Methods for preventing and treating depression

Abstract

In some embodiments, a method of treating or preventing a mood disorder is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.

Description

Technical Field

[0001] This article provides compounds and methods for the prevention and treatment of depression and related conditions. Background Technology

[0002] Mood disorders can be described as a mental disorder in which a subject's general emotional state or mood is distorted or inconsistent with the environment and interferes with their ability to perform daily living functions. Common mood states include sadness, emptiness, or irritability. A common mood disorder is depression.

[0003] Depression, also known as major depressive disorder or clinical depression, is a severe mood disorder. Depression is more than just sadness. Sadness is a normal emotion that can be triggered by a specific event or situation, such as losing a job, the end of a relationship, or the death of a loved one. Depression manifests itself in a combination of factors related to the duration of negative feelings, its impact on an individual's health, and its impact on their daily functioning. The person may have good reason to feel happy, yet loses the ability to experience joy or pleasure and is likely to suffer distress in dealing with tasks, relationships, and daily life.

[0004] People with depression experience persistent feelings of sadness and hopelessness and lose interest in activities they once enjoyed. Depression can be diagnosed, for example, according to guidelines in the Diagnostic and Statistical Manual of Mental Disorders (DSM). Symptoms identified in the DSM include: persistent depressed mood, diminished interest or pleasure in almost all activities, significantly decreased or increased appetite, slowed thinking and reduced physical activity, fatigue, feelings of worthlessness or excessive guilt, impaired ability to think or concentrate, and recurrent thoughts of death or suicide. Typically, individuals experience significant distress or impairment in social or occupational functioning.

[0005] Current treatments for depression include talk therapy and medication. However, current medications often target neurotransmitter uptake and are accompanied by serious, sometimes severe, side effects. These side effects can be difficult to diagnose in individuals already suffering from mental disorders. Furthermore, individual responses to typical antidepressant treatments vary, and it may take a long time to test several therapies to find an effective treatment. Therefore, there is a need for medications that can target alternative pathways to treat depression and other mood disorders, provide symptom improvement in a shorter timeframe, and offer reduced side effects. Summary of the Invention

[0006] This article provides compounds and methods for the prevention and treatment of mood disorders, including, for example, depression.

[0007] In some embodiments, a method for treating or preventing depression is provided, the method comprising administering to a patient in need a therapeutically effective amount of a compound, or a deuterated analog thereof, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, or a mixture of stereoisomers, capable of promoting spinogenesis in the patient's prefrontal cortex. Attached Figure Description

[0008] Figure 1 This is a graph showing the number of total spines, mushroom spines, short and thick spines, and long and thin spines per 100 μm in WT and 3xTg-AD mice treated with the carrier and treated with compound 1 at 3, 10, and 30 mg / kg. Detailed Implementation

[0009] Generally, the compounds and methods described herein provide for the administration of compounds that offer benefits in the treatment and prevention of mood disorders and their symptoms. In some embodiments, these compositions and methods can be used to treat mood disorders, such as depression. Typically, the active ingredient or main ingredient will comprise a pharmaceutical agent, such as a compound as described herein, or a deuterated analogue of a compound, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, or a mixture of stereoisomers. The active ingredient or main ingredient may also comprise one or more additional pharmaceutically active materials.

[0010] I. Definition The following description illustrates exemplary embodiments of the present technology. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0011] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0012] A pediatric patient is someone under the age of 18. A juvenile patient is someone who has not yet reached physical maturity.

[0013] The term "spinogenesis" and similar terms refer in their usual and conventional sense to the development (e.g., growth and / or maturation) of dendritic spines in neurons. In some embodiments, the compounds provided herein promote dendritic spinogenesis without affecting spine morphology. This promotion is relative to the absence of application of the compound.

[0014] As used herein, the term "dendrite" refers to the branching extension of a neuronal cell. Dendrites are typically responsible for receiving electrochemical signals transmitted from the axons of adjacent neurons. The term "dendritic spines" refers to protoplasmic projections on a neuronal cell, such as on its dendrites. In some embodiments, dendritic spines can be described as having a membranous neck that terminates at a head (e.g., a head-like apex). Dendritic spines are classified according to their shape: headless, elongated, short and stout, mushroom-shaped, or branching. Dendritic spine density refers to the total number of dendritic spines per unit length of a neuronal cell. For example, dendritic spine density can be given as the number of dendritic spines per micrometer.

[0015] The term "dendritic spine formation," etc., in its usual and conventional sense refers to the process that results in an increase in the number or development of dendritic spines. The term "dendritic spine morphology," etc., in its usual and conventional sense refers to the physical characteristics (e.g., shape and structure) of dendritic spines. Improvement in dendritic spine morphology is a change in shape (e.g., an increase in length or width) that leads to an increase in function (e.g., an increase in the number of contacts between neurons or a decrease in the gaps between adjacent neurons (e.g., the synaptic cleft). Exemplary methods for such characterization, as known in the art and disclosed herein, include measuring the dimensions (i.e., length and width) of the dendritic spines. Therefore, the term "improved dendritic spine morphology" generally refers to an increase in the length, width, or both of the dendritic spines.

[0016] "Binding" refers to the process by which at least two different kinds of compounds (e.g., chemical compounds including biomolecules or cells) come close enough to react or interact, resulting in the formation of a complex. For example, the binding of two different kinds (e.g., a protein and a compound described herein) can lead to the formation of a complex, where these kinds interact through non-covalent or covalent bonds. In some embodiments, the resulting complex is formed when two different kinds (e.g., a protein and a compound described herein) interact through non-covalent bonds (e.g., electrostatic, van der Waals, or hydrophobic).

[0017] As defined herein, the terms "activation," "activate," "activating," etc., relating to protein-activator (e.g., agonist) interactions mean positively influencing (e.g., increasing) the activity or function of a protein relative to the absence of an activator (e.g., the compounds described herein).

[0018] As defined herein, the terms "inhibition," "inhibit," and "inhibiting" have the meanings commonly understood by those skilled in the art. When referring to protein-inhibitor (e.g., antagonist) interactions, the terms "inhibition," "inhibit," and "inhibiting" mean a negative impact (e.g., a reduction) on the functional activity of the protein relative to its functional activity in the absence of the inhibitor.

[0019] A hyphen ('-') not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH2 is attached via a carbon atom. A dash before or at the end of a chemical group is for convenience; a chemical group may or may not be depicted with one or more dashes without losing its usual meaning. A wavy line drawn through a line in the structure indicates the attachment point of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0020] prefix ''C u-v '' indicates that the following groups have u to v carbon atoms. For example, ''C 1-6 'alkyl' indicates that the alkyl group has 1 to 6 carbon atoms.

[0021] This article's references to "about" a certain value or parameter include (and describe) references to that value or parameter. itself Examples of embodiments. In some embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In some still embodiments, the term "about" includes the indicated amount ± 1%. Additionally, the term "about X" includes a description of "X". Furthermore, unless the context clearly indicates otherwise, the singular forms "a" and "the" include plural references. Thus, for example, reference to "the compound" includes a variety of such compounds, and reference to "the assay" includes reference to one or more assays and their equivalents known to those skilled in the art.

[0022] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. For example, the term includes straight-chain and branched hydrocarbon groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0023] "Substituted alkyl" refers to an alkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryl, carboxyl, carboxylic acid ester, (carboxylic acid ester)amino, (carboxylic acid ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkenyl, substituted cycloalkenyl, guanidinyl, halogenated, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, nitro, -SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0024] "Alkenyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl groups can contain any number of carbons, such as C2, C3, C4, C5, etc. 2-3 C 2-4 C 2-5 C 2-6 C 2-7 C 2-8 C 2-9 C 2-10 C3, C 3-4 C 3-5 C 3-6 C4, C 4-5 C 4-6 C5, C 5-6And C6. The alkenyl group can have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (vinyl or ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl or 1,3,5-hextrienyl. The alkenyl group can be substituted or unsubstituted.

[0025] "Substituted alkenyl" refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, which are selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryl, carboxyl, carboxylic acid ester, (carboxylic acid ester)amino, (carboxylic acid ester)amino, (carboxylic acid ester)amino, (carboxylic acid ester)amino, (carboxylic acid ester)amino, alkyl ... Ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy and thiol, provided that any hydroxyl or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[0026] The term "acyl" refers to groups such as HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-. Acyl groups include the acetyl group CH3C(O)-.

[0027] "Acylamino" refers to the group -NR 47 C(O)alkyl, -NR 47 C(O) substituted alkyl groups, -NR 47 C(O)cycloalkyl, -NR 47 C(O) substituted cycloalkyl groups, -NR 47 C(O)cycloalkenyl, -NR 47 C(O)-substituted cycloalkenyl, -NR 47C(O) alkenyl, -NR 47 C(O)-substituted alkenyl groups, -NR 47 C(O) aryl, -NR 47 C(O)-substituted aryl, -NR 47 C(O) heteroaryl, -NR 47 C(O)-substituted heteroaryl, -NR 47 C(O) heterocycle and -NR 47 C(O)-substituted heterocycles, where R 47 It is hydrogen or alkyl.

[0028] "Acyloxy group" refers to alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-.

[0029] "Alkyne" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C360, C460, C560, C6 ... 2-20 acetylsyl), 2 to 8 carbon atoms (i.e., C 2-8 acetylsyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 The term "alkynyl" refers to a non-branched or branched hydrocarbon group. It also includes groups having at least one carbon-carbon triple bond and one carbon-carbon double bond.

[0030] "Alkoxy" refers to the group -O-alkyl, where the alkyl group is as defined herein. For example, alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, and n-pentoxy. "Substituted alkoxy" refers to the group -O- (substituted alkyl), where the substituted alkyl group is as defined herein.

[0031] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogen.

[0032] "Alkylthio" refers to the "alkyl-S-" group.

[0033] An acyl group is defined as -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0034] "Amide group" refers to both the "C-amide group" (which refers to the group -C(O)NR) y R z It also refers to the "N-amide" group (which refers to the -NR group). y C(O)R z ), where R y and R z The elements are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may optionally be substituted.

[0035] "Amino" refers to the group -NH2. "Substituted amino" refers to the group -NR. 48 R 49 ， Where R 48 and R 49 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocycle and -SO2-substituted heterocycle, and wherein R 48 and R 49 Optionally, it can be linked together with the nitrogen it is bonded to to form a heterocyclic or substituted heterocyclic group, provided that R 48 and R 49 None of them are hydrogen.

[0036] "Amino carbonyl" refers to the group -C(O)NR 50 R 51 , where R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 50 and R 51Optionally, it is attached together with the nitrogen to form a heterocyclic or substituted heterocyclic group. 'Aminocarbonylamino' refers to the group -NR. 47 C(O)NR 50 R 51 , where R 47 It is hydrogen or alkyl; R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; and wherein R 50 and R 51 Optionally, it is linked together with the nitrogen to form a heterocyclic or substituted heterocyclic group.

[0037] "Aminocarbonyloxy" refers to the group -OC(O)NR 50 R 51 , where R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 50 and R 51 Optionally, it is linked together with the nitrogen to form a heterocyclic or substituted heterocyclic group.

[0038] "Aminosulfonyl" refers to the group -SO2NR 50 R 51 , where R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 50 and R 51 Optionally, it is linked together with the nitrogen to form a heterocyclic or substituted heterocyclic group.

[0039] "Aminosulfonyloxy" refers to the group -O-SO2NR 50 R 51 , where R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R50 and R 51 Optionally, it is attached together with the nitrogen to form a heterocyclic or substituted heterocyclic group.

[0040] "Aminosulfonamide" refers to the group -NR 47 SO2NR 50 R 51 , where R 47 It is hydrogen or alkyl; R 50 and R 51 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle; and wherein R 50 and R 51 Optionally, it is attached together with the nitrogen to form a heterocyclic or substituted heterocyclic group.

[0041] "Amino group" refers to the group -C (=NR) 52 )NR 50 R 51 , where R 50 R 51和 R 52 Independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 50 and R 51 Optionally, it is attached together with the nitrogen to form a heterocyclic or substituted heterocyclic group.

