value standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7. In some instances, the psychomotor function test can provide a "p-value" and a "d-value" according to any combination of its individual embodiments, such as a p-value of less than about 0.09, wherein the d-value effect size is greater than about 0.7.

[0105] In some embodiments, administration of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof improves visual attention in treated subjects relative to untreated subjects. Visual attention is demonstrated by an improvement in choice retention time and is measured as performance speed (Log 10In some embodiments, the improvement of visual attention is measured by selecting an improvement in retention time. In some embodiments, the improvement of visual attention is evaluated by the Cogstate identification test. In some embodiments, relative to untreated subjects, administration of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof provides an improvement in the performance of the visual attention speed of the treated subject. Relative to untreated subjects, the visual attention speed improvement between treated subjects can be measured. In some instances, visual attention speed improvement can be provided by a log10 reaction time (milliseconds) less than about 2.80, 2.79, 2.78, 2.77, 2.76, 2.75, 2.74, 2.73, 2.72, 2.71 or 2.70. In some instances, the visual attention speed improvement can be at least about (log10, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some instances, the p-value probability measure of the visual attention test of the treated subject group is less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09, 0.08, 0.07, 0.06, or 0.05. In some instances, the visual attention can provide a Cohen's d value standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, or 0.6. In some examples, a visual attention test can provide a "p-value" and a "d-value" according to any combination of its individual embodiments, such as a p-value of less than about 0.05, wherein the d-value effect size is greater than about 0.6.

[0106] In some embodiments, relative to untreated subjects, the use of Formula I compounds or its pharmaceutically acceptable salt, solvate or prodrug provides an improvement in the learning and memory of treated subjects. Learning and memory are demonstrated by the improvement of visual recognition learning, and are measured with the accuracy (inverse sine ratio correction) of performance. In some embodiments, the improvement of learning and memory is demonstrated by the improvement of visual recognition learning. In some embodiments, the improvement of learning and memory is evaluated by Cogstate single card learning test. In some embodiments, relative to untreated subjects, the use of Formula I compounds or its pharmaceutically acceptable salt, solvate or prodrug improves the learning and memory accuracy ratio (i.e., inverse sine ratio correction) of treated subjects by at least about X%. Relative to untreated subjects, the learning and memory accuracy between treated subjects can be measured to improve. In some instances, learning and memory accuracy tests can be provided by at least about 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09 or 1.10 inverse sine accuracy. In some instances, the p-value probability measure for the learning and memory accuracy test for the treated subject group is less than about 0.9. In some instances, the visual attention test can provide a Cohen's d-value standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.15, or 0.19. In some instances, the visual attention test can provide a "p-value" and a "d-value" according to any combination of its individual embodiments, such as a p-value less than about 0.9, wherein the d-value effect size is greater than about 0.15.

[0107] In some embodiments, relative to untreated subjects, the use of Formula I compounds or its pharmaceutically acceptable salt, solvate or prodrug provides an improvement in the working memory of treated subjects. In some embodiments, the improvement of working memory is evaluated by Cogstate One Back Working Memory Test, and is measured by the number of errors. In some embodiments, relative to untreated subjects, the use of Formula I compounds or its pharmaceutically acceptable salt, solvate or prodrug improves the number of working memory errors of treated subjects by at least about X%. Relative to untreated subjects, the working memory improvement between treated subjects can be measured. In some instances, a working memory test can be provided by a log10 reaction time less than about 2.90, 2.89, 2.88, 2.87, 2.86, 2.85, 2.84, 2.83, 2.82, 2.81 or 2.80. In some instances, the working memory test improvement can be at least about (log10, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some instances, the p-value probability measure for the working memory test for the treated group of subjects is less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01. In some instances, the working memory test can provide a Cohen's d value standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8. In some instances, the visual attention test can provide a "p value" and a "d value" according to any combination of its individual embodiments, such as a p value less than about 0.01, wherein the d value effect size is greater than about 0.8.

[0108] In some embodiments, relative to untreated subjects, the use of Formula I compound or its pharmaceutically acceptable salt, solvate or prodrug provides an improvement in the visual associative memory of treated subjects. In some embodiments, visual associative memory is evaluated by Cogstate continuous paired associative learning test (Cogstate Continuous Paired Associate Learning Test), and is measured with the number of errors. Relative to untreated subjects, visual associative memory improvement between treated subjects can be measured. In some instances, visual associative memory test can be provided by error scoring less than 25 points, 24 points, 23 points, 22 points, 21 points, 20 points, 19 points, 18 points, 17 points, 16 points, 15 points, 14 points, 13 points, 12 points, 11 points or 10 points in a total score of 30. In some instances, a visual associative memory test can be provided by improving error scoring by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 points. In some instances, the p-value probability measure of the visual associative memory test for the treated subject group is less than about 0.5. In some instances, the visual associative memory test can provide a Cohen's d value standardized difference between two means (i.e., treated and untreated subjects) of at least about 0.1, 0.2, 0.3, or 0.4. In some examples, a visual associative memory test can provide a "p-value" and a "d-value" according to any combination of its individual embodiments, such as a p-value less than about 0.5, wherein the d-value effect size is greater than about 0.4.

[0109] Compounds of formula I

[0110] It has been surprisingly found that compounds of formula I can be used to treat or prevent depression in subjects resistant to antidepressant therapy and / or to treat or prevent depression-related cognitive impairment in subjects resistant to antidepressant therapy. Embodiments of the methods and uses described herein comprise administering a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0111] As used herein, the compound of formula I has the following chemical structure:

[0112]

[0113] Where R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered carbocyclic group, 3-10 membered heterocyclic group, -CN, -CF3, -OR 3 、-SR 3 、-NR 3 R 4 、-COR 3 、-CO2R 3 、-CONR 3 R 4 、-NR 3 COR 4 、-SO2R 3 、-SO2NR 3 R 4 and-NR 3 S02R 4 .

[0114] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 C 1-6 In some embodiments, R 1 For-OC 1-6 In some embodiments, R 1 C 1-6 In some embodiments, R 1 For-OC 1-6 In some embodiments, R 1 C 2-6 In some embodiments, R 1 C 2-6 In some embodiments, R 1 is a 3-10 membered carbocyclic group. 1 is a 6-membered carbocyclic group. 1 is a 5-membered carbocyclic group. 1 is a 3-10 membered heterocyclic group. 1 is a 6-membered heterocyclic group. 1 is a 5-membered heterocyclic group. 1 In some embodiments, R1 In some embodiments, R 1 For-OR 3 In some embodiments, R 1 For-SR 3 In some embodiments, R 1 For-NR 3 R 4 In some embodiments, R 1 For-COR 3 In some embodiments, R 1 -CO2R 3 In some embodiments, R 1 For-CONR 3 R 4 In some embodiments, R 1 For-NR 3 COR 4 In some embodiments, R 1 SO2R 3 In some embodiments, R 1 SO2NR 3 R 4 In some embodiments, R 1 For-NR 3 S02R 4 .

[0115] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 C 1-6 In some embodiments, R 2 For-OC 1-6 In some embodiments, R 2 C 1-6 In some embodiments, R 2 For-OC 1-6 In some embodiments, R 2 C 2-6 In some embodiments, R 2 C 2-6 In some embodiments, R 2 is a 3-10 membered carbocyclic group. 2 is a 6-membered carbocyclic group.2 is a 5-membered carbocyclic group. 2 is a 3-10 membered heterocyclic group. 2 is a 6-membered heterocyclic group. 2 is a 5-membered heterocyclic group. 2 In some embodiments, R 2 In some embodiments, R 2 For-OR 3 In some embodiments, R 2 For-SR 3 In some embodiments, R 2 For-NR 3 R 4 In some embodiments, R 2 For-COR 3 In some embodiments, R 2 -CO2R 3 In some embodiments, R 2 For-CONR 3 R 4 In some embodiments, R 2 For-NR 3 COR 4 In some embodiments, R 2 SO2R 3 In some embodiments, R 2 SO2NR 3 R 4 In some embodiments, R 2 For-NR 3 S02R 4 .

[0116] If present, each 3-10 membered carbocyclyl and 3-10 membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -CF3, -OR 5 、-SR 5 、-NR 5 R 6 、-COR 5 、-CO2R 5 、-CONR 5 R 6 、-NR 5COR 6 、-SO2R 5 、-SO2NR 5 R 6 and-NR 5 S02R 6 .

