Lumateperone and its derivatives for modulating the nervous system

Abstract

The present disclosure relates to the use of compounds of formula (I), compounds of formula (II), and related analogs to enhance neuritogenesis, enhance neurite outgrowth, enhance neural growth, neural connectivity, synaptic density, dendritic spine density, dendritic spine size, and excitatory neurotransmission in the brain (e.g., in the medial prefrontal cortex), and other methods and uses related thereto.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to and the benefit of U.S. Provisional Application No. 63 / 485,858, filed February 17, 2023, and U.S. Provisional Application No. 63 / 496,661, filed April 17, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to the use of lumateperone, its related analogs, and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines for enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural growth, neural connectivity, synaptic density, dendritic spine density, dendritic spine size, and excitatory neurotransmission in the brain (e.g., in the prefrontal cortex). [Background technology]

[0003] Lumateperone has the formula:

[0004] [ka] Has 5-HT 2A This novel therapeutic agent possesses potent receptor antagonism (Ki=0.5nM) consistent with in vivo partial agonism at presynaptic D2 receptors and antagonism at postsynaptic D2 receptors (Ki=32nM), activity as a mesolimbic / mesocortical selective dopamine receptor protein phosphorylation modulator, high D1 receptor affinity (Ki=52nM), and inhibition of the serotonin transporter (SERT) (Ki=26-62nM, using different assays for SERT activity).

[0005] Lumateperone is primarily known for its usefulness in treating the positive and negative symptoms of schizophrenia. It possesses dual properties at the dopamine D2 receptor, acting as both a postsynaptic antagonist and a presynaptic partial agonist. Lumateperone also stimulates phosphorylation of glutamatergic NMDA NR2B (GluN2B) receptors in a mesolimbic-specific manner. This regional selectivity in brain regions thought to mediate the efficacy of antipsychotic drugs, coupled with serotonergic, glutamatergic, and dopaminergic interactions, is thought to provide antipsychotic efficacy against the positive, negative, affective, and cognitive symptoms associated with schizophrenia.

[0006] Lumateperone also exhibits serotonin reuptake inhibition, which provides antidepressant activity for the treatment of schizoaffective disorder, comorbid depression, and / or as a monotherapy for bipolar depression or major depressive disorder. Lumateperone is also useful for the treatment of bipolar disorder and other psychiatric and neurodegenerative disorders, particularly the labile behaviors associated with dementia, autism, and other CNS diseases. These characteristics can improve the quality of life and enhance social functioning of patients with schizophrenia, allowing them to more fully integrate into their families and workplaces.

[0007] Lumateperone exhibited dose-dependent differential effects, with low doses showing a significant increase in 5-HT 2A While selectively targeting the D2 receptor, higher doses increasingly interact with the D2 receptor. As a result, lower doses are useful for treating sleep, aggressive behavior, and agitation. Higher doses can treat acute exacerbations and residual schizophrenia, bipolar disorder, and mood disorders.

[0008] Lumateperone's highly unique pharmacological profile results in it possessing some properties of both atypical antipsychotics (APDs) and selective serotonin reuptake inhibitors (SSRIs). It has been shown to enhance glutamatergic neurotransmission by acting on both NMDA and AMPA receptor conductance in rat medial prefrontal cortex (mPFC) slices. The effects of lumateperone are consistent with those of other rapid-acting antidepressant therapies, including the combined use of olanzapine (a D2 receptor antagonist APD) and fluoxetine (an SSRI) and the use of ketamine.

[0009] Lumateperone is approved in the United States for the treatment of schizophrenia and bipolar depression and is being developed for the treatment of agitation in schizophrenia, bipolar depression, and dementia, including Alzheimer's disease.

[0010] Lumateperone and related compounds are 5-HT 2A For the treatment of disorders related to receptor modulation, such as anxiety, depression, psychosis, and schizophrenia, it is disclosed in U.S. Patent No. 6,552,017; U.S. Patent No. 7,071,186; U.S. Patent No. 7,183,282; and U.S. Patent Reissue No. RE39,680. U.S. Patent No. 8,598,119, U.S. Patent No. 9,616,061, and U.S. Patent No. 10,117,867, each of which is incorporated herein by reference, disclose the use of lumateperone for the treatment of depression, schizophrenia, and sleep disorders. U.S. Pat. Nos. 11,053,245 and 11,124,514, each of which is incorporated herein by reference, disclose the use of lumateperone for the treatment of combined psychotic and depressive disorders, and sleep disorders, depressive disorders, and / or mood disorders in patients with psychosis or Parkinson's disease, and for the treatment or prevention of disorders associated with dementia, particularly unstable behavior or mood, such as agitation, irritability, violent / aggressive behavior, anger, physical or emotional outbursts, and psychosis and sleep disorders associated with dementia.

[0011] U.S. Pat. No. 8,648,077, incorporated herein by reference, discloses a method for preparing crystalline toluenesulfonic acid addition salts of certain substituted heterocyclic-fused gamma-carbolines, such as the toluenesulfonic acid addition salt of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.

[0012] Nos. 10,077,267, 10,688,097, and 2021 / 0008065, each of which is incorporated herein by reference, show that deuterated forms of lumateperone and related compounds have improved metabolic stability.

[0013] U.S. Patent Application Publication No. 2021 / 0060009 discloses the use of lumateperone and its deuterium analogs for the acute treatment of anxiety and depression (e.g., for the treatment of acute anxiety and acute depression). Conventional antidepressants often take weeks or months to achieve their full effect and are therefore generally ineffective for the acute treatment of depression. This delayed onset of action increases the risk of suicidal behavior. Unlike conventional antidepressants, which primarily act on the monoamine neurotransmitter domain (i.e., serotonin, norepinephrine, and dopamine), ketamine is a selective NMDA receptor antagonist, acting through a system not directly related to monoamines. This is the primary reason why ketamine exhibits much more rapid antidepressant action than conventional antidepressants. Ketamine directly antagonizes extrasynaptic glutamatergic NMDA receptors, resulting in indirect activation of AMPA-type glutamate receptors. Downstream effects involve the brain-derived neurotrophic factor (BDNF) and mTOR (e.g., mTORC1) kinase pathways (signaling pathways). Lumateperone has been shown to have activity similar to that of ketamine in NMDA / AMPA receptors and downstream BDNF and mTOR signaling, and thus lumateperone can produce rapid antidepressant effects similar to those of ketamine. See, for example, Dutheil et al., J. Neurosci., 43(5):863-877 (2023); Titulaer et al., Eur. Neuropsychopharm., 62:22-35 (2022).

[0014] Serotonin, also known as 5-hydroxytryptamine (5-HT), is a neurotransmitter widely distributed in the brain. Drugs that directly or indirectly target 5-HT, such as 5-HT receptor agonists and selective serotonin reuptake inhibitors, are widely used in psychiatry and have found use in the treatment of many mood disorders and psychoses. However, strong 5-HT agonists tend to induce hallucinations, a dangerous side effect. Experiments suggest that classical hallucinogenic psychotomimetic serotonin agonists, such as LSD (D-lysergic acid diethylamide) and psilocybin (via its active metabolite psilocin), may be highly effective in treating many neuropsychiatric disorders, especially depression. However, these drugs cannot be used in practice due to their hallucinogenic side effects. Therefore, efforts have been made to develop novel compounds with similar pharmacological profiles in hallucinogenic psychotomimetic activity but without hallucinogenic activity.

[0015] Psilocybin is a serotonergic psychotomimetic substance derived from hallucinogenic mushrooms of the genus Psilocybe. Psilocybin itself is inactive, but is a prodrug of the active compound psilocin, which is formed via rapid enzymatic dephosphorylation:

[0016] [ka]

[0017] Psilocin is 5-HT 2AIt is the most notably potent agonist at the serotonin receptor, with less activity at other serotonin receptors. Psilocybin possesses similar mind-altering effects to LSD (lysergic acid diethylamide), mescaline, ibogaine, and DMT (N,N-dimethyltryptamine), including euphoria, visual and auditory hallucinations, altered cognition, a distorted sense of time, and the perception of spiritual experiences. Additionally, it can induce nausea and anxiety attacks (e.g., "bad trips"). Effects can last from 2 to 6 hours. Psilocybin offers significant untapped therapeutic potential, for example, in the treatment of depression, but is hindered by its widespread classification as a controlled substance.

[0018] Recently, psilocybin has been studied in mice for its ability to promote dendritic spine growth in mouse frontal cortex cells. Shao et al., Neuron, 109(16):2535-2544 (2021). Neurons communicate with each other primarily through the transfer of signals across synapses. A synapse is a junction between the cell membranes of two neurons (or between a neuron and a muscle cell), where neurotransmitter molecules are released from the presynaptic side of the synapse and relay signals by binding to receptors on the postsynaptic side of the synapse. Most neurons have a cell body with many short, branched extensions called dendrites and one long extension called an axon. Dendrites have many small surface spikes called dendritic spines, which terminate in synapses that connect neurons to other neurons. These dendritic synapses serve as pathways for neurons to receive messages from other neurons, while axons terminate at synapses that are used to transmit messages to other neurons (or muscle cells). Thus, dendrites and dendritic spines, as well as axons, are essential for the ability of nerve cells to communicate with each other.

[0019] The majority of neurons are multipolar, meaning that they have a cell body with numerous process extensions called neurites. Both dendrites and axons are considered types of neurites. The term neurite is often used, particularly in neuronal cell cultures or in immature or developing neurons in vivo, because it can be difficult to distinguish between growing axons and growing dendrites before cell differentiation is complete. Thus, the sprouting and subsequent growth of neurites is called neuritogenesis (or neurite outgrowth), which includes both dendritic and axonal growth, especially in immature neuronal cells. The initial sprouting of a neurite is a three-step process: first, the cell's original circular shape subdivides to generate a sprout, then the sprout transforms into a neurite, and then the neurite transforms into an axon or dendrite.

[0020] Neuritogenesis can be studied using different qualitative or quantitative indicators, such as indicators based on histological or immunochemical staining of cell cultures. Indicators include cell size or length, the total number of neurites per cell, neurite length (for individual neurons and / or overall length), the number of neurite branch points, the number of neurite bases, the number of neurite nodes, the total number of neurite terminals, and the overall length of the neuron, with or without its branches. All of these can be measured using automated or semi-automated image analysis techniques. The dendritic branching of all neurites can also be measured or predicted, for example, using Sholl analysis. Several assays have been disclosed for neuritogenesis analysis and can be used to test the compounds disclosed herein. See, e.g., Li, S. et al., "Evaluation of Chemical Compounds that Inhibit Neurite Outgrowth in iPSC-derived Human Neurons," Neurotoxicology 83:137-145 (2021); Li, Z. et al., "High-throughput neurite outgrowth assay using GFP-labeled iPSC-derived neurons," Curr Protoc. 2(9):e542 (2022); Duchemin, C. et al., "Compounds with different pharmacological profiles enhance the neurite outgrowth in Human iPSC-derived neurons (Poster), iForum 2016 (available at Neurofit.com).

