Methods for prevention and treatment of depression

Abstract

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

Description

Attorney Docket No. 62WD-385403-WO METHODS FOR PREVENTION AND TREATMENT OF DEPRESSION FIELD

[0001] Provided herein are compounds and methods for prevention and treatment of depression and related disorders. BACKGROUND

[0002] A mood disorder may be described as a psychiatric disorder in which a subject’s general emotional state or mood is distorted or inconsistent with the circumstances, and interferes with the subject’s ability to carry out functions of daily life. Common mental states include sadness, emptiness or irritability. A common mood disorder is depression.

[0003] Depression, otherwise known as major depressive disorder or clinical depression, is a serious mood disorder. Depression is more than just sadness. Sadness is a normal emotion that may arise from a specific event or situation, for example, loss of a job, the end of a relationship, or the death of a loved one. Depression is evident in a combination of factors relating to the duration of negative feelings, impact on a person’s health, and the effect upon the person’s ability to function in daily life. The person may have every reason in the world to be happy and yet lose the ability to experience joy or pleasure, and is likely to suffer in conduct of their affairs, interpersonal relationships, and daily life.

[0004] Those who suffer from depression experience persistent feelings of sadness and hopelessness and lose interest in activities they once enjoyed. Depression may be diagnosed, for example according to the guidelines of 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, significant decrease or increase in appetite, a slowing down of thought and a reduction of physical movement, fatigue, feelings of worthlessness or excessive guilt, diminished ability to think or concentrate, and recurrent thoughts of death or suicidal ideation. Generally, the individual will suffer significant distress or impairment in social or occupational functioning.

[0005] Current treatments for depression include talk therapy, and pharmaceutical intervention. However, current pharmaceutical treatments generally target the uptake of neurotransmitters, and suffer from serious, sometimes severe side effects. The side effectsSMRH:4908-5304-8610.11Attorney Docket No. 62WD-385403-WO may be difficult to diagnose in individuals that already suffer from psychological disturbance. Additionally, each individual reacts differently to treatment by typical antidepressants, and long periods of time in which several therapies are tested may be needed to find an effective treatment. Therefore, there is a need for drugs that treat depression and other mood disorders by targeting alternative pathways, that offer improvement of symptoms in a shorter time period, and that afford reduced side effects. SUMMARY

[0006] Provided herein are compounds and methods for prevention and treatment of mood disorders, including, for example, depression.

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

[0008] FIG. 1 is a chart showing number of total, mushroom, stubby and thin spines per 100 μm for WT and 3xTg-AD mice treated with vehicle and treated with Compound 1 at 3, 10, and 30 mg / kg. DETAILED DESCRIPTION

[0009] Generally the compounds and methods described herein provide for the administration of compounds that provide benefit in the treatment and prevention of mood disorders and symptoms thereof. In some embodiments, the compositions and methods are useful for treating a mood disorder, which may be depression. Generally, the active ingredient or principal ingredient will include an agent, such as a compound, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers of a compound as described herein. The active ingredient or principal ingredient may also include one or more additional pharmaceutically active materials.SMRH:4908-5304-8610.12Attorney Docket No. 62WD-385403-WO I. Definitions

[0010] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

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

[0012] A “pediatric patient” is a person less than 18 years of age. A “juvenile patient” is a person who has not reached physical maturity.

[0013] The term “spinogenesis” and the like refer, in the usual and customary sense, to development (e.g. growth and / or maturation) of dendritic spines in neurons. In some embodiments, the compounds provided herein promote spinogenesis without affecting spine morphology. The promotion is relative to the absence of administration of the compound.

[0014] As used herein, the term “dendrite” refers to the branched extension of a neuron cell. Dendrites are typically responsible for receiving electrochemical signals transmitted from the axon of an adjacent neuron. The terms “dendritic spines” or “dendrite spines” refer to protoplasmic protuberances on a neuron cell (e.g., on a dendrite). In some embodiments, dendritic spines may be described as having a membranous neck which may be terminated with a capitulum (e.g., head). Dendritic spines are classified according to their shape: headless, thin, stubby, mushroom, or branched. Dendritic spine density refers to the total number of dendritic spines per unit length of a neuron cell. For example, the dendritic spine density may be given as the number of dendritic spines per micron.

[0015] The term “dendritic spine formation” and the like refer, in the usual and customary sense to processes which lead to an increased number of dendritic spines or increased development of dendritic spines. The term “dendritic spine morphology” and the like refer, in the usual and customary sense, to physical characterization of a dendritic spine (e.g., shape and structure). Improvement of dendritic spine morphology is a change in morphology (e.g., increase in length or increase in width) that results in increased functionality (e.g., increased number of contacts between neurons or decreased space between neighboring neurons (e.g.,SMRH:4908-5304-8610.13Attorney Docket No. 62WD-385403-WO synaptic cleft)). As known in the art and disclosed herein, exemplary methods for such characterization include measurement of the dimensions (i.e., length and width) of dendritic spines. Accordingly, the term “improving dendritic spine morphology” generally refers to an increase in length, width, or both length and width of a dendritic spine.

[0016] “Binding” refers to at least two distinct species (e.g. chemical compounds including biomolecules, or cells) to becoming sufficiently proximal to react or interact thereby resulting in the formation of a complex. For example, the binding of two distinct species (e.g., a protein and a compound described herein) may result in the formation of a complex wherein the species are interacting via non-covalent or covalent bonds. In some embodiments, the resulting complex is formed when two distinct species (e.g., a protein and a compound described herein) interact via non-covalent bonds (e.g., electrostatic, van der Waals, or hydrophobic).

[0017] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein-activator (e.g. agonist) interaction means positively affecting (e.g. increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator (e.g. compound described herein).

[0018] As defined herein, the terms “inhibition,” “inhibit,” “inhibiting” and the like, are to be given their customary meanings to those of skill in the art. In reference to a protein- inhibitor (e.g. antagonist) interaction, the terms “inhibition,” “inhibit,” “inhibiting” mean negatively affecting (e.g. decreasing) the functional activity of the protein relative to the functional activity of the protein in the absence of the inhibitor.

[0019] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.

[0020] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.SMRH:4908-5304-8610.14Attorney Docket No. 62WD-385403-WO

[0021] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0022] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0023] “Substituted alkyl” refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy nitro, -SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.

[0024] “Alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C6. Alkenyl groups 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 (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl,SMRH:4908-5304-8610.15Attorney Docket No. 62WD-385403-WO 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0025] “Substituted alkenyl” refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy and thiol and with the proviso that any hydroxyl or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[0026] “Acyl” refers to the groups H-C(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 includes the “acetyl” group CH3C(O)-.

[0027] “Acylamino” refers to the groups -NR47C(O)alkyl, -NR47C(O)substituted alkyl, -NR47C(O)cycloalkyl, -NR47C(O)substituted cycloalkyl, -NR47C(O)cycloalkenyl, -NR47C(O)substituted cycloalkenyl, -NR47C(O)alkenyl, -NR47C(O)substituted alkenyl, -NR47C(O)aryl, -NR47C(O)substituted aryl, -NR47C(O)heteroaryl, -NR47C(O)substituted heteroaryl, -NR47C(O)heterocyclic, and -NR47C(O)substituted heterocyclic, wherein R47is hydrogen or alkyl.

[0028] “Acyloxy” refers to the groups 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-.SMRH:4908-5304-8610.16Attorney Docket No. 62WD-385403-WO

[0029] “Alkynyl” refers to an unbranched or branched hydrocarbon group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4alkynyl). The term “alkynyl” also includes those groups having at least one carbon-carbon triple bond and a carbon-carbon double bond.

[0030] “Alkoxy” refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy. “Substituted alkoxy” refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein.

[0031] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

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

[0033] “Acyl” refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0034] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRzand an “N-amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0035] “Amino” refers to the group -NH2. “Substituted amino” refers to the group -NR48R49, wherein R48and R49are 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, heterocyclic, substituted heterocyclic, -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cylcoalkyl, -SO2-cycloalkenyl, -SO2-substituted cylcoalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic, and wherein R48and R49are optionally joined, together with the nitrogen boundSMRH:4908-5304-8610.17Attorney Docket No. 62WD-385403-WO thereto to form a heterocyclic or substituted heterocyclic group, provided that R48and R49are both not hydrogen.

[0036] “Aminocarbonyl” refers to the group -C(O)NR50R51, wherein R50and R51are 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, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group. “Aminocarbonylamino” refers to the group -NR47C(O)NR50R51, wherein R47is hydrogen or alkyl; R50and R51are 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, heterocyclic, and substituted heterocyclic; and, wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0037] “Aminocarbonyloxy” refers to the group -O-C(O)NR50R51, wherein R50and R51are 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, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0038] “Aminosulfonyl” refers to the group -SO2NR50R51, wherein R50and R51are 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, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0039] “Aminosulfonyloxy” refers to the group -O-SO2NR50R51wherein R50and R51are 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, heterocyclic, andSMRH:4908-5304-8610.18Attorney Docket No. 62WD-385403-WO substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0040] “Aminosulfonylamino” refers to the group -NR47SO2NR50R51, wherein R47is hydrogen or alkyl; R50and R51are 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, heterocyclic, and substituted heterocyclic; and, wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0041] “Amidino” refers to the group -C(=NR52)NR50R51, wherein R50, R51, and R52are 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, heterocyclic, and substituted heterocyclic, and wherein R50and R51are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group.

[0042] “Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). The condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like), provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl. “Substituted aryl” refers to aryl groups which are substituted with 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, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.SMRH:4908-5304-8610.19Attorney Docket No. 62WD-385403-WO

[0043] “Arylene” refers to a divalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings. “Substituted arylene” refers to an arylene having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents as defined for aryl groups.