[0117] In some embodiments, the 3-10 membered carbocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10 membered carbocyclyl is substituted with one or more C 1-6 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more -OC 1-6 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more C 1-6 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more -OC 1-6 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more C 2-6 In some embodiments, the 3-10 membered carbocyclyl is replaced by one or more C 2-6 In some embodiments, the 3-10 membered carbocyclyl is substituted with one or more -CN substituents. In some embodiments, the 3-10 membered carbocyclyl is substituted with one or more -CF3 substituents. In some embodiments, the 3-10 membered carbocyclyl is substituted with one or more -OR 5 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more -SR 5 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more -COR 5 In some embodiments, the 3-10 membered carbocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10 membered carbocyclyl is substituted with one or more -CO2R 5 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more -CONR 5 R 6 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more -NR 5 COR 6 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more -SO2R 5 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more -SO2NR 5 R 6 In some embodiments, the 3-10 membered carbocyclic group is replaced by one or more -NR 5 S02R 6 Substituent substitution.

[0118] In some embodiments, R 1 is a 6-membered carbocyclic group and is substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -CF3, -OR 5 、-SR 5 、-NR 5 R 6 、-COR 5 、-CO2R 5 、-CONR 5 R 6 、-NR 5 COR 6 、-SO2R 5 、-SO2NR 5 R 6 and-NR 5 S02R 6 In some embodiments, R 1 is a 5-membered carbocyclic group and is substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -CF3, -OR 5 、-SR 5 、-NR 5 R 6 、-COR 5 、-CO2R 5 、-CONR 5 R 6 、-NR 5 COR 6 、-SO2R 5 、-SO2NR 5 R 6 and-NR 5 S02R 6 .

[0119] In some embodiments, the 3-10 membered heterocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10 membered heterocyclyl is substituted with one or more C 1-6In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more -OC 1-6 In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more C 1-6 In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more -OC 1-6 In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more C 2-6 In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more C 2-6 In some embodiments, the 3-10 membered heterocyclyl is substituted with one or more -CN substituents. In some embodiments, the 3-10 membered heterocyclyl is substituted with one or more -CF3 substituents. In some embodiments, the 3-10 membered heterocyclyl is substituted with one or more -OR 5 In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more -SR 5 In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more -COR 5 In some embodiments, the 3-10 membered heterocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10 membered heterocyclyl is substituted with one or more -CO2R 5 In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more -CONR 5 R 6 In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more -NR 5 COR 6 In some embodiments, the 3-10 membered heterocyclic group is replaced by one or more -SO2R 5 In some embodiments, the 3-10 membered heterocyclic group is replaced by one or more -SO2NR 5 R 6 In some embodiments, the 3-10 membered heterocyclyl is replaced by one or more -NR 5 S02R 6 Substituent substitution.

[0120] In some embodiments, R 2 is a 6-membered carbocyclic group and is substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -CN, -CF3, -OR 5 、-SR 5 、-NR 5 R 6 、-COR 5 、-CO2R 5 、-CONR 5 R 6 、-NR 5 COR 6 、-SO2R 5 、-SO2NR 5 R 6 and-NR 5 S02R 6 In some embodiments, R 2 is a 5-membered carbocyclic group and is substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -CF3, -OR 5 、-SR 5 、-NR 5 R 6 、-COR 5 、-CO2R 5 、-CONR 5 R 6 、-NR 5 COR 6 、-SO2R 5 、-SO2NR 5 R 6 and-NR 5 S02R 6 .

[0121] If present, R 3 and R 4 Each independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, 3-7 membered carbocyclic group and 3-7 membered heterocyclic group.

[0122] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 C 1-6 In some embodiments, R 3 is a 3-7 membered carbocyclic group. 3 is a 3-7 membered carbocyclic group. 3is a 5-membered carbocyclic group. 3 It is a 6-membered carbocyclic group.

[0123] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 C 1-6 In some embodiments, R 4 is a 3-7 membered carbocyclic group. 4 is a 3-7 membered carbocyclic group. 4 is a 5-membered carbocyclic group. 4 It is a 6-membered carbocyclic group.

[0124] If present, R 5 and R 6 Each independently selected from hydrogen and C 1-6 Alkyl group.

[0125] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 C 1-6 alkyl.

[0126] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 C 1-6 alkyl.

[0127] In some embodiments, R 1 and R 2 Each is independently selected from the group consisting of hydrogen, halogen, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, -OH, -CN and -NH2. If present, each 3-10 membered carbocyclyl and 3-10 membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2 and C 1-6 alkyl.

[0128] In some embodiments, R 1 and R 2 Each is independently selected from the group consisting of: hydrogen, halogen, 6-membered carbocyclyl, 6-membered heterocyclyl, -OH, -CN and -NH2. If present, each 6-membered carbocyclyl and 6-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of: hydrogen, halogen, -OH, -CN, -CF3, -NH2 and C 1-6 alkyl.

[0129] In some embodiments, R 1 Selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2 and C1-6 Alkyl, and R 2 Independently selected from the group consisting of:

[0130]

[0131] In some embodiments, R 1 is hydrogen, and R 2 Independently selected from the group consisting of:

[0132]

[0133] In some embodiments, R 1 is a halogen, and R 2 Independently selected from the group consisting of:

[0134]

[0135] In some embodiments, R 1 is -OH, and R 2 Independently selected from the group consisting of:

[0136]

[0137] In some embodiments, R 1 is -CN, and R 2 Independently selected from the group consisting of:

[0138]

[0139]

[0140] In some embodiments, R 1 is -CF3, and R 2 Independently selected from the group consisting of:

[0141]

[0142] In some embodiments, R 1 is -NH2, and R 2 Independently selected from the group consisting of:

[0143]

[0144] In some embodiments, R 1 C 1-6 Alkyl, and R 2 Independently selected from the group consisting of:

[0145]

[0146] In some embodiments, R 1 is chlorine, and R 2 Independently selected from the group consisting of:

[0147]

[0148] In some embodiments, R 1 is bromine, and R 2 Independently selected from the group consisting of:

[0149]

[0150]

[0151] In some embodiments, R 1 is fluorine, and R 2 Independently selected from the group consisting of:

[0152]

[0153] In some embodiments, R 1 is iodine, and R 2 Independently selected from the group consisting of:

[0154]

[0155] In some embodiments, R 2 Selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2 and C 1-6 Alkyl, and R 1 Independently selected from the group consisting of:

[0156]

[0157] In some embodiments, R 2 is hydrogen, and R 1 Independently selected from the group consisting of:

[0158]

[0159] In some embodiments, R 2 is a halogen, and R 1 Independently selected from the group consisting of:

[0160]

[0161]

[0162] In some embodiments, R 2 is -OH, and R1 Independently selected from the group consisting of:

[0163]

[0164] In some embodiments, R 2 is -CN, and R 1 Independently selected from the group consisting of:

[0165]

[0166] In some embodiments, R 2 is -CF3, and R 1 Independently selected from the group consisting of:

[0167]

[0168] In some embodiments, R 2 is -NH2, and R 1 Independently selected from the group consisting of:

[0169]

[0170] In some embodiments, R 2 C 1-6 Alkyl, and R 1 Independently selected from the group consisting of:

[0171]

[0172]

[0173] In some embodiments, R 2 is chlorine, and R 1 Independently selected from the group consisting of:

[0174]

[0175] In some embodiments, R 2 is bromine, and R 1 Independently selected from the group consisting of:

[0176]

[0177] In some embodiments, R 2 is fluorine, and R 1 Independently selected from the group consisting of:

[0178]

[0179] In some embodiments, R2 is iodine, and R 1 Independently selected from the group consisting of:

[0180]

[0181] In some embodiments, R 1 and R 2 Each independently selected from the group consisting of:

[0182]

[0183]

[0184] In some embodiments, the compound of Formula I is selected from the group consisting of:

[0185]

[0186] In some embodiments, the compound of formula I is:

[0187]

[0188] In some embodiments, the compound of formula I is:

[0189]

[0190] In some embodiments, the compound of formula I is:

[0191]

[0192] In some embodiments, the compound of formula I is:

[0193]

[0194] In some embodiments, the compound of formula I is:

[0195]

[0196] In some embodiments, the compound of formula I is:

[0197]

[0198] In some embodiments, the compound of formula I is:

[0199]

[0200] In some embodiments, the compound of formula I is:

[0201]

[0202] As will be appreciated by those skilled in the art, compounds of Formula I include any stereoisomer of the depicted structure. That is, compounds of Formula I include racemic mixtures.