[0021] Several neurological disorders, including depression, are associated with synaptic atrophy in specific brain regions and the resulting loss of intercellular connectivity. In other words, damaged or injured brains lose the interconnections between neurons at dendritic synapses. For example, imaging of patients with major depressive disorder (MDD) frequently reveals that they suffer measurable atrophy in the dorsal prefrontal cortex (PFC). Additionally, postmortem observations of MDD patients confirm what has previously been highlighted by preclinical rodent depression models: reduced levels of proteins involved in the mammalian target of rapamycin (mTOR) signaling pathway in the PFC. The significance of these changes is further reinforced by the discovery that stress induces atrophy of stress-vulnerable hippocampal neurons and pyramidal neurons in the medial PFC (mPFC), and that this atrophy is accompanied by a reduction in AMPA receptors, mTORC1 signaling, and brain-derived neurotrophic factor (BDNF).

[0022] Some drugs with rapid antidepressant effects, such as ketamine and psilocybin, have been suggested to exert these effects in part by promoting the growth of new dendritic spines and, in turn, the formation of new synaptic connections in the brain (so-called brain "structural remodeling" or "synaptic plasticity"). It has been suggested that such antidepressants work, at least in part, by inducing a transient increase in mTORC1 activity in the brain, leading to an increase in synaptic spine density in the mPFC. Neuroimaging experiments suggest that functional connectivity improved in the right lateral PFC of patients with MDD after ketamine treatment.

[0023] Using an in vivo rodent model, Shao et al. demonstrated that a single dose of psilocybin resulted in a measurable increase in dendritic spine density within one day, as well as an increase in spine head width. Shao further showed that the measurable changes in dendritic spine density persisted for at least one month after a single dose of psilocybin. Shao specifically demonstrated in both male and female mice that the increase in dendritic spine density was due to an increased rate of formation, rather than a decreased rate of elimination. Interestingly, approximately 30% of 5-HT 2A 5-HT at receptor-blocking doses 2A Pretreatment with the receptor antagonist ketanserin was sufficient to block psilocybin-induced head-twitch responses (a functional indicator of serotonin receptor activity) but did not eliminate psilocybin-induced growth of dendritic spines. Shao et al. did not rule out the possibility that residual receptors unaffected by ketanserin may be involved in dendritic remodeling. Finally, Shao also showed that these structural effects in medial prefrontal cortical neurons were associated with increased excitatory neurotransmission (minimal excitatory postsynaptic currents, mEPSCs) in the medial prefrontal cortex.

[0024] However, psilocybin is a potent hallucinogen. It is currently unclear whether structural modifications of psilocybin can separate its hallucinogenic effects from its structural remodeling effects. While this requires therapies that result in neural structural remodeling in other settings, it is particularly important for psychiatric patients (e.g., schizophrenia or related disorders) in whom even mild hallucinogenic side effects can severely exacerbate their psychotic disorder. Similarly, patients with dementia are at increased risk for severe adverse events from drug-induced hallucinations due to their diminished ability to recognize side effects. Many patients have contraindications for hallucinogenic psychotomimetic therapies, and thus, drugs without hallucinogenic side effects are needed.

[0025] Thus, there is a need for novel drug molecules that can provide the serotonin receptor-mediated structural remodeling effects recently demonstrated for psilocybin, but without the hallucinogenic side effects. Summary of the Invention

[0026] Psilocybin is 5-HT 2A While lumateperone is a strong agonist of the 5-HT 2A Shao et al. found that both the hallucinogenic effects of psilocybin and its effects on neuronal structural remodeling are related to 5-HT 2A Lumateperone has no serotonin receptor agonist activity and is therefore non-hallucinogenic. However, while lumateperone has the same neurostructural remodeling effects in the brain as psilocybin, this effect may instead be mediated through enhancement of mTOR signaling (although it is not yet known whether psilocybin similarly has direct or indirect effects on mTOR signaling, it appears to be down-regulating 5-HT receptor activity on prefrontal cortex neurons). 2AIt is possible that psilocybin agonism at the receptor activates mTOR signaling. Specifically, without being bound by theory, by activating D1 receptors in the brain (e.g., in the mPFC and / or amygdala), lumateperone leads to FYN kinase-mediated phosphorylation of the GluN2B subunit of the NMDA receptor, thereby enhancing NMDA-mediated neurotransmission in prefrontal neurons. This results in increased glutamate release, which enhances AMPA-mediated currents, BDNF release, and mTORC1 activation. Increased synaptogenesis is associated with enhanced mTORC1 signaling in the PFC. Recent experiments have shown that acute administration of lumateperone stimulates mTORC1-related signaling pathways in the PFC as well as some important genes coding for neurotrophic factors, such as BDNF and VEGF. Consistent with this theory, it has surprisingly been found that lumateperone can induce structural remodeling in the brain, e.g., enhancing neuronal growth, neural connectivity, synaptic density, dendritic spine density, dendritic spine size, and excitatory neurotransmission, e.g., in the medial prefrontal cortex. Analogs of lumateperone and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines are expected to have similar properties.

[0027] Additionally, several novel compounds (octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines) have recently been disclosed in International Application No. PCT / US2023 / 86562, the entire contents of which are incorporated herein by reference, which inhibit the serotonin 5-HT 2A These receptors are classical G q It can function through coupled signaling cascades or through an alternative beta-arrestin-mediated signaling cascade. qIt has been suggested that 5-HT-mediated signaling cascades are involved in the hallucinogenic effects of conventional psychotomimetic substances, and that ligands that exhibit a bias for beta-arrestin recruitment may provide psychotomimetic therapeutic benefits, such as antidepressant activity, without the associated hallucinogenic side effects. Compounds disclosed in International Application PCT / US2023 / 86562 inhibit 5-HT 2A The compounds exhibit a functional bias towards receptor beta-arrestin signaling. While many of the disclosed compounds are either partial or full agonists of beta-arrestin signaling, G q These other compounds are either inactive or antagonistic to beta-arrestin signaling, whereas these other compounds are antagonistic in both pathways but have a functional bias toward beta-arrestin signaling.

[0028] Thus, the present disclosure provides methods for enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, e.g., in the medial prefrontal cortex region of the brain, comprising administering to the subject an effective amount of lumateperone, its related analogs, its deuterated analogs, and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines in free form or in a pharmaceutically acceptable salt form. In some embodiments of this aspect, the enhanced neural growth, enhanced neural connectivity, increased synapse density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission is characterized by or caused by enhanced neuritogenesis and / or enhanced neurite outgrowth (e.g., characterized by an increase in the total number of neurites per neuron, neurite length (individual length and / or total neuron length), number of branch points on neurites, number of neurite bases, number of neurite nodes, total number of neurite terminals, total neuron length (with or without branching), and total amount of neurite dendritic branching), and / or is characterized by or associated with changes in synaptic neurotransmitter receptor or neurotransmitter transporter density.

[0029] The present disclosure further provides a method for enhancing neuritogenesis and / or neurite outgrowth in the brain of a subject in need thereof, e.g., in the medial prefrontal cortex region of the brain, comprising administering to the subject an effective amount of lumateperone, its related analogs, its deuterated analogs, and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines in free form or in pharmaceutically acceptable salt form. In some embodiments of this aspect, enhanced neuritogenesis and / or neurite outgrowth is characterized by an increase in the total number of neurites per neuron, neurite length (individual length and / or total neuron length), number of branch points on neurites, number of neurite bases, number of neurite nodes, total number of neurite terminals, total neuron length (with or without branches), and total amount of neurite dendritic branches. In some embodiments, enhanced neuritogenesis and / or enhanced neurite outgrowth is also associated with changes in synaptic neurotransmitter receptor or neurotransmitter transporter density.

[0030] The present disclosure further provides a method for enhancing neural growth, enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in neural cells or neural tissue (e.g., cell culture), in vitro or in vivo, comprising contacting the neural cells or neural tissue with an effective amount of lumateperone, its related analogs, its deuterated analogs, and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline, in free form or in pharmaceutically acceptable salt form. DETAILED DESCRIPTION OF THE INVENTION

[0031] In a first aspect, the present disclosure provides a method for enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, comprising administering an effective amount of a compound of Formula I or a compound of Formula II, as described herein below.

[0032] Thus, in a first embodiment of the first aspect, the present disclosure provides a method (Method 1) for enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, for example, in the prefrontal cortex region of the brain, comprising administering to a subject an effective amount of a compound of Formula I (Compound I):

[0033] [ka] wherein X is selected from -O-, -S-, -N(H), and -N(CH3)-, and Y is selected from -O-, -C(O)-, -CH(OH)-, and -CH(OCH3). or a deuterium analog thereof in free form or a pharmaceutically acceptable salt form to a subject.