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

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

[0046] “Aralkyl” refers to an aryl group pendant to an alkyl group. Examples of aralkyl groups include benzyl, phenethyl, and 3-naphthylpropyl.

[0047] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group –O- C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0048] “Carboxyl” or “carboxy” refers to –COOH, or salts thereof.

[0049] “Carboxyl ester” or “carboxy 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. “(Carboxyl ester)amino” refers to the group -NR47C(O)(O)-alkyl, -NR47C(O)(O)-substituted alkyl, -NR47C(O)O-alkenyl, -NR47C(O)(O)-substituted alkenyl, -NR47C(O)(O)-aryl, -NR47C(O)(O)-substituted-aryl, -NR47C(O)(O)-cycloalkyl, -NR47C(O)(O)-substituted cycloalkyl, -NR47C(O)(O)-cycloalkenyl, -NR47C(O)(O)-substituted cycloalkenyl, -NR47C(O)(O)-heteroaryl, -NR47C(O)(O)-substituted heteroaryl, -NR47C(O)(O)-heterocyclic, and -NR47C(O)(O)-substituted heterocyclic. “(Carboxyl ester)oxy” refers to the group -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -SMRH:4908-5304-8610.110Attorney Docket No. 62WD-385403-WO O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic.

[0050] “Cyano” refers to the group -CN.

[0051] “Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, C6-8, C3-9, C3-10, C3-11, and C3-12. 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 cycloalkyl groups which are partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated 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 cycloalkyl is a saturated monocyclic C3-8 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a saturated monocyclic C3-6 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl and cycloalkenyl groups can be substituted or unsubstituted. “Substituted cycloalkyl” and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, and thiol.SMRH:4908-5304-8610.111Attorney Docket No. 62WD-385403-WO

[0052] “Cycloalkyloxy” refers to -O-cycloalkyl. “Substituted cycloalkyloxy” refers to -O-(substituted cycloalkyl). “Cycloalkenyloxy” refers to -O-cycloalkenyl. “Substituted cycloalkenyloxy” refers to -O-(substituted cycloalkenyl).

[0053] “Guanidino” refers to the group -NHC(=NH)NH2.

[0054] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0055] “Imino” refers to a group -C(NR)R, wherein each R is independently alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0056] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0057] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, 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 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 assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms can also be useful, including, but not limited to,SMRH:4908-5304-8610.112Attorney Docket No. 62WD-385403-WO B, Al, Si and P. The 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. Any suitable number of heteroatoms can be included in the heteroaryl groups, 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. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, which may or may not contain a heteroatom, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, benzofuran, indolizine or benzothiene. The heteroaryl groups can be fused to non-aromatic ring systems, which may or may not contain a heteroatom, provided that the point of attachment is through an atom of the aromatic heteroaryl group. For example, the nitrogen and / or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→O), sulfinyl, or sulfonyl moieties. Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thizolyl, and furanyl. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted. “Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.

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

[0060] “Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, or partially saturated, ring system having from 3 to 12 ring members and from 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. The heteroatoms can also be oxidized, such as, but not limitedSMRH:4908-5304-8610.113Attorney Docket No. 62WD-385403-WO to, -S(O)- and -S(O)2-. Heterocycloalkyl 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. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, 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. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, or sulfonyl moieties. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with C1-6 alkyl, oxo (=O), nitro (-NO2), or sulfonyl (-S(O)2-), among many others. “Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.

[0061] “Heterocyclyloxy” refers to the group -O-heterocyclyl. “Substituted heterocyclyloxy” refers to the group -O-(substituted heterocyclyl).

[0062] “Oxo” refers to the group (=O) or (O).

[0063] “Spirocycloalkyl” and “spiro ring systems” refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure:.SMRH:4908-5304-8610.114Attorney Docket No. 62WD-385403-WO

[0064] “Sulfonyl” refers to the group -S(O)2R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl. “Substituted sulfonyl” refers to the group -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cylcoalkyl, -SO2-cycloalkenyl, -SO2-substituted cylcoalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, -SO2-substituted heterocyclic. Substituted sulfonyl includes groups such as methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. “Substituted sulfonyloxy” refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cylcoalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cylcoalkenyl, -OSO2-aryl, -OSO2-substit uted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substituted heterocyclic.

[0065] “Alkylsulfonyl” refers to the group -S(O)2R, where R is alkyl.

[0066] “Alkylsulfinyl” refers to the group -S(O)R, where R is alkyl.

[0067] As used herein, the term “saccharide” refers to a sugar, such as a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide. Monosaccharides include, but are not limited to, glucose, ribose and fructose. Disaccharides include, but are not limited to, sucrose and lactose. Oligosaccharides refers to 2 to 10 sugars linked together preferably through an alpha linkage. Examples of oligosaccharides include maltose, lactose, sucrose, and the like. Polysaccharides include, but are not limited to, cellulose, hemicellulose and lignocellulose or starch. Saccharides or sugars useful in the present 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 aldol and pyranose forms thereof, as well as D and L isomers thereof.

[0068] “Thiocyanate” refers to the group –SCN.

[0069] “Thioxo” or “thione” refer to the group (=S) or (S).

[0070] A substituted ring can be substituted with one or more fused and / or spiro cycles. Such fused cycles include a fused cycloalkyl, a fused heterocyclyl, a fused aryl, a fused heteroaryl ring, each of which rings can be unsubstituted or substituted. Such spiro cyclesSMRH:4908-5304-8610.115Attorney Docket No. 62WD-385403-WO include a fused cycloalkyl and a fused heterocyclyl, each of which rings can be unsubstituted or substituted.

[0071] The groups defined above can optionally be substituted by 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, such as unsubstituted C1-6alkyl. Alternatively, R’ and R”, or R” and R”’, when attached to the same nitrogen, are combined with the nitrogen to which they are attached to form a heterocycloalkyl or heteroaryl ring, as defined above.

[0072] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three. In other words, each of the above definitions is constrained by a limitation that, 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, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0074] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. The term “optionally substituted”SMRH:4908-5304-8610.116Attorney Docket No. 62WD-385403-WO with reference to a group is intended to be construed as describing the unsubstituted group and the group substituted by the indicated or defined substituent(s).

[0075] A protecting group may be any known in the art, for example, as described in Peter G. M. 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 may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise all tautomers.

[0077] Any formula or structure given herein is also intended to represent isotopically labeled forms of the compounds as well as unlabeled forms. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an isotope having the indicated atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure, or counter-ions thereto, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium),11C,13C,14C,15N,18F,31P,32P,35S,36Cl and125I. Various isotopically labeled compounds are possible under the present disclosure, for example those into which radioactive isotopes such as3H,13C and14C are incorporated. Such isotopically labelled compounds may be useful 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 in radioactive treatment of patients.

[0078] The disclosure also includes “deuterated analogs” of compounds, and counter-ions thereto, in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing the half-life of a compound when administered to a mammal, particularly a human. 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 means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.SMRH:4908-5304-8610.117Attorney Docket No. 62WD-385403-WO

[0079] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound.

[0080] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent enrichment of deuterium above a naturally occurring level at the indicated position.

[0081] Compounds described herein may be present as a salt, such as a pharmaceutically acceptable salt. Compounds are capable of forming salts such as acid and / or base salts. Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. Salts of compounds described herein can be prepared according to procedures described herein and as known in the art.

[0082] The term “pharmaceutically acceptable salt” of a given compound, refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acidSMRH:4908-5304-8610.118Attorney Docket No. 62WD-385403-WO addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. 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- toluene-sulfonic acid, salicylic acid, isobutyric acid, suberic acid, lactic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, 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 alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (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), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (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- cycloalkyl amines (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, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n- propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Methods of preparing a salt also include mixing a compound by redox reaction with an active metal, or by exchange of ions, for example, due to differing solubility of salts.

[0083] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen,SMRH:4908-5304-8610.119Attorney Docket No. 62WD-385403-WO provided that the designated atom’s normal valence is not exceeded. If not specified, the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, aryl, -N3, carbamoyl, carboxyl, carboxyl ester, -CN, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, -OH, imino, oxo, -NO2, alkylsulfinyl, -SO3H, alkylsulfonyl, thiocyanate, -SH, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorine atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

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

[0085] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. ExceptSMRH:4908-5304-8610.120Attorney Docket No. 62WD-385403-WO insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0086] “Treatment” or “treating” provides a beneficial or desired result, e.g., an improvement in one or more clinical indicia of a disorder. Beneficial or desired results may include one or more of the following: decreasing or ameliorating one or more symptoms of the disorder, and / or diminishing the extent of the disorder; (e.g., stabilizing the disorder, preventing or delaying the worsening or progression of the disorder); providing partial or total remission of the disorder; enhancing effect of another medication; increasing the quality of life; and / or prolonging survival in a population of patients.

[0087] “Prevention” or “preventing” means blocking development of a disorder, or symptoms thereof. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk of or has a family history of the disorder. Prevention may comprise delay in reaching predefined disease milestones or reduction in appearance or progression of a marker.

[0088] “Subject” refers to an animal, such as a mammal, e.g. a human that may benefit from administration of a compound described herein. The methods described herein may be useful in human therapy 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 person, the subject may be referred to as a “patient.”

[0089] The term “therapeutically effective amount” or “effective amount” of a compound described herein means an amount sufficient to effect treatment when administered to a subject, to provide a benefit as described herein. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a mood disorder. The therapeutically effective amount may vary depending on the subject, the disorder being treated, the weight and age of the subject, the severity of the disorder, and the manner of administering, which can readily be determined by a medical practitioner.