[0203] As used herein, the compound of Formula Ia has the following chemical structure:

[0204]

[0205] R 1 and R 2 The definitions of are the same as those provided for compounds of formula I. That is, the compounds of formula I differ from compounds of formula Ia in that the stereochemistry in compounds of formula Ia has been resolved.

[0206] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, has a specific stereochemistry, as depicted in the following chemical structure:

[0207]

[0208] When having such specific stereochemistry, the compound of Formula Ia is also known as "UE2343" or "Xanamem" and has the CAS number: 1346013-80-6. The chemical name (i.e., IUPAC name) of Formula Ia is (5-(1H-pyrazol-4-yl)thiophen-3-yl)(3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-8-yl)methanone.

[0209] The compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof can be prepared by any suitable method as will be understood by those skilled in the art. The compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof can be prepared according to the procedures described in WO 2011135276, which is further incorporated herein by reference.

[0210] Salt

[0211] It may be convenient or desirable to prepare, purify and / or handle the corresponding salt of the compound, e.g., a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts", J. Pharm. Sci., Vol. 66, pp. 1-19.

[0212] For example, if the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO - ), then a suitable cation may be used to form a salt. Examples of suitable inorganic cations include, but are not limited to, Na + and K + Alkali metal ions such as Ca 2+ and Mg 2+ Alkaline earth cations such as Al 3+ Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4 + ) and substituted ammonium ions (e.g., NH3R + NH2R2 + 、NHR3 + NR4 + Examples of suitable substituted ammonium ions include, but are not limited to, those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. Common examples of quaternary ammonium ions are N(CH3)4 + .

[0213] If the compound is cationic or has a functional group that can be cationic (e.g., -NH2 can be -NH3 + ), then a suitable anion can be used to form a salt. Examples of suitable inorganic cations include, but are not limited to, inorganic cations derived from inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid. Examples of suitable organic anions include, but are not limited to, organic anions derived from organic acids, including 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, benzenesulfonic acid, propionic acid, pyruvic acid, salicylic ring, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from polymeric acids including tannic acid and carboxymethyl cellulose.

[0214] A pharmaceutically acceptable salt may involve another molecule including, for example, acetate ions, succinate ions, or other counterions. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions. It will also be understood that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure, as the salts may be used as intermediates in the preparation of pharmaceutically acceptable salts, or may be useful during storage or transportation. Unless otherwise provided herein, reference to a particular compound also includes its salt.

[0215] Solvates and Hydrates

[0216] It may be convenient or desirable to prepare, purify and / or process the corresponding solvate of the compound. It will be understood by those skilled in the art of organic chemistry and / or medicinal chemistry that many organic compounds can form complexes with solvents in which the organic compound reacts or the organic compound precipitates or crystallizes from the solvent. Such complexes are referred to as "solvates", and as used herein, the term "solvate" refers to such complexes of a solute (e.g., a compound, a salt of a compound) and a solvent. Examples of solvents that can form pharmaceutically acceptable solvates include, but are not limited to, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. If the solvate is water, the solvate can be conveniently referred to as "hydrate". In certain embodiments, a pharmaceutically acceptable solvate is a pharmaceutically acceptable hydrate. Hydrates can be, for example, monohydrates, dihydrates, trihydrates, etc. Unless otherwise provided herein, reference to a specific compound also includes its solvate.

[0217] Prodrug

[0218] It may be convenient or desirable to prepare, purify and / or process a compound in the form of a prodrug. As used herein, the term "prodrug" refers to a compound that produces a desired active compound when metabolized (e.g., in vivo). Typically, a prodrug is inactive or less active than the desired active compound, but may provide favorable handling, administration or metabolic characteristics.

[0219] Moreover, as will be appreciated by those skilled in the art of organic chemistry and / or medicinal chemistry, some prodrugs are enzymatically activated to produce the active compound or compounds that produce the active compound in further chemical reactions. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

[0220] Methods and uses

[0221] The present disclosure provides a method for treating or preventing depression in a subject resistant to antidepressant treatment and / or treating or preventing depression-related cognitive impairment in a subject resistant to antidepressant treatment. The method may comprise administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof to the subject. The present disclosure also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for treating depression in a subject resistant to antidepressant treatment and / or treating depression-related cognitive impairment in a subject resistant to antidepressant treatment. The compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof can be used to manufacture a drug for treating depression in a subject resistant to antidepressant treatment and / or treating depression-related cognitive impairment in a subject resistant to antidepressant treatment.

[0222] It will be understood that the dosage regimens and compositions as described herein can be applied to any embodiment or example of the embodiments or examples of the methods as described herein.

[0223] Dosage regimen

[0224] As used herein, "therapeutically effective amount" refers to the administration of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof in such an amount that is sufficient to alleviate or prevent one or more of the symptoms of the disease or condition being treated to a certain extent, generally without undue adverse side effects, or to achieve the desired pharmacological effect or therapeutic improvement with a reduced side effect profile. The result can be a reduction and / or alleviation of the signs, symptoms or causes of the disease or condition, or any other desired biological system changes. In some embodiments, the term "therapeutically effective amount" refers to the administration of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof in such an amount that is sufficient to cause relief of symptoms associated with antidepressant-resistant depression and / or related cognitive disorders. For example, a therapeutically effective amount can be determined by routine experiments, including but not limited to dose escalation clinical trials. The phrase "therapeutically effective amount" includes, for example, a preventive and therapeutic effective amount. In some embodiments, the preventive and therapeutic effective amount is an amount sufficient to prevent antidepressant-resistant depression and / or related cognitive disorders. It should be understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject due to variations in the metabolism of the compound and any of the subject's age, weight, general condition, condition being treated, severity of condition being treated, and the judgment of the prescribing physician. In any individual case, an "appropriate effective amount" or "therapeutically effective amount" may be determined by one of ordinary skill in the art using routine experimentation.

[0225] The amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof that will effectively treat and / or prevent a specific disorder or condition disclosed herein will depend on the nature of the disorder or condition and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be used to help identify the optimal dosage range. Such techniques are known to those skilled in the art.

[0226] The precise dosage administered to a subject will also depend on the route of administration and the severity of the disease or condition, and should be determined according to the practitioner's judgment and the circumstances of each subject. For example, a suitable dosage range for oral administration is generally about 0.001 mg to 1000 mg of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof per kilogram of body weight.

[0227] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered in an amount to deliver a total daily dose (in mg) of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, 150 or 200. In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered in an amount to deliver a total daily dose (in mg) of less than about 200, 150, 100, 75, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 or 1. The total daily dose can be provided in a range between any two amounts of these upper and / or lower limits. For example, the total daily dose may be provided in an amount between about 1 and 100 mg, between about 5 and 75 mg, between about 10 and 50 mg, between about 15 and 45 mg, or between about 20 and 40 mg.

[0228] In some embodiments, a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to a subject at a predetermined frequency. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to a subject according to a dosage regimen in which the compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered once a day, twice a day, three times a day or four times a day. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to a subject according to a dosage regimen in which the compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered once a day. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to a subject according to a dosage regimen in which the compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered twice a day. In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to a subject according to a dosage regimen in which the compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered three times a day. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered to the subject according to the dosage regimen, and the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered four times a day in the dosage regimen. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered to the subject according to the dosage regimen, and the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered multiple times a day in the dosage regimen. In some examples, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered once a day with a dosage between about 10mg and 30mg (for example, with about 20mg). In other examples, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered twice a day with a single dose between about 5mg and 20mg (for example, with a single dose of 10mg). In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered three times a day with a single dose between about 5mg and 15mg (for example, with a single dose of about 10mg).

[0229] In some embodiments, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to a subject at a predetermined frequency and / or duration. For example, the duration of about or at least about 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 2 years or 5 years can be continued according to the administration (e.g., frequency) of any embodiment as described herein. As long as the subject receives a therapeutic effect, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof can be continuously administered.

[0230] As used herein, the terms "administer" and "administering" are used to refer to the introduction of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, into a subject. When administration is for therapeutic purposes, a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided at or after the onset of symptoms of cognitive deterioration. The therapeutic administration of this substance helps alleviate any symptoms or prevents the occurrence of additional symptoms. When administration is for the purpose of preventing or reducing the likelihood of cognitive deterioration, a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided before any visible or detectable symptoms. Preventive administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, helps alleviate subsequent symptoms or prevents or reduces the likelihood of symptoms occurring entirely.