[0034] In a further embodiment of the first embodiment of the first aspect, the present disclosure provides: 1.1. Method 1, wherein in the compound of formula I, X is -O- or -S-; 1.2. Method 1, wherein in the compound of formula I, X is -N(H) or -N(CH3)-; 1.3. Method 1, wherein in the compound of formula I, X is -N(CH3)-; 1.4. Method 1 or any of methods 1.1 to 1.3, wherein in the compound of formula I, Y is -O-; 1.5. Method 1 or any of methods 1.1 to 1.3, wherein in the compound of formula I, Y is -C(O)-; 1.6. Method 1 or any of methods 1.1 to 1.3, wherein in the compound of formula I, Y is -CH(OH)-; 1.7. The compound of formula I is

[0035] [ka] or a deuterium analog thereof; 1.8. The compound of formula I is

[0036] [ka] or a deuterium analog thereof; 1.9. The compound of formula I is

[0037] [ka] or a deuterium analog thereof; 1.10. The compound of formula I is

[0038] [ka] or a deuterium analog thereof, 1.11. Method 1 or any of methods 1.1-1.10, wherein the compound of formula I or a deuterated analog thereof is in the form of a free base; 1.12. Method 1 or any of methods 1.1-1.11, wherein the compound of Formula I or a deuterated analog thereof is in the form of a pharmaceutically acceptable salt; 1.13. Method 1.12, wherein the pharmaceutically acceptable salt is a toluenesulfonic acid addition salt (e.g., mono-tosylate or bis-tosylate); 1.14. The compound of formula I or its deuterium analog is non-deuterated lumateperone, i.e., has the following structure:

[0039] [ka] Method 1 or any of methods 1.1 to 1.13; 1.15. Method 1, or any of methods 1.1-1.14, wherein the compound of formula I or a salt thereof is in a deuterated form, e.g., the deuterium:protium ratio for at least one specified carbon-bonded hydrogen atom is significantly higher than the natural isotope ratio, e.g., at least 2×, e.g., at least 10× higher; 1.16. The deuterium analog of the compound of formula I is

[0040] [ka] wherein D represents hydrogen positions having substantially more than natural deuterium bonding (i.e., substantially more than 0.0156%), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99% deuterium bonding, in free form or in a pharmaceutically acceptable salt form, e.g., tosylate form, of Method 1.15; 1.17. Any of the preceding methods, providing enhanced neural growth in the subject's brain (e.g., in the prefrontal cortex region of the brain); 1.18. Any of the preceding methods, providing increased neural connectivity within the subject's brain (e.g., in the prefrontal cortex region of the brain); 1.19. Any of the preceding methods, providing an increase in synaptic density in the subject's brain (e.g., in the prefrontal cortex region of the brain); 1.20. Any of the preceding methods, providing an increase in dendritic spine density in the subject's brain (e.g., in the prefrontal cortex region of the brain); 1.21. Any of the preceding methods, providing an increase in dendritic spine size (e.g., an increase in spine head width and / or an increase in spine process length) in the subject's brain (e.g., in the prefrontal cortex region of the brain); 1.22. Any of the preceding methods, providing increased excitatory neurotransmission (e.g., enhanced glutamatergic transmission or increased rate of mEPSCs) in the subject's brain (e.g., in the prefrontal cortex region of the brain); 1.23. Method 1, or any of methods 1.1-1.22, providing enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the medial prefrontal cortex region of the brain) within less than 4 weeks of initiating administration of the compound of Formula I or a deuterium analog thereof, e.g., within less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days after initiating treatment with the compound of Formula I or a deuterium analog thereof; 1.24. Method 1, or any of methods 1.1-1.23, wherein at least 50% of the peak enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the prefrontal cortex region of the brain) is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months, after cessation of administration of the compound of Formula I or a deuterated analog thereof; 1.25. Method 1, or any of methods 1.1-1.24, wherein at least 50% of the peak enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months, after administration of a single dose of a compound of Formula I or a deuterated analog thereof, as measured in the subject's brain (e.g., in the prefrontal cortex region of the brain), e.g., by in vivo imaging (e.g., MRI); 1.26. Enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission are characterized or caused by enhanced neuritogenesis and / or enhanced neurite outgrowth, and / or increased synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., an increase or decrease in such receptor or transporter density), e.g., serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B ), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density; 1.27. Enhance neuritogenesis and / or enhance neurite outgrowth and / or decrease synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., increase or decrease such receptor or transporter density), e.g., serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density; 1.28. Method 1.26 or 1.27, wherein enhanced neuritogenesis or enhanced neurite outgrowth is characterized by an increase in one or more of the following: total number of neurites per neuron, neurite length (individual length and / or total neuron length), number of branch points on neurites, number of neurite bases, number of neurite nodes, total number of neurite terminals, total neuron length (with or without branching), and total amount of neurite dendritic branching (e.g., measured or predicted using Sholl analysis); 1.29. Any of the aforementioned methods that do not cause hallucinogenic side effects; 1.30. Any of the preceding methods wherein the compound of formula I or a deuterated analog thereof is administered in a daily dose equivalent to 1 to 100 mg of the free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 50 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg of the free base; 1.31. Any of the preceding methods, wherein the compound of formula I or a deuterated analog thereof is administered at a dose equivalent to 1-100 mg of the free base, e.g., 1-75 mg, or 1-60 mg, or 1-50 mg, or 1-40 mg, or 1-30 mg, or 1-20 mg, or 1-10 mg of the free base, every other day, or every two days, or every three days, or every four days, or every five days, or every six days, or every seven days; 1.32. Method 1, or any of methods 1.1-1.31, wherein the compound of Formula I or a deuterated analog thereof is administered as a unit dosage form for oral administration (e.g., enteral), e.g., as a tablet or capsule; 1.33. Method 1.32, wherein a unit dosage form for oral administration (e.g., enteral), e.g., a tablet or capsule, comprises a compound of Formula I or a deuterated analog thereof in an amount equivalent to 1 to 100 mg of free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of free base, and a pharmaceutically acceptable diluent or carrier; 1.34. Method 1, or any of methods 1.1-1.31, wherein the compound of Formula I or a deuterated analog thereof is administered as a unit dosage form for subcutaneous or transmucosal administration, e.g., an orally disintegrating tablet or film for sublingual or buccal administration; 1.35. Method 1.34, wherein a unit dosage form for subcutaneous or transmucosal administration, e.g., an orally disintegrating tablet or film for sublingual or buccal administration, comprises a compound of Formula I or a deuterated analog thereof in an amount equivalent to 0.5 to 30 mg of free base, e.g., 1 to 10 mg of free base, and a pharmaceutically acceptable diluent or carrier; 1.36. Method 1, or any of methods 1.1-1.31, wherein the compound of Formula I or a deuterated analog thereof is administered as a long-acting injectable (LAI) composition, e.g., an LAI composition for intramuscular or subcutaneous injection; 1.37. Method 1.36, wherein the dose of the LAI composition is sufficient to provide the equivalent of a daily dose of 1 to 100 mg of free base of Compound I or a deuterated analog thereof, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of free base, released over a period of time ranging from about 1 week to about 3 months, e.g., from about 1 week to about 8 weeks, or from about 1 week to about 6 weeks, or from about 1 week to about 4 weeks, or from about 1 week to about 3 weeks, or from about 1 week to about 2 weeks; 1.38. Method 1.36 or 1.37, wherein the LAI composition comprises a compound of Formula I or a deuterated analog thereof dissolved, dispersed, suspended, or encapsulated within a polymer matrix; 1.39. Method 1.38, wherein the polymer matrix comprises one or more biocompatible and biodegradable polymers, as defined herein, such as poly(hydroxycarboxylic acids), poly(amino acids), cellulose polymers, modified cellulose polymers, polyamides, and polyesters; 1.40. Method 1.39, wherein the one or more polymers comprise polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta-hydroxybutyric acid, poly(lactic acid-glycolic acid) copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, polyglycolic acid-polyethylene glycol copolymer, poly(alkyl alpha-cyanoacrylate), e.g., poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoester), polycarbonate, polyortho-carbonate, polyamino acid, (e.g., poly-gamma-L-alanine, poly-gamma-benzyl-L-glutamic acid or poly-γ-methyl-L-glutamic acid), and / or hyaluronic acid ester; 1.41. Method 1.39, wherein the one or more polymers comprise polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic-co-glycolic acid) copolymer; 1.42. Method 1.39, wherein the one or more polymers include a poly(lactic acid-glycolic acid) copolymer, e.g., poly-d,l-lactide-co-glycolide; 1.43. Any of the preceding methods in which the subject is an animal; 1.44. Any of the preceding methods, wherein the subject is a human (e.g., a patient suffering from a neuropsychiatric disorder); 1.45. Method 1.44, wherein the subject is a patient suffering from anxiety or depression, e.g., bipolar depression, major depressive disorder (MDD), post-traumatic stress disorder, or treatment-resistant depression; 1.46. Method 1.45, wherein the subject is a patient suffering from treatment-resistant depression (e.g., depression that has not responded to treatment with an antidepressant selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof); 1.47. Method 1.45, in which the subject is a patient suffering from bipolar depression or major depressive disorder; 1.48. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate, or sequential administration, of an antidepressant (e.g., selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof); 1.49. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate or sequential administration, of an NMDA receptor antagonist, e.g., an NMDA receptor antagonist chosen from ketamine (e.g., S-ketamine and / or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine, and agmatine, or any combination thereof; 1.50. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate or sequential administration, of an NMDA receptor allosteric modulator, e.g., an NMDA receptor glycine site modulator, e.g., rapastinel, nebostinel, apimostinel, D-cycloserine, or any combination thereof; 1.51. Any of the preceding methods, wherein the subject has previously received treatment with, and has had an unresponsive or inadequate response to, or is suffering from undesirable side effects from, another antidepressant, e.g., a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), or a serotonin receptor antagonist; 1.52. Any of the preceding methods wherein the compound of Formula I or a deuterium analog thereof is administered as monotherapy, e.g., the compound of Formula I or a deuterium analog thereof is not administered concurrently or in conjunction with an antidepressant, antipsychotic, or anxiolytic; 1.53. Any of the preceding methods, wherein the compound of Formula I or a deuterated analog thereof is administered without the direct supervision of a healthcare professional (e.g., the compound is self-administered by the subject (e.g., patient)); 1.54. Any of the preceding methods that do not include supervision or observation of the subject (e.g., patient) by a health care professional during or after administration (e.g., within 2 hours after administration) of a dose of the compound of Formula I or a deuterated analog thereof; 1.55. Any of the foregoing methods that do not expose the subject (e.g., patient) to risk of sedation, dissociation, abuse, misuse, or suicidal ideation; 1.56. Any of the preceding methods, wherein administration of a dose of a compound of Formula I or a deuterated analog thereof does not result in hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours, e.g., an increase in systolic and / or diastolic blood pressure of more than 10 mmHg, or more than 20 mmHg, or more than 30 mmHg, or more than 40 mmHg within 30 minutes to 4 hours after said dosing; 1.57. Any of the preceding methods, which does not result in cognitive decline in a subject (e.g., a patient); 1.58. Any of the preceding methods, wherein the subject (e.g., patient) has been diagnosed with or is at risk for aneurysmal vascular disease (e.g., thoracic aortic, abdominal aortic, intracranial, or peripheral artery aneurysm), arteriovenous malformation, or intracerebral hemorrhage; 1.59. Any of the preceding methods, wherein the subject (e.g., patient) is receiving concomitant treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 1.60. Any of the preceding methods, wherein the subject (e.g., patient) is not receiving concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 1.61. Any of the preceding methods, wherein the subject (e.g., patient) is unresponsive to ketamine (e.g., S-ketamine) or cannot be treated with ketamine because, for example, ketamine is contraindicated in said subject (e.g., patient);

[0041] In another aspect, the disclosure provides a compound of Formula I, or a deuterated analog thereof, as previously described herein, in free form or a pharmaceutically acceptable salt form, for use in enhancing neural growth, increasing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, e.g., for use in any of Methods 1 et seq.