[0090] The term “refractory” means that a subject having a mood disorder has previously been resistant to treatment of the disorder. For example, one or more symptoms of the mood disorder persisted following treatment. In some embodiments, the subject is refractory to treatment with an antidepressant as described herein.SMRH:4908-5304-8610.121Attorney Docket No. 62WD-385403-WO

[0091] The term “marker” means a characteristic of a subject that indicates a risk for developing a disorder. For example, a marker may be a genetic indicator associated with a disorder; a marker may be a personal history of the disorder; a marker may be a family history, e.g., a genetic relative or relatives having had the disorder or a related disorder; or a marker may be a physiological indicator such as a test result.

[0092] The terms “hallucinogen” and “hallucinogenic” refer to substances that, when administered to a subject, causes perceptual anomalies. Examples of hallucinogenic substances include ketamine, 3,4-methylenedioxy-methamphetamine (MDMA), bufotenin, phencyclidine (PCP), lysergic acid diethylamide (LSD), mescaline, psilocybin, salvia divinorum, dimethyltryptamine (DMT), and gamma-hydroxybutyric acid. Compounds that are hallucinogens may also be referred to as “psychedelic.” In some embodiments, the hallucinogen is selected from ketamine, LSD, psilocybin, and MDMA. In some embodiments, the hallucinogen is ketamine. Treatment Methods and Uses

[0093] Described herein are methods for the prevention and treatment of mood disorders by administering to a patient an effective amount of a compound that induces spinogenesis. Contrary to expectation, the present disclosure demonstrates that an increase in dendritic spine density may provide benefit in the treatment of mood disorders such as depression. The methods described herein may also provide for treatment with reduced side effects, and / or for treatment of subjects who are refractory to treatment with one or more antidepressants.

[0094] Although administration of ketamine has been linked to anti-depressant activity, the mechanism of action is not well understood. Ketamine is believed to have a number of activities in the brain. However, such observations are relatively recent and not well-studied. Complicating matters, ketamine may have varying physiological effects over the long term. For example, it is believed that ketamine’s activity in the short term may arise from promotion of activity in dormant spines. Importantly, ketamine is classified as a hallucinogen and is known to cause perceptual anomalies, including dissociative effects. Such effects make ketamine a poor choice for many patients, including, for example, juvenile or pediatric patients, or patients with histories of psychosis.

[0095] In some embodiments, a compound described herein is useful in the treatment of a mood disorder. A mood disorder is a principally psychiatric disorder in which a patient’sSMRH:4908-5304-8610.122Attorney Docket No. 62WD-385403-WO general emotional state or mood is distorted or inconsistent with the circumstances, and interferes with the patient’s ability to carry out functions of daily life. The subject may be sad, empty or irritable, or may have periods of negative feeling alternating with feelings of 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. Those who suffer from depression may experience persistent feelings of sadness and hopelessness and lose interest in activities they once enjoyed. Aside from the emotional problems caused by depression, individuals can also present with a physical symptom such as chronic pain or digestive issues. To be diagnosed with depression, symptoms generally should be present for at least two weeks. Depression may be diagnosed by a person of skill in the art, for example according to the guidelines of the Diagnostic and Statistical Manual of Mental Disorders (“DSM”). The DSM outlines the following criterion to make a diagnosis of depression. Currently, according to the DSM-5 diagnostic criteria, for a diagnosis of depression the individual must be experiencing five or more symptoms during the same 2-week period and at least one of the symptoms should be either (1) depressed mood or (2) loss of interest or pleasure. Symptoms identified in the DSM include: 1. Depressed mood most of the day, nearly every day. 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day. 3. Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day. 4. A slowing down of thought and a reduction of physical movement (observable by others, not merely subjective feelings of restlessness or being slowed down). 5. Fatigue or loss of energy nearly every day. 6. Feelings of worthlessness or excessive or inappropriate guilt nearly every day. 7. Diminished ability to think or concentrate, or indecisiveness, nearly every day. 8. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

[0097] To receive a diagnosis of depression, these symptoms must cause the individual clinically significant distress or impairment in social, occupational, or other important areas of functioning. The DSM also provides for specifiers of diagnosed depression: (1) WithSMRH:4908-5304-8610.123Attorney Docket No. 62WD-385403-WO Mixed Features – This specifier allows for the presence of manic symptoms as part of the depression diagnosis in patients who do not meet the full criteria for a manic episode; and (2) With Anxious Distress – The presence of anxiety in patients may affect prognosis, treatment options, and the patient’s response to them.

[0098] Depression is more than just sadness. The difference between sadness and depression does not lie in the extent to which a person feels down, but rather in a combination of factors relating to the duration of these negative feelings, other symptoms, bodily impact, and the effect upon the individual’s ability to function in daily life. Sadness is a normal emotion that may arise from a specific event or situation, for example, loss of a job, the end of a relationship, or the death of a loved one. One marker of depression is that a person suffering from depression generally feels sad or hopeless about all aspects of life. The individual may have every reason in the world to be happy and yet lose the ability to experience joy or pleasure, and is likely to suffer in conduct of their affairs, interpersonal relationships, and daily life.

[0099] Depression has many causative factors. Contributing factors to depression may include stressors such as physical abuse, psychological abuse, traumatic event(s), personal conflicts, loss of relationship with a loved one, social isolation, illness, substance abuse, or use of certain medication. A subject may have a genetic predisposition to depression. A subject may have suffered physical trauma affecting the brain such as a traumatic brain injury (TBI) or chronic traumatic encephalopathy (CTE). In some instances, depression is idiopathic. Classes of depression include major depressive disorder — prolonged and persistent periods of extreme sadness; bipolar disorder — also called manic depression or bipolar affective disorder, depression that includes alternating times of depression and mania; seasonal affective disorder (SAD) — a form of depression most often associated with fewer hours of daylight in the far northern and southern latitudes from late fall to early spring; cyclothymic disorder — a disorder that causes emotional ups and downs that are less extreme than bipolar disorder; premenstrual dysphoric disorder — mood changes and irritability that occur during the premenstrual phase of a woman's cycle and go away with the onset of menses; persistent depressive disorder (dysthymia) — long-term (chronic) but low-grade depression; disruptive mood dysregulation disorder — a disorder of chronic, severe and persistent irritability in children that often includes frequent temper outbursts that are inconsistent with the child's developmental age; depression related to medical illness — aSMRH:4908-5304-8610.124Attorney Docket No. 62WD-385403-WO persistent depressed mood and a significant loss of pleasure in most or all activities that's directly related to the physical effects of another medical condition; and depression induced by substance use or medication ― depression symptoms that develop during or soon after substance use or withdrawal or after exposure to a medication.

[0100] In some embodiments provided is a method of treating a mood disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein to the patient. In some embodiments, the mood disorder is depression. In some embodiments, the patient may be refractory to treatment with an antidepressant. The antidepressant may be an antidepressant described herein.

[0101] In further embodiments, the compositions and methods are provided for alleviating, reducing, or reversing a symptom of a mood disorder. The symptom may be any symptom described herein, or known to practitioners, for example, as described in the DSM.

[0102] Symptoms of depression may include anxiety, loss of interest in daily activities; pessimism, persistent negativity; sadness, emptiness or feeling down, feelings of worthlessness, feelings of helplessness, feelings of hopelessness; fatigue, tiredness or lack of energy; low self-esteem, self-criticism and / or feeling incapable; difficulty concentrating, difficulty remembering details, and / or difficulty making decisions; persistent irritability, hostility and / or excessive anger; decreased activity, effectiveness and / or productivity; avoidance of social activities; feelings of guilt and / or worry over the past; poor appetite or overeating; suicidal ideation; low sex drive and / or loss of interest in sex; sleep disturbances, insomnia, early-morning wakefulness, or sleeping too much; restlessness, loss of interest in pleasurable activities; overeating or appetite loss; unexplained aches, unexplained pains, unexplained headache, persistent cramps, persistent digestive problems; suicidal ideation, and a suicidal act.

[0103] The loss of synapses that utilize the amino acid glutamate as a neurotransmitter (“glutamatergic” synapses) has been appreciated as an important characteristic of certain neurodegenerative diseases. Importantly, about 90% of glutamatergic synapses involve a post-synaptic dendritic spine. The majority of synapses lost in neurodegenerative conditions are those in which the axon makes contact with a dendritic spine, so-called “axospinous synapses.” Under normal conditions, changes in the density, shape, and protein composition of dendritic spines impact the strength of synaptic communication, and are the basis ofSMRH:4908-5304-8610.125Attorney Docket No. 62WD-385403-WO several forms of synaptic change (i.e. “plasticity”) involved in learning and memory, cognitive flexibility, adaptation to injury and disease, and other processes.

[0104] The role of spine density in the progress of mood disorders is not well understood. However, it has been observed that stress may reduce synapse density. Since many cognitive disorders exhibits abnormalities in the form and function of dendritic spines, it would be desirable to target them directly using a small molecule to alter or alleviate these spine changes. Such treatments may have benefit in reducing side effects associated with many psychoactive drugs such as typical antidepressants, including sensory anomalies. Thus, the development of novel methods to increase spine density could have important implications for treatment of mood disorders including depression.