[0231] The compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug can be administered by any suitable route. Examples include, but are not limited to, oral, topical, transdermal, intranasal, vaginal, rectal, intraarterial, intramuscular, intraosseous, intraperitoneal, epidural and intrathecal. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is administered orally.

[0232] As will be appreciated by those skilled in the art, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug can be applied to the subject according to the fasting state of the subject. For example, the subject can apply the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug before, during or after a meal. In certain embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is applied to the subject before a meal (that is, the subject is in a fasting state). In certain embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is applied to the subject at the time of a meal. In certain embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug is applied to the subject at a certain interval (that is, 30 minutes, 1 hour, 2 hours, 3 hours, etc.) after a meal.

[0233] Composition

[0234] Compositions suitable for use in the methods and uses described herein include a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof is present as a composition. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof is present as a pharmaceutical composition.

[0235] The disclosure also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients, stabilizers, etc. The carrier must be pharmaceutically acceptable in the sense that it is compatible with the other ingredients of the formulation and is not excessively harmful to its recipient. Generally, suitable pharmaceutically acceptable carriers are known in the art and are selected based on end-use applications. Pharmaceutically acceptable carriers can be used as diluents, dispersants or carriers for other optional components of active agents and compositions. Pharmaceutically acceptable carriers can also contain materials commonly used in pharmaceutical products, and can be in various forms. For example, the carrier can be water, liquid or solid emollients, silicone oils, emulsifiers, surfactants, solvents, humectants, thickeners, powders, propellants, etc.

[0236] In some embodiments, the composition is a pharmaceutical composition, and wherein the composition comprises a pharmaceutically acceptable excipient.

[0237] The composition may, for example, contain a solvent such as water (eg, water for injection) or a pharmaceutically acceptable organic solvent.

[0238] The composition may further include diluents, buffers, citrate esters, trehalose, binders, disintegrants, thickeners, lubricants, preservatives (including antioxidants), inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antistatic agents, sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines, fatty acids and fatty esters, steroids (e.g., cholesterol)), and chelating agents (e.g., EDTA, zinc and other such suitable cations).

[0239] The compositions of the present disclosure may also include polymeric excipients / additives or carriers, such as polyvinylpyrrolidone; derivatized celluloses, such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose; Ficoll (a polymer sugar); hydroxyethyl starch (HES); dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin); polyethylene glycol; and pectin.

[0240] Other pharmaceutical carriers, excipients, optional ingredients and / or additives suitable for use in the compositions according to the present disclosure are listed in "Remington: The Science & Practice of Pharmacy", Supplement 19th Edition, Williams and Williams, (1995); and in "Physician's Desk Reference", Supplement 52nd Edition, Medical Economics, Montvale, NJ (1998); and in "Handbook of Pharmaceutical Excipients", Third Edition, Editor AH Kibbe, Pharmaceutical Press, 2000.

[0241] The compounds of Formula I of the present disclosure, or pharmaceutically acceptable salts, solvates or prodrugs thereof, can be formulated into compositions, including compositions suitable for inhalation into the lungs by aerosol, parenteral (including intraperitoneal, intravenous, subcutaneous or intramuscular injection) or oral administration.

[0242] The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of incorporating a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof into a carrier which constitutes one or more accessory ingredients.

[0243] Generally, the composition is prepared by incorporating a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, into a liquid carrier to form a solution or suspension, or alternatively, by incorporating a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, into a formulation component suitable for forming a solid (optionally a particulate product), and then, if necessary, shaping the product into the desired delivery form.

[0244] In some embodiments, the composition is formulated for oral delivery. For example, the composition for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. The composition for oral administration can contain one or more optional medicaments, such as sweeteners, such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, wintergreen oil or cherry; coloring agents; and preservatives to provide pharmaceutically palatable preparations. In addition, in the case of tablet or pill form, the composition can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over an extended period of time. Oral compositions can include standard vehicles, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such vehicles are preferably pharmaceutical grade. The oral compositions described herein may contain from about 1% to about 95% by weight of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, and the oral compositions may be administered once, twice, three times, four times, five times or more daily. The oral compositions described herein may contain at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% by weight of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. The oral compositions described herein may contain less than about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% by weight of a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The oral compositions described herein may contain a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a weight percent (e.g., between about 5 and 20 wt%) within the range provided by any two of these upper and / or lower limits.

[0245] In some embodiments, the composition is formulated for parenteral delivery. For example, in one embodiment, the composition can be a sterile, lyophilized, crystalline or amorphous composition suitable for reconstitution in an aqueous vehicle prior to injection.

[0246] In one embodiment, compositions suitable for parenteral administration conveniently comprise a sterile aqueous preparation of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which may, for example, be formulated to be isotonic with the blood of the recipient.

[0247] Also provided are pharmaceutical compositions suitable for administration by inhalation as aerosols. These formulations comprise solutions or suspensions of compounds of formula I or pharmaceutically acceptable salts, solvates or prodrugs thereof. The desired formulation can be placed in a small chamber and atomized. Atomization can be achieved by forming multiple liquid droplets or solid particles comprising compounds of formula I or pharmaceutically acceptable salts, solvates or prodrugs thereof by compressed air or ultrasonic energy.

[0248] As discussed below, the compounds of Formula I disclosed herein, or pharmaceutically acceptable salts, solvates or prodrugs thereof, can be administered, for example, in combination with one or more additional pharmaceutically active agents. Thus, in some embodiments, the composition comprises a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers, and one or more additional pharmaceutically active agents.

[0249] Typically, the composition comprises a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof in a therapeutically effective amount. In some embodiments, a therapeutically effective amount is provided by a single dose. In some embodiments, a therapeutically effective amount is provided by one or more doses administered as part of a treatment course, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or more than 27 doses.

[0250] Those skilled in the art will appreciate that the amount of the compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, present in the composition will vary depending on the other ingredients present in the composition, the desired effect, etc. In some embodiments, the composition comprises a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, at a concentration between about 0.001 mg / mL to 1000 mg / mL, 0.01 mg / mL to 500 mg / mL, 0.1 mg / mL to 50 mg / mL. In some embodiments, the composition comprises a concentration between about 1 wt% and 99 wt%, between 1 wt% and 90 wt%, between 1 wt% and 85 wt%, between 1 wt% and 80 wt%, between 1 wt% and 75 wt%, between 1 wt% and 70 wt%, between 1 wt% and 65 wt%, between 1 wt% and 60 wt%, between 1 wt% and 55 wt%, between 1 wt% and 50 wt%, between 1 wt% and 45 wt%, between 1 wt% and 40 wt%, between 1 wt% and 35 wt%, between 1 wt% and 30 wt%, between 5 wt% and 99 wt%, between 10 wt% and 99 wt%, between 15 wt% and 99 wt%, between 20 wt% and 99 wt%, between 25 wt% and 99 % to 99wt%, between 30wt% and 99wt%, between 35wt% and 99wt%, between 40wt% and 99wt%, between 45wt% and 99wt%, between 50wt% and 99wt%, between 54wt% and 99wt%, between 60wt% and 99wt%, between 65wt% and 99wt%, between 70wt% and 99wt%, between 75wt% and 99wt%, between 80wt% and 99wt%, between 85wt% and 99wt%, between 90wt% and 99wt%, between 5wt% and 90wt%, between 20wt% and 80wt%, between 30wt% and 70wt%, or between 40wt% and 60wt% of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0251] In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug can be administered in combination with another therapeutic agent. The other therapeutic agent can be any one or more antidepressants according to any one or more examples thereof as described herein. For example, a compound of formula 1 according to any one or more examples thereof as described herein and any one or more SSRI and / or SNRI antidepressants. In some embodiments, the methods and uses described herein also involve co-administering one or more substances other than the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug to the subject. The term "co-administered" indicates that each of at least two compounds is administered during a time range in which the corresponding biological activity or action period overlaps. Therefore, the term includes continuous and co-extended administration of the compound. Similar to the administration of the compound, co-administration of more than one substance can be for treatment and / or prevention purposes. If more than one substance or compound is co-administered, the administration routes of the two or more substances do not have to be the same. The scope of the methods and uses described herein is not limited by the characteristics of the one or more substances that can be co-administered with the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug. For example, the composition comprising the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug can be co-administered with fluid or other materials that can alleviate, reduce, prevent or remove the symptoms of the subject who is subjected to cognitive degeneration, shows the symptoms of cognitive degeneration or is in the risk of bearing cognitive degeneration. The fluid type that can be co-administered with the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug should be specific to the surrounding conditions of the specific subject who is subjected to bacterial infection, shows the symptoms of bacterial infection or is in the risk of bearing bacterial infection. For example, the fluid that can be co-administered with the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug includes but is not limited to electrolytes and / or water, saline solutions (such as sodium chloride and sodium bicarbonate), and whole blood, plasma, serum, serum albumin and colloidal solution.