[0042] In another aspect, the disclosure provides the use of a compound of Formula I, or a deuterated analog thereof, as previously described herein, in free form or a pharmaceutically acceptable salt form, in the manufacture of a medicament for enhancing neural growth, increasing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, e.g., in the medial prefrontal cortex region of the brain, e.g., for any of Methods 1 et seq.

[0043] In a second embodiment of the first aspect, the present disclosure provides a method (Method 2) for enhancing neural growth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, comprising administering to a subject an effective amount of a compound of Formula II (Compound II):

[0044] [ka] [In the formula, X is S, S(O), S(O)2, O, CH2, CHR b , C(R b )2, NH, N(R a ) (e.g., N(CH3)), NC(O)-R a , NC(O)-OR a , NC(O)-O-CH2-OR a , N-CH2-OC(O)-R a , N + (=O - ), spiro-bonded C 3~6 cycloalkyl (e.g., cyclopropane), or spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-linked C 3~6 Cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHR c , -C(O)-, C(R c )2, spiro bond C 3~6cycloalkyl (e.g., cyclopropane), or spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein the spiro-linked C 3~6 Cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(R d ), -C(O)-, -C(OH)-, -C(OC 1~6 alkyl), -C(=N-OH)-, -C(=N-OC 1~6 Alkyl)-, spiro bond C 3~6 Cycloalkyl (e.g., cyclopropane), spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -O(CH2) p O- (wherein p is 2, 3, or 4 (e.g., p is 2)), and the spiro bond C 3~6 Cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; A is H, C 3~6 cycloalkyl (e.g., cyclopropyl or cyclohexyl), aryl (e.g., phenyl), or heteroaryl, wherein said cycloalkyl, aryl, or heteroaryl is substituted with 0 to 5 R groups; Each R is independently selected from the group consisting of aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkyl sulfonyl (e.g., methyl sulfonyl), C 1~6 Alkoxy (e.g., methoxy, ethoxy), C 1~6 Alkylthio (e.g., methylthio), halo (e.g., F), cyano, C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is selected from aryl (optionally substituted with halo), halo, C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkyl sulfonyl (e.g., methyl sulfonyl), C 1~6 Alkoxy (e.g., methoxy), C 1~6 Alkylthio (e.g., methylthio), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Cycloalkoxy (e.g., cyclopropoxy), amino, C 1~6 Alkylamino (e.g., methylamino), di(C 1~6 alkyl)amino (e.g., dimethylamino), (C 1~6 Alkyl)(C 1~6 optionally further substituted with one or more groups selected from: alkyl)amino (e.g., methylethylamino), and hydroxy; R a and R d are each independently 1~20 alkyl (e.g., methyl or tert-butyl), and C 1~2 alkylaryl (e.g., benzyl or phenethyl); R b and R c are each independently 1~6 Alkyl (e.g., methyl, ethyl, tert-butyl), C 1~6 Alkoxy, C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Cycloalkoxy (e.g., cyclopropoxy), and C 1~2 alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2, n is 1, 2, 3, 4, or 5, provided that when Z is -C(O)-, X is CH2 or O, and m is 2, then n is not 3; when Z is -C(O)-, X is CH2, and m is 1, then n is not 3; Z is -C(O)- or -O- and X is NH or N(R a ) and if m is 1, then n is not 3, When Z is O, X is NCH3, Y is -C(O)-, and m is 1, then n is not 3. in free form or in a salt form (e.g., a pharmaceutically acceptable salt form) to a subject.