[0042] "Ar" or "aryl" refers to a compound with a single ring ( For example phenyl) or multiple fused rings ( For example A monovalent aromatic carbocyclic group (naphthyl or anthracene) consisting of 6 to 14 carbon atoms. The fused ring may or may not be aromatic. For example2-Benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc., provided that the attachment site is located on an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl. "Substituted aryl" refers to an aryl group substituted by 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy Substituted aryloxy groups, carboxyl groups, carboxylic acid esters, (carboxylic acid ester)amino groups, (carboxylic acid ester)oxy groups, cyano groups, cycloalkyl groups, substituted cycloalkyl groups, cycloalkoxy groups, substituted cycloalkoxy groups, cycloalkenyl groups, substituted cycloalkenyl groups, substituted cycloalkenyl groups, guanidinyl groups, halogenated groups, hydroxyl groups, heteroaryl groups, substituted heteroaryl groups, heteroaryloxy groups, substituted heteroaryloxy groups, heterocyclic groups, substituted heterocyclic groups, heterocyclic groups, substituted heterocyclic groups, nitro groups, SO3H groups, substituted sulfonyl groups, substituted sulfonyloxy groups, and thiols.

[0043] "Arylidene" refers to a divalent aromatic carbocyclic group having 6 to 14 carbon atoms having a monocyclic or multiple fused rings. "Substituted arylidene" refers to an arylidene having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents as defined for an aryl group.

[0044] "Aryloxy group" refers to the group -O-aryl, where the aryl group is as defined herein. Exemplary aryloxy groups include phenoxy and naphthoxy groups. "Substituted aryloxy group" refers to the group -O-(substituted aryl).

[0045] "Carbonyl" refers to the divalent group -C(O)- (i.e. -C(=O)-).

[0046] "Aryl group" refers to an aryl group that hangs over an alkyl group. Examples of aryl groups include benzyl, phenethyl, and 3-naphthylpropyl.

[0047] "Carbamoyl" refers to both the "O-carbamoyl" group (which refers to the group –OC(O)NR) y R z It also refers to the "N-carbamoyl" group (which refers to the -NR group). y C(O)OR z ), where R y and R z The elements are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may optionally be substituted.

[0048] The carboxyl group (or carboxy) refers to –COOH or its salt.

[0049] "Carboxylic acid ester" refers to the group -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)O-alkenyl, -C(O)(O)-substituted alkenyl, -C(O)(O)-aryl, -C(O)(O)-substituted aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, -C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic, and -C(O)(O)-substituted heterocyclic. "(Carboxylic acid ester)amino" refers to the group -NR. 47 C(O)(O)-alkyl, -NR 47 C(O)(O)-substituted alkyl group, -NR 47 C(O)O-alkenyl, -NR 47 C(O)(O)-substituted alkenyl, -NR 47 C(O)(O)-Aryl, -NR 47 C(O)(O)-substituted aryl, -NR 47 C(O)(O)-cycloalkyl, -NR 47 C(O)(O)-substituted cycloalkyl, -NR 47 C(O)(O)-cycloalkenyl, -NR 47 C(O)(O)-substituted cycloalkenyl, -NR 47 C(O)(O)-heteroaryl, -NR 47 C(O)(O)-substituted heteroaryl, -NR 47 C(O)(O)-heterocyclic ring and -NR 47 C(O)(O)-substituted heterocycles. '(carboxylic acid ester)oxy' refers to the groups -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocycles.

[0050] "Cyano" refers to the group -CN.

[0051] "Cycloalkyl" refers to a monocyclic, fused bicyclic, or bridged polycyclic compound containing 3 to 12 ring atoms, or the indicated number of atoms. Cycloalkyl groups can contain any number of carbons, such as C64. 3-6 C 4-6 C 5-6 C 3-8 C 4-8 C 5-8 C 6-8 C 3-9 C 3-10 C 3-11 and C 3-12 Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. 'Cycloalkenyl' refers to a partially unsaturated cycloalkyl group having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. When the cycloalkyl group is a saturated monocyclic C 3-8 When cycloalkyl is used, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl group is a saturated monocyclic C 3-6 When cycloalkyl is used, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl and cycloalkenyl groups may be substituted or unsubstituted. "Substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl or cycloalkenyl groups having 1 to 5, or preferably 1 to 3, substituents selected from the group consisting of: oxo, thio, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted Aryl, aryloxy, substituted aryloxy, carboxyl, carboxylic acid ester, (carboxylic acid ester)amino, (carboxylic acid ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenoxy, substituted cycloalkenoxy, guanidinyl, halogenated, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclic, substituted heterocyclic, substituted heterocyclic, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy and thiol.

[0052] "Cycloalkoxy" refers to -O-cycloalkyl. "Substituted cycloalkoxy" refers to -O-(substituted cycloalkyl). "Cycloalkenoxy" refers to -O-cycloalkenyl. "Substituted cycloalkenoxy" refers to -O-(substituted cycloalkenyl).

[0053] The 'guanidinyl' group refers to the group -NHC(=NH)NH2.

[0054] 'Hydroxyl (hydroxy or hydroxyl)' refers to the -OH group.

[0055] "Imine" refers to the group -C(NR)R, wherein each R is independently an alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl group; each of which may be optionally substituted as defined herein.

[0056] "Halogen" or "halogenated" includes fluorinated, chlorinated, brominated, and iodinated. "Halogenated alkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted by more than one halogen, it can be designated by using a prefix corresponding to the number of halogen moieties attached. Dihalogenated and trihalogenated alkyl groups refer to alkyl groups substituted by two ("di") or three ("tri") halogenated groups (which may, but do not necessarily, be the same halogen). Examples of halogenated alkyl groups include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0057] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl groups include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0058] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring combination containing 5 to 16 ring atoms, wherein 1 to 5 ring atoms are heteroatoms, such as N, O, or S. Additional heteroatoms can also be useful, including but not limited to B, Al, Si, and P. These heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups can include any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Heteroaryl groups can include any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. A heteroaryl group may have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. The heteroaryl group may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetraazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5- isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also be fused to aromatic ring systems, which may or may not contain heteroatoms, such as a phenyl ring, to form members including, but not limited to, benzopyrrole (such as indole and isoindole), benzopyridine (such as quinoline and isoquinoline), benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine (such as phthalazine and zoline), benzothiophene, benzofuran, indoleazine, or benzothiane. Heteroaryl groups can also be fused to non-aromatic ring systems, which may or may not contain heteroatoms, provided that the attachment point passes through an atom of the aromatic heteroaryl group. For example, the nitrogen and / or sulfur ring atoms of the heteroaryl group may optionally be oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Certain non-limiting examples include pyridyl, pyrrole, indole, thiophene, oxazolyl, thiazolyl, and furanyl. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted. A substituted heteroaryl group is a heteroaryl group substituted by 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents, selected from the group consisting of the same substituents as defined for substituted aryl groups.

[0059] "Heteroaryloxy group" refers to -O-heteroaryl group. "Substituted heteroaryloxy group" refers to the group -O- (substituted heteroaryl group).

[0060] "Heterocyclic" or "heterocyclic of" or "heterocyclic alkyl" or "heterocyclic group" refers to a saturated or partially saturated ring system having 3 to 12 ring members and 1 to 4 heteroatoms of N, O, and S. Additional heteroatoms can also be useful, including but not limited to B, Al, Si, and P. These heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heterocyclic alkyl groups can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Heterocyclic alkyl groups can contain any suitable number of heteroatoms, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocyclic alkyl groups may include groups such as aziridine, aziridine butane, pyrrolidine, piperidine, aziridine heptane, aziridine octane, quinine ring, pyrazolidine, imidazoline, piperazine (1,2-, 1,3- and 1,4- isomers), ethylene oxide, oxacyclobutane, tetrahydrofuran, oxane (tetrahydropyran), oxacycloheptane, thioheptane, thioheptane, thioheptane, thioheptane (tetrahydrothiophene), thiazoline (tetrahydrothiaran), oxazolidine, isoxazolidine, thiazoline, isothiazolidine, dioxopentane, dithiopentane, morpholine, thiomorpholine, dioxane, or dithiazoline. Heterocyclic alkyl groups may also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, dihydroindole. In fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the attachment point is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety. The heterocyclic alkyl group may be unsubstituted or substituted. For example, the heterocyclic alkyl group may be C 1-6 Alkyl, oxo (=O), nitro (-NO2), or sulfonyl (-S(O)2-) are substituted. "Substituted heterocyclic" or "substituted heterocyclic alkyl" or "substituted heterocyclic group" refers to a heterocyclic group that is substituted by 1 to 5, or preferably 1 to 3, substituents that are the same as those defined for the substituted cycloalkyl group.

[0061] "Heterocyclic oxy group" refers to the -O- heterocyclic group. "Substituted heterocyclic oxy group" refers to the -O- (substituted heterocyclic group).

[0062] "O" refers to a group (=O) or (O).

[0063] "Spirocycloalkyl" and "spirocyclic system" refer to a divalent cyclic group having 3 to 10 carbon atoms, which has a cycloalkyl or heterocycloalkyl ring with spiro linkage (a linkage formed by a single atom that is the only common member of the ring), as illustrated by the following structures: .

[0064] "Sulfoyl" refers to the group -S(O)2R, where R is an alkyl, haloalkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl group. Examples of sulfonyl groups are methanesulfonyl, ethanesulfonyl, benzenesulfonyl, and toluenesulfonyl. "Substituted sulfonyl" refers to groups such as -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic. Substituted sulfonyl groups include groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. "Substituted sulfonyloxy" refers to the groups -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substituted heterocyclic.

[0065] "alkylsulfonyl" refers to the group -S(O)2R, where R is an alkyl group.

[0066] "alkyl sulfinyl" refers to the group -S(O)R, where R is an alkyl group.

[0067] As used herein, the term "sugar" refers to sugars such as monosaccharides, disaccharides, oligosaccharides, or polysaccharides. Monosaccharides include, but are not limited to, glucose, ribose, and fructose. Disaccharides include, but are not limited to, sucrose and lactose. Oligosaccharides are sugars consisting of 2 to 10 sugars preferably linked together by α-bonds. Examples of oligosaccharides include maltose, lactose, sucrose, etc. Polysaccharides include, but are not limited to, cellulose, hemicellulose, lignocellulose, or starch. Sugars or sugars that can be used in this invention include any and all naturally occurring sugars, such as, but not limited to, glucose, glucuronic acid, iduronic acid, galactose, fucose, glucosamine, N-acetylglucosamine, fructose, sialic acid, including their aldosterone and pyranose forms, and their D and L isomers.

[0068] The "thiocyanate group" refers to the –SCN group.

[0069] "Thioxo" or "thione" refers to the group (=S) or (S).

[0070] The substituted ring may be replaced by one or more fused rings and / or spirocyclic rings. Such fused rings include fused cycloalkyl, fused heterocyclic, fused aryl, and fused heteroaryl rings, wherein each of the rings may be unsubstituted or substituted. Such spirocyclic rings include spirocycloalkyl and spiroheterocyclic groups, wherein each of the rings may be unsubstituted or substituted.

[0071] The groups defined above may optionally be substituted with any suitable number and type of substituents. Representative substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, haloalkyl, haloalkoxy, -OR', =O, -OC(O)R', -(O)R', -O2R', -ONR'R'', -OC(O)NR'R'', =NR', =N-OR', -NR'R'', -NR''C(O)R', -NR'-(O)NR''R''', -NR''C(O)OR', -NH-(NH2)=NH, -NR'C(NH2)=NH, -NH-(NH2)=NR', -SR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -N3, and -NO2. R', R'', and R''' each independently refer to hydrogen, unsubstituted alkyl groups, such as unsubstituted C 1-6 Alkyl group. Alternatively, when R' and R'', or R'' and R''', are attached to the same nitrogen, they combine with the nitrogen to which they are attached to form a heterocyclic alkyl or heteroaryl ring as defined above.