[0252] The composition can be food or beverage, or provided in food or beverage. The composition can be a veterinary product, such as a food product for dogs or cats. The composition can be a feed additive, a supplement or a medical food. In certain embodiments, the compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug can be incorporated into food products and beverages. The compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug can be impregnated, mixed, emulsified, sprayed or coated on a carrier, such as cellulose, methylcellulose, glucose, cycloglucose, cyclodextrin, maltitol and fiber. Delivery can also be enhanced with various surfactants, lipids, complexes, solvents and cosolvent drug delivery systems known in the pharmaceutical field to improve bioavailability, absorption and efficacy. As used herein, the term "food" or "food product" includes any edible product for human or non-human intake, such as but not limited to supplements, snacks (sweet and salty), foods containing cocoa, spices, beverages, dietary supplements and formulations, including supplements for animal health and nutrition. Additional ingredients desired in the resulting food product can be added at any point in the processing.

[0253] The present disclosure includes food products comprising one or more compounds of Formula I as active ingredients, alone or in combination with other active ingredients.

[0254] In some embodiments, a composition is provided, comprising a compound of formula I according to any one or more examples thereof as described herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and any one or more antidepressants. For example, a composition comprising a compound of formula 1 according to any one or more examples thereof as described herein and any one or more SSRI and / or SNRI antidepressants.

[0255] It will be appreciated that administration of the compound may be provided in a variety of forms, depending on the application and the subject.

[0256] Examples

[0257] Overview: Materials and Methods

[0258] Formulations comprising compounds of Formula Ia are tested on human subjects to evaluate use in the prevention and / or treatment of antidepressant-resistant depression and related cognitive disorders.

[0259] As described herein, the compound of formula Ia was synthesized and characterized according to the procedures described in WO 2011135276, which is incorporated herein by reference. The compound of formula Ia is also known as UE2343 or (5-(1H-pyrazol-4-yl)thiophen-3-yl)(3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-8-yl)methanone. Xanamem TMContains the compound of formula Ia as an active ingredient.

[0260] Example 1

[0261] XanaMDD: A double-blind, placebo-controlled, parallel-group study evaluating 10 mg daily Xanamem TM Efficacy and safety for cognition and depression in patients with treated major depressive disorder with persistent depressive disorder and cognitive impairment.

[0262] Research Centres: Multi-centre, with up to 10 sites across Australia.

[0263] Study Design: This was a randomized, placebo-controlled, parallel-group, double-blind trial in individuals diagnosed with a current episode of MDD who continued to experience cognitive difficulties and depressive symptoms.

[0264] Individuals aged ≥18 years and ≤70 years, diagnosed with a current MDD episode according to the DSM V criteria using the Brief International Neuropsychiatric Interview (Lecrubier et al., 1997) when screened by a psychiatrist will be eligible for inclusion in the trial. Participants have been treated with SSRI, SNRI or atypical antidepressants for at least 6 weeks and have persistent depressive symptoms (HAM-D>17) and poor cognition as determined by patient self-report. Trial participants will also need to show a 0.5SD disorder, according to the WAIS coding test, relative to age, education and gender-related norms, to demonstrate cognitive impairment.

[0265] Participants will be prescreened to assess possible eligibility. After consent, a psychiatric interview will be conducted and a WAIS coding test will be administered to confirm psychiatric and cognitive inclusion / exclusion criteria. A screening blood sample will also be collected.

[0266] Participants will participate in the trial for up to 14 weeks. The trial consists of a screening period (up to 4 weeks), a 6-week treatment period, and a follow-up period (4 weeks). Participants will be randomized 1:1 to daily Xanamem 10 mg or matching placebo. Approximately 120 participants will be enrolled.

[0267] Participants who meet eligibility criteria and have screening blood drawn ≤14 days before their scheduled Day 1 will proceed directly to Day 1, the baseline treatment visit. Participants whose screening visit occurs >14 days and whose eligibility has not yet been confirmed will be asked to visit the study site for a second screening visit between Days -3 and -1 to collect additional baseline clinical laboratory assessments.

[0268] On Day 1 prior to dosing, participants will confirm inclusion / exclusion criteria, including confirmation of persistent depressive symptoms (HAM-D) and cognitive difficulties (WAIS codes). A baseline assessment will be performed, including two Cogstate Neuropsychological Test Battery (NTB) assessments, at least 1 hour apart. The NTB contains numeric and paper-based measures of the domains of attention, executive function, and episodic memory.

[0269] Participants will take the study product on site with or after food and according to the randomized schedule.

[0270] At all follow-up visits, participants should take the study product at home with food or after food, and record the time of administration in the drug intake diary. If the participant forgets to take his study product before the visit, the participant can take the study product at the research site (or if the participant does not bring his medicine to the clinic, take it at home later). Follow-up visits will be conducted 4 weeks after the last administration of the study product to conduct final safety and efficacy durability assessments. Additional research details are provided below:

[0271]

[0272]

[0273]

[0274]

[0275] Xanamem TM Formulations and placebo capsules

[0276] Table 1. Xanamem TM 10mg capsule formulation

[0277] Components Weight per unit Formulation percentage w / w% UE2343 powder 10mg 10.53 lactose 170.5mg 84.47 Croscarmellose Sodium 7.6mg 4.00 talc 0.95mg 0.50 Magnesium Stearate 0.95mg 0.50 total 190mg 100％

[0278] Table 2. Placebo capsule formulation

[0279] Components Weight per unit Formulation percentage w / w% lactose 180.5mg 95 Croscarmellose Sodium 7.6mg 4.00 talc 0.95mg 0.50 Magnesium Stearate 0.95mg 0.50 total 190mg 100％

[0280] The Cogstate test battery may include the following tests: Detection Test, Identification Test, Single Card Learning Test, Single Recall Working Memory Test, and Continuous Paired Associate Learning Test (CPAL; Paired Associate Learning).

[0281] Detection Test

[0282] The Cogstate detection test is a measure of simple reaction time and has been shown to provide an effective assessment of psychomotor function. For this test, the subject presses the "yes" response key as soon as he detects an event (the card presented in the center of the computer screen turns face up). The software measures the response time to detect each event.

[0283] Identification Test

[0284] The Cogstate Identification Test is a measure of choice reaction time and has been shown to provide an effective assessment of visual attention. In this test, an event occurs in the center of a computer screen (a card turns face-up), and the subject decides "yes" or "no" based on whether the event meets a predefined and unchanging criterion (i.e., is the color of the card red?). The software measures the speed and accuracy of each response.

[0285] Single card learning test

[0286] The Single Card Learning Test is a continuous visual recognition learning test that assesses visual learning within the pattern separation model (Yassa et al., 2010). The theoretical model of the pattern separation model stipulates that information is organized in orthogonal and distinct non-overlapping representations so that new memories can be quickly stored without interference. The Single Card Learning Test has been shown to be an effective learning and memory test.

[0287] In this test, participants focus on the card in the center of the screen and answer the question "Have you seen this card before in this test?" If the answer is yes, the participant is instructed to press the "yes" button, otherwise if the answer is no, the participant will press the "no" button. A normal playing card (no joker) is displayed.

[0288] In this test, six cards are randomly drawn from the deck and repeated throughout the test. These four cards are interspersed with distractors (non-repeated cards). The test ends after 50 trials, and correct trials after anticipation are not rearranged. The primary performance measure for this test is the proportion of correct answers (accuracy), which is normalized using an arcsine square root transformation.

[0289] Single-recall working memory test

[0290] The Cogstate single recall memory test is an effective working memory measure. In this test, the subject is shown a single stimulus in the center of the computer screen (the cards are turned face up). The subject decides "yes" or "no" based on whether the current card matches the card that has been seen in the immediately previous trial. The software measures the speed and accuracy of each response.