[0105] Thus, provided herein are compounds that promote spinogenesis. Spinogenesis may be observed as an increase in the average number of spines per neuron, or a unit length of a neuron, which may be referred to as an increase in dendritic spine density. Spinogenesis may be observed as an improvement in dendritic spine morphology. For example, an improvement in dendritic spine morphology may be observed as an increase in average size of spine heads. Spinogenesis may be observed as an improvement in dendritic spine size, spine plasticity, spine motility, spine density and / or synaptic function. Spinogenesis may be observed as an increase in local spatial average of membrane potential. Spinogenesis may be observed as an increase in postsynaptic concentration (e.g., volume-averaged) of Ca2+. Spinogenesis may be observed as an increase in the average ratio of matured to immature spines. In some embodiments, a compound described herein increases the dendritic spine density relative to a control. In some embodiments, a compound described herein increases the dendritic spine density relative to that observed at the time that treatment is initiated. In some embodiments, the increase in dendritic spine density results in a reduction in symptoms of a mood disorder in a subject or patient. In some embodiments, the increase in dendritic spine density is accounted for by anatomical observation. In some embodiments, the increase in dendritic spine density is observed in the prefrontal cortex, e.g., the medial prefrontal cortex.

[0106] In some embodiments, the average dendritic spine density, relative to the time that treatment with a compound described herein is initiated, 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 the numbers, end points inclusive. In some embodiments, the dendritic spine density, relativeSMRH:4908-5304-8610.126Attorney Docket No. 62WD-385403-WO to the time that treatment with a compound described herein is initiated, increases by about 50% to about 500%. In some embodiments, the dendritic spine density, relative to the time that treatment with a compound described herein is initiated, increases by about 100% to about 300%. In some embodiments, the dendritic spine density, relative to the time that treatment with a compound described herein is initiated, increases by about 200% to about 300%. In some embodiments, the duration of treatment with a compound 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.

[0107] In some embodiments, the method increases spine density through 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 the numbers, end points inclusive, relative to a control (e.g., the spine density in the absence of the compound). In some embodiments, the method increases the average spine density about 50% to about 500% relative to a control (e.g., the spine density in the absence of the compound). In some embodiments, the method increases the spine density about 100% to about 300% relative to a control (e.g., the spine density in the absence of the compound). In some embodiments, the method increases the spine density about 200% to about 300% relative to a control (e.g., the spine density in the absence of the compound).

[0108] In some embodiments, the method increases spine density through increasing a neuron length. In some embodiments, the method increases the average neuron length, relative to the time that treatment with a compound described herein is initiated, by about 100 nm, 300 nm, 500 nm, 700 nm, 1 micron, 2 microns, 3 microns, 4 microns, 5 microns, 7 microns, 10 microns, 15 microns, 20 microns, 25 microns, or any range between any two of the numbers, end points inclusive. In some embodiments, the method increases the average neuron length about 500 nm to about 25 microns relative to a control (e.g., the neuron length in the absence of the compound). In some embodiments, the method increases the neuron length about 10% to about 300% relative to a control (e.g., the neuron length in the absence of the compound). In some embodiments, the method increases the neuron length about 200% to about 300% relative to a control (e.g., the neuron length in the absence of the compound).SMRH:4908-5304-8610.127Attorney Docket No. 62WD-385403-WO

[0109] In some embodiments, the method increases the average number of spines per neuron, relative to the time that treatment with a compound described herein is initiated. In some embodiments, average number spines per unit length of a neuron increases 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 more, or any range between any two of the numbers, end points inclusive.

[0110] In some embodiments, the time to realize a change in spine density or spine morphology described herein, for example, 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.

[0111] In some embodiments, the subject has been found to suffer abnormal dendritic spine morphology, spine size, spine plasticity, spine motility, spine density and / or abnormal synaptic function. For example, a subject may experience reduced dendritic spine density following anesthesia (e.g., anesthesia during a surgery) or surgery. In some embodiments, the mood disorder is associated with an abnormal (e.g., reduced) level of dendritic spine density.

[0112] In some embodiments, the method comprises administering to the 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) binds selectively to it, and not to other glutamate receptors. The NMDA receptor is a glutamate receptor and ion channel protein found in nerve cells. It is activated when glutamate and glycine or D-serine bind to it, and when activated it allows positively charged ions to flow through the cell membrane. The NMDA receptor is believed to be important for controlling synaptic plasticity and memory function. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. While the opening and closing of the ion channel is primarily gated by ligand binding, the current flow through the ion channel is voltage dependent. Ca2+flux through NMDA receptors is thought to be critical in synaptic plasticity. The voltage-dependence of current through the channel is mainly due to binding of Mg2+or Zn2+ions to the protein as described above. In some embodiments, a compound described herein may promote dendritic spine formation by inhibiting the NMDA receptor. In some embodiments, a compound described herein blocks NMDA receptor activity, optionally at the 2A subunit thereof.SMRH:4908-5304-8610.128Attorney Docket No. 62WD-385403-WO

[0113] In some embodiments, a compound described herein may promote NMDA receptor activity, optionally at the 2A subunit thereof.

[0114] In some embodiments, the mood disorder is related to (e.g. characterized by) an accumulation of amyloid plaques. In some embodiments, the mood disorder results from a traumatic brain injury or from chronic traumatic encephalopathy. In some embodiments, the subject has not suffered a traumatic brain injury or chronic traumatic encephalopathy. In some embodiments, the depression is not a result of substance abuse or another medical condition. In some embodiments, administration of a hallucinogen, for example ketamine, to the patient is not advised. Compounds

[0115] Provided herein are agents that promote spinogenesis. Such agents are surprisingly found to be useful in the treatment of mood disorders. The agent may be a compound provided herein.

[0116] The compound may be a 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 a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein subscripts n and p are independently selected from 0, 1 or 2; each R1is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, thiol, and nitro; A is an arylene or heteroarylene, having 1 to 4 heteroatoms;SMRH:4908-5304-8610.129Attorney Docket No. 62WD-385403-WO W is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; X is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is as defined above, provided that when A is arylene, and Y is -S- or -NR2-, then X is not -S-; Y is selected from the group consisting of -O-, -S-, -SO-, S(O)2-, and -NR2-, wherein R2is as defined above; and Z is selected from the group consisting of -N(CH3)2CH2CH2OC(O)CH3 and -(CH2CH(R3)O)q-T, wherein subscript q is an integer selected from 1 to 100, R3is 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 a bond, phosphate, and sulfate.

[0117] In some embodiments, provided is a compound according to Formula Ib, Formula Ic, Formula Id, Formula Ie, and / or Formula Ig:SMRH:4908-5304-8610.130Attorney Docket No. 62WD-385403-WO or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein R1, R2, A, Y, Z, n and p are as defined above with respect to formula I and formula Ia; and subscript m is selected from 0, 1 or 2.

[0118] In some embodiments, provided is a compound, or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, selected from:SMRH:4908-5304-8610.131Attorney Docket No. 62WD-385403-WO

[0119] In some embodiments, provided is a compound according to Formula Ih:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscripts n and p are independently selected from 0, 1 or 2; subscript q is an integer selected from 2 to 8; and each R1and R2are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonyl, aminosulfonyl, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, sulfonyl, substituted sulfonyl, thiol, thioalkyl, and nitro.

[0120] In some embodiments, provided is a compound, or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, as described herein, selected from:SMRH:4908-5304-8610.132Attorney Docket No. 62WD-385403-WOSMRH:4908-5304-8610.133Attorney Docket No. 62WD-385403-WOSMRH:4908-5304-8610.134Attorney Docket No. 62WD-385403-WO

[0121] In some embodiments, provided is a compound according to Formula Ij:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein: subscript q is an integer selected from 4 or 6; R3, R4, R5, and R6are independently selected from the group consisting of hydrogen halo, – CH3, and –OCH3; andSMRH:4908-5304-8610.135Attorney Docket No. 62WD-385403-WO R7, R8, R9and R10are independently selected from the group consisting of hydrogen, halo, – CH3, –CF3, –OCH3, –OCF3, phenyl, –NO2; wherein at least six of said R groups are hydrogen.

[0122] In some embodiments, provided is a compound, or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, selected from:

[0123] In some embodiments, the compound is(Compound 1), or pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0124] The compound may be a compound described in International Patent Publication No. WO2017120198.

[0125] In some embodiments, the compound is a compound of formula II:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein Y is – NR33-, O, or –S-; R31is independently halogen, -CX31, -CHX31, -CH2X31, -OCX31S, - OCHX31, -OCH2X31, -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 heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R32is independently halogen, -CX3232 32 3, -CHX 2, -CH2X32, -OCX323, -OCHX 2, -OCH2X32, - CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -SMRH:4908-5304-8610.136Attorney Docket No. 62WD-385403-WO 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 heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each of X31and X32are independently halogen; each of z1 and z2 is independently an integer from 0 to 4; and z3 is an integer from 1 to 12.

[0126] In some embodiments, the compound is a compound of formula IIa:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein R1is independently halogen, —CX11 3, —CHX 2, —CH2X1, —OCX13, —OCHX12, -OCH2X1, —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; R2is independently halogen, —CX23, —CHX22, —CH2X2, —OCX23, —OCHX22, — OCH2X2, —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; X1and X2are independently halogen; z1 and z2 are independently an integer from 0 to 4; and n is an integer from 1 to 12.SMRH:4908-5304-8610.137Attorney Docket No. 62WD-385403-WO

[0127] In some embodiments, the compound is, or pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof..

[0128] In some embodiments, the compound is, or pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0129] In some embodiments, the compound is a compound of formula III:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide 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 at least one of R5-R8and one of R1-R4 is H; and P is selected from the group consisting ofSMRH:4908-5304-8610.138Attorney Docket No. 62WD-385403-WOwherein m is an integer between 1 and 20; n is 0, 1, or 2; q is an integer between 1 and 20; R9-R16are 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 R9-R12and one of R13-R16is H; and X is hydrogen, methyl, or ethyl.