[0072] It should be understood that, of all the substituents defined above, polymers obtained by defining a substituent as having further substituents (e.g., substituted aryl groups having substituted aryl groups as substituents, which themselves are substituted by substituted aryl groups, etc.) are not intended to be included herein. In such cases, the maximum number of such substituents is three. In other words, each of the above definitions is subject to the following limitation: for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[0073] Certain commonly used alternative chemical names may be used. For example, divalent groups, such as divalent "alkyl" groups, divalent "aryl" groups, etc., may also be referred to as "alkylene" (or "alkylenyl") groups and "arylene" (or "arylenyl") groups, respectively. Furthermore, unless otherwise explicitly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl), the last mentioned group contains the atoms that link that moiety to the remainder of the molecule.

[0074] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. Furthermore, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may or may not be substituted by a portion other than hydrogen. The term "optionally substituted" with respect to groups is intended to be interpreted as describing unsubstituted groups and groups substituted by the indicated or defined substituents.

[0075] The protecting group can be any protecting group known in the art, such as those described in Peter GM Wuts and Theodora W. Greene, Greene's protective groups in organic synthesis (Wiley-Interscience, 2007).

[0076] Some compounds exist as tautomers. For example, amide-containing compounds can exist in equilibrium with imine tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers, those skilled in the art will understand that the compound includes all tautomers.

[0077] Any formula or structure given herein is also intended to represent both isotopically labeled and unlabeled forms of the compound. Isotopically labeled compounds have the structure described by the formula given herein, except that one or more atoms are replaced by isotopes having the indicated atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure or their counterions include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotopically labeled compounds are possible under this disclosure, for example, those doped with radioactive isotopes such as 3 H, 13 C and 14Those containing C. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for use in patients undergoing radiotherapy.

[0078] This disclosure also includes "deuterated analogues" of compounds and their counterions, wherein one to n hydrogen atoms attached to a carbon atom are replaced with deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds can exhibit increased metabolic resistance and, therefore, can be used to increase the half-life of compounds when administered to mammals, particularly humans. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0079] The deuterium-labeled or substituted therapeutic compounds of this disclosure can possess improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages stemming from greater metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or an improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by performing the procedures disclosed in the schemes or examples, and the preparation described below, by replacing the unlabeled reagent with an readily available isotopically labeled reagent. It should be understood that deuterium in this context is considered a substituent in the compound.

[0080] The concentration of such heavier isotopes (specifically deuterium) can be defined by an isotope enrichment factor. In the compounds disclosed herein, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition. Therefore, in the compounds disclosed herein, any atom specifically designated as deuterium (D) is intended to indicate that deuterium is enriched at the indicated position above naturally occurring levels.

[0081] The compounds described herein may exist in the form of salts, such as pharmaceutically acceptable salts. The compounds are capable of forming salts, such as acidic salts and / or basic salts. Pharmaceutically acceptable salts, hydrates, solvates, tautomer forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means a compound, salt, composition, dosage form, or other material that can be used to prepare pharmaceutical compositions suitable for veterinary or human use. Salts of the compounds described herein may be prepared according to procedures described herein and known in the art.

[0082] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed with inorganic acids and salts formed with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared according to the conventional procedure for preparing acid addition salts from base compounds, by dissolving the free base in a suitable solvent and treating the solution with an acid. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, isobutyric acid, succinic acid, and lactic acid. Similarly, pharmaceutically acceptable basic addition salts can be prepared from inorganic and organic bases. For example, salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), and dienylamines (i.e., HN(alkenyl)2). Suitable amines include trienylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines, to name only, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc. Methods for preparing salts also include mixing the compound with an active metal via a redox reaction, or by ion exchange, for example, due to the different solubilities of the salt.

[0083] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. If not specified, such one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, aryl, -N3, carbamoyl, carboxyl, carboxyl ester, -CN, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, -OH, imino, oxo, -NO2, alkylsulfinyl, -SO3H, alkylsulfonyl, thiocyanate, -SH, thionyl, or combinations thereof. Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of further substituents (e.g., a substituted aryl group having a substituted alkyl group itself substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substituents in the compounds described herein is three. For example, successive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituted element of that group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halogenated, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halogenated, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is substituted. In other embodiments, these substituents may be further substituted with halogenated, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is unsubstituted.

[0084] A solvate is a solid form of a compound in which solvent molecules are incorporated. Solvates are formed through the interaction of a solvent and a compound. A hydrate is a solvate in which water is the solvent. Solvates of salts of the compounds described herein are also provided.

[0085] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition should be considered. Complementary active ingredients may also be incorporated into the composition.

[0086] "Treatment" provides a beneficial or desired outcome, such as improvement in one or more clinical indicators of the condition. Beneficial or desired outcomes may include one or more of the following: reduction or improvement of one or more symptoms of the condition, and / or alleviation of the severity of the condition (e.g., stabilizing the condition, preventing or delaying the worsening or progression of the condition); providing partial or complete remission of the condition; enhancing the effect of another medication; improving quality of life; and / or prolonging the survival of a patient population.

[0087] "Prevention" refers to blocking the development of a disease or its symptoms. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of the disease or have a family history of the disease. Prevention may include delaying the attainment of predefined disease milestones or reducing the appearance or progression of biomarkers.

[0088] "Subject" refers to an animal, such as a mammal, like a human, that could benefit from the administration of the compounds described herein. The methods described herein can be used for human therapeutics and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. When the subject is a human, the subject may be referred to as a "patient".

[0089] The term "therapeutic effective amount" or "effective amount" as used for the compounds described herein means an amount sufficient to achieve treatment and provide the benefits described herein when administered to a subject. For example, a therapeutic effective amount could be an amount sufficient to reduce the symptoms of a mood disorder. Therapeutic effective amounts can vary depending on the subject, the condition being treated, the subject's weight and age, the severity of the condition, and the method of administration, which can be readily determined by a medical practitioner.

[0090] The term "treatment-resistant" means that a subject with a mood disorder has previously shown resistance to treatment for the condition. For example, one or more symptoms of the mood disorder persist after treatment. In some embodiments, the subject is treatment-resistant to antidepressants as described herein.

[0091] The term "marker" refers to a characteristic of a subject that indicates the risk of developing a condition. For example, a marker can be a genetic indicator associated with the condition; a marker can be a personal medical history of the condition; a marker can be a family history, such as genetic relatives who have the condition or related conditions; or a marker can be a physiological indicator, such as a test result.

[0092] The terms "hallucinogen" and "psychedelic" refer to substances that cause perceptual abnormalities when administered to a subject. Examples of hallucinogenic substances include ketamine, 3,4-methylenedioxymethamphetamine (MDMA), bufotalin, phencyclidine (PCP), lysergic acid diacetamide (LSD), mescaline, serotonin, psychedelic sage, dimethyltryptamine (DMT), and gamma-hydroxybutyric acid. Compounds that are hallucinogens may also be referred to as "hallucinogens." In some embodiments, the hallucinogen is selected from ketamine, LSD, serotonin, and MDMA. In some embodiments, the hallucinogen is ketamine.

[0093] Treatment methods and uses This article describes a method for the prevention and treatment of mood disorders by administering an effective amount of a compound that induces dendritic spine formation to a patient. Contrary to expectations, this disclosure demonstrates that increased dendritic spine density can provide benefits in the treatment of mood disorders such as depression. The methods described herein can also provide treatment with reduced side effects, and / or treatment for subjects refractory to one or more antidepressants.

[0094] Although ketamine administration has been associated with antidepressant activity, its mechanism of action is not fully understood. Ketamine is believed to have multiple activities in the brain. However, such observations are relatively new and not well-studied. Complicating matters is that ketamine may produce different physiological effects over the long term. For example, the short-term activity of ketamine is believed to be caused by the promotion of activity in dormant spikes. Importantly, ketamine is classified as a hallucinogen and is known to cause perceptual disturbances, including dissociative effects. These effects make ketamine a poor choice for many patients, including, for example, adolescents or pediatric patients, or those with a history of mental illness.

[0095] In some embodiments, the compounds described herein may be used to treat mood disorders. Mood disorders are major mental disorders in which a patient's general emotional state or mood is distorted or inconsistent with the environment and interferes with the patient's ability to perform daily living functions. Subjects may be sad, empty, or irritable, or may have periods alternating with periods of negative feelings and excessive happiness (mania).

[0096] In some embodiments, the mood disorder may be depression. Depression, sometimes referred to as major depressive disorder or clinical depression, is a common but serious mood disorder. People with depression may experience persistent feelings of sadness and hopelessness and lose interest in activities they once enjoyed. In addition to the emotional problems caused by depression, individuals may also exhibit physical symptoms such as chronic pain or digestive problems. To be diagnosed with depression, symptoms should generally be present for at least two weeks. Depression can be diagnosed by those skilled in the art, for example, according to the guidelines in the Diagnostic and Statistical Manual of Mental Disorders ("DSM"). The DSM outlines the following criteria for making a diagnosis of depression. Currently, according to the DSM-5 diagnostic criteria, for a diagnosis of depression, an individual must experience five or more symptoms within the same two-week period, and at least one of these symptoms should be (1) a depressed mood or (2) a loss of interest or pleasure. The symptoms identified in the DSM include: 1. I am in a depressed mood for most of the day.

[0097] 2. Interest or pleasure in all or almost all activities is significantly reduced for most of the day.

[0098] 3. Significant weight loss or gain when not dieting, or almost daily decrease or increase in appetite.

[0099] 4. Slowed thinking and reduced physical activity (observable by others, not just subjective restlessness or slowness).

[0100] 5. Fatigue or loss of energy almost every day.

[0101] 6. Almost daily feelings of worthlessness or excessive or inappropriate guilt.

[0102] 7. A diminished ability to think or concentrate almost daily, or indecisiveness.

[0103] 8. Recurring thoughts of death, suicidal ideation without a specific plan, or suicide attempts or specific suicide plans.

[0104] To obtain a diagnosis of depression, these symptoms must cause significant clinical distress or impairment in social, occupational, or other important areas of functioning in an individual. The DSM also provides descriptions of diagnosed depression: (1) with mixed features—this description allows the presence of manic symptoms as part of a diagnosis of depression in patients who do not meet all the criteria for a manic episode; and (2) with anxiety distress—the presence of anxiety in a patient may affect prognosis, treatment options, and the patient’s response to them.

[0105] Depression is more than just sadness. The difference between sadness and depression lies not in the degree to which a person feels depressed, but in the combination of factors associated with the duration of these negative feelings, other symptoms, physical effects, and impact on an individual's daily functioning. Sadness is a normal emotion that can be triggered by a specific event or situation, such as unemployment, the end of a relationship, or the death of a loved one. A hallmark of depression is that a person with depression typically feels sadness or despair in all aspects of life. The individual may have good reason to feel happy, yet loses the ability to experience joy or happiness and is likely to suffer in dealing with affairs, relationships, and daily life.

[0106] Depression has many contributing factors. These factors can include stressors such as physical abuse, psychological abuse, traumatic events, personal conflict, loss of a loved one, social isolation, illness, substance abuse, or the use of certain medications. Subjects may have a genetic predisposition to depression. Subjects may have experienced physical trauma affecting the brain, such as traumatic brain injury (TBI) or chronic traumatic encephalopathy (CTE). In some cases, depression is idiopathic. Categories of depression include major depressive disorder—long-term and persistent extreme sadness; bipolar disorder—also known as manic-depressive disorder or bipolar affective disorder, which includes periods of depression and mania; seasonal affective disorder (SAD)—a form of depression most often associated with less daylight in far northern and far southern latitudes from late autumn to early spring; cyclothymic disorder—a condition that causes mood swings that are not as extreme as bipolar disorder; premenstrual anxiety disorder—mood changes and irritability that occur before menstruation in women and disappear with the onset of menstruation; persistent depressive disorder (dysthymia)—long-term (chronic) but low-grade depression; disruptive mood disorder—a condition of chronic, severe, and persistent irritability in children, which typically includes frequent outbursts of temper inconsistent with the child's developmental age; medically related depression—persistent depressed mood and a significant loss of pleasure in most or all activities directly related to the physical effects of another medical condition; and substance- or drug-induced depression—depressive symptoms that occur during or shortly after substance use or withdrawal, or after exposure to the drug.