[0291] Continuous Paired Associate Learning Test (CPAL; paired associate learning)

[0292] The Continuous Paired Associates Learning Test is a measure of visual associative memory and uses a well-validated paired associates learning paradigm in which subjects have to learn the locations of many amoeba-like shapes on a computer screen.

[0293] This test consists of a single amoeba-like shape displayed in the center of the screen surrounded by a number of blue-filled circles. Underneath all but two of the blue spheres are amoeba-like shapes, one of which matches the central display; the remaining two circles are distractors. During the exposure phase of the test, all of the pattern-location associations to be remembered are presented simultaneously on the computer screen.

[0294] After a five-second delay, the central position shows a pattern, and this indicates that the subject should touch the position in the periphery containing the same pattern. This process continues until the participant has confirmed all pattern position associations. The learning phase begins with the same test display presented during the exposure phase, except that now all peripheral positions are shown as blue spheres. One of the patterns presented in the exposure phase is presented in the central position. With the presentation of this pattern, the subject needs to select the peripheral position where the same pattern is hidden under the blue sphere. This process continues until the correct position of each pattern is found.

[0295] Finding the correct position for all patterns in a group is defined as a learning trial. There are six learning trials. After a 10-30 minute delay, a single trial delayed recall condition can be used for this test. The software records each action as an error or as a correct action.

[0296] Timing of the Cogstate Test Battery

[0297] Table 3 shows the timing of the Cogstate test suite.

[0298] Table 3. Trials and timing of each test in the cognitive battery

[0299]

[0300] Cognitive outcome measures

[0301] Although each of the cognitive tests to be used produces multiple outcome measures, research conducted by Cogstate identified a set of measures that are optimal for detecting cognitive changes in clinical trials at both the group and individual levels.

[0302] For each cognitive test, a single outcome measure was selected from each test in the battery to minimize experimental error rate. Each outcome measure was selected because it was shown to be optimal for detecting changes because:

[0303] - is drawn from a data distribution that contains only a small probability of floor or ceiling effects and has no restriction on the range of possible performance values; and

[0304] - It is drawn from a distribution that is normal or can be corrected to be normal by using an appropriate mathematical transformation (e.g., log base 10 or arcsine).

[0305] Table 4 summarizes the outcome measures for the tests used.

[0306] Table 4. Cognitive suite of suggested outcome measures

[0307]

[0308]

[0309] * Reaction times longer than 5 seconds (ie, log10

[5000] ) were excluded as reflecting an abnormally slow response. # For this test, the total n errors in a single administration were controlled so that patients who did not understand the test were not tested unnecessarily.

[0310] Example 2

[0311] XanaCIDD: A double-blind, randomized, placebo-controlled, parallel-group trial to evaluate Safety, tolerability, and efficacy in adults with cognitive impairment due to depression.

[0312] Trial Sites: This clinical trial will be conducted at multiple sites in Australia and the United Kingdom.

[0313] Study Design: This was a phase 2, randomized, placebo-controlled, parallel-group, double-blind, proof-of-concept trial in individuals diagnosed with MDD who continued to experience cognitive impairment and depressive symptoms.

[0314] Individuals aged ≥18 years and ≤75 years diagnosed with a current episode of MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria using the Mini-International Neuropsychiatric Interview (MINI) at screening by a recognized medical professional will be eligible for inclusion in the trial. Participants must be taking a stable dose of a first-line or second-line antidepressant approved for the treatment of depression (but not a tricyclic antidepressant, monoamine oxidase inhibitor, or vortioxetine) for at least 6 weeks, or have a history of prior antidepressant use, have persistent depressive symptoms (Hamilton Depression Rating Scale [HAM-D] ≥17), and have poor cognition as determined by an affirmative response to any aspect of a single-question test about the perceived problems of their thinking ('Questions about cognition'). Trial participants will also need to demonstrate cognitive impairment by demonstrating a 0.5SD impairment relative to age- and education-related norms on the Brief and Simple Index of Cognition (BASIC) box-filling subtest.

[0315] After providing informed consent, assessments will be performed according to the assessment schedule (Table 8). The MINI will be performed to confirm relevant inclusion / exclusion criteria. Participants will complete a familiarization session and practice administration of each of the cognitive efficacy assessments during the screening period to ensure that the participant understands each procedure and to reduce any potential learning effects during the treatment period.

[0316] Participants will participate in the trial for up to 14 weeks. The trial consists of a screening period (up to 4 weeks), a 6-week treatment period, and a follow-up period (4 weeks). Participants will be randomized 1:1 to receive 10 mg of Xanamem daily or matching placebo. Approximately 160 participants will be enrolled.

[0317] Participants who meet the eligibility criteria and have a screening blood sample drawn ≤14 days before their scheduled Day 1 visit will proceed directly to Day 1, the Baseline Visit. Participants whose Screening Visit occurred >14 days before their scheduled Day 1 visit will need to travel to the trial site for a second Screening Visit between Days -13 and -3 to have an additional Screening Blood Sample drawn and a medical history reviewed.

[0318] During the Day 1 Baseline Visit, all baseline assessments will be conducted according to the Assessment Schedule (Table 8). Cognitive assessments contain numeric and paper-based measures of the domains of attention, executive function, and episodic memory, and include selected tests from the Cogstate CTB.

[0319] On Day 1, participants will be on site with or without food and take the study product (IP) according to the randomized schedule. Both the site staff treating the participants and the participants themselves will be blinded to the treatment being administered.

[0320] During the treatment period, three (3) follow-up visits (EOT visits) will be conducted at Weeks 2, 4, and 6 for safety and efficacy assessments. Some visits may be conducted remotely away from the trial site. On all follow-up visit days, participants should take the IP at home in the morning with or without food, and record their dosing time in their medication intake diary. If a participant goes to the clinic for a visit and forgets to take their IP before the visit, the participant can take the IP at the trial site (or later at home if the participant did not bring their medication to the clinic).

[0321] A final follow-up visit (EOS visit) will be conducted at Week 10, 4 weeks after the last IP dose, for final safety and efficacy durability assessments. Additional study details are provided below:

[0322]

[0323]

[0324]

[0325]

[0326]

[0327] Xanamem TM and placebo formulations

[0328] Table 5. Xanamem TM and placebo capsules, using representative doses of 0 mg and 10 mg (for Example 2)

[0329] Components Function Placebo 10mg Xanamem Active pharmaceutical ingredients 0mg 10mg lactose Thinner 180.5mg 170.5mg Croscarmellose Sodium Disintegrants 7.6 mg 7.6mg talc Glidants 0.95mg 0.95mg Magnesium Stearate Lubricants 0.95mg 0.95mg

[0330] Questions about cognition

[0331] Potential participants will be asked the following one-question test about perceived cognitive impairment to determine eligibility for inclusion in the trial:

[0332] 'Now that you've been depressed, have you noticed any problems with your thinking? 'Thought problems can include:

[0333] Poor memory

[0334] Slow thinking

[0335] ●Difficulty in making decisions

[0336] Stay focused

[0337] ●“Brain fog”?

[0338] Potential participants who answer 'yes' to 1 or more of the above symptoms will be eligible for the trial.

[0339] Brief Index of Cognitive Completion Subtest

[0340] BASIC is a brief paper and pencil assessment of the major cognitive domains relevant to neuropsychological research. It contains a test paradigm that has previously been shown to be a reliable, effective and sensitive cognitive measure. The fill-in-the-box subtest is an effective version of the standard symbol matching paradigm, in which participants need to match paired Japanese characters with Arabic numerals to complete the box matrix. Specifically, it assesses processing speed, associative memory, working memory, attention skills and written motor speed. The test score reflects the number of correctly encoded numbers in the 60-second test period.

[0341] Cognitive assessment

[0342] Participants will complete a familiarization session at Screening Visit 1 and practice administration of each of the cognitive efficacy assessments (Cogstate CTB test, HVLT-R, CFT, LFT, and A and B lines) to ensure understanding of the testing procedures and reduce any potential learning effects during the treatment period (see Assessment Schedule [Table 8]).

[0343] Evaluation Order

[0344] The following sequence is required for cognitive and psychiatric assessments, which should be performed prior to any blood draws:

[0345] ●The Cogstate CTB begins with a comprehensive assessment of attention (detection test, identification test, and single recall test) and then the IDSST-S and single card study

[0346] CFT and LFT

[0347] HVLT-R

[0348] MADRS (if assessed by local rater)

[0349] ●A and B connection test

[0350] ●Other scales and questionnaires (PSQI, BPI, PGI-S, and PGI-I).