[0045] In a further embodiment of the second embodiment of the first aspect, the present disclosure provides: 2.1. Method 2, wherein in the compound of formula II, X is S, S(O), or S(O)2; 2.2. Method 2, wherein in the compound of formula II, X is O; 2.3. In compounds of formula II, X is CH2, CHR b , or C(R b )2, Method 2; 2.4.R b independently C 1~6 alkyl (e.g., methyl), Method 2.3; 2.5. Method 2, wherein in the compound of formula II, X is CH2; 2.6. Method 2, wherein in the compound of formula II, X is NH; 2.7. In compounds of formula II, X is N(R a ), Method 2; 2.8. In compounds of formula II, X is NC(O)-R a Method 2; 2.9. In the compound of formula II, X is NC(O)-OR a Method 2; 2.10. In the compound of formula II, X is NC(O)—O—CH—OR a Method 2; 2.11. In the compound of formula II, X is N—CH—OC(O)—R a Method 2; 2.12. In the compound of formula II, R a C 1~2 Method 2, or any of methods 2.4-2.11, wherein the alkylaryl is (e.g., benzyl or phenethyl); 2.13. In compounds of formula II, R a C 1~20 Method 2 or any of methods 2.4 to 2.11, wherein R is alkyl (e.g., methyl or tert-butyl); 2.14. In compounds of formula II, R a C 10~20 Method 2 or any of methods 2.4 to 2.11, wherein the aryl group is alkyl (e.g., decyl or dodecyl); 2.15. In compounds of formula II, R a C 1~15 Method 2 or any of methods 2.4 to 2.11, wherein the alkyl is alkyl (e.g., hexyl or octyl); 2.16. In the compound of formula II, R a C 7~15 Method 2 or any of methods 2.4 to 2.11, wherein the aryl group is alkyl (e.g., heptyl or nonyl); 2.17. In compounds of formula II, R a C 1~6 Method 2 or any of methods 2.4 to 2.11, wherein the alkyl group is alkyl (e.g., butyl or hexyl); 2.18. In compounds of formula II, Ra C 1~4 Method 2 or any of methods 2.4 to 2.11, wherein the alkyl group is alkyl (e.g., n-butyl or tert-butyl); 2.19. In the compound of formula II, R a C 1~3 Method 2 or any of methods 2.4 to 2.11, wherein R is alkyl (e.g., propyl or isopropyl); 2.20. In the compound of formula II, R a C 1~2 Method 2 or any of methods 2.4 to 2.11, wherein R is alkyl (e.g., methyl or ethyl); 2.21. Method 2 or any of methods 2.4-2.11, wherein in the compound of formula II, X is N(CH3); 2.22. In the compound of formula II, X is a spiro bond C 3~6 cycloalkyl (e.g., cyclopropane), Method 2; 2.23. In the compound of formula II, the spiro bond C 3~6 Method 2.22, wherein cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 2.24. In the compound of formula II, the spiro bond C 3~6 Method 2.22, where cycloalkyl is cyclopropane; 2.25. Method 2, wherein in the compound of formula II, X is a spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane); 2.26. Method 2.25, wherein in the compound of formula II, the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; 2.27. Method 2.25, wherein in the compound of formula II, the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridines; 2.28. The spiro bond C 3~6 Method 2 or any of methods 2.22-2.27, wherein cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted; 2.29. The spiro bond C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Method 2, or any of methods 2.22-2.27, substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; 2.30. Method 2 or any of methods 2.1-2.29, wherein in the compound of formula II, Y is CH2; 2.31. Method 2 or any of methods 2.1 to 2.29, wherein in the compound of formula II, Y is —C(O)—; 2.32. In the compound of formula II, Y is CHR c or C(R c )2, Method 2 or any of Methods 2.1 to 2.29; 2.33. In the compound of formula II, each R c But independently, C 1~6 alkyl, compound 2.32; 2.34. In the compound of formula II, each R c is independently selected from methyl, ethyl, and propyl, compound 2.32; 2.35. In the compound of formula II, Y is a spiro bond C 3~6 Method 2 or any of methods 2.1-2.29, wherein the cycloalkyl (e.g., cyclopropane) is cycloalkyl; 2.36. In the compound of formula II, the spiro bond C 3~6 Method 2.35, wherein cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 2.37. In the compound of formula II, the spiro bond C 3~6 Method 2.35, where cycloalkyl is cyclopropane; 2.38. Method 2 or any of methods 2.1-2.29, wherein in the compound of formula II, Y is a spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane); 2.39. Method 2.38, wherein in the compound of formula II, the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; 2.40. Method 2.39, in which the spiro-linked 3- to 6-membered heterocycloalkyl in the compound of formula II is aziridine; 2.41. The spiro bond C 3~6 Method 2 or any of methods 2.35-2.40, wherein cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted; 2.42. The spiro bond C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Method 2, or any of methods 2.35-2.40, substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; 2.43. Method 2 or any of methods 2.1-2.42, wherein in the compound of formula II, Z is a bond; 2.44. Method 2 or any of methods 2.1-2.42, wherein in the compound of formula II, Z is S, S(O), or S(O)2; 2.45. Method 2 or any of methods 2.1 to 2.42, wherein in the compound of formula II, Z is O; 2.46. Method 2 or any of methods 2.1 to 2.42, wherein in the compound of formula II, Z is NH; 2.47. In compounds of formula II, Z is N(R a), for example, N(CH3), Method 2 or any of Methods 2.1 to 2.42; 2.48. Method 2 or any of methods 2.1 to 2.42, wherein in the compound of formula II, Z is —C(O)—; 2.49.Z is -C(OH)-, -C(OC 1~6 alkyl), -C(=N-OH)-, -C(=N-OC 1~6 alkyl)-, and optionally 1~6 Method 2 or any of methods 2.1-2.42, wherein alkyl is methyl; 2.50. In the compound of formula II, Z is a spiro bond C 3~6 Method 2 or any of methods 2.1-2.42, wherein the cycloalkyl (e.g., cyclopropane) is cycloalkyl; 2.51. In the compound of formula II, the spiro bond C 3~6 Method 2.50, wherein cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 2.52. In the compound of formula II, the spiro bond C 3~6 Method 2.50, in which the cycloalkyl is cyclopropane; 2.53. Method 2 or any of methods 2.1-2.42, wherein in the compound of formula II, Z is a spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane); 2.54. Method 2.53, wherein in the compound of formula II, the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; 2.55. Method 2.53, in which the spiro-linked 3- to 6-membered heterocycloalkyl in the compound of formula II is aziridine; 2.56. The spiro bond C 3~6 Method 2 or any of methods 2.49-2.55, wherein cycloalkyl or 3- to 6-membered heterocycloalkyl is unsubstituted; 2.57. The spiro bond C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is C1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Method 2, or any of methods 2.49-2.55, substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; 2.58. Method 2, or any of methods 2.1-2.57, wherein in the compound of formula II, A is a 6-10 membered aryl ring, e.g., a 6-10 membered aryl ring selected from phenyl and naphthyl substituted with 0-5 R groups; 2.59. Method 2 or any of methods 2.1-2.57, wherein in the compound of Formula II, A is a 5-10 membered heteroaryl ring substituted with 0-5 R groups; 2.60. In compounds of formula II, A is furan, thiophene (e.g., thiophen-2-yl), pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyridine (e.g., pyrid-4-yl), 2-oxopyridine (e.g., 2-oxopyridin-1(2H)-yl), pyrimidine, pyridazine, pyrazine, benzofuran (e.g., benzofuran-4-yl, or benzofuran-7-yl, or 2-methylbenzofuran-4-yl), dihydrobenzofuran (e.g., 2,3-dihydrobenzofuran-7-yl), benzothiophene, indole (e.g., indol-1-yl, indol-3-yl, or indol-5-yl), benzoxazole, benzothiazoline, Method 2.59, wherein the benzotriazole is selected from an indazole, a benzimidazole (e.g., benzo[d]imidazol-1-yl), a benzisoxazole (e.g., benzo[d]isoxazol-3-yl, or benzo[d]isoxazol-4-yl), a benzisothiazole (e.g., benzo[d]isothiazol-3-yl), a benzotriazole (e.g., benzo[d][1,2,3-triazol-1-yl), an indazole (e.g., indazol-1-yl, indazol-3-yl, or indazol-7-yl), a quinoline (e.g., quinolin-8-yl), an isoquinoline (e.g., isoquinolin-7-yl), a quinazoline (e.g., quinazolin-7-yl), and a quinoxaline (e.g., quinoxalin-5-yl); 2.61. Method 2.60, wherein in the compound of formula II, A is substituted with 0 R groups; 2.62. Method 2.60, in which in the compound of formula II, A is substituted with one R group; 2.63. Method 2.60, in which in the compound of formula II, A is substituted with two R groups; 2.64. Method 2.58, in which in the compound of formula II, A is a phenyl ring substituted with 0-5 R groups; 2.65. Method 2.64, in which one R group is present in the compound of formula II; 2.66. Method 2.64, in which in the compound of formula II the R group is located in the para position of the phenyl ring; 2.67. Method 2.64, in which in the compound of formula II the R group is located in the meta position of the phenyl ring; 2.68. Method 2.64, in which in the compound of formula II the R group is located in the ortho position of the phenyl ring; 2.69. In the compound of formula II, there are two R groups, Method 2.64; 2.70. Method 2.69, in which in the compound of formula II the R groups are located at the ortho and para positions of the phenyl ring; 2.71. Method 2.69, in which the R groups in the compound of formula II are located at the meta and para positions of the phenyl ring; 2.72. Method 2.69, in which in the compound of formula II, the R groups are located at the ortho and meta positions on the same side of the phenyl ring; 2.73. Method 2.69, in which in the compound of formula II, the R groups are located at the ortho and meta positions on opposite sides of the phenyl ring; 2.74. Method 2.69, in which in the compound of formula II the R groups are located at the two ortho positions of the phenyl ring; 2.75. Method 2.69, in which in the compound of formula II the R groups are located at the two meta positions of the phenyl ring; 2.76. In the compound of formula II, there are three R groups, Method 2.64; 2.77. Method 2.76, in which in the compound of formula II, the R groups are located at the two ortho and para positions of the phenyl ring; 2.78. In the compound of formula II, there are four R groups, Method 2.64; 2.79. In the compound of formula II, there are five R groups, Method 2.64; 2.80. Method 2, or any of methods 2.1 through 2.79, wherein in the compound of Formula II, each R group is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, F, Cl, cyano, hydroxy, 2-methoxyethoxy, methylsulfonyl, methylthio, cyclopropoxy, cyclopropylmethoxy, methylamino, 4-fluorophenoxy, and (4-fluorobenzyl)oxy; 2.81. In the compound of formula II, A is phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 3-chloro-4-fluorophenyl, 2-cyano-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-methyl-4-fluorophenyl, 3-methyl-4-fluorophenyl, 2-methoxy-4-fluorophenyl, 2-methoxy-5-fluorophenyl, 2-fluoro-4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl Method 2, or any of Methods 2.1 through 2.80, wherein the aryl group is selected from the group consisting of phenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 2-hydroxyphenyl, 2,5-dimethoxyphenyl, 2-trifluoromethyoxyphenyl, 3-trifluoromethylphenyl, 2-(methylsulfonyl)phenyl, 3-(methylthio)phenyl, 4-(methoxyethoxy)phenyl, 4-(4-fluorobenzyloxy)phenyl, 4-(4-fluorophenoxy)phenyl, 3-cyclopropoxyphenyl, 3-(cyclopropylmethoxy)phenyl, and 2-(methylamino)phenyl; 2.82. In the compound of formula II, A is pyrid-4-yl, thiophen-2-yl, indol-1-yl, indol-3-yl, 5-fluoroindol-3-yl, indazol-1-yl, indazol-3-yl, indazol-7-yl, benzofuran-4-yl, benzofuran-7-yl, 2,3-dihydrobenzofuran-7-yl, 2-methylbenzofuran-7-yl, benzo[d]isoxazol-3-yl, benzo[d]isoxazol-4-yl Method 2, or any of methods 2.1 through 2.80, wherein the benzo[d]isoxazol-7-yl, 6-fluorobenzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, benzo[d]imidazol-1-yl, benzo[d][1,2,3]triazol-1-yl, isoquinolin-7-yl, quinolin-8-yl, quinoxalin-5-yl, quinazolin-7-yl, and 2-oxopyridin-1(2H)-yl; 2.83. Method 2 or any of methods 2.1 through 2.80, wherein in the compound of Formula II, A is selected from the group consisting of phenyl, 2-ethylphenyl, 4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, benzofuran-7-yl, benzo[d]isoxazol-3-yl, and benzo[d]isothiazol-3-yl; 2.84. Method 2 or any of methods 2.1 to 2.83, wherein in the compound of formula II, m is 1; 2.85. Method 2 or any of methods 2.1 to 2.83, wherein m is 2 in the compound of formula II; 2.86. Method 2 or any of methods 2.1 to 2.85, wherein in the compound of formula II, n is 2; 2.87. Method 2 or any of methods 2.1 to 2.85, wherein in the compound of formula II, n is 3; 2.88. Method 2 or any of methods 2.1 to 2.85, wherein in the compound of formula II, n is 4; 2.89. Method 2 or any of methods 2.1 to 2.85, wherein in the compound of formula II, n is 5; 2.90. Method 2 or any of methods 2.1 through 2.89, wherein in the compound of Formula II, X is S, O, CH2, NH, N(CH3), or spiro-linked cyclopropyl, Y is CH2, C(O), or spiro-linked cyclopropyl, and Z is a bond, -O-, -C(O)-, -O(CH2)2O-, or -C(=NOCH3)-; 2.91. Method 2 or any of methods 2.1 through 2.89, wherein in the compound of Formula II, X is N(CH3) or spiro-linked cyclopropyl, Y is CH2, C(O), or spiro-linked cyclopropyl, and Z is a bond, -O-, or -C(O)-; 2.92. The compound of formula II is a compound of formula Ia:

[0046] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 2.93. The compound of formula II is a compound of formula Ib:

[0047] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 2.94. The compound of formula II is a compound of formula Ic:

[0048] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 2.95. The compound of formula II is a compound of formula Id:

[0049] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 2.96. The compound of formula II is a compound of formula Ie:

[0050] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 2.97. Method 2 or any of methods 2.1 to 2.96, wherein in the compound of formula II, n is 4 and Z is a bond; 2.98. Method 2 or any of methods 2.1 to 2.96, wherein in the compound of formula II, n is 3 and Z is -O- or -C(O)-; 2.99. Method 2 or any of methods 2.1 to 2.96, wherein in the compound of formula II, n is 3 and Z is a bond; 2.100. Method 2 or any of methods 2.1 to 2.96, wherein in the compound of formula II, n is 2 and Z is —O— or —C(O)—; 2.101. Method 2 or any of methods 2.1 to 2.96, wherein in the compound of formula II, n is 2 and Z is a bond; 2.102. Method 2 or any of methods 2.1 through 2.96, wherein in the compound of formula II, n is 1 and Z is —O— or —C(O)—; 2.103. Method 2 or any of methods 2.1 through 2.96, wherein in the compound of formula II, n is 1 and Z is a bond; 2.104. In compounds of formula II, A is H or C 3~6 Method 2 or any of methods 2.1 through 2.103, wherein Z is a bond or -C(O)- and n is 1, 2, or 3; 2.105. Compounds of formula II, each independently in free form or in the form of a pharmaceutically acceptable salt or

[0051] [ka] Method 2 or any of methods 2.1 to 2.104, selected from the group consisting of: 2.106. The compound of formula II is

[0052] [ka] and the variables are as follows:

[0053] [Table 1-1]

[0054] [Table 1-2]

[0055] [Table 1-3]

[0056] [Table 1-4]

[0057] [Table 1-5]

[0058] [Table 1-6]

[0059] [Table 1-7] wherein Cyp refers to a spiro-linked cyclopropyl ring], each independently in free form or a pharmaceutically acceptable salt or form. 2.107. The compound of formula II is

[0060] [ka] and the variables are as follows:

[0061] [Table 2] Method 2, or any of methods 2.1 to 2.105, as defined in any of the preceding paragraphs. 2.108. Method 2 or any of methods 2.1-2.107, wherein the compound of formula II is in free form; 2.109. Method 2, or any of methods 2.1-2.107, wherein the compound of formula II is in the form of a salt, e.g., a pharmaceutically acceptable salt; 2.110. Method 2 or any of methods 2.1 to 2.107, wherein the compound of formula II is in the form of an acid addition salt, for example, a hydrochloride or toluenesulfonate salt; 2.111. Method 2, or any of methods 2.1-2.110, wherein the compound of formula II is in substantially pure diastereomeric form (i.e., substantially free from other diastereomers); 2.112. Method 2 or any of methods 2.1 to 2.110, wherein the compound of formula II has a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%; 2.113. Method 2 or any of methods 2.1-2.112, wherein the compound of formula II is in solid form, e.g., crystalline form; 2.114. Method 2, or any of methods 2.1-2.113, wherein the compound of formula II is in isolated or purified form (e.g., at least 90%, or at least 95%, or at least 98%, or at least 99% pure); 2.115. The compound of formula II inhibits 5-HT at a concentration of 100 nM by at least 60%, for example, at a concentration of 100 nM by at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%. 2A Method 2 or any of methods 2.1 to 2.114, having receptor binding affinity; 2.116. The compound of formula II has a 5-HT activity of less than 250 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM. 2A Receptor dissociation constant (K d ) Method 2 or any of methods 2.1 to 2.115; 2.117. The compound of formula II is 5-HT 2A Method 2, or any of methods 2.1-2.116, wherein the agonist is a partial agonist or a full agonist of receptor-mediated beta-arrestin signaling; 2.118. The compound of Formula II has an E of less than 90%, or less than 80%, or less than 70%, or less than 60%, or less than 50%, or less than 40%, or less than 30%, or less than 20%, or less than 10% of that of a full agonist (e.g., alpha-methylserotonin). max Method 2.117, which is a partial agonist of beta-arrestin signaling having 2.119. The compound of formula II is 5-HT 2A EC for beta-arrestin agonism of the receptor of less than 500 nM, or less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM50 having method 2.117 or 2.118; 2.120. A compound of Formula II has a relative intrinsic activity (RA) of beta-arrestin signaling of less than 1.0 compared to the reference compound alpha-methylserotonin. i ), e.g., having a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or between 0.1 and 0.8, or between 0.2 and 0.8, or between 0.4 and 0.8, or between 0.5 and 0.8, or between 0.2 and 0.6, or between 0.2 and 0.5, or between 0.2 and 0.4, or between 0.5 and 1.0, or between 0.5 and 0.9, or between 0.5 and 0.8, or between 0.6 and 0.9, or between 0.6 and 0.8, Methods 2.117, 2.118, or 2.119; 2.121. A compound of Formula II has a relative intrinsic activity (RA) of beta-arrestin signaling of greater than 1.0 compared to the reference compound alpha-methylserotonin. i ), e.g., methods 2.117, 2.118, or 2.119, having a relative intrinsic activity of 1.0 to 1.2, or 1.0 to 1.4, or 1.0 to 1.6; 2.122. The compound of formula II is 5-HT 2A Method 2 or any of methods 2.1 to 2.116, wherein the compound is an antagonist of receptor-mediated beta-arrestin signaling; 2.123. The compound of formula II is 5-HT 2A IC of less than 300 nM, or less than 200 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM for beta-arrestin antagonism of the receptor 50 having, Method 2.122; 2.124. The compound of formula II is 5-HT 2A Method 2, or any of methods 2.1 through 2.116, that is not an antagonist of receptor-mediated beta-arrestin signaling; 2.125. The compound of formula II is 5-HT 2AIC greater than 10 nM, or greater than 50 nM, or greater than 100 nM, or greater than 250 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 5000 nM, or greater than 10,000 nM for beta-arrestin antagonism of the receptor 50 having, Method 2.124; 2.126. The compound of formula II is 5-HT 2A Method 2 or any of methods 2.1 to 2.125, which are not or are weak agonists of receptor-mediated Gq signaling; 2.127. The compound of Formula II has an E of less than 90%, or less than 80%, or less than 70%, or less than 60%, or less than 50%, or less than 40%, or less than 30%, or less than 20%, or less than 10% compared to a full agonist (e.g., alpha-methylserotonin). max , preferably less than 50%, or less than 30%, or less than 10% E max Method 2.126, which is a partial agonist of Gq signaling having 2.128. The compound of formula II is 5-HT 2A EC for Gq agonism of the receptor greater than 10 nM, or greater than 25 nM, or greater than 50 nM, or greater than 100 nM, or greater than 150 nM, or greater than 200 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 2000 nM, or greater than 5000 nM, or greater than 10,000 nM 50 with method 2.126 or 2.127; 2.129. The compound of formula II has a Gq signaling relative intrinsic activity (RA) of less than 1.0 compared to the reference compound alpha-methylserotonin. i), e.g., having a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or between 0.1 and 0.8, or between 0.2 and 0.8, or between 0.4 and 0.8, or between 0.5 and 0.8, or between 0.2 and 0.6, or between 0.2 and 0.5, or between 0.2 and 0.4, or between 0.5 and 1.0, or between 0.5 and 0.9, or between 0.5 and 0.8, or between 0.6 and 0.9, or between 0.6 and 0.8, Methods 2.126, 2.127, or 2.128; 2.130. The compound of formula II is 5-HT 2A Method 2 or any of methods 2.1 to 2.129, which is an antagonist of receptor-mediated Gq signaling; 2.131. The compound is 5-HT 2A IC of less than 10 nM, or less than 25 nM, or less than 50 nM, or less than 100 nM, or less than 150 nM, or less than 200 nM, or less than 500 nM for receptor Gq antagonism 50 having, Method 2.130; 2.132. The compound of formula II is 5-HT 2A Method 2, or any of methods 2.1 through 2.131, having a bias ratio (beta-arrestin / Gq) relative to receptor agonism of at least 2, or at least 5, or at least 10, or at least 25, or at least 50, or at least 100, or at least 150, or at least 200, or at least 500, or at least 1000, or at least 10,000, or the bias ratio is undetermined (i.e., the compound has any degree of beta-arrestin agonism and zero Gq agonism); 2.133. Method 2, or any of methods 2.1-2.132, wherein the compound of formula II is an antagonist or agonist of the D1 and / or D2 dopamine receptor (e.g., has at least 70% receptor affinity at 100 nM concentration or an IC50 of less than 100 nM); 2.134. Compounds of formula II exhibit no activity at D1 and / or D2 dopamine receptors (e.g., less than 50% receptor affinity at 100 nM concentration and / or an EC2 of greater than 500 nM). 50 Or IC 50 ), method 2, or any of methods 2.1 to 2.132; 2.135. The compound of formula II is an antagonist of the serotonin transporter (e.g., has a receptor binding affinity of at least 70% at a concentration of 100 nM or an IC of less than 100 nM). 50 ), method 2, or any of methods 2.1 to 2.134; 2.136. Compounds of formula II exhibit no activity at the serotonin transporter (e.g., less than 50% receptor binding affinity at 100 nM concentration and / or an EC2 of greater than 500 nM). 50 Or IC 50 ), method 2, or any of methods 2.1 to 2.134; 2.137. The compound of Formula II is an agonist, antagonist, or partial agonist of the mu opioid receptor (e.g., at a 100 nM concentration, has a receptor binding affinity of at least 70% or an EC of less than 100 nM). 50 Or IC 50 ), method 2, or any of methods 2.1 to 2.136; 2.138. Compounds of Formula II exhibit no activity at the mu opioid receptor (e.g., a receptor binding affinity of less than 50% at 100 nM concentration and / or an EC2 of greater than 500 nM). 50 Or IC 50 ), method 2, or any of methods 2.1 to 2.136; 2.139. Method 2, or any of methods 2.1-2.138, wherein the compound of Formula II is non-hallucinogenic, e.g., when in therapeutic amounts for the treatment of a neuropsychiatric disorder described herein (e.g., depression, anxiety, etc.), the compound does not cause visual or auditory hallucinations, visual distortions (e.g., objects and surfaces appearing to drift, morph, waver, or melt within the field of vision), escapism, dissociation, delirium, or unwanted altered states of consciousness; 2.140. Method 2 or any of methods 2.1-2.139, wherein the compound of formula II does not elicit a head-twitch response in an animal test model or is an antagonist of a DOI-induced head-twitch response; 2.141. Method 2 or any of methods 2.1-2.140, wherein the compound of formula II is effective in a murine model of depression (tail suspension test or forced swim test); 2.142. Method 2 or any of methods 2.1-2.141, wherein the compound of formula II is effective in an animal model of social anxiety disorder or anhedonia; 2.143. The compound of formula II is 5-HT 2B Method 2 or any of methods 2.1 to 2.142, which has no agonist activity (e.g., an EC50 greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); 2.144. The compound of formula II is 5-HT 2B Method 2, or any of methods 2.1 to 2.143, having antagonist activity (e.g., an IC50 of less than 1000 nM, or less than 500 nM, or less than 250 nM, or less than 100 nM, or less than 50 nM, or less than 25 nM, or less than 15 nM); 2.145. The compound of formula II is 5-HT 2c Method 2 or any of methods 2.1 to 2.144, having agonist activity (e.g., an EC50 of less than 1000 nM, or less than 500 nM, or less than 250 nM, or less than 100 nM, or less than 50 nM, or less than 25 nM, or less than 15 nM); 2.146. The compound of formula II is 5-HT 2C Method 2 or any of methods 2.1 to 2.144, which does not have antagonist activity (e.g., IC50 greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); 2.147. Method 2, or any of methods 2.1-2.146, wherein the compound of Formula II binds to alpha-1A adrenergic receptors (e.g., has a binding affinity, Ki, of less than 1000 nM, or less than 500 nM, or less than 250 nM, or less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 50 nM, or less than 25 nM); 2.148. Method 2 or any of methods 2.1-2.147, wherein the compound of formula II does not cause psychosis (e.g., long-term or intermittent psychosis); 2.149. Method 2 or any of methods 2.1 through 2.148, wherein the compound of Formula II does not promote self-harm or harm to others in the patient; 2.150. Method 2, or any of methods 2.1 through 2.149, wherein the compound of formula II does not cause valvular heart disease or pulmonary arterial hypertension, e.g., the compound is safely administered to patients with cardiac comorbidities; 2.151. Method 2 or any of methods 2.1-2.150, wherein the compound of formula II does not cause abuse or dependence (e.g., physical or psychological dependence); 2.152. The compound of formula II is adenosine A2A, alpha-1A adrenergic, alpha-2A adrenergic, beta-1 adrenergic, beta-2 adrenergic, GABA-A benzodiazepine site (BZD, central), CB1 cannabinoid, CB2 cannabinoid, cholecystokinin CCK1, endothelin-A (ETA), NMDA, histamine H1, histamine H2, MAO-A, mus Muscarinic M1, Muscarinic M2, Muscarinic M3, Nicotinic acetylcholine (neuronal alpha-4-beta-2), Delta opioid, Kappa opioid, Mu opioid, Serotonin-1A, Serotonin-1B, Serotonin-3, Glucocorticoid (GR), Androgen (AR), Vasopressin V1A, Cardiac calcium channel (dihydropyridine site), hERG potassium channel, Voltage-gated potassium channel K V , the method of any of methods 2.1 to 2.151, wherein the ion channel is functionally inactive at one or more receptors and ion channels: sodium channel (site 2), norepinephrine transporter, dopamine transporter, and / or serotonin transporter; 2.153. Method 2.152, wherein the compound of Formula II has in vitro receptor activity (vs. agonism or antagonism) for any one or more of said receptors or ion channels of less than 60% inhibition of radioligand binding (e.g., at a 100 