[0107] In some embodiments, a method for treating a mood disorder in a patient in need is provided, the method comprising administering to the patient a therapeutically effective amount of a compound as described herein. In some embodiments, the mood disorder is depression. In some embodiments, the patient may be refractory to treatment with antidepressants. The antidepressant may be an antidepressant as described herein.

[0108] In other embodiments, compositions and methods are provided for alleviating, reducing, or reversing symptoms of mood disorders. The symptoms can be any symptoms described herein or known to the practitioner, such as those described in the DSM.

[0109] Symptoms of depression can include anxiety; loss of interest in daily activities; pessimism, persistent negativity; sadness, emptiness, or feelings of depression, worthlessness, helplessness, or hopelessness; fatigue, tiredness, or lack of energy; low self-esteem, self-criticism, and / or feelings of inadequacy; difficulty concentrating, remembering details, and / or making decisions; persistent irritability, hostility, and / or excessive anger; decreased activity, efficiency, and / or productivity; avoidance of social activities; feelings of guilt and / or worry about the past; loss of appetite or overeating; suicidal ideation; decreased libido and / or loss of interest in sex; sleep disturbances, insomnia, early awakening, or excessive sleep; restlessness, loss of interest in pleasurable activities; overeating or loss of appetite; unexplained pain, unexplained headaches, persistent cramps, persistent digestive problems; suicidal ideation and suicidal behavior.

[0110] The loss of synapses that utilize the amino acid glutamate as a neurotransmitter ('glutamatergic' synapses) has been recognized as a key feature of certain neurodegenerative diseases. Importantly, approximately 90% of glutamatergic synapses involve postsynaptic dendritic spines. The majority of synapses lost in neurodegenerative conditions are those where the axon contacts the dendritic spines, known as 'axon-spine synapses'. Under normal conditions, variations in the density, shape, and protein composition of dendritic spines affect the strength of synaptic communication and are the basis for several forms of synaptic change (i.e., 'plasticity') involved in learning and memory, cognitive flexibility, adaptation to injury and disease, and other processes.

[0111] The role of spike density in the progression of mood disorders is not fully understood. However, stress has been observed to decrease synaptic density. Since many cognitive disorders exhibit abnormalities in the morphology and function of dendritic spikes, it is desirable to use small molecules to directly target them to alter or alleviate these spike changes. Such treatments could offer benefits in reducing side effects, including paresthesia, associated with many psychoactive medications, such as typical antidepressants. Therefore, developing novel approaches to increase spike density may be of great significance for the treatment of mood disorders, including depression.

[0112] Therefore, this paper provides compounds that promote dendritic spine formation. Dendritic spine formation can manifest as an increase in the average number of spines per neuron or per unit length of neuron, which can be referred to as an increase in dendritic spine density. Dendritic spine formation can manifest as an improvement in dendritic spine morphology. For example, an improvement in dendritic spine morphology can manifest as an increase in the average size of the spine head. Dendritic spine formation can manifest as an improvement in dendritic spine size, spine plasticity, spine mobility, spine density, and / or synaptic function. Dendritic spine formation can manifest as an increase in the local spatial average value of membrane potential. Dendritic spine formation can manifest as Ca 2+ An increase in postsynaptic concentration (e.g., volume-average). Dendritic spine formation can manifest as an increase in the average ratio of mature to immature spines. In some embodiments, the compounds described herein increase dendritic spine density relative to a control. In some embodiments, the compounds described herein increase dendritic spine density relative to the dendritic spine density observed at the start of treatment. In some embodiments, the increase in dendritic spine density leads to a reduction in mood disorder symptoms in the subject or patient. In some embodiments, the increase in dendritic spine density is illustrated by anatomical observation. In some embodiments, the increase in dendritic spine density is observed in the prefrontal cortex, such as the medial prefrontal cortex.

[0113] In some embodiments, the average dendritic spine density increases by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two of these figures, including the endpoints, relative to when treatment begins with the compound described herein. In some embodiments, the dendritic spine density increases by about 50% to about 500% relative to when treatment begins with the compound described herein. In some embodiments, the dendritic spine density increases by about 100% to about 300% relative to when treatment begins with the compound described herein. In some embodiments, the dendritic spine density increases by about 200% to about 300% relative to when treatment begins with the compound described herein. In some embodiments, the duration of treatment with the compounds described herein is 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, four weeks, twelve weeks, four months, or one year.

[0114] In some embodiments, the method increases spine density by promoting the formation of new spines. In some embodiments, the method increases the average spine density by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000%, or any range between any two of these figures, including the endpoints, relative to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases the average spine density by about 50% to about 500% relative to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases the spine density by about 100% to about 300% relative to a control (e.g., spine density in the absence of the compound). In some embodiments, the method increases the spine density by about 200% to about 300% relative to a control (e.g., spine density in the absence of the compound).

[0115] In some embodiments, the method increases spike density by increasing neuron length. In some embodiments, the method increases the average neuron length by about 100 nm, 300 nm, 500 nm, 700 nm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 7 μm, 10 μm, 15 μm, 20 μm, 25 μm, or any range between any two of these numbers, including endpoints, relative to when treatment begins with the compound described herein. In some embodiments, the method increases the average neuron length by about 500 nm to about 25 μm relative to a control (e.g., neuron length in the absence of the compound). In some embodiments, the method increases the neuron length by about 10% to about 300% relative to a control (e.g., neuron length in the absence of the compound). In some embodiments, the method increases the neuron length by about 200% to about 300% relative to a control (e.g., neuron length in the absence of the compound).

[0116] In some embodiments, the method increases the average number of spines per neuron relative to when treatment begins with the compounds described herein. In some embodiments, the average number of spines per unit length of neuron is increased by at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or about 1000 or more, or any range between any two of these numbers, including the endpoints.

[0117] In some embodiments, the time to achieve the changes in spine density or spine morphology described herein (e.g., average dendritic spine density, average spine density, average neuron length, or average number of spines per neuron) is 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.

[0118] In some embodiments, subjects have been found to suffer from abnormal dendritic spine morphology, spine size, spine plasticity, spine mobility, spine density, and / or abnormal synaptic function. For example, subjects may experience reduced dendritic spine density during or after anesthesia (e.g., anesthesia during surgery). In some embodiments, mood disorders are associated with abnormal (e.g., reduced) levels of dendritic spine density.

[0119] In some embodiments, the method includes administering to a subject an effective amount of a compound that inhibits the N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor is so named because the agonist molecule N-methyl-D-aspartate (NMDA) selectively binds to this receptor, but not to other glutamate receptors. The NMDA receptor is a glutamate receptor and ion channel protein found in nerve cells. The receptor is activated when glutamate and glycine or D-serine bind to it, and when activated, it allows positively charged ions to flow across the cell membrane. The NMDA receptor is believed to be important for controlling synaptic plasticity and memory function. Activation of the NMDA receptor results in the opening of a cation-nonselective ion channel. While the opening and closing of the ion channel is primarily gated by ligand binding, the current flowing through the ion channel is voltage-dependent. The Ca2+ flow through the NMDA receptor… 2+ Flux is considered crucial in synaptic plasticity. The voltage dependence of the current through this channel is primarily due to Mg as described above. 2+ or Zn 2+ Ion binding to proteins. In some embodiments, the compounds described herein can promote dendritic spine formation by inhibiting NMDA receptors. In some embodiments, the compounds described herein block NMDA receptor activity, optionally at its 2A subunit.

[0120] In some embodiments, the compounds described herein can promote (optionally at their 2A subunit) NMDA receptor activity.

[0121] In some embodiments, the mood disorder is related to (e.g., characterized by) the accumulation of amyloid plaques. In some embodiments, the mood disorder is caused by traumatic brain injury or chronic traumatic encephalopathy. In some embodiments, the subject has not suffered from traumatic brain injury or chronic traumatic encephalopathy. In some embodiments, the depression is not the result of substance abuse or another medical condition. In some embodiments, the administration of hallucinogens, such as ketamine, to the patient is not recommended.

[0122] compound This article provides agents that promote dendritic spine formation. Such agents have unexpectedly been found to be useful in treating mood disorders. These agents may be compounds provided in this article.

[0123] The compound may be the compound described in International Patent Publication No. WO 2019 / 028164. In some embodiments, the compound is a compound of Formula I or Formula Ia: Or its pharmaceutically acceptable salts, solvates and / or N-oxides, wherein Subscript n and p Independently selected from 0, 1, or 2; Each R 1 Independently selected from the group consisting of: hydrogen, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxylic acid ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, hydroxyl, thiol and nitro. A is an arylene or heteroarylene having 1 to 4 heteroatoms; W is selected from the following groups: -O-, -S-, -SO-, -S(O)2-, and -NR. 2 -, where R 2 Choose from the group consisting of: hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic alkyl, and substituted heterocyclic alkyl; X is selected from the following groups: -O-, -S-, -SO-, -S(O)2-, and -NR. 2 -, where R 2 As defined above, the prerequisite is that A is aryl and Y is -S- or -NR. 2 - At this time, X is not -S-; Y is selected from the following groups: -O-, -S-, -SO-, S(O)2-, and -NR. 2 -, where R 2 As defined above; and Z is selected from the following groups: -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R) 3 )O) q -T, where the subscript q R is an integer selected from 1 to 100. 3 T is selected from the group consisting of hydrogen and methyl, and T is selected from the group consisting of hydrogen, alkyl, substituted alkyl, -L-monosaccharide and -L-oligosaccharide, wherein L is selected from the group consisting of bond, phosphate ester and sulfate ester.

[0124] In some embodiments, compounds according to formula Ib, formula Ic, formula Id, formula Ie and / or formula Ig are provided: Or its pharmaceutically acceptable salts, solvates and / or N-oxides, wherein R 1 R 2 A, Y, Z n and p As defined above regarding equations I and Ia; and Subscript m Choose from 0, 1, or 2.

[0125] In some embodiments, compounds selected from the following, or pharmaceutically acceptable salts, solvates, and / or N-oxides thereof, are provided: , , , , , , , , , , , , , , , , ,and .

[0126] In some embodiments, compounds according to formula Ih are provided: (Ih), Or its pharmaceutically acceptable salts, solvates and / or N-oxides, wherein: Subscript n and p Independently selected from 0, 1, or 2; Subscript qIt is an integer selected from 2 to 8; and Each R 1 and R 2 The group consisting independently of the following: halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, amide, amino carbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxylic acid ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.

[0127] In some embodiments, compounds as described herein, or pharmaceutically acceptable salts, solvates, and / or N-oxides thereof, are provided, selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0128] In some embodiments, compounds according to formula Ij are provided: (Ij), Or its pharmaceutically acceptable salts, solvates and / or N-oxides, wherein: Subscript qIt is an integer selected from 4 or 6; R 3 R 4 R 5 and R 6 Independently select from the following groups: hydrogen, halogenated, –CH3, and –OCH3; and R 7 R 8 R 9 and R 10 Choose independently the group consisting of the following: hydrogen, halogen, –CH3, –CF3, –OCH3, –OCF3, phenyl, –NO2; At least six of the R groups are hydrogen atoms.

[0129] In some embodiments, compounds selected from the following, or pharmaceutically acceptable salts, solvates, and / or N-oxides thereof, are provided: and .

[0130] In some embodiments, the compound is (Compound 1) Or its pharmaceutically acceptable salts, solvates and / or N-oxides.

[0131] The compound may be the compound described in International Patent Publication No. WO2017120198.

[0132] In some embodiments, the compound is a compound of formula II: II; Or its pharmaceutically acceptable salts, solvates and / or N-oxides, wherein Y is –NR 33 -、O or –S-;R 31 Independently, it is halogen, -CX 31 -CHX 31 -CH2X 31 -OCX 31 S、-OCHX 31 -OCH2X 31-CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 32 Independently, it is halogen, -CX 32 3. -CHX 32 2. -CH2X 32 -OCX 32 3. -OCHX 32 2. -OCH2X 32 -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X 31 and X 32 Each of z1 and z2 is independently a halogen; each of z1 and z2 is independently an integer from 0 to 4; and z3 is an integer from 1 to 12.