[0351] Evaluate

[0352] Cogstate Cognitive Test Battery (CTB)

[0353] The customized Cogstate CTB will be used to assess the extent to which once-daily 10 mg Xanamem improves performance in multiple cognitive domains (attention, executive function, and episodic memory) from baseline to each trial visit compared to placebo. The assessment requires participants to perform a variety of digital tasks and each session takes approximately 19 minutes, as outlined in Table 7.

[0354] Table 7 - Tests included in Cogstate CTB

[0355] Test (cognitive domain) Approximate time required (minutes) Test (psychomotor function) 3 Identification (Attention) 3 Single Review (Working Memory) 4 Single card learning (visual learning) 6 International Number Symbol Substitution Test—Symbols (Processing Speed) 3 Estimated total time for Cogstate CTB 19

[0356] International Number Symbol Substitution Test—Symbols (Processing Speed)

[0357] The International Digit Symbol Substitution Test is a cognitive test that measures response speed, attention, working memory, and visual spatial processing. The test requires the subject to match a symbol with a number based on key information and copy the symbol into the space below the number line within a limited time (usually 90 seconds to 180 seconds). The score is the number of correct symbols.

[0358] Hopkins Verbal Learning Test-Revised (HVLT-R)

[0359] HVLT-R is a list learning test for oral administration, and the test will be used to assess the degree of performance of 10mg Xanamem in verbal learning and memory (recognition and recall) compared with placebo from baseline to each test visit.HVLT-R uses a list of 12 nouns, wherein 4 words are extracted from each classification (Benedict1998) in 3 semantic classifications, and the ability of the participant to recall the words read aloud by the assessor is assessed based on it.This test will only use the instant recall component of HVLT-R.Assessment costs approximately 5 to 10 minutes.

[0360] Category Fluency Test (CFT) and Letter Fluency Test (LFT)

[0361] The CFT and LFT measure performance in the areas of language and executive function and are paper-based tests of verbal fluency. The CFT measures the spontaneous production of words representing different categories (such as animals, fruits, and vegetables) in 1 minute. One (1) category is tested at each applicable trial visit, and the same category should not be tested for a given participant at the next visit. The LFT measures the spontaneous production of words beginning with a specified letter in 1 minute (3 different letters are assessed at each applicable trial visit, such as F, A, and S). The assessment takes approximately 5 minutes. The change in the number of correct words produced using 10 mg Xanamem compared to baseline will be compared to placebo.

[0362] Montgomery-Asberg Depression Rating Scale (MADRS)

[0363] MADRS is a 10-item diagnostic questionnaire for assessing the severity of depressive episodes, and is designed to be sensitive to treatment effects (Montgomery 1979). MADRS includes problems for the following symptoms: obvious sadness, reported sadness, inner tension, reduced sleep, decreased appetite, difficulty concentrating, fatigue, perceived incompetence, pessimistic thoughts and suicidal thoughts. Each score is 0 to 6, and the total score range is 0 to 60. The higher the score, the more serious the depression is. MADRS will be used to assess the degree of improvement of depressive symptoms from baseline to each trial visit compared with placebo. It will be administered by a recognized medical professional interviewing the participant, and it takes 20 to 60 minutes to complete. MADRS can be administered by a local assessor during the trial visit, or administered separately by a central assessor during the visit window of the relevant trial visit.

[0364] Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Improvement (PGI-I)

[0365] The PGI-S and PGI-I enable participants to provide their perception of the severity of their symptoms and an assessment of any improvements observed during the trial. Participants will be prompted to describe their personal overall perception of their depression and cognitive impairment. For the PGI-S, participants will rate the severity of their symptoms on a seven-point scale: 1, absent; 2, very mild; 3, mild; 4, moderate; 5, moderately severe; 6, severe; and 7, very severe. The 7-point scale for the PGI-I is rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worsened; 6, much worsened; or 7, very much worsened. The PGI-S and PGI-I each take approximately 5 minutes to complete.

[0366] A and B connection test

[0367] The A and B scramble test is a paper-based test used to assess the extent to which 10 mg Xanamem improves performance in processing speed and executive function from baseline to each trial visit compared to placebo. It has demonstrated sensitive results in previous clinical trials of patients with MDD (McIntyre 2014). Part A of the test assesses complex attention and requires participants to connect randomly positioned numbered circles as quickly as possible. Part B assesses executive function and requires connecting circled letters and numbers in alternating numbers and letters order (i.e., 1-A-2-B, etc.) as quickly as possible, alternating between numbers and letters. The A and B scramble test takes approximately 10 minutes to complete.

[0368] Assessment Timeline

[0369] Table 8 - Assessment Timeline

[0370]

[0371]

[0372]

[0373] Abbreviations: β-HCG = β-human chorionic gonadotropin; BASIC = Brief Cognitive Index; C-SSRS = Columbia-Suicidality Severity Rating Scale; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment visit; ET = early termination; FSH = follicle-stimulating hormone; IP = investigational product; NA = not applicable; PGI-I = Patient Global Impression of Improvement; PGI-S = Patient Global Impression of Severity; PK = pharmacokinetics; (X) = only as clinically indicated.

[0374] a Participants whose Screening Visit occurs >14 days prior to their scheduled Day 1 will need to travel to the trial site for a 2nd Screening Visit between Days -13 and -3 to have an additional Screening blood sample collected and medical history reviewed.

[0375] b Any other unspecified assessments may be performed at the investigator's discretion during unscheduled safety visits.

[0376] c The EOT visit should be scheduled on or after the last day of treatment (Day 42 [+5 days]) to ensure completion of the full course of IP, taking the visit window into account.

[0377] d Medical history was reviewed only at the 2nd Screening Visit.

[0378] e Peripheral nerve examination will be performed at Screening as part of a complete physical examination and at other visits only as clinically indicated.

[0379] f At the discretion of the investigator, up to 2 repeat measurements were allowed at Screening to confirm eligibility. At all other times, if the initial BP and / or HR was elevated, an additional repeat measurement should be performed and used as the reported measurement. gAn ECG will be performed at Screening. ECGs should be performed at subsequent treatment visits (Baseline, Week 2, Week 4, Week 6, and Follow-up Visits) only if clinically indicated.

[0380] h Clinical safety laboratories include hematology and clinical chemistry. Whenever possible, clinical safety laboratories should be performed last, after other participant-facing activities.

[0381] I Women of childbearing potential will be screened for pregnancy. A pregnancy screening test will be performed by testing a blood sample for the presence of beta-HCG (collected as part of the clinical chemistry sample). At all other visits, a urine test strip will be used to test for pregnancy. During screening, FSH will be measured in postmenopausal women to confirm menopausal status.

[0382] j Eligibility will be determined by administering the Mini-International Neuropsychiatric Interview (MINI) during the screening period by a recognized medical professional. This assessment should be performed after other general medical assessments performed during the screening period.

[0383] k Each participant should undergo multiple efficacy tests in the same order at each visit, with the order recorded in the source documents.

[0384] l For familiarization / learning purposes, a familiarization session and practice administration for each cognitive efficacy assessment will be conducted at screening.

[0385] m Two Cogstate CTB assessments will be performed during Baseline Visit 2 (Day 1), at least one hour apart.

[0386] n PGI-S will be performed at multiple visits, whereas PGI-I will be performed only at EOT (Visit 6).

[0387] o On Day 1, participants will take their first dose of IP (Xanamem or placebo) with or without food at the site. Food may be provided by the trial site or by the participant. Participants should take their IP in the morning at home with or without food every other day during the treatment period, including on the days of the trial follow-up visits.

[0388] pParticipants will be required to bring their placebo / IP bottle with them to the EOT visit to calculate the measurability of the trial medication and their completed medication intake diary with them at all visits during the treatment period to calculate IP compliance. q Samples for PK analysis can be collected at any convenient time during the study visits.

[0389] Note: For consistency of assessment, all visits should be scheduled in the morning (morning) if possible.

[0390] Those skilled in the art will appreciate that many changes and / or modifications may be made to the above-described embodiments without departing from the general broad scope of the present disclosure. Therefore, the embodiments of the present invention should be considered in all aspects as illustrative and not restrictive.