nM test concentration), e.g., less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% inhibition; 2.154. Method 2, or any of methods 2.1-2.153, wherein the compound of formula II is orally bioavailable (e.g., at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40% oral bioavailability); 2.155. Any of the preceding methods, providing enhanced neural growth within the subject's brain (e.g., in the prefrontal cortex region of the brain); 2.156. Any of the preceding methods, providing increased neural connectivity within the subject's brain (e.g., in the prefrontal cortex region of the brain); 2.157. Any of the preceding methods providing an increase in synaptic density in the subject's brain (e.g., in the prefrontal cortex region of the brain); 2.158. Any of the preceding methods, providing an increase in dendritic spine density in the subject's brain (e.g., in the prefrontal cortex region of the brain); 2.159. Any of the preceding methods, providing an increase in dendritic spine size (e.g., an increase in spine head width and / or an increase in spine process length) within the subject's brain (e.g., in the prefrontal cortex region of the brain); 2.160. Any of the preceding methods, providing increased excitatory neurotransmission (e.g., enhanced glutamatergic transmission or increased rate of mEPSCs) within the subject's brain (e.g., in a prefrontal cortex region of the brain); 2.161. Method 2, or any of methods 2.1-2.160, providing enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the medial prefrontal cortex region of the brain) within less than 4 weeks of initiating administration of a compound of Formula II, e.g., within less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days after initiating treatment with a compound of Formula II; 2.162. Method 2, or any of methods 2.1-2.161, wherein at least 50% of the peak enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the prefrontal cortex region of the brain) is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months after administration of the compound of Formula II has stopped; 2.163. Method 2, or any of methods 2.1-2.162, wherein at least 50% of the peak enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months, after administration of a single dose of a compound of Formula II, as measured in the subject's brain (e.g., in the prefrontal cortex region of the brain), e.g., by in vivo imaging (e.g., MRI); 2.164. Enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission are characterized or caused by enhanced neuritogenesis and / or enhanced neurite outgrowth, and / or increased synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., increased or decreased density of such receptor or transporter), e.g., serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B ), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density; 2.165. Enhance neuritogenesis and / or enhance neurite outgrowth and / or increase synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., increase or decrease such receptor or transporter density), e.g., serotonin receptors (e.g., 5-HT 2A, or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B ), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density; 2.166. Method 2, 2.123, or 2.165, wherein enhanced neuritogenesis or enhanced neurite outgrowth is characterized by an increase in one or more of the following: total number of neurites per neuron, neurite length (individual length and / or total neuron length), number of branch points on neurites, number of neurite bases, number of neurite nodes, total number of neurite terminals, total neuron length (with or without branching), and total amount of neurite dendritic branching (e.g., measured or predicted using Sholl analysis); 2.167. Any of the aforementioned methods that do not cause hallucinogenic side effects; 2.168. Any of the preceding methods, wherein the compound of formula II is administered in a daily dose equivalent to 1 to 100 mg of the free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 50 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg of the free base; 2.169. Any of the preceding methods, wherein the compound of formula II is administered at a dose equivalent to 1 to 100 mg of the free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 50 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg of the free base, at a frequency of every other day, or every two days, or every three days, or every four days, or every five days, or every six days, or every seven days; 2.170. Method 2, or any of methods 2.1-2.169, wherein the compound of formula II is administered as a unit dosage form for oral administration (e.g., enteral), e.g., as a tablet or capsule; 2.171. Method 2.170, wherein a unit dosage form, e.g., a tablet or capsule, for oral administration (e.g., enteral) comprises a compound of formula II equivalent to 1 to 100 mg of free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of free base, and a pharmaceutically acceptable diluent or carrier; 2.172. Method 2, or any of methods 2.1-2.171, wherein the compound of formula II is administered as a unit dosage form for subcutaneous or transmucosal administration, e.g., an orally disintegrating tablet or film for sublingual or buccal administration; 2.173. Method 2.172, in which a unit dosage form for subcutaneous or transmucosal administration, e.g., an orally disintegrating tablet or film for sublingual or buccal administration, comprises a compound of formula II equivalent to 0.5 to 30 mg of free base, e.g., 1 to 10 mg of free base, and a pharmaceutically acceptable diluent or carrier; 2.174. Method 2, or any of methods 2.1-2.173, wherein the compound of formula II is administered as a long-acting injectable (LAI) composition, e.g., an LAI composition for intramuscular or subcutaneous injection; 2.175. Method 2.174, wherein the dose of the LAI composition is sufficient to provide the equivalent of a daily dose of 1 to 100 mg of free base of the compound of formula II, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of free base, released over a period of time ranging from about 1 week to about 3 months, e.g., from about 1 week to about 8 weeks, or from about 1 week to about 6 weeks, or from about 1 week to about 4 weeks, or from about 1 week to about 3 weeks, or from about 1 week to about 2 weeks; 2.176. Method 2.174 or 2.175, wherein the LAI composition comprises a compound of formula II dissolved, dispersed, suspended, or encapsulated within a polymer matrix; 2.177. Method 2.176, wherein the polymer matrix comprises one or more biocompatible and biodegradable polymers, as defined herein, such as poly(hydroxycarboxylic acids), poly(amino acids), cellulose polymers, modified cellulose polymers, polyamides, and polyesters; 2.178. Method 2.177, wherein the one or more polymers comprise polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta-hydroxybutyric acid, poly(lactic acid-glycolic acid) copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, polyglycolic acid-polyethylene glycol copolymer, poly(alkyl alpha-cyanoacrylate), e.g., poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoester), polycarbonate, polyortho-carbonate, polyamino acids, (e.g., poly-gamma-L-alanine, poly-gamma-benzyl-L-glutamic acid, or poly-γ-methyl-L-glutamic acid), and / or hyaluronic acid ester; 2.179. Method 2.177, wherein the one or more polymers comprise polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic acid-glycolic acid) copolymer; 2.180. Method 2.177, wherein the one or more polymers include a poly(lactic acid-glycolic acid) copolymer, e.g., poly-d,l-lactide-co-glycolide; 2.181. Any of the foregoing methods in which the subject is an animal; 2.182. Any of the preceding methods, wherein the subject is a human (e.g., a patient suffering from a neuropsychiatric disorder); 2.183. Method 2.182, in which the subject is a patient suffering from anxiety or depression, e.g., bipolar depression, major depressive disorder (MDD), post-traumatic stress disorder, or treatment-resistant depression; 2.184. Method 2.183, wherein the subject is a patient suffering from treatment-resistant depression (e.g., depression that has not responded to treatment with an antidepressant selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof); 2.185. Method 2.184, in which the subject is a patient suffering from bipolar depression or major depressive disorder; 2.186. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate, or sequential administration, of an antidepressant (e.g., selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof); 2.187. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate or sequential administration, of an NMDA receptor antagonist, e.g., an NMDA receptor antagonist selected from ketamine (e.g., S-ketamine and / or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine, and agmatine, or any combination thereof; 2.188. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate or sequential administration, of an NMDA receptor allosteric modulator, e.g., an NMDA receptor glycine site modulator, e.g., rapastinel, nebostinel, apimostinel, D-cycloserine, or any combination thereof; 2.189. Any of the preceding methods, wherein the subject has previously received treatment with, and has had an unresponsive or inadequate response to, or is suffering from undesirable side effects from, another antidepressant, e.g., any one or more of a selective serotonin reuptake inhibitor (SSRI), serotonin reuptake inhibitor (SRI), tricyclic antidepressant, monoamine oxidase inhibitor, norepinephrine reuptake inhibitor (NRI), dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor), or serotonin receptor antagonist; 2.190. Any of the preceding methods wherein the compound of Formula II is administered as monotherapy, e.g., the compound of Formula II is not administered concurrently or in conjunction with an antidepressant, antipsychotic, or anxiolytic; 2.191. Any of the preceding methods, wherein the compound of Formula II is administered without the direct supervision of a healthcare professional (e.g., the compound is self-administered by the subject (e.g., patient)); 2.192. Any of the preceding methods that do not include supervision or observation of the subject (e.g., patient) by a health care professional during or after administration (e.g., within 2 hours after administration) of a dose of the compound of Formula II; 2.193.Any of the foregoing methods that do not expose the subject (e.g., patient) to risk of sedation, dissociation, abuse, misuse, or suicidal ideation; 2.194. Any of the preceding methods, wherein the administration of a dose of a compound of Formula II does not result in hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours after administration, e.g., an increase in systolic and / or diastolic blood pressure of more than 10 mmHg, or more than 20 mmHg, or more than 30 mmHg, or more than 40 mmHg within 30 minutes to 4 hours after said administration; 2.195. Any of the preceding methods, which does not result in cognitive decline in a subject (e.g., a patient); 2.196. Any of the preceding methods, wherein the subject (e.g., patient) has been diagnosed with or is at risk for aneurysmal vascular disease (e.g., aneurysm of the thoracic aorta, abdominal aorta, intracranial, or peripheral artery), arteriovenous malformation, or intracerebral hemorrhage; 2.197. Any of the preceding methods, wherein the subject (e.g., patient) is receiving concomitant treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 2.198. Any of the preceding methods, wherein the subject (e.g., patient) is not receiving concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 2.199. Any of the aforementioned methods, wherein the subject (e.g., patient) cannot be treated with ketamine (e.g., S-ketamine) because the subject (e.g., patient) is unresponsive to ketamine or, for example, ketamine is contraindicated in said subject (e.g., patient).