[0133] In some embodiments, the compound is a compound of formula IIa: Or its pharmaceutically acceptable salts, solvates and / or N-oxides, wherein R 1 Independently, it is halogen, -CX 1 3. —CHX 1 2、—CH2X 1 —OCX 1 3. —OCHX 1 2. -OCH2X 1—CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 Independently, it is halogen, -CX 2 3. —CHX 2 2、—CH2X 2 —OCX 2 3. —OCHX 2 2. —OCH2X 2 —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X 1 and X 2 It is a halogen on its own; z1 and z2 are independent integers from 0 to 4; and n is an integer from 1 to 12.

[0134] In some embodiments, the compound is or its pharmaceutically acceptable salts, solvates and / or N-oxides.

[0135] In some embodiments, the compound is or its pharmaceutically acceptable salts, solvates and / or N-oxides.

[0136] In some embodiments, the compound is a compound of formula III: III Or pharmaceutically acceptable salts, solvates, and / or N-oxides thereof, wherein R1-R8 are selected from the group consisting of: hydrogen, deuterium, tritium, fluoride, chloride, bromide, iodide, hydroxide, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, wherein R5 -R 8 At least one of R1 and one of R4 is H; and P chooses a group composed of the following items. Where m is an integer between 1 and 20; n is 0, 1, or 2; q is an integer between 1 and 20; R9-R 16 Choose the group composed of the following: hydrogen, deuterium, tritium, fluoride, chloride, bromide, iodide, hydroxide, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, where R9-R 12 At least one of them and R 13 -R 16 One of them is H; And X is hydrogen, methyl, or ethyl.

[0137] In some embodiments, the compound of formula III is a compound of formula IIIa: IIIa R1-R8 are selected from the group consisting of: hydrogen, deuterium, tritium, fluoride, chloride, bromide, iodide, hydroxide, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, wherein at least one of R5-R8 and one of R1-R4 is H; and P is... Where m is an integer between 1 and 20; q is an integer between 1 and 20; R9-R 16 Choose the group composed of the following: hydrogen, deuterium, tritium, fluoride, chloride, bromide, iodide, hydroxide, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, where R9-R 12 At least one of them and R 13 -R 16 One of them is H; and X is hydrogen, methyl or ethyl.

[0138] In some embodiments, the compound is selected from , Or its pharmaceutically acceptable salts, solvates and / or N-oxides.

[0139] In some embodiments, the compound is not ketamine. In some embodiments, the compound does not cause perceptual abnormalities in subjects. In some embodiments, the compound is not a hallucinogen. In some embodiments, the compound is not hallucinogenic.

[0140] Combination therapy When used to treat or prevent the aforementioned diseases and conditions, the compounds described herein may be administered in combination with one or more other therapies, such as other therapeutic agents approved for the treatment or prevention of specific diseases or conditions, and more particularly therapies and / or therapeutic agents considered to form current standards of care.

[0141] In one embodiment, the compounds disclosed herein may be used in combination with one or more other therapeutic agents that are being used and / or developed for the treatment of mood disorders. When combination therapy is contemplated, these active agents may be administered simultaneously, separately, or sequentially in one or more pharmaceutical compositions. In some embodiments, the one or more other therapeutic agents are antidepressants.

[0142] In some embodiments, the antidepressant is selected from the group consisting of: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, serotonin-norepinephrine-dopamine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, or tetracyclic antidepressants.

[0143] In some embodiments, the antidepressant is a serotonin and norepinephrine reuptake inhibitor selected from the group consisting of: levomirnacitabine, venlafaxine, norvenlafaxine, sibutramine, nefazodone, mirnacitabine, duloxetine and bisifafine, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers or mixtures of stereoisomers.

[0144] In some embodiments, the antidepressant is a serotonin-norepinephrine-dopamine reuptake inhibitor selected from the group consisting of: tersofencin and brassofencin, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers.

[0145] In some embodiments, the antidepressant is a monoamine oxidase inhibitor selected from the group consisting of isocarboxazid, moclobemide, phenelzine, transphenylcyclopropionamide, selegiline, rasagiline, nialamine, isoniazid, isopronicotinamide, and toloxacin, or deuterated analogs thereof, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers.

[0146] In some embodiments, the antidepressant is a tricyclic antidepressant selected from the group consisting of butiline, amoxapine, amitriptyline, nortriptyline, clomipramine, desipramine, duthiramine, doxepin, imipramine, dibenzapine, iproindole, lofepramine, octopiol, protriptyline, and trimipramine, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers.

[0147] In some embodiments, the antidepressant is a tetracyclic antidepressant selected from the group consisting of: maprotiline, mianserin, mirtazapine, septoprolol, amoxapine, quetiapine, benzotamine, loxapine, macindo, alprazoline, esmirtazapine, oxaprotiline, cilazindo, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers.

[0148] In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor selected from the group consisting of: fluoxetine, norfluoxetine, citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers.

[0149] In some embodiments, the antidepressant is ketamine, esketamine, bupropion, mirtazapine, vilazorone, vortioxetine, aripiprazole, or St. John's wort, or a deuterated analogue thereof, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, or a mixture of stereoisomers. In some embodiments, the antidepressant is ketamine or esketamine.

[0150] The one or more additional therapeutic agents may be sedative-hypnotic drugs, such as chloral hydrate, estazolam, flurazepam hydrochloride, pentobarbital, sodium pentobarbital, sodium phenobarbital, secobarbital sodium, temazepam, triazolam, zaleplon, or zolpidem tartrate; anticonvulsants, such as acetazolamide sodium, carbamazepine, clonazepam, dipotassium chlordiazepoxide, diazepam, sodium valproate, ethosuximide, fosphenytoin sodium, gabapentin, lamotrigine, magnesium sulfate, phenobarbital, sodium phenobarbital, phenytoin, phenytoin sodium, primidone, tiagabine hydrochloride, topiramate, sodium valproate, or valproic acid; and anti-anxiety drugs, such as alprazolam, buspirone hydrochloride, chlordiazepoxide, dipotassium chlordiazepoxide, diazepam, doxepin hydrochloride, hydroxyzine enbrel, hydroxyzine hydrochloride, diazepam, doxepin hydrochloride, hydroxyzine enbrel, hydroxyzine hydrochloride, diazepam, doxepin, hydroxyzine enbrel, hydroxyzine enbrel, diazepam ... Hydroxyzine hydroxynaphthyl acid, lorazepam, meprobamate, midazolam hydrochloride, or oxazepam; antipsychotics, such as chlorpromazine hydrochloride, clozapine, fluphenazine decanterate, fluphenazine enanthate, fluphenazine hydrochloride, haloperidol, haloperidol decanterate, haloperidol lactate, loxapine hydrochloride, loxapine succinate, mesoridazine besylate, morphinone hydrochloride, olanzapine, perphenazine, pimozide, prochlorperazine, quetiapine fumarate, risperidone, thioridazine hydrochloride, tevothixol, tevothixol hydrochloride, and trifluoperazine hydrochloride; central nervous system stimulants, such as amphetamine sulfate, caffeine, dextroamphetamine sulfate, doxapram hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride, modafinil, pimoxim, or phentermine hydrochloride; anti-Parkinson's drugs, such as amantadine hydrochloride. Alkanetams, benzalkonium mesylate, biperidone hydrochloride, biperidone lactate, bromocriptine mesylate, carbidopa-levodopa, entacapone, levodopa, pergolide mesylate, pramipexole dihydrochloride, ropinirole hydrochloride, selegiline hydrochloride, tocapone, or trihexyphenidyl hydrochloride; central nervous system agents, such as bupropion hydrochloride, donepezil hydrochloride, fluperidone, fluvoxamine maleate, lithium carbonate, lithium citrate, naratriptan hydrochloride, nicotine resin complexes, nicotine transdermal systems, propofol, rizatriptan benzoate, sibutramine hydrochloride monohydrate, sumatriptan succinate, tacrine hydrochloride, or zolmitriptan; cholinergic drugs (e.g., parasympathomimetic drugs), such as clobecylcholine, phenobarbital chloride, neostigmine bromostigmine, neostigmine methylsulfate. Hydrosine salicylate or pyridostigmine bromide; anticholinergic drugs, such as atropine sulfate, dicyclovir hydrochloride, glycopyrronium bromide, hyoscyamine, hyoscyamine sulfate, bromopropylate, scopolamine, butyl scopolamine bromide, or scopolamine hydrobromide; adrenergic drugs (sympathomimetic drugs), such as dobutamine hydrochloride, dopamine hydrochloride, metaraminol bitartrate, norepinephrine bitartrate. Phenylephrine, phenylephrine hydrochloride, pseudoephedrine hydrochloride, or pseudoephedrine sulfate; adrenergic blockers (sympathetic nerve blockers), such as dihydroergotamine mesylate, ergotamine tartrate, mesiergot maleate, or propranolol hydrochloride; skeletal muscle relaxants, such as baclofen, caripdrol, chlorzoxazone, cyclobenzaline hydrochloride, dantrolene sodium, mesobamoline, or tizanidine hydrochloride;Neuromuscular blocking agents, such as atracurium besylate, cisatracurium besylate, doxachloride, mirtazachlor, pancuronium bromide, pipecuronium bromide, rascuolium bromide, rocuronium bromide, succinylcholine chloride, tubocurarine chloride, or vecuronium bromide; or corticosteroids, such as betamethasone, betamethasone acetate, or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, etc. Dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cyclopentylpropionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tert-butyl ethyl ester, prednisolone, triamcinolone, triamcinolone acetonide, or triamcinolone diacetate.

[0151] One or more of the following therapeutic agents may be tacrine, donepezil, galantamine, rivastigmine, memantine, levodopa, carbidopa, rissuva, rasagiline, tocapone, entacapone, clozapine, desipramine, citalopram, nortriptyline, paroxetine, atomoxetine, venlafaxine, amantadine, donepezil, rivastigmine, bromocriptine, cabergoline, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, benserazide, selegiline, omega-47, CEP-1347, isradipine, DOPA, lithium, riluzole, levetiracetam. Cestane, ezogabaline, pregabalin, rufenamide, felbamate, carbamazepine, valproate, sodium valproate, lamotrigine, phenytoin, oxcarbazepine, ethosuximide, gabapentin, tiagabine, topiramate, vigabatrin, phenobarbital, primidone, clonazepam, interferon β-1a, interferon β-1b, mitoxantrone, natezumab, fingolimod, natezumab, teriflunomide, dimethyl fumarate, glatiramer, ATOH1 gene therapy, ozanenezumab, alimolol, telasimi, dexramopexole, pridopidine, or galantamine; or phosphoglycerate kinase (PGK) as described in US 2018 / 0147263. In some embodiments, the one or more additional therapeutic agents may be acetylcholinesterase inhibitors (AChEIs), such as acotiamide, α-pinene, ambecium chloride, demeton-methyl bromide, DFP (diisopropyl fluorophosphate), donepezil, ethanochlor, galantamine, huperzine A, lactucin, latotrigine, neostigmine, physostigmine, pyridostigmine, diphenoxyphosphonocholine, levamisole, rosmarinic acid, tacrine, empamin, zanapazine, ganstamine, fenserline, phenethyl norsemomoslin (PENC), semolina, thiamethoxamomoslin, SPH 1371 (galantamine plus), ER 127528, RS 1259, or F3796. In some embodiments, the one or more additional therapeutic agents may be amyloid-clearing antibodies, such as bavizumab, sorazzumab, gantezumab, crimetzumab, ponizumab, BAN2401, or aducanumab.