[0130] In some embodiments, the compound of formula III is a compound of formula IIIa: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 at least one of R5-R8 and one of R1-R4 is H; and P iswherein m is an integer between 1 and 20; q is an integer between 1 and 20; R9-R16are selected from the group consisting of hydrogen, deuterium, tritium, fluoride, chloride,SMRH:4908-5304-8610.139Attorney Docket No. 62WD-385403-WO bromide, iodide, hydroxide, amino, methylamino, dimethylamino, trimethylammonium, methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, wherein at least one of R9-R12 and one of R13-R16 is H; and X is hydrogen, methyl, or ethyl.

[0131] In some embodiments, the compound is selected fromor pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

[0132] In some embodiments, the compound is not ketamine. In some embodiments, the compound does not cause perceptual anomalies in the subject. In some embodiments, the compound is not a psychedelic. In some embodiments, the compound is not hallucinogenic. Combination Therapies

[0133] When used for the treatment or prevention of the diseases and disorders described above, a compound described herein may be administered together with one or more additional therapies, for example additional therapeutic agents approved for use in the treatment or prevention of the particular disease or disorder, and more particularly therapies and / or therapeutic agents considered to form the current standard of care.

[0134] In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents that are being used and / or developed to treat a mood disorder. Where combination therapy is envisaged, the active agents may be administered simultaneously, separately or sequentially in one or more pharmaceuticalSMRH:4908-5304-8610.140Attorney Docket No. 62WD-385403-WO compositions. In some embodiments, the one or more additional therapeutic agents is an antidepressant.

[0135] In some embodiments, the antidepressant is selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor, a serotonin noradrenaline dopamine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, a monoamine oxidase inhibitor, a tricyclic antidepressant, or a tetracyclic antidepressant.

[0136] In some embodiments, the antidepressant is a serotonin and norepinephrine reuptake inhibitor selected from the group consisting of levomilnacipran, venlafaxine, desvenlafaxine, sibutramine, nefazodone, milnacipran, duloxetine, and bicifadine, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0137] In some embodiments, the antidepressant is a serotonin noradrenaline dopamine reuptake inhibitor selected from the group consisting of tesofensine and brasofensine, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0138] In some embodiments, the antidepressant is a monoamine oxidase inhibitor selected from the group consisting of isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iproclozide, and toloxatone, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0139] In some embodiments, the antidepressant is a tricyclic antidepressant selected from the group consisting of butriptyline, amoxapine, amitriptyline, nortriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, dibenzepin, iprindole, lofepramine, opipramol, protriptyline, and trimipramine, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0140] In some embodiments, the antidepressant is a tetracyclic antidepressant selected from the group consisting of maprotiline, mianserin, mirtazapine, setiptilinem, amoxapine, quetiapine, benzoctamine, loxapine, mazindol, aptazapine, esmirtazapine, oxaprotiline,SMRH:4908-5304-8610.141Attorney Docket No. 62WD-385403-WO ciclazindol, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0141] 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 a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0142] In some embodiments, the antidepressant is ketamine, esketamine, bupropion, mirtazapine, vilazodone, vortioxetine, aripiprazole, or St. John’s Wort, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof. In some embodiments, the antidepressant is ketamine or esketamine.

[0143] The one or more additional therapeutic agents may be a sedative-hypnotic such as chloral hydrate, estazolam, flurazepam hydrochloride, pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbital sodium, temazepam, triazolam, zaleplon, or zolpidem tartrate; an anticonvulsant such as acetazolamide sodium, carbamazepine, clonazepam, clorazepate dipotassium, diazepam, divalproex sodium, ethosuximde, fosphenytoin sodium, gabapentin, lamotrigine, magnesium sulfate, phenobarbital, phenobarbital sodium, phenytoin, phenytoin sodium, primidone, tiagabine hydrochloride, topiramate, valproate sodium, or valproic acid; an antianxiety drug such as alprazolam, buspirone hydrochloride, chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium, diazepam, doxepin hydrochloride, hydroxyzine embonate, hydroxyzine hydrochloride, hydroxyzine pamoate, lorazepam, mephrobamate, midazolam hydrochloride, or oxazepam; an antipsychotic drug such as chlorpromazine hydrochloride, clozapine, fluphenazine decanoate, fluephenazine enanthate, fluphenazine hydrochloride, haloperidol, haloperidol decanoate, haloperidol lactate, loxapine hydrochloride, loxapine succinate, mesoridazine besylate, molindone hydrochloride, olanzapine, perphenazine, pimozide, prochlorperazine, quetiapine fumarate, risperidone, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, and trifluoperazine hydrochloride; a central nervous system stimulant such as amphetamine sulfate, caffeine, dextroamphetamine sulfate, doxapram hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride, modafinil, pemoline, or phentermine hydrochloride; an antiparkinsonian such as amantadine hydrochloride, benztropine mesylate, biperiden hydrochloride, biperiden lactate, bromocriptine mesylate, carbidopa-levodopa,SMRH:4908-5304-8610.142Attorney Docket No. 62WD-385403-WO entacapone, levodopa, pergolide mesylate, pramipexole dihydrochloride, ropinirole hydrochloride, selegiline hydrochloride, tolcapone, or trihexyphenidyl hydrochloride; a central nervous system agent such as bupropion hydrochloride, donepezil hydrochloride, droperidol, fluvoxamine maleate, lithium carbonate, lithium citrate, naratriptan hydrochloride, nicotine polacrilex, nicotine transdermal system, propofol, rizatriptan benzoate, sibutramine hydrochloride monohydrate, sumatriptan succinate, tacrine hydrochloride, or zolmitriptan; a cholinergic (e.g., parasymathomimetic) such as bethanechol chloride, edrophonium chloride, neostigmine bromide, neostigmine methylsulfate, physostigmine salicylate, or pyridostigmine bromide; an anticholinergic such as atropine sulfate, dicyclomine hydrochloride, glycopyrrolate, hyoscyamine, hyoscyamine sulfate, propantheline bromide, scopolamine, scopolamine butylbromide, or scopolamine hydrobromide; an adrenergic (sympathomimetics) such as dobutamine hydrochloride, dopamine hydrochloride, metaraminol bitartrate, norepinephrine bitartrate, phenylephrine hydrochloride, pseudoephedrine hydrochloride, or pseudoephedrine sulfate; an adrenergic blocker (sympatholytic) such as dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, or propranolol hydrochloride; a skeletal muscle relaxant such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine hydrochloride, dantrolene sodium, methocarbamol, or tizanidine hydrochloride; a neuromuscular blocker such as atracurium besylate, cisatracurium besylate, doxacurium chloride, mivacurium chloride, pancuronium bromide, pipecuronium bromide, rapacuronium bromide, rocuronium bromide, succinylcholine chloride, tubocurarine chloride, or vecuronium bromide; or a corticosteroid such as betamethasone, betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, or triamcinolone diacetate.

[0144] The one or more additional therapeutic agent may be tacrine, donepezil, galantamine, rivastigmine, memantine, levodopa, carbidopa, lisuride, rasagiline, tolcapone, entacapone, clozapine, desipramine, citalopram, nortriptyline, paroxetine, atomoxetine, venlafaxine, amantadine, donepezil, rivastigmine, bromocriptine, cabergoline, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, benserazide, selegiline, omigapil, CEP-SMRH:4908-5304-8610.143Attorney Docket No. 62WD-385403-WO 1347, isradipine, DOPA, lithium, riluzole, levetiracetam, ezogabine, pregabalin, rufmamide, felbamate, carbamazepine, valproate, sodium valproate, lamotrigine, phenytoin, oxcarbazepine, ethosuximide, gabapentin, tiagabine, topiramate, vigabatrin, phenobarbital, primidone, clonazepam, interferon beta-la, interferon beta-lb, mitoxantrone, natalizumab, fmgolimod, natalizumab, teriflunomide, dimethyl fumarate, glatiramer, ATOH1 gene therapy, ozanezumab, arimoclomol, tirasemtiv, dexpramipexole, pridopidine, or galantamine; or a phosphoglycerate kinase (PGK) as described in US 2018 / 0147263. In some embodiments, the one or more additional therapeutic agent may be an acetyl-cholinesterase inhibitor (AChEI), for example, acotiamide, alpha-pinene, ambenonium, demecarium, DFP (diisopropylfluorophosphate), donepezil, edrophonium, galantamine, huperzine A, lactucopicrin, ladostigil, neostigmine, physostigmine, pyridostigmine, dyflos, echothiophate, rivastigmine, rosmarinic acid, tacrine, ungeremine, zanapezil, ganstigmine, phenserine, phenethylnorcymserine (PENC), cymserine, thiacymserine, SPH 1371 (galantamine plus), ER 127528, RS 1259, or F3796. In some embodiments, the one or more additional therapeutic agent may be an amyloid-clearing antibody, for example, bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, BAN2401, or aducanumab.