Claims

1. A method for treating or preventing depression in a subject resistant to antidepressant therapy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof: Where R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered carbocyclic group, 3-10 membered heterocyclic group, -CN, -CF3, -OR 3 、-SR 3 、-NR 3 R 4 、-COR 3 、-CO2R 3 、-CONR 3 R 4 、-NR 3 COR 4 、-SO2R 3 、-SO2NR 3 R 4 and-NR 3 S02R 4 ; where R 3 and R 4 Each independently selected from the group consisting of: Hydrogen, C 1-6 wherein each of the 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -CF3, -OR 5 、-SR 5 、-NR 5 R 6 、-COR 5 、-CO2R 5 、-CONR 5 R 6 、-NR 5 COR 6 、-SO2R 5 、-SO2NR 5 R 6 and-NR 5 S02R 6 ; and where R 5 and R 6 Each independently selected from hydrogen and C 1-6 Alkyl group.

2. A method for treating or preventing depression-related cognitive impairment in a subject resistant to antidepressant therapy, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof: Where R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered carbocyclic group, 3-10 membered heterocyclic group, -CN, -CF3, -OR 3 、-SR 3 、-NR 3 R 4 、-COR 3 、-CO2R 3 、-CONR 3 R 4 、-NR 3 COR 4 、-SO2R 3 、-SO2NR 3 R 4 and-NR 3 S02R 4 ; where R 3 and R 4 Each independently selected from the group consisting of: Hydrogen, C 1-6 wherein each of the 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -CF3, -OR 5 、-SR 5 、-NR 5 R 6 、-COR 5 、-CO2R 5 、-CONR 5 R 6 、-NR 5 COR 6 、-SO2R 5 、-SO2NR 5 R 6 and-NR 5 S02R 6 ; and where R 5 and R 6 Each independently selected from hydrogen and C 1-6 Alkyl group.

3. The method according to claim 1 and claim 2, wherein the treatment is for depression and depression-related cognitive impairment in the subject.

4. The method according to any one of claims 1 to 3, wherein the compound of formula I is a compound of formula Ia or a pharmaceutically acceptable salt, solvate or prodrug thereof: Where R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered carbocyclic group, 3-10 membered heterocyclic group, -CN, -CF3, -OR 3 、-SR 3 、-NR 3 R 4 、-COR 3 、-CO2R 3 、-CONR 3 R 4 、-NR 3 COR 4 、-SO2R 3 、-SO2NR 3 R 4 and-NR 3 S02R 4 ; Where R 3 and R 4 are independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, 3-7 membered carbocyclyl and 3-7 membered heterocyclyl; wherein each 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 3-7 membered carbocyclyl and 3-7 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -CF3, -OR 5 , -SR 5 、 -NR 5 R 6 、 -COR 5 、 -CO2R 5 、 -CONR 5 R 6 、 -NR 5 COR 6 、 -SO2R 5 、 -SO2NR 5 R 6 and -NR 5 S02R 6 ; and where R 5 and R 6 Each independently selected from hydrogen and C 1-6 Alkyl group.

5. The method according to any one of claims 1 to 4, wherein R 1 and R 2 each independently selected from the group consisting of hydrogen, halogen, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, -OH, -CN and -NH2; and wherein each 3-10 membered carbocyclyl and 3-10 membered heterocyclyl, if present, may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2 and C 1-6 alkyl.

6. The method according to any one of claims 1 to 5, wherein R 1 and R 2 each independently selected from the group consisting of hydrogen, halogen, 6-membered carbocyclyl, 6-membered heterocyclyl, -OH, -CN, and -NH2; and wherein each 6-membered carbocyclyl and 6-membered heterocyclyl, if present, may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and C 1-6 alkyl.

7. The method according to any one of claims 1 to 6, wherein R 1 Selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2 and C 1-6 Alkyl, and R 2 Independently selected from the group consisting of:

8. The method according to any one of claims 1 to 7, wherein the compound of formula I is selected from the group consisting of:

9. The method according to any one of claims 1 to 8, wherein the compound of formula I is:

10. The method according to any one of claims 1 to 9, wherein the compound of formula Ia is:

11. The method of any one of claims 1 to 10, wherein the subject who is resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of: serotonin specific reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NARIs), norepinephrine and specific serotonin antidepressants (NaSSAs), melatonin agonists (MAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), reversible inhibitors of monoamine oxidase (RIMAs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and serotonin modulators (SMs).

12. The method of any one of claims 1 to 11, wherein the subject who is resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of imipramine, amitriptyline, dosulpiride, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, citalopram, sertraline, paroxetine, tianeptine, nefazodone, venlafaxine, desvenlafaxine, duloxetine, reboxil, mirtazapine, phenelzine, tranylcypromine, moclobemide, reboxetine, mianserin, agomelatine, and vortioxetine.

13. The method of any one of claims 1 to 12, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs).

14. The method of claim 13, wherein the SSRI is selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dapoxetine, indapine, zimelidine, alapropylate, sampropazine, cevanchloramine, femoxetine, ifoxetine, omecamylamine, panuramine, pyramide, and seroxetine.

15. The method of claim 13, wherein the SSRI is selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline.

16. The method of any one of claims 1 to 15, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of norepinephrine reuptake inhibitors (NARIs).

17. The method of claim 16, wherein the NARI is reboxetine.

18. The method of any one of claims 1 to 17, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of norepinephrine and specific serotonergic antidepressants (NaSSA).

19. The method of claim 18, wherein the NaSSA is selected from mirtazapine and mianserin.

20. The method of any one of claims 1 to 19, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of melatonin agonists (MA).

21. The method according to claim 20, wherein the MA is agomelatine.

22. The method of any one of claims 1 to 21, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of serotonin and norepinephrine reuptake inhibitors (SNRIs).

23. The method of claim 22, wherein the SNRI is selected from the group consisting of atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, and venlafaxine.

24. The method of any one of claims 1 to 23, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of reversible inhibitors of monoamine oxidase (RIMA).

25. The method of claim 24, wherein the RIMA is moclobemide.

26. The method of any one of claims 1 to 25, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of tricyclic antidepressants (TCAs).

27. The method of claim 26, wherein the TCA is selected from the group consisting of amitriptyline, clomipramine, dosulpirine, imipramine, nortriptyline, and doxepin.

28. The method of any one of claims 1 to 27, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of monoamine oxidase inhibitors (MAOIs).

29. The method of claim 28, wherein the MAOI is selected from phenelzine and tranylcypromine.

30. The method of any one of claims 1 to 29, wherein the subject resistant to antidepressant treatment is resistant to one or more antidepressants selected from the group consisting of serotonin modulators (SM).

31. The method of claim 30, wherein the SM is vortioxetine.

32. The method of any one of claims 1 to 31, wherein the subject resistant to antidepressant treatment is a subject resistant to treatment for major depressive disorder (MDD).

33. The method of claim 32, wherein the MDD is diagnosed by identifying a subject having a HAM-D of at least 17 or a DSM-V criteria of at least 20 using the Brief International Neuropsychiatric Interview.

34. The method of any one of claims 1 to 33, wherein the administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, provides an improvement in depression in the treated subject relative to an untreated subject.

35. The method according to any one of claims 1 to 34, wherein the MADRS test criteria are used to determine improvement in depression in the treated subject.

36. The method of any one of claims 1 to 35, wherein the depression-related cognitive impairment in a subject resistant to antidepressant treatment is a subject having at least a 0.5 SD impairment as measured by the WAIS coding relative to age, education, and gender.

37. The method of any one of claims 1 to 36, wherein the administration of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof provides an improvement in cognitive ability in the treated subject relative to an untreated subject using one or more test standard methods selected from the Cogstate Neuropsychological Test Standards, the Hopkins Verbal Learning Test, the Controlled Word Association Test, and the A and B Trail Making Test.

38. The method of claim 37, wherein the administration of the compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, provides improvement by demonstrating a change from baseline in executive function and / or episodic memory.

39. The method of any one of claims 1 to 37, wherein the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered in an amount to deliver a total daily dose of about 1 to 70 mg of Formula I or about 5 to 40 mg of Formula I.

40. The method of any one of claims 1 to 39, wherein the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered in a single once-daily dose or a twice-daily dose.

41. The method of any one of claims 1 to 40, wherein the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered at a twice daily dose of 10 mg / dose.

42. The method of any one of claims 1 to 41, wherein the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered orally or with food.

43. The method of any one of claims 1 to 42, wherein the subject is between 18 and 75 years old.

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