[0152] In some embodiments, the one or more additional therapies are acceptance and commitment therapy, Adlerian therapy, animal-assisted therapy, applied behavior analysis, art therapy, attachment therapy, biofeedback, brain stimulation therapy, counseling, cognitive behavioral therapy, cognitive processing therapy, cognitive stimulation therapy, cultural sensitivity therapy, dialectical behavior therapy, eclectic therapy, emotion-focused therapy, existential therapy, experiential therapy, expressive arts therapy, eye movement desensitization and reprocessing therapy, family systems therapy, feminist therapy, forensic psychotherapy, Gestalt therapy, hypnotherapy, imagery-based therapy, integrative therapy, internal family systems therapy, interpersonal psychotherapy, Jungian therapy, marriage and family therapy, mindfulness-based therapy, mindfulness-based cognitive therapy, motivational interviewing, multicultural therapy, narrative therapy, and neurolinguistic programming. Sequential therapy, neurofeedback, parent-child interaction therapy (PCIT), person-centered therapy, play therapy, positive psychology, extended exposure therapy, psychoanalytic therapy, psychodynamic therapy, psychological testing and assessment, rational emotive behavior therapy, reality therapy, relationship therapy, sandplay therapy, social recovery therapy, solution-focused brief therapy, somatic therapy, strengths-based therapy, structural family therapy, Gottman method, therapeutic intervention, transpersonal therapy, trauma-focused cognitive behavioral therapy, humanistic therapy, Gestalt therapy, psychodynamic therapy, talk therapy, group therapy, counseling, psychoanalysis, cognitive behavioral therapy, yoga, tai chi, deep breathing, progressive muscle relaxation, meditation, acupuncture, transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), or electroconvulsive therapy (ECT).

[0153] In some embodiments, the compounds described herein are administered as a single therapy.

[0154] Reagent test kit This document also provides a kit comprising the compound described herein, or a deuterated analog thereof, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer or a mixture of stereoisomers, optionally a second active ingredient, and suitable packaging. In one embodiment, the kit further includes instructions for use. In one aspect, the kit comprises the compound described herein, or a deuterated analog thereof, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer or a mixture of stereoisomers, as a component of a pharmaceutical composition, and a label and / or instructions for use of the pharmaceutical composition in treating the indications described herein, including diseases or conditions.

[0155] This document also provides articles comprising the compounds described herein, or their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers, in a suitable container. The container may be a vial, wide-mouth bottle, ampoule, pre-filled syringe, nebulizer, aerosol dispenser, dropper, or intravenous bag.

[0156] Pharmaceutical Compositions and Administration Methods The compounds described herein are typically administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising one or more of the compounds described herein, typically including the compounds described herein, their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers, and one or more pharmaceutically acceptable carriers selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable carriers may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical industry. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (edited by GS Banker and CT Rhodes).

[0157] These pharmaceutical compositions can be administered in single or multiple doses. The pharmaceutical compositions can be administered by various methods, including, for example, rectal, sublingual, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition can be administered via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0158] One mode of administration is parenteral, such as by injection. The pharmaceutical compositions described herein may be contained in forms for administration by injection, including, for example, aqueous or oil suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, glucose, or sterile aqueous solutions, and similar drug carriers.

[0159] Oral administration may be another route of administration for the compositions described herein. Administration may be via, for example, capsules or enteric-coated tablets. In the preparation of pharmaceutical compositions comprising at least one compound described herein or its deuterated analogue, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, or a mixture of stereoisomers, the active ingredient is typically diluted with an excipient and / or encapsulated within a carrier, which may be in the form of capsules, pouches, paper, or other containers. When the excipient acts as a diluent, it may be in the form of a solid, semi-solid, or liquid material that can act as a mordant, carrier, or medium for the active ingredient. Therefore, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0160] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, astragalus gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. These formulations may additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0161] The pharmaceutical composition and any container therein for dispensing the pharmaceutical composition may be sterilized. The pharmaceutical composition may also contain adjuvants, such as preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, salts for altering osmotic pressure, viscosity modifiers, or buffers.

[0162] Compositions comprising at least one compound described herein (such as the compound described herein, its deuterated analogues, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers) can be formulated using methods known in the art to provide a rapid, sustained, or delayed release of the active ingredient upon administration to a subject. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use with the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured for continuous, pulsed, or on-demand delivery of medications.

[0163] To prepare solid compositions (such as tablets), a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of the compound described herein or its deuterated analogue, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, or a mixture of stereoisomers. When these preformulation compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition, making it easy to further fractionate the composition into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0164] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action or protection from the acidic conditions of the stomach. For example, the tablets or pills may comprise an internal dose component and an external dose component, the latter covering the former in the form of a coating. The two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to be delivered intact into the duodenum or to be released with a delay. Various materials may be used for such an enteric coating or coating, including a variety of polymeric acids and mixtures of polymeric acids with such materials as shellac, hexadecyl alcohol, and cellulose acetate.

[0165] This pharmaceutical composition can be formulated for nasal administration. Such pharmaceutical compositions may comprise one or more active ingredients in different physical states, such as the compounds described herein, their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers. For example, these active ingredients may be dissolved or suspended in a liquid carrier. These active ingredients may be in a dry form. This dry form may be a powder. The active ingredient in powder form may be amorphous or crystalline. For example, the compounds described herein, their deuterated analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers may be amorphous or crystalline. Crystalline active materials may be hydrates or solvates.

[0166] Solid compounds, or their salts or crystals, may be present in the formulation at a selected average particle size. These particles may have an average particle size (longest dimension) of 10 nm, 100 nm, 300 nm, 500 nm, 1 µm, 10 µm, 50 µm, 100 µm, 300 µm, or 500 µm, or a range between any two values.

[0167] Administration can be performed by inhalation or inhalation. Compositions for inhalation or inhalation may comprise solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered via oral or nasal inhalation. The effect may be local or systemic. In a particular embodiment, the effect is a local effect on cranial tissue. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizer, or the nebulizer may be attached to a mask plug or an intermittent positive pressure ventilation machine. The solution, suspension, or powder composition can preferably be administered orally or nasally from a device that delivers the formulation in a suitable manner. Pharmaceutical compositions for inhalation or inhalation may be aerosols.

[0168] The pharmaceutical composition may comprise a liquid suspension or solution containing about 0.05%, about 0.1%, about 0.3%, about 0.5%, about 0.7%, about 1%, about 2%, about 3%, about 4%, or about 5% w / w of the active ingredient. The liquid may contain water and / or alcohol. The liquid may contain a pH adjuster such that the pH is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, or a range thereof.

[0169] The pharmaceutical composition may contain a pharmaceutically acceptable preservative. Preservatives suitable for use herein include, but are not limited to, those that protect the solution from contamination by pathogenic particles, including phenethyl alcohol, benzalkonium chloride, benzoic acid, or benzoates such as sodium benzoate. In some embodiments, the pharmaceutical composition contains from about 0.01% to about 1.0% w / w benzalkonium chloride, or from about 0.01% to about 1% v / w phenethyl alcohol. The preservative may also be present in an amount from about 0.01% to about 1%, preferably from about 0.002% to about 0.02% by weight or volume of the composition.

[0170] The pharmaceutical composition may also contain one or more of an emulsifier, wetting agent, or suspending agent, ranging from about 0.01% to about 90%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about 0.01% to about 10%, or about 0.01% to about 1% w / w. Such pharmaceutical agents used herein include, but are not limited to, polyoxyethylene sorbitan fatty acid esters or polysorbate esters, including, but not limited to, polyethylene sorbitan monooleate (polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (2) 0) Sorbitan monostearate; lecithin; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane-1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum; astragalus gum; gum arabic; xanthan gum; ebony gum; pectin; amidated pectin; ammonium phosphatidylcholine; microcrystalline cellulose; methylcellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose; ethyl methylcellulose; carboxymethyl cellulose; sodium, potassium, and calcium salts of fatty acids. Salts; monoglycerides and diglycerides of fatty acids; acetates of monoglycerides and diglycerides of fatty acids; lactates of monoglycerides and diglycerides of fatty acids; citrates of monoglycerides and diglycerides of fatty acids; tartaric esters of monoglycerides and diglycerides of fatty acids; monoacetyl tartaric esters and diacetyl tartaric esters of monoglycerides and diglycerides of fatty acids; mixed acetates and tartaric esters of monoglycerides and diglycerides of fatty acids; sucrose esters of fatty acids; sucrose esters. Oil esters; polyglycerol esters of fatty acids; polyglycerol esters of castor oil polycondensed fatty acids; propane-1,2-diol esters of fatty acids; sodium stearoyl-2-lactic acid; calcium stearoyl-2-lactic acid; stearoyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; soap bark extract; polyglycerol esters of soybean oil dimerized fatty acids; oxidized polymerized soybean oil; and pectin extract.

[0171] In another embodiment, the pharmaceutical composition for nasal administration may be provided in powder form. For example, a powdered nasal composition may be used directly as a powder for a unit dosage form. If desired, the powder may be filled into a capsule (such as a hard gelatin capsule). The contents of the capsule or single-dose device may be administered using, for example, a blower.

[0172] Therefore, a method for treating mood disorders may include the following steps: administering a pharmaceutical composition comprising the compound described herein or a salt thereof to a subject in need via nasal administration.

[0173] Dosage The specific dose level of the active ingredient (such as the compound described herein) for any particular subject will depend on a variety of factors, including the activity of the particular compound used, the age, weight, general health, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity of the specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. A dose between about 0.1 and 150 mg / kg may be suitable. In some embodiments, about 0.1 to 100 mg / kg may be suitable. In other embodiments, a dose between 0.5 and 60 mg / kg may be suitable. Standardization based on subject weight is particularly useful when adjusting doses among subjects with large differences in body size, such as when using the drug in children and adults, or when converting an effective dose for non-human subjects (e.g., dogs) to a dose suitable for human subjects.

[0174] The daily dose can also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound described herein or its salts may be from about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0175] When administered nasally, the total daily dose for human subjects may be from 1 mg to 1,000 mg, about 1,000 to 2,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day. In various embodiments, the daily dose may be about 10 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg, or a range thereof.

[0176] The active ingredient or pharmaceutical composition thereof may be administered once, twice, three times, or four times daily using any of the suitable modes described above. Furthermore, administration or treatment may continue for several days; for example, a treatment cycle typically lasts at least 7, 14, or 28 days. Treatment cycles are well-known and are often alternated between cycles with rest periods of approximately 1 to 28 days (typically approximately 7 or 14 days). In other embodiments, treatment cycles may also be continuous. Administration or treatment may continue indefinitely.

[0177] In certain embodiments, the method includes administering to a subject an initial daily dose of about 1 to 800 mg of the compound described herein, and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, or once a week.

[0178] In some embodiments, the method includes administering a dose to a subject once a month, twice a month, once a week, twice a week, or three times a week in the amounts provided herein. In such embodiments, administration may continue for one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, twelve months, fourteen months, eighteen months, one year, two years, three years, five years, or indefinitely. In some embodiments, a method is provided that includes administering the compound described herein at a frequency of three times a week to once a month.

[0179] Example Example 1 animal Social defeat experiments were conducted, for example, according to Becker C, Zeau B, Rivat C, Blugeot A, Hamon M, Benoliel JJ, Repeated social defeat-induced depression-like behavioral and biological alterations in rats: involvement of cholecystokinin. Mol Psychiatry. 2008; 13:1079–1092. Male Sprague-Dawley (SD) rats weighing 300–325 g (8 weeks old) upon arrival at the laboratory were used as experimental intruders or control animals. They were housed for 10 days in individual cages (length: 45 cm; width: 25 cm; height: 17 cm) in a chronobiological animal facility. This chronobiological facility was equipped with equidistant, soundproof, temperature-controlled (21.0 ± 1.0 ℃) compartments with filtered air. Each compartment had its own light-dark cycle control. Long Evans (LE) rats weighing 700–800 g were used as resident rats in the adversarial encounters. Upon arrival at the laboratory, they were housed for one month in suitable cages (length: 45 cm; width: 45 cm; height: 17 cm) with a neutered female. Resident rats were then selected based on reliable aggressive behavior assessed in confrontation with intruders. During the social frustration procedure, the female was removed from the cage. The same 10 LE rats were used for all consecutive series of experiments. All animals were maintained under controlled environmental conditions (22 ± 1 °C, 60% relative humidity, 12 / 12 h light-dark cycle, light on at 07:00, food and water freely available).