[0145] In some embodiments, the one or more additional therapies is acceptance and commitment therapy, Adlerian Therapy, animal-assisted therapy, applied behavior analysis, art therapy, attachment-based therapy, biofeedback, brain stimulation therapy, coaching, cognitive behavioral therapy, cognitive processing therapy, cognitive stimulation therapy, culturally sensitive therapy, dialectical behavior therapy, eclectic therapy, emotionally focused therapy, existential therapy, experiential therapy, expressive arts therapy, eye movement desensitization and reprocessing therapy, family systems therapy, feminist therapy, forensic therapy, gestalt therapy, hypnotherapy, Imago relationship therapy, integrative therapy, internal family systems therapy, interpersonal psychotherapy, Jungian therapy, marriage and family therapy, mentalization-based therapy, mindfulness-based cognitive therapy, motivational interviewing, multicultural therapy, narrative therapy, neuro- linguistic programming therapy, neurofeedback, parent-child interaction therapy (PCIT), person-centered therapy, play therapy, positive psychology, prolonged exposure therapy, psychoanalytic therapy, psychodynamic therapy, psychological testing and evaluation, rational emotive behavior therapy, reality therapy, relational therapy, sandplay therapy, social recovery therapy, solution-focused brief therapy, somatic therapy, strength-based therapy, structural family therapy, the Gottman method, therapeutic intervention, transpersonalSMRH:4908-5304-8610.144Attorney Docket No. 62WD-385403-WO therapy, trauma-focused cognitive behavior 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).

[0146] In some embodiments, a compound described herein is administered as a monotherapy. Kits

[0147] Provided herein are also kits that include compounds described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, optionally a second active ingredient, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, as a component of a pharmaceutical composition and a label and / or instructions for use of the pharmaceutical composition in the treatment of the indications, including the diseases or conditions, described herein.

[0148] Provided herein are also articles of manufacture that include a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, nebulizer, aerosol dispensing device, dropper, or intravenous bag. Pharmaceutical Compositions and Modes of Administration

[0149] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein, including generally a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents andSMRH:4908-5304-8610.145Attorney Docket No. 62WD-385403-WO fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0150] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain some embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0151] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0152] Oral administration may be another route for administration of the compositions described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, 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 and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0153] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calciumSMRH:4908-5304-8610.146Attorney Docket No. 62WD-385403-WO silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0154] The pharmaceutical composition and any container in which it is distributed may be sterilized. The pharmaceutical composition may also contain adjuvants such as preservatives, stabilizers, emulsifiers or suspending agents, wetting agents, salts for varying the osmotic pressure, viscosity alerting agents, or buffers.

[0155] The compositions that include at least one compound described herein, such as a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional 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 in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0156] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.SMRH:4908-5304-8610.147Attorney Docket No. 62WD-385403-WO

[0157] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0158] The pharmaceutical composition may be formulated for nasal administration. Such pharmaceutical compositions may include one or more active ingredients, such as a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, in varying physical states. For example, the active ingredients may be dissolved or suspended in a liquid carrier. The active ingredients may be in a dry form. The dry form may be a powder. Active ingredients in a powder may be amorphous or crystalline. For example, a compound described herein, or a deuterated analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, may be amorphous or crystalline. The crystalline active material may be a hydrate or a solvate.

[0159] Solid compounds, or a salt or crystal thereof, may be present in a formulation in a selected average particle size. The particles may have an average particle size (in 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.

[0160] Administration may be by inhalation or insufflation. Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route. Effects may be local or systemic. In a particular embodiment, the effect is local to cranial tissues. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittentSMRH:4908-5304-8610.148Attorney Docket No. 62WD-385403-WO positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. A pharmaceutical composition for inhalation or insufflation may be an aerosol.

[0161] The pharmaceutical composition may comprise a liquid suspension or solution comprising 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 active ingredients. The liquid may comprise water and / or an alcohol. The liquid may include a pH adjusting agent 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 of values therebetween.

[0162] The pharmaceutical composition may comprise a pharmaceutically acceptable preservative. Preservatives suitable for use herein include, but are not limited to, those that protect the solution from contamination with pathogenic particles, including phenylethyl alcohol, benzalkonium chloride, benzoic acid, or benzoates such as sodium benzoate. In certain some embodiments, the pharmaceutical composition comprises from about 0.01% to about 1.0% w / w of benzalkonium chloride, or from about 0.01% and about 1% v / w phenylethyl alcohol. Preserving agents may also be present in an amount from about 0.01% to about 1%, preferably about 0.002% to about 0.02% by total weight or volume of the composition.

[0163] The pharmaceutical composition may also comprise 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 of one or more of an emulsifing agent, a wetting agent or a suspending agent. Such agents for use herein include, but are not limited to, polyoxyethylene sorbitan fatty esters or polysorbates, 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 mono-oleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithins; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane-1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum; tragacanth; acacia; xanthan gum; karaya gum; pectin; amidated pectin; ammonium phosphatides; microcrystalline cellulose; methyl cellulose; hydroxypropylcellulose; hydroxypropylmethylcellulose; ethylmethylcellulose;SMRH:4908-5304-8610.149Attorney Docket No. 62WD-385403-WO carboxymethylcellulose; sodium, potassium and calcium salts of fatty acids; mono-and di- glycerides of fatty acids; acetic acid esters of mono- and di-glycerides of fatty acids; lactic acid esters of mono-and di-glycerides of fatty acids; citric acid esters of mono-and di- glycerides of fatty acids; tartaric acid esters of mono-and di-glycerides of fatty acids; mono- and diacetyltartaric acid esters of mono-and di-glycerides of fatty acids; mixed acetic and tartaric acid esters of mono-and di-glycerides of fatty acids; sucrose esters of fatty acids; sucroglycerides; polyglycerol esters of fatty acids; polyglycerol esters of polycondensed fatty acids of castor oil; propane-1,2-diol esters of fatty acids; sodium stearoyl-2lactylate; calcium stearoyl-2-lactylate; stearoyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; extract of quillaia; polyglycerol esters of dimerised fatty acids of soya bean oil; oxidatively polymerised soya bean oil; and pectin extract.

[0164] In a further embodiment, the pharmaceutical composition for nasal administration may be provided in the form of a powder. For example, a powdery nasal composition can be directly used as a powder for a unit dosage form. If desired, the powder can be filled in capsules such as hard gelatine capsules. The contents of the capsule or single dose device may be administered using e.g. an insufflator.

[0165] Thus, a method for treating a mood disorder may include the step of administering nasally a pharmaceutical composition comprising a compound described herein, or a salt thereof, to a subject in need thereof. Dosing

[0166] The specific dose level of an active ingredient of the present application, for example a compound described herein, for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful whenSMRH:4908-5304-8610.150Attorney Docket No. 62WD-385403-WO adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non- human subject such as dog to a dosage suitable for a human subject.

[0167] The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound described herein, or a salt thereof, may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 20 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day, or between about 15 to 150 mg / day.

[0168] When administered nasally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg / day, between about 10-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day, or between about 100-150 mg / day. In various embodiments, the daily dosage is 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 of values therebetween.

[0169] The active ingredients of the present application or the pharmaceutical compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous. Administration or treatment may be continued indefinitely.

[0170] In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.

[0171] In some embodiments, the method comprises administering to the subject a dose in an amount provided herein once a month, twice a month, once a week, twice a week, or thriceSMRH:4908-5304-8610.151Attorney Docket No. 62WD-385403-WO a week. In such embodiments, dosing may be continued for one month, two months, three months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 12 months, 14 months, 18 months, one year, two years, three years, five years, or indefinitely. In some embodiments, provided is a method comprising administering a compound described herein at a frequency of between thrice a week and once a month. EXAMPLES Example 1 Animals

[0172] Social defeat experiments are carried out, for example, in accordance with 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) on their arrival in the laboratory, serve as experimental intruder or control animals. They are housed in individual cages (l: 45 cm; w: 25 cm; h: 17 cm) for 10 days before the beginning of the experiments, in a chronobiologic animal facility. The chronobiologic facility is equipped with equispaced, soundproof, temperature-controlled (21.0±1.0 °C) compartments provided with filtered air. Each compartment has its own light– dark cycle control. Long Evans (LE) rats, weighing 700–800 g, serve as resident rats in confrontation encounters. At their arrival in the laboratory, they are housed in appropriate cages (l: 45 cm; w: 45 cm; h: 17 cm) together with a ligatured female for 1 month. Then, the residents are chosen for their reliable aggressive behavior as assessed during confrontations with intruders. During the social-defeat procedure, the females are removed from the cages. The same 10 LE rats are used for all the successive series of experiments. All animals are kept under controlled environmental conditions (22±1 °C, 60% relative humidity, 12 / 12 h light–dark cycle with lights on at 0700, food and water ad libitum). Social-defeat procedure

[0173] The behavioral procedure consists of conditioning sessions with the same pairs of residents and intruders. The 45-min conditioning sessions are started at 1000. They are divided into two consecutive periods. During period I (30-min), intruders are placed alone in a protective cage without cover (l: 25 cm; w: 25 cm; h: 30 cm) inside the resident home cage. The resident home cage has no cover and was surrounded by a 100 cm high wire-meshSMRH:4908-5304-8610.152Attorney Docket No. 62WD-385403-WO enclosure (l: 45 cm; w: 45 cm). The protective cage allows unrestricted visual, auditory and olfactory interactions with the resident but precluded close physical contact. During period II (15-min), the protective cage is removed (defeated intruders) allowing physical confrontation. Generally, intruders are attacked within 30 s, and three to four confrontations of ≈10 s each occurred, during which the intruding animal is always dominated by the resident rat and adopted submissive posture, that is, when the defeated rat is on its back under the resident rat for approximately 5 s. The total duration of encounters was ≈1 min for the whole 15 min period II. During physical confrontations, intruders are exceptionally wounded and only at skin-deep level in such cases (in less than 5% of confrontation sessions). Nondefeated intruders are subjected to the same procedure, but without the resident rat for the whole 15 min period II. Therefore, they are never physically attacked and defeated by the resident. The 45-min conditioning session is repeated once daily for 4 days on week 1. During weeks 2 and 3, intruders are subjected to the social-defeat procedure once daily for 2 days, and on week 4, the procedure is repeated again once daily for 4 days. One group of animals is intended for behavioral and physiological analyses and another group for microdialysis experiments. For the latter, after the last conditioning session, that is, 25 days after the first session, intruders are implanted with a guide cannula, and 4 days later, with a microdialysis probe.

[0174] In separate experiments, control rats are kept in their home cage during 40 days. Body weight

[0175] Body weights of defeated and nondefeated rats, treated or not with a compound described herein are measured daily at 0900, before (7 days), during (25 days) and after (4 days) the social-defeat procedure. Adrenal gland weight

[0176] 5 days after the last conditioning session, defeated and nondefeated intruders, treated or not with a compound described herein are decapitated and adrenals are removed, dissected free of adhering fat and weighed. Sweet water consumptionSMRH:4908-5304-8610.153Attorney Docket No. 62WD-385403-WO

[0177] From 1 week before the beginning of the conditioning sessions (D7 to D1) until 5 days after the last conditioning session, two bottles (one filled with water and the other one containing 1.5% sucrose) are continuously available to rats. Sucrose and water intakes are measured daily at 0900. Bottles are switched every day from left to right side of the cage throughout the experiment in order to avoid any place preference. Sweet water consumption is calculated as a percentage of control values. Food consumption

[0178] Food intake is measured daily at 0900, before (7 days), during (25 days) and after (5 days) the social-defeat procedure. Data are expressed as the sum of daily food intakes measured in each animal group during each week. Forced swimming test

[0179] An adapted version of the forced swimming test (FST) originally described by Porsolt et al. is used. Experiments are performed between 0930 and 1300. Five days after the last conditioning session, SD rats are individually placed into glass cylinders (40 cm height; 20 cm diameter) containing 29 cm of water at 30±1°C. After 8 min, they are transferred to a 30°C drying environment for 15 min. The water is changed after each animal's session and the cylinder cleaned to avoid the influence of alarm pheromones left behind by the previous animal. The immobility time is measured with a stopwatch. A rat is considered immobile when floating and making only the necessary movements to keep its nostrils above the water surface. A trained experimenter blind to the treatment made animal observation and measurements. Both room and water temperatures are monitored at the end of each session. Each rat is individually subjected to only one swimming session. Cell proliferation and hippocampal volume BrdU labeling

[0180] On day 29, rats receive two injections of bromodeoxyuridine (BrdU) at 2-h interval. After 24 h (proliferation) or 28 days (differentiation) of the first BrdU injection (day 30, day 58), animals are anesthetized with 375 mg kg−1i.p. of chloral hydrate. Transcardiac perfusion with saline is carried out to clear the blood, followed by 4% cold paraformaldehyde (PFA) in phosphate-buffered saline (PBS). After perfusion, brains are postfixed overnight in 4%SMRH:4908-5304-8610.154Attorney Docket No. 62WD-385403-WO PFA / PBS at 4°C. The day after, serial sections (40-μm thickness) are cut through the entire hippocampus plates 26–40) on a freezing microtome, and sections are stored overnight in PBS at 4°C. Immunohistochemistry

[0181] The next day, free-floating sections are used for the immunohistochemical visualization of BrdU labeling. After several PBS rinses, sections are incubated for 5 min in 3% H2O2to get rid of endogenous peroxidases. They are then washed in PBS, incubated for 30 min in 2 N HCl followed by 30 min in 0.1 M boric acid. After blocking with 5% horse serum in 0.1% Triton X-100, sections are incubated with mouse anti-BrdU antibodies (1:500; Dakocytomation, Trappes, France) overnight at 4°C, then for 2 h with a secondary antibody (1:400; biotinylated horse anti-mouse). After amplification with an avidin–biotin complex, sections are exposed to diaminobenzidine, washed with PBS and mounted onto microscope slides. Slices are processed for counterstaining with cresyl violet and coverslipped. All slides were coded prior to analysis.

[0182] For triple immunolabeling (differentiation), sections are simultaneously incubated overnight at 4°C with rat anti-BrdU antibodies (1:100), mouse anti-NeuN antibodies (1:500), rabbit anti-GFAP antibodies (1:300). After washing, sections are incubated for 2 h with biotinylated anti-rat IgG, then for a further 2 h with secondary anti-mouse CY5, secondary anti-rabbit Alexa Fluor 568 and streptavidin Alexa Fluor 488. After washing, slices are mounted onto microscope slides and finally coverslipped. Quantification of BrdU labeling

[0183] Every sixth section throughout the whole hippocampus is processed for the quantification of BrdU immunohistochemical labeling. Using this spacing ensures that the same neuron is not counted in two sections. All BrdU-labeled cells in the dentate gyrus (granule cell layer, GCL) and hilus are counted in each section by an experimenter blind to the slide code. To distinguish single cells within clusters, all counts are performed at × 400 and × 1000 under a light microscope. A cell is counted as being in the subgranular zone (SGZ) of the dentate gyrus if within or touching the SGZ. Cells that are located at a distance corresponding to more than two cells away from the SGZ are classified as hilar cells. The total number of BrdU-labeled cells per section is determined and multiplied by 6 to obtain the total number of cells per dentate gyrus (see). Phenotypic analysis of fluorescently labeledSMRH:4908-5304-8610.155Attorney Docket No. 62WD-385403-WO BrdU cells is performed using a confocal microscope. Cells are scanned and optically sectioned in the Z plane.

[0184] For the volumetric analysis of GCL, the layer is carefully demarcated on both right and left sides in each section and its area is calculated using Lucia GF version 4.71. The delimited areas are summed for each animal and multiplied by 240 μm (that is, thickness of the slice plus distance between serial sections) to obtain an estimate of GCL total volume. Microdialysis

[0185] After 24 h of the last conditioning session, intruders are anesthetized with chloral hydrate (375 mg kg−1, i.p.). A stainless-steel guide cannula is placed at coordinates allowing the tip to be just above the frontal cortex: anteroposterior, +2.7 mm from bregma; lateral, −1.7 mm from bregma; horizontal, −0.8 mm from the skull. The cannula is then secured to the skull with dental cement, and the skin was sutured. Animals are kept in individual cages for 4 days before the microdialysis experiment.

[0186] The day before the experiment, the rats are placed in a Plexiglas microdialysis bowl (35 cm in diameter) with free access to food and water. The next morning, a microdialysis probe (cutoff: 20 000 Da; outer diameter 0.5 mm; 2 mm in length) is introduced into the guide cannula so as to protrude by 2 mm into the Fr2 area of frontal cortex. In rats, the Fr2 region is considered as an area of the prefrontal cortex. The probe was continuously perfused at a flow rate of 3.0 μl min−1with an artificial CSF (aCSF). To allow dialysis to reach steady state around the probe membrane, perfusion was performed for 90 min (washout period) before collection of the first fraction. Then, 11 fractions of 90 μl (each corresponding to 30 min of perfusion) are collected at 0°C and immediately frozen at −30°C until determination of their CCK-like material (CCKLM) contents with a sensitive radioimmunoassay (RIA).

[0187] The in vitro recovery of CCKLM is estimated as follows. Briefly, the microdialysis probes are immersed in a solution containing a known concentration of exogenous CCK and recovery is calculated as the percentage of CCKLM quantified in the microdialysates over that present in the original solution. This percentage is recorded.

[0188] During the microdialysis procedure, 2 min before the beginning of the collection of the eighth fraction, intruders (either defeated or nondefeated) are subjected to the period I of the social-defeat procedure (see above). Each rat is gently moved to the protective cageSMRH:4908-5304-8610.156Attorney Docket No. 62WD-385403-WO placed inside the usual resident home cage for the 30-min period I and then back to the microdialysis bowl. This is done without having to detach the swivel arm. Thus, during the microdialysis procedure, intruders are threatened, but not defeated by the resident.

[0189] Correct placement of microdialysis probes is verified by histological examination. Thus, at the end of the experiment, rats are deeply anesthetized with chloral hydrate (375 mg kg−1, i.p.), and killed by decapitation. Brains are removed, rapidly frozen in isopentane and stored at −20 °C. They are sectioned in a cryostat and stained with cresyl violet for verification of probe location. When a probe is incorrectly placed, corresponding results were discarded. Drugs and treatments

[0190] Treatment with a compound described herein is started the day after the last conditioning session of week 1 (day 5) and maintained until the day of microdialysis experiment or killing for HPA axis activity determination, cell proliferation quantification or volumetric analysis of the hippocampus (day 30). Physiological and behavioral data

[0191] Differences in body weight, sweet water consumption and food intake, adrenal gland weight, corticosterone levels, hippocampal cell proliferation and immobility time (FST) are measured to determine the compound’s efficacy.

[0192] Models of depression include chronic intermittent stress (e.g., alone and followed by forced swim), as described in, for example, Willner P., The chronic mild stress (CMS) model of depression: History, evaluation and usage, Neurobiology of Stress (2017) 6, 78-93; social defeat model as described in, for example, Golden, S.A. et al., A standardized protocol for repeated social defeat stress in mice, Nat Protoc. ; 6(8): 1183–1191; or a model described in, for example, Krishnan et al., Animal Models of Depression: Molecular Perspectives, Curr Top Behav Neurosci. 2011; 7: 121–147, which models include models of acute stress and models of secondary or iatrogenic depression.