[0180] Social Frustration Program The behavioral program consisted of conditioned experimental periods with identical resident and intruder pairings. The 45-minute conditioned experimental periods began at 10:00. They were divided into two consecutive periods. During period I (30 minutes), the intruder was placed alone in an uncovered protective cage (length: 25 cm; width: 25 cm; height: 30 cm) within the resident's cage. The resident's cage was uncovered and surrounded by a 100 cm high wire mesh fence (length: 45 cm; width: 45 cm). The protective cage allowed unrestricted visual, auditory, and olfactory interactions with the resident, but excluded close physical contact. During period II (15 minutes), the protective cage (the defeated intruder) was removed, allowing physical confrontation. Typically, the intruder was attacked within 30 seconds, and three to four confrontations occurred, each lasting approximately 10 seconds, during which the intruder was always dominated by the resident rat and adopted a compliant posture, i.e., when the defeated rat lay supine under the resident rat for approximately 5 seconds. The total duration of confrontation was approximately 1 minute throughout the entire 15-minute period II. During physical confrontation, intruders were rarely injured, and in such cases, only at the superficial level of the skin (in less than 5% of the confrontation test periods). Unfrustrated intruders underwent the same procedure, but without resident rats throughout the entire 15-minute period II. Therefore, they were never physically attacked or frustrated by the residents. The 45-minute conditioned test period was repeated daily for 4 days during week 1. During weeks 2 and 3, intruders underwent a social frustration procedure once daily for 2 days, and in week 4, the procedure was again repeated daily for 4 days. One group of animals was used for behavioral and physiological analysis, and another group was used for microdialysis experiments. For the latter, a guide cannula was implanted into the intruders 25 days after the last conditioned test period, and a microdialysis probe was implanted 4 days later.

[0181] In the separate experiment, control rats were kept in their cages for 40 days.

[0182] weight Body weights of frustrated and unfrustrated rats treated with or untreated with the compounds described herein were measured daily at 09:00 before (7 days), during (25 days), and after (4 days) the social frustration program.

[0183] Adrenal weight Five days after the final conditioning experiment, defeated and undefeated invaders, treated with or untreated with the compounds described herein, were decapitated, and the adrenal glands were removed, dissected to remove attached fat, and weighed.

[0184] Sweet water consumption From one week before the start of the conditioned period (D7 to D1) until five days after the last conditioned period, two bottles (one filled with water and the other containing 1.5% sucrose) were continuously available to the rats. Sucrose and water intake were measured daily at 09:00. Throughout the experiment, the bottles were rotated daily from left to right of the cage to avoid any positional preference. Sweetened water consumption was calculated as a percentage of the control value.

[0185] Food consumption Food intake was measured daily at 09:00 before (7 days), during (25 days), and after (5 days) the social frustration program. Data are expressed as the sum of daily food intake measured weekly in each animal group.

[0186] Forced swimming test Originally used by Porsolt et al. An adapted version of the Forced Swimming Test (FST) described. Experiments were conducted between 09:30 and 13:00. Five days after the last conditioned experimental period, SD rats were individually placed in glass cylinders (40 cm high; 20 cm diameter) containing water at a height of 29 cm and a temperature of 30 ± 1 °C. After 8 minutes, they were transferred to a dry environment at 30 °C for 15 minutes. The water was changed and the cylinders were cleaned after each animal's experimental period to avoid the influence of alarm pheromones left by the previous animal. Immobility time was measured using a stopwatch. A rat was considered immobile when it floated and only made necessary movements to keep its nostrils above the water surface. Animal observation and measurements were performed by trained experimenters unaware of the treatment. Room and water temperatures were monitored at the end of each experimental period. Each rat underwent only one swimming experimental period individually.

[0187] Cell proliferation and hippocampal volume BrdU mark On day 29, rats received two injections of bromodeoxyuridine (BrdU) at 2-hour intervals. 24 hours (proliferation) or 28 days (differentiation) after the first BrdU injection (days 30 and 58), they were given 375 mg / kg of bromodeoxyuridine (BrdU). -1 Animals were anesthetized with chloral hydrate intraperitoneally (ip). Blood was removed by cardiac perfusion with saline, followed by cold paraformaldehyde (PFA) in phosphate-buffered saline (PBS). After perfusion, the brain was post-fixed overnight at 4°C in 4% PFA / PBS. The following day, continuous sections (40 μm thick) spanning the entire hippocampus (plates 26–40) were cut using a cryostat and stored overnight at 4°C in PBS.

[0188] Immunohistochemistry On the second day, BrdU-labeled immunohistochemical visualization was performed using free-floating sections. After several PBS washes, sections were incubated in 3% H2O2 for 5 minutes to remove endogenous peroxidase. They were then washed in PBS, incubated in 2 N HCl for 30 minutes, followed by incubation in 0.1 M boric acid for 30 minutes. After blocking with 5% horse serum in 0.1% Triton X-100, sections were incubated overnight at 4°C with mouse anti-BrdU antibody (1:500; Dakocytomation, Trappes, France), followed by incubation for 2 hours with a secondary antibody (1:400; biotinylated horse anti-mouse). After amplification with the avidin-biotin complex, sections were exposed to diaminobenzidine, washed with PBS, and mounted on microscope slides. Sections were counterstained with cresol violet and covered with coverslips. All slides were coded prior to analysis.

[0189] For triple immunolabeling (differentiation), the slides were simultaneously incubated overnight at 4°C with rat anti-BrdU antibody (1:100), mouse anti-NeuN antibody (1:500), and rabbit anti-GFAP antibody (1:300). After washing, the slides were incubated with biotinylated anti-rat IgG for 2 hours, and then with the secondary antibody mouse CY5, the secondary antibody rabbit Alexa Fluor 568, and streptavidin Alexa Fluor 488 for another 2 hours. After washing, the slides were mounted on a microscope slide and finally covered with a coverslip.

[0190] Quantitative analysis of BrdU labeling Every sixth slice running through the entire hippocampus was processed for quantification of BrdU immunohistochemical labeling. This spacing ensured that the same neuron was not counted in two slices. All BrdU-labeled cells in the dentate gyrus (granular cell layer, GCL) and hippocampus were counted in each slice by an experimenter unaware of the slide coding. To distinguish individual cells within clusters, all counts were performed under an optical microscope at ×400 and ×1000. Cells located within or in contact with the subgranular zone (SGZ) of the dentate gyrus were counted as being in the SGZ. Cells located more than two cells away from the SGZ were classified as hippocampal cells. The total number of BrdU-labeled cells in each slice was determined and multiplied by 6 to obtain the total number of cells in each dentate gyrus (see [reference]). Phenotypic analysis of the fluorescently labeled BrdU cells was performed using confocal microscopy. Z Cells are scanned and optically sectioned in a plane.

[0191] For volumetric analysis of the GCL, the right and left sides of the layer were carefully delineated in each slice, and its area was calculated using Lucia GF version 4.71. The delineated areas for each animal were summed and multiplied by 240 μm (i.e., the slice thickness plus the distance between consecutive slices) to obtain an estimate of the total GCL volume.

[0192] microdialysis 24 hours after the last conditioned period, chloral hydrate (375 mg kg) -1 The intruder was anesthetized (intraperitoneally). A stainless steel guiding cannula was placed at coordinates where the tip was positioned directly above the frontal cortex: anteroposteriorly, +2.7 mm from the anterior fontanelle; laterally, -1.7 mm from the lateral side of the anterior fontanelle; horizontally, -0.8 mm from the skull. The cannula was then secured to the skull with dental adhesive, and the skin was sutured. Animals were isolated for 4 days prior to the microdialysis experiment.

[0193] The day before the experiment, rats were placed in a plexiglass microdialysis bowl (35 cm in diameter) with free access to food and water. The following morning, a microdialysis probe (cutoff: 20,000 Da; outer diameter: 0.5 mm; length: 2 mm) was introduced into the guide cannula, protruding 2 mm into the Fr2 region of the prefrontal cortex. In rats, the Fr2 region is considered a region of the prefrontal cortex. Artificial CSF (aCSF) was administered at a rate of 3.0 μl / min. -1 The probe was continuously perfused at a flow rate of [value missing]. To allow dialysis to reach steady state around the probe membrane, a 90-minute perfusion (wash period) was performed before collecting the first fraction. Then, 11 90 μl fractions (each corresponding to a 30-minute perfusion) were collected at 0 °C and immediately frozen at -30 °C until their CCK-like substance (CCKLM) content was determined by sensitive radioimmunoassay (RIA).

[0194] CCKLM in vitro Recovery is estimated as follows. In short, the microdialysis probe is immersed in a solution containing a known concentration of exogenous CCK, and the recovery is calculated as the percentage of a quantified amount of CCKLM in the microdialysis solution relative to the CCKLM present in the original solution. This percentage is recorded.

[0195] During the microdialysis procedure, two minutes before the start of the eighth fraction collection, the intruder (frustrated or unfrustrated) is subjected to a social frustration procedure in Period I (see above). Each rat is gently moved to a protective cage placed in its usual resident cage for 30 minutes in Period I, and then returned to the microdialysis bowl. This can be done without removing the rotating arm. Thus, during the microdialysis procedure, the intruder is threatened but not frustrated by the resident.

[0196] The correct placement of the microdialysis probe was verified by histological examination. Therefore, at the end of the experiment, chloral hydrate (375 mg / kg) was used. -1 Rats were deeply anesthetized (intraperitoneally) and euthanized by decapitation. Brains were removed, rapidly frozen in isopentane, and stored at -20°C. Sections were prepared using a cryostat and stained with cresol purple to verify probe placement. Results from incorrect probe placement were discarded.

[0197] Drugs and treatment Treatment with the compounds described herein began on the day following the last conditioned-out period of week 1 (day 5) and continued until the day of the microdialysis experiment or the day of sacrifice for HPA axis activity assay, cell proliferation quantification, or hippocampal volume analysis (day 30).

[0198] Physiological and behavioral data Differences in body weight, sugar water consumption and food intake, adrenal gland weight, corticosterone levels, hippocampal cell proliferation, and fibrillation time (FST) were measured to determine the efficacy of the compound.

[0199] Models of depression include chronic intermittent stress (e.g., swimming alone followed by forced swimming), as described, for example, in Willner P., The chronic mild stress (CMS) model of depression: History, evaluation and usage, Neurobiology of Stress (2017) 6, 78–93; social defeat models, as described, for example, Golden, SA et al., A standardized protocol for repeated social defeat stressin mice, Nat Protoc.; 6(8): 1183–1191; or models described, for example, Krishnan et al., Animal Models of Depression: Molecular Perspectives, Curr Top Behav Neurosci. 2011; 7:121–147, which include acute stress models and secondary or iatrogenic depression models.

[0200] Dendritic spine formation, for example in the prefrontal cortex, can be performed by any suitable method, including, for example, Golgi staining, gene gun labeling with fluorescent dyes, DiI labeling, Molecular Probes Cell Tracker™ CM-DiI, and structured illumination microscopy. An example method for Golgi staining is presented in Rosoklija et al., Reliable and Durable Golgi Staining of Brain Tissue from Human Autopsies and Experimental Animals, J Neurosci Methods, (June 15, 2014) 230: 20–29. Gene gun labeling can be performed, for example, according to Arsenault, J. et al., Regioselective Biolistic Targeting in Organonotypic Brain Slices Using a Modified Gene Gun. J. Vis. Exp. (2014), 92,e52148. DiI can be performed, for example, according to Gan, WB et al., Multicolor 'DiOlistic' labeling of the nervous system using lipophilic dye combinations. Neuron (2000) 27, 219–225. An example of structured illumination microscopy is described in Schouten et al., Imaging Dendritic Spines of Rat Primary Hippocampal Neurons using Structured Illumination Microscopy, JVis Exp. (2014) 87.