[0193] Spinogenesis, for example, in the prefrontal cortex, may be conducted by any suitable method including, for example, by Golgi staining, biolistic labeling with fluorescent dyes, DiI labeling, Molecular Probes Cell Tracker™ CM-DiI, and structured illuminationSMRH:4908-5304-8610.157Attorney Docket No. 62WD-385403-WO 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, (2014 June 15) 230: 20–29. biolistic labeling may be conducted, for example, according to Arsenault, J., et al., Regioselective Biolistic Targeting in Organotypic Brain Slices Using a Modified Gene Gun. J. Vis. Exp. (2014), 92, e52148. DiI may be conducted according to, for example, Gan, W. B., et al., Multicolor “DiOlistic” labeling of the nervous system using lipophilic dye combinations. Neuron (2000) 27, 219– 225. An example of structed illumination microscopy is described in Schouten et al., Imaging Dendritic Spines of Rat Primary Hippocampal Neurons using Structured Illumination Microscopy, J Vis Exp. (2014) 87. Results

[0194] The in vivo experiments demonstrate that Compound 1, by reversing a neuroanatomical substrate of depression – synapse loss in prefrontal cortex - is useful in treating a mood disorder such as depression. To evaluate the effects of Compound 1, WT (wild type) and 3xTg-AD mice (triple transgenic mouse model of Alzheimer’s disease) were dosed with either vehicle or Compound 1 at 3, 10, or 30mg / kg. Following 4 weeks of daily administration of Compound 1 via intraperitoneal injection, the mice were sacrificed and Golgi staining was performed to analyze dendritic spine synapse density and morphology.

[0195] It was found that Compound 1 increased dendritic spine density in the 3xTg-AD model. Without wishing to be bound by theory, it is believed that restoration of synapses can mediate the rapid antidepressant effects of ketamine and / or psychedelics. As shown in FIG. 1, 3xTg-AD mice treated with vehicle have significantly reduced dendritic spine density compared to vehicle-treated WT mice, particularly in mushroom type spine profiles. These deficits in dendritic spines in 3xTg-AD mice were reversed by treatment with Compound 1 (e.g., at 10- and 30-mg / kg). Example 2

[0196] Methods described herein can be useful for treating or preventing a mood disorder such as depression. The present example illustrates a method of treating or preventing depression by administering Compound 1 to a subject in need thereof.SMRH:4908-5304-8610.158Attorney Docket No. 62WD-385403-WO

[0197] A randomized, placebo-controlled study is conducted in adult participants diagnosed with schizophrenia, a prevalent psychotic disorder with frequent co-morbid depression and anxiety. Participants will be screened from Day -35 to Day -5 including confirmation of a primary diagnosis of schizophrenia using the Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2 (or as approved with sponsor medical monitor), and a Positive and Negative Syndrome Scale (PANSS) total score ≥ 70.

[0198] Participants will be allocated to either Compound 1 or placebo in a 1:1 ratio. There are two cohorts of n=16, with 8 placebo and 8 active in each cohort. A total of n=32 participants. The initial dose of the compound (e.g., Compound 1) is 300 mg. Patients can receive a dose (e.g., a daily dose) of the compound (e.g., Compound 1) for up to about 6 weeks.

[0199] In clinic, participants will be given sufficient amount of placebo or the compound for daily (AM) dosing to last until the next scheduled clinical site visit on Day 22 ± 2 days (21 days ± 2 days). Participants will be contacted by telephone on Days 8, 15, 29, 36 to assess for adverse events, concomitant medication use, and a verbal compliance check and a week after dosing is complete on Day 50. All visits and telephone calls after Day 1 will have a window of ± 2 days. Participants will return to the clinic on Day 71 ± 7 for final efficacy and safety assessments.

[0200] One or more symptoms of depression (e.g., a symptom described herein, or known to practitioners, for example, as described in the DSM) can be alleviated, reduced, or reversed following commencement of the treatment.

[0201] 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 belongs.

[0202] The disclosures illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intentionSMRH:4908-5304-8610.159Attorney Docket No. 62WD-385403-WO in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible.

[0203] Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation of the disclosures embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.

[0204] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.SMRH:4908-5304-8610.160

Claims

Attorney Docket No. 62WD-385403-WO WHAT IS CLAIMED IS:

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

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

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

4. The method of claim 2, wherein the antidepressant is selected from the group consisting of esketamine, levomilnacipran, venlafaxine, desvenlafaxine, sibutramine, nefazodone, milnacipran, duloxetine, bicifadine, tesofensine, brasofensine, isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iproclozide, toloxatone, butriptyline, amoxapine, amitriptyline, nortriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, dibenzepin, iprindole, lofepramine, opipramol, protriptyline, trimipramine, fluoxetine, norfluoxetine, citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, sertraline, maprotiline, mianserin, mirtazapine, setiptilinem, amoxapine, quetiapine, benzoctamine, loxapine, mazindol, aptazapine, esmirtazapine, oxaprotiline, ciclazindol, bupropion, mirtazapine, vilazodone, vortioxetine, aripiprazole, and St. John’s Wort.

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

6. The method of claim 1, wherein administration is continued for a duration of at least four weeks.

7. The method of claim 1, wherein administration is continued for a duration of at least twelve weeks.RH:4908-5304-8610.161Attorney Docket No. 62WD-385403-WO 8. The method of claim 1, wherein administration is continued for a duration of at least four months.

9. The method of claim 1, wherein administration is continued 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 is not yet diagnosed with depression but exhibits at least one marker of depression.

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

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

15. The method of claim 12, wherein the marker of depression is self-reporting by the patient.

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

17. The method of claim 10, wherein the symptom of depression is anxiety, loss of interest in daily activities; pessimism, persistent negativity; sadness, emptiness or feeling down, feelings of worthlessness, feelings of helplessness, feelings of hopelessness; fatigue, tiredness or lack of energy; low self-esteem, self-criticism and / or feeling incapable; difficulty concentrating, difficulty remembering details, and / or difficulty making decisions; persistent irritability, hostility and / or excessive anger; decreased activity, effectiveness and / or productivity; avoidance of social activities; feelings of guilt and / or worry over the past; poor appetite or overeating; suicidal ideation; low sex drive and / or loss of interest in sex; sleep disturbances, insomnia, early-morning wakefulness, or sleeping too much; restlessness, loss of interest in pleasurable activities; overeating or appetite loss; unexplained aches,RH:4908-5304-8610.162Attorney Docket No. 62WD-385403-WO unexplained pains, unexplained headache, persistent cramps, persistent digestive problems; or suicidal ideation, or a suicidal act.

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

19. The method of any preceding claim, wherein the patient is a pediatric patient.

20. The method of any preceding claim, wherein the compound is not hallucinogenic.

21. The method of any preceding claim, wherein the patient has not previously been administered an antidepressant.

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

23. The method of claim 22, wherein the antidepressant is a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor, a serotonin noradrenaline 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 inhibitor is selected from the group consisting of levomilnacipran, venlafaxine, desvenlafaxine, sibutramine, nefazodone, milnacipran, duloxetine, and bicifadine; the serotonin noradrenaline dopamine reuptake inhibitor is selected from the group consisting of tesofensine and brasofensine; the monoamine oxidase inhibitor is selected from the group consisting of isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazid, iproclozide, and toloxatone; the tricyclic antidepressant is selected from the group consisting of butriptyline, amoxapine, amitriptyline, nortriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, dibenzepin, iprindole, lofepramine, opipramol, protriptyline, 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, setiptilinem, amoxapine, quetiapine, benzoctamine, loxapine, mazindol, aptazapine, esmirtazapine, oxaprotiline, and ciclazindol.RH:4908-5304-8610.163Attorney Docket No. 62WD-385403-WO 25. The method of claim 22, wherein the antidepressant is ketamine, esketamine, bupropion, mirtazapine, vilazodone, vortioxetine, aripiprazole, or St. John’s Wort.

26. The method of any preceding claim, wherein the method comprises administering the compound at a frequency of between thrice a week and once a month.

27. The method of any preceding claim, wherein the compound is a compound of formula I or formula Ia:I Ia or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein subscripts n and p are independently selected from 0, 1 or 2; each R1is independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, carboxyl, carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, hydroxyl, thiol, and nitro; A is an arylene or heteroarylene, having 1 to 4 heteroatoms; W is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl; X is selected from the group consisting of -O-, -S-, -SO-, -S(O)2-, and -NR2-, wherein R2is as defined above, provided that when A is arylene, and Y is -S- or -NR2-, then X is not - S-; Y is selected from the group consisting of -O-, -S-, -SO-, S(O)2-, and -NR2-, wherein R2is as defined above; andRH:4908-5304-8610.164Attorney Docket No. 62WD-385403-WO Z is selected from the group consisting of -N(CH3)2CH2CH2OC(O)CH3and -(CH2CH(R3)O)q-T, wherein subscript q is an integer selected from 1 to 100, R3is 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 a bond, phosphate, and sulfate.

28. The method of any preceding claim, wherein the compound is a compound of formula II:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof, wherein Y is –NR33-, O, or –S-; R31is independently halogen, -CX31, -CHX31, -CH2X31, -OCX31S, -OCHX31, -OCH2X31, - 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 heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R32is independently halogen, -CX3232 3, -CHX 2, -CH2X32, -OCX3232 3, -OCHX 2, -OCH2X32, - 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 heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each of X31and X32are independently halogen; each of z1 and z2 is independently an integer from 0 to 4; and z3 is an integer from 1 to 12.RH:4908-5304-8610.165Attorney Docket No. 62WD-385403-WO 29. The method of any preceding claim, wherein the compound is:(Compound 1), or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof., or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

31. The method of any one of claims 1-28, wherein the compound is:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

32. The method of any one of claims 1-28, wherein the compound is:or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.

33. The method of any one of claims 1-28, wherein the compound is:, or a pharmaceutically acceptable salt, solvate, and / or an N-oxide thereof.RH:4908-5304-8610.166

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