[0201] result In vivo experiments demonstrated that compound 1, by reversing the neuroanatomical basis of depression—synaptic loss in the prefrontal cortex—could be used to treat mood disorders such as depression. To evaluate the effects of compound 1, WT (wild-type) and 3xTg-AD mice (a triple transgenic mouse model of Alzheimer's disease) were administered a load of compound 1 at doses of 3, 10, or 30 mg / kg. After daily administration of compound 1 via intraperitoneal injection for 4 weeks, mice were sacrificed and Golgi staining was performed to analyze dendritic spine synapse density and morphology.

[0202] Compound 1 was found to increase dendritic spine density in the 3xTg-AD model. Not wishing to be bound by theory, it is believed that synaptic recovery may mediate the rapid antidepressant effects of ketamine and / or hallucinogens. Figure 1 As shown, compared with WT mice treated with the drug, 3xTg-AD mice treated with the drug had a significantly reduced dendritic spine density, particularly in terms of mushroom-shaped spine morphology. These defects in dendritic spines in 3xTg-AD mice were reversed by treatment with compound 1 (e.g., at 10- and 30- mg / kg).

[0203] Example 2 The methods described herein can be used to treat or prevent mood disorders, such as depression. This example demonstrates a method of treating or preventing depression by administering compound 1 to a subject in need.

[0204] This randomized, placebo-controlled study will be conducted in adult participants diagnosed with schizophrenia (a common mental disorder with frequent comorbid depression and anxiety). Participants will be screened from day -35 to day -5, including confirmation of a preliminary diagnosis of schizophrenia using the Brief International Neuropsychiatric Interview (MINI) version 7.0.2 for research on schizophrenia and psychotic disorders (or a version approved by the sponsor’s medical monitor), and a total score of ≥70 on the Positive and Negative Syndrome Scale (PANSS).

[0205] Participants will be assigned to either compound 1 or placebo in a 1:1 ratio. There are two cohorts of n=16, each with 8 placebo recipients and 8 active drug recipients. A total of n=32 participants will be included. The initial dose of the compound (e.g., compound 1) will be 300 mg. Patients may receive the compound (e.g., compound 1) at doses (e.g., daily doses) for up to approximately 6 weeks.

[0206] In the clinical setting, participants will be given an adequate amount of placebo or compound for daily (AM) dosing until the next scheduled clinical site visit, i.e., day 22 ± 2 (day 21 ± 2). Participants will be contacted by telephone on days 8, 15, 29, and 36 to assess adverse events, concomitant medication use, and conduct verbal compliance checks, and again one week after the completion of dosing (day 50). All visits and telephone calls after day 1 will have a ± 2-day window. Participants will return to the clinic on day 71 ± 7 for final efficacy and safety evaluation.

[0207] One or more symptoms of depression (e.g., the symptoms described in this article, or symptoms known to practitioners, such as those described in the DSM) may be reduced, decreased, or reversed after the start of treatment.

[0208] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0209] The disclosures illustratively described herein may be practiced appropriately in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as "comprising," "including," and "containing" should be interpreted broadly and without limitation. Furthermore, the terms and expressions used herein have been adopted as terminology in the specification and are not limiting, and the use of such terms and expressions is not intended to exclude any equivalents or portions thereof of the features shown and described, but it should be recognized that various modifications may be made.

[0210] Therefore, it should be understood that although this disclosure has been specifically disclosed through preferred embodiments and optional features, those skilled in the art can make modifications, improvements, and variations to the disclosure embodied herein, and such modifications, improvements, and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided herein represent preferred embodiments, are exemplary, and are not intended to be a limitation on the scope of this disclosure.

[0211] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated in their entirety by reference as if they were individually incorporated by reference. In the event of any conflict, this specification (including definitions) shall prevail.

Claims

1. A method for treating or preventing depression, the method comprising administering to a patient in need a therapeutically effective amount of a compound, or a deuterated analog thereof, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, or a mixture of stereoisomers, capable of promoting dendritic spine formation in the prefrontal cortex of the patient.

2. The method according to claim 1, wherein the patient is refractory to treatment with at least one antidepressant.

3. The method according to claim 2, wherein the antidepressant is a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor, a serotonin-norepinephrine-dopamine reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor, a monoamine oxidase inhibitor, a tricyclic antidepressant, or a tetracyclic antidepressant.

4. The method according to claim 2, wherein the antidepressant is selected from the group consisting of: esketamine, levamisole, venlafaxine, norvenlafaxine, sibutramine, nefazodone, mirtazapine, duloxetine, bisifazole, tersofensine, prazofensine, isocarboxazid, moclobemide, phenelzine, transphenylcyclopropionamide, selegiline, rasagiline, nipramine, isoniazid, isopropylchlorohydrin, toloxacin, butiline, amoxapine, amitriptyline, nortriptyline, clomipramine, desipramine, Duthiramine, doxepin, imipramine, dibenzaprine, iprotinin, lofepramine, ocipiprine, protriptyline, trimethaprine, fluoxetine, norfluoxetine, citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, sertraline, maprotiline, mianserin, mirtazapine, septiline, amoxapine, quetiapine, benzothiapine, loxapine, maindole, alprazopine, esmirtazapine, oxaptiline, cilaratinole, bupropion, mirtazapine, verazordone, vortioxetine, aripiprazole, and St. John's wort.

5. The method of claim 1, wherein the patient was diagnosed with depression within 24 hours prior to administration.

6. The method of claim 1, wherein the application lasts for a duration of at least four weeks.

7. The method of claim 1, wherein the application lasts for a duration of at least twelve weeks.

8. The method of claim 1, wherein the application lasts for a duration of at least four months.

9. The method of claim 1, wherein the application lasts for a duration of at least one year.

10. The method of claim 1, wherein the patient exhibits at least one symptom of depression.

11. The method of claim 1, wherein the patient does not exhibit symptoms of depression.

12. The method of claim 1, wherein the patient has not been diagnosed with depression, but exhibits at least one marker of depression.

13. The method of claim 12, wherein the biomarker of depression is a family history of depression.

14. The method of claim 12, wherein the marker of depression is a personal history of depressive symptoms.

15. The method of claim 12, wherein the marker of depression is the patient's self-report.

16. The method of claim 1, wherein the patient has not been diagnosed with depression but has undergone surgery and / or anesthesia within the past year, two years or three years.

17. The method of claim 10, wherein the symptoms of said depression are anxiety, loss of interest in daily activities; pessimism, persistent negativity; sadness, emptiness or feelings of depression, worthlessness, helplessness, or despair; fatigue, tiredness, or lack of energy; low self-esteem, self-criticism, and / or feelings of inadequacy; difficulty concentrating, difficulty remembering details, and / or difficulty making decisions; persistent irritability, hostility, and / or excessive anger; decreased activity, efficiency, and / or productivity; avoidance of social activities; guilt and / or worry about the past; loss of appetite or overeating; suicidal ideation; decreased libido and / or loss of interest in sex; sleep disturbances, insomnia, early awakening, or excessive sleep; restlessness, loss of interest in pleasurable activities; overeating or loss of appetite; unexplained pain, unexplained headache, persistent cramps, persistent digestive problems; or suicidal ideation or suicidal behavior.

18. The method according to any of the preceding claims, wherein the patient is prone to depression.

19. The method according to any of the preceding claims, wherein the patient is a pediatric patient.

20. The method according to any of the preceding claims, wherein the compound is not hallucinogenic.

21. The method according to any of the preceding claims, wherein the patient has not previously been given an antidepressant.

22. The method according to any of the preceding claims, wherein the method further comprises administering an antidepressant to the patient.

23. The method of claim 22, wherein the antidepressant is a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor, a serotonin-norepinephrine-dopamine reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor, a monoamine oxidase inhibitor, a tricyclic antidepressant, or a tetracyclic antidepressant.

24. The method of claim 23, wherein the serotonin and norepinephrine reuptake inhibitors are selected from the group consisting of: levomirnazepine, venlafaxine, norvenlafaxine, sibutramine, nefazodone, mirnazepine, duloxetine, and bisifadin; the serotonin-norepinephrine-dopamine reuptake inhibitors are selected from the group consisting of: tersofencin and brassofencin; the monoamine oxidase inhibitors are selected from the group consisting of: isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, niilapramide, isoniazid, isopronicotinamide, and toloxacin; and the tricyclic antidepressant is selected from the group consisting of: The following are selected from the group consisting of: butiline, amoxapine, amitriptyline, nortriptyline, clomipramine, desipramine, duthiramine, doxepin, imipramine, dibenzapine, ipratindole, lofepramine, octopiol, propiline, and trimipramine; and the selective serotonin reuptake inhibitor is selected from the group consisting of: fluoxetine, norfluoxetine, citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline; and the tetracyclic antidepressant mirtazapine is selected from the group consisting of: maprotiline, mianserin, mirtazapine, septiline, amoxapine, quetiapine, benzothiapine, loxapine, macindole, alprazopine, esmirtazapine, oxaptiline, and cilazindole.

25. The method of claim 22, wherein the antidepressant is ketamine, esketamine, bupropion, mirtazapine, verazordone, vortioxetine, aripiprazole, or St. John's wort.

26. The method according to any of the preceding claims, wherein the method comprises applying the compound at a frequency of three times a week to once a month.

27. The method according to any preceding claim, wherein the compound is a compound of formula I or Ia: Or its pharmaceutically acceptable salts, solvates and / or N-oxides, wherein Subscript n and p Independently selected from 0, 1, or 2; Each R 1 Independently selected from the group consisting of: hydrogen, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxylic acid ester, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, hydroxyl, thiol and nitro. A is an arylene or heteroarylene having 1 to 4 heteroatoms; W is selected from the following groups: -O-, -S-, -SO-, -S(O)2-, and -NR. 2 -, where R 2 Choose from the group consisting of: hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic alkyl, and substituted heterocyclic alkyl; X is selected from the following groups: -O-, -S-, -SO-, -S(O)2-, and -NR. 2 -, where R 2 As defined above, the prerequisite is that A is aryl and Y is -S- or -NR. 2 - At this time, X is not -S-; Y is selected from the following groups: -O-, -S-, -SO-, S(O)2-, and -NR. 2 -, where R 2 As defined above; and Z is selected from the following groups: -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R) 3 )O) q -T, where the subscript q R is an integer selected from 1 to 100. 3 Choose from the group consisting of hydrogen and methyl, and T choose from the group consisting of: hydrogen, alkyl, substituted alkyl, -L-monosaccharide and -L-oligosaccharide, where L chooses from the group consisting of: bond, phosphate ester and sulfate ester.

28. The method according to any preceding claim, wherein the compound is a compound of formula II: II; Or its pharmaceutically acceptable salts, solvates and / or N-oxides, wherein Y is –NR 33 -、O or –S-; R 31 Independently, it is halogen, -CX 31 -CHX 31 -CH2X 31 -OCX 31 S、-OCHX 31 -OCH2X 31 -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -C(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 32 Independently, it is halogen, -CX 32 3. -CHX 32 2. -CH2X 32 -OCX 32 3. -OCHX 32 2. -OCH2X 32 -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X 31 and X 32 Each of them is a halogen independently; Each of z1 and z2 is an integer from 0 to 4 independently; and z3 is an integer from 1 to 12.

29. The method according to any preceding claim, wherein the compound is: (Compound 1), Or its pharmaceutically acceptable salts, solvates and / or N-oxides.

30. The method according to any one of claims 1 to 28, wherein the compound is: ， Or its pharmaceutically acceptable salts, solvates and / or N-oxides.

31. The method according to any one of claims 1 to 28, wherein the compound is: or , Or its pharmaceutically acceptable salts, solvates and / or N-oxides.

32. The method according to any one of claims 1 to 28, wherein the compound is: ,or Or its pharmaceutically acceptable salts, solvates and / or N-oxides.

33. The method according to any one of claims 1 to 28, wherein the compound is: ， Or its pharmaceutically acceptable salts, solvates and / or N-oxides.

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