[0062] In another aspect, the disclosure provides a compound of Formula II, as previously described herein, in free form or a pharmaceutically acceptable salt form, for use in enhancing neural growth, increasing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, e.g., for use in any of Methods 2 et seq.

[0063] In another aspect, the disclosure provides for the use of a compound of Formula II, as previously described herein, in free form or in pharmaceutically acceptable salt form, in the manufacture of a medicament for enhancing neural growth, increasing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, e.g., in the medial prefrontal cortex region of the brain, e.g., for any of Methods 2 et seq.

[0064] In a first embodiment of the second aspect, the present disclosure provides a method (Method 3) for enhancing neuritogenesis and / or neurite outgrowth in the brain of a subject in need thereof, for example in the prefrontal cortex region of the brain, comprising administering an effective amount of a compound of formula I (Compound I):

[0065] [ka] wherein X is selected from -O-, -S-, -N(H), and -N(CH3)-, and Y is selected from -O-, -C(O)-, -CH(OH)-, and -CH(OCH3). or a deuterium analog thereof in free form or a pharmaceutically acceptable salt form to a subject.

[0066] In a further embodiment of the second aspect, the present disclosure provides: 3.1. Method 3, wherein in the compound of formula I, X is -O- or -S-; 3.2. Method 3, wherein in the compound of formula I, X is —N(H) or —N(CH3)—; 3.3. Method 3, wherein in the compound of formula I, X is -N(CH3)-; 3.4. Method 3 or any of methods 3.1 to 3.3, wherein in the compound of formula I, Y is -O-; 3.5. Method 3 or any of methods 3.1 to 3.3, wherein in the compound of formula I, Y is -C(O)-; 3.6. Method 3 or any of methods 3.1 to 3.3, wherein in the compound of formula I, Y is —CH(OH)—; 3.7. The compound of formula I is

[0067] [ka] or a deuterium analog thereof; 3.8. The compound of formula I is

[0068] [ka] or a deuterium analog thereof; 3.9. The compound of formula I is

[0069] [ka] or a deuterium analog thereof; 3.10. The compound of formula I is

[0070] [ka] or a deuterium analog thereof; 3.11. Method 3 or any of methods 3.1-3.10, wherein the compound of Formula I or a deuterated analog thereof is in the form of the free base; 3.12. Method 3, or any of methods 3.1-3.11, wherein the compound of Formula I or a deuterated analog thereof is in the form of a pharmaceutically acceptable salt; 3.13. Method 3.12, wherein the pharmaceutically acceptable salt is a toluenesulfonic acid addition salt (e.g., mono-tosylate or bis-tosylate); 3.14. The compound of formula I or a deuterium analog thereof is non-deuterated lumateperone, i.e., has the following structure:

[0071] [ka] Method 3 or any of methods 3.1 to 3.13; 3.15. Method 3, or any of methods 3.1-3.14, wherein the compound of Formula I or a salt thereof is in a deuterated form, e.g., the deuterium:protium ratio for at least one specified carbon-bonded hydrogen atom is significantly higher than the natural isotope ratio, e.g., at least 2×, e.g., at least 10× higher; 3.16. The deuterated analog of the compound of formula I is

[0072] [ka]

[0073] [ka] wherein D represents hydrogen positions having substantially more than natural deuterium bonding (i.e., substantially more than 0.0156%), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99% deuterium bonding; 3.17. Any of the preceding methods, providing enhanced neural growth in the subject's brain (e.g., in the prefrontal cortex region of the brain); 3.18. Any of the preceding methods, providing increased neural connectivity within the subject's brain (e.g., in the prefrontal cortex region of the brain); 3.19. Any of the preceding methods, providing an increase in synaptic density in the subject's brain (e.g., in the prefrontal cortex region of the brain); 3.20. Any of the preceding methods, providing an increase in dendritic spine density in the subject's brain (e.g., in the prefrontal cortex region of the brain); 3.21. Any of the preceding methods, providing an increase in dendritic spine size (e.g., an increase in spine head width and / or an increase in spine process length) in the subject's brain (e.g., in the prefrontal cortex region of the brain); 3.22. Any of the preceding methods, providing increased excitatory neurotransmission (e.g., enhanced glutamatergic transmission or increased rate of mEPSCs) in the subject's brain (e.g., in the prefrontal cortex region of the brain); 3.23. Method 3, or any of methods 3.1-3.22, providing enhanced neuritogenesis, enhanced neurite outgrowth, enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the medial prefrontal cortex region of the brain) within less than 4 weeks of initiating administration of the compound of Formula I or a deuterium analog thereof, e.g., within less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days after initiating treatment with the compound of Formula I or a deuterium analog thereof; 3.24. Method 3, or any of methods 3.1-3.23, wherein at least 50% of the peak enhanced neuritogenesis, enhanced neurite outgrowth, enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the prefrontal cortex region of the brain) is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months after cessation of administration of the compound of Formula I or a deuterated analog thereof; 3.25. Method 3, or any of Methods 3.1-3.24, wherein at least 50% of the peak enhanced neuritogenesis, enhanced neurite outgrowth, enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months, after administration of a single dose of a compound of Formula I or a deuterated analog thereof; 3.26. Enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission caused by enhanced neuritogenesis and / or enhanced neurite outgrowth, and / or increased synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., increased or decreased density of such receptor or transporter), e.g., serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B ), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density; 3.27. Method 3, or any of methods 3.1-3.26, wherein the method enhances neuritogenesis and / or enhances neurite outgrowth within less than 4 weeks of initiating administration of the compound of Formula I or a deuterium analog thereof, e.g., within less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days after initiating treatment with the compound of Formula I or a deuterium analog thereof; 3.28. Method 3, or any of methods 3.1-3.27, wherein the enhanced neuritogenesis or enhanced neurite outgrowth is characterized by an increase in one or more of the following: total number of neurites per neuron, neurite length (individual length and / or total neuron length), number of branch points on neurites, number of neurite bases, number of neurite nodes, total number of neurite terminals, total neuron length (with or without branching), and total amount of neurite dendritic branching (e.g., measured or predicted using Sholl analysis); 3.29. Any of the foregoing methods that do not cause hallucinogenic side effects; 3.30. Any of the preceding methods wherein the compound of formula I or a deuterated analog thereof is administered in a daily dose equivalent to 1 to 100 mg of the free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 50 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg of the free base; 3.31. Any of the preceding methods, wherein the compound of Formula I or a deuterated analog thereof is administered at a dose equivalent to 1 to 100 mg of the free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 50 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg of the free base, every other day, or every two days, or every three days, or every four days, or every five days, or every six days, or every seven days; 3.32. Method 3, or any of methods 3.1-3.31, wherein the compound of Formula I or a deuterated analog thereof is administered as a unit dosage form for oral administration (e.g., enteral), e.g., as a tablet or capsule; 3.33. Method 3.32, wherein a unit dosage form for oral administration (e.g., enteral), e.g., a tablet or capsule, comprises a compound of Formula I or a deuterated analog thereof in an amount equivalent to 1 to 100 mg of free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of free base, and a pharmaceutically acceptable diluent or carrier; 3.34. Method 3, or any of methods 3.1-3.31, wherein the compound of Formula I or a deuterated analog thereof is administered as a unit dosage form for subcutaneous or transmucosal administration, e.g., an orally disintegrating tablet or film for sublingual or buccal administration; 3.35. Method 3.34, wherein a unit dosage form for subcutaneous or transmucosal administration, e.g., an orally disintegrating tablet or film for sublingual or buccal administration, comprises a compound of Formula I or a deuterated analog thereof in an amount equivalent to 0.5 to 30 mg of free base, e.g., 1 to 10 mg of free base, and a pharmaceutically acceptable diluent or carrier; 3.36. Method 3, or any of methods 3.1-3.31, wherein the compound of Formula I or a deuterated analog thereof is administered as a long-acting injectable (LAI) composition, e.g., an LAI composition for intramuscular or subcutaneous injection; 3.37. Method 3.36, wherein the dose of the LAI composition is sufficient to provide the equivalent of a daily dose of 1 to 100 mg of the free base of the compound of Formula I or a deuterated analog thereof, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of the free base, released over a period of time ranging from about 1 week to about 3 months, e.g., from about 1 week to about 8 weeks, or from about 1 week to about 6 weeks, or from about 1 week to about 4 weeks, or from about 1 week to about 3 weeks, or from about 1 week to about 2 weeks; 3.38. Method 3.36 or 3.37, wherein the LAI composition comprises a compound of Formula I or a deuterated analog thereof dissolved, dispersed, suspended, or encapsulated within a polymer matrix; 3.39. Method 3.38, wherein the polymer matrix comprises one or more biocompatible and biodegradable polymers, as defined herein, such as poly(hydroxycarboxylic acids), poly(amino acids), cellulose polymers, modified cellulose polymers, polyamides, and polyesters; 3.40. Method 3.39, wherein the one or more polymers comprise polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta-hydroxybutyric acid, poly(lactic acid-glycolic acid) copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, polyglycolic acid-polyethylene glycol copolymer, poly(alkyl alpha-cyanoacrylate), e.g., poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoester), polycarbonate, polyortho-carbonate, polyamino acid, (e.g., poly-gamma-L-alanine, poly-gamma-benzyl-L-glutamic acid, or poly-γ-methyl-L-glutamic acid), and / or hyaluronic acid ester; 3.41. Method 3.39, wherein the one or more polymers comprise polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic-co-glycolic acid) copolymer; 3.42. Method 3.39, wherein the one or more polymers include a poly(lactic acid-glycolic acid) copolymer, e.g., poly-d,l-lactide-co-glycolide; 3.43. Any of the preceding methods in which the subject is an animal; 3.44. Any of the preceding methods, wherein the subject is a human (e.g., a patient suffering from a neuropsychiatric disorder); 3.45. Method 3.44, wherein the subject is a patient suffering from anxiety or depression, e.g., bipolar depression, major depressive disorder (MDD), post-traumatic stress disorder, or treatment-resistant depression; 3.46. Method 3.45, wherein the subject is a patient suffering from treatment-resistant depression (e.g., depression that has not responded to treatment with an antidepressant selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof); 3.47. Method 3.45, in which the subject is a patient suffering from bipolar depression or major depressive disorder; 3.48. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate, or sequential administration, of an antidepressant (e.g., selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof); 3.49. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate or sequential administration, of an NMDA receptor antagonist, e.g., an NMDA receptor antagonist chosen from ketamine (e.g., S-ketamine and / or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine, and agmatine, or any combination thereof; 3.50. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate or sequential administration, of an NMDA receptor allosteric modulator, e.g., an NMDA receptor glycine site modulator, e.g., rapastinel, nebostinel, apimostinel, D-cycloserine, or any combination thereof; 3.51. Any of the preceding methods, wherein the subject has previously received treatment with, and has had an unresponsive or inadequate response to, or is suffering from undesirable side effects from, another antidepressant, e.g., a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), or a serotonin receptor antagonist; 3.52. Any of the preceding methods wherein the compound of Formula I or a deuterium analog thereof is administered as monotherapy, e.g., the compound of Formula I or a deuterium analog thereof is not administered concurrently or together with an antidepressant, antipsychotic, or anxiolytic; 3.53. Any of the preceding methods, wherein the compound of Formula I or deuterated analog thereof is administered without the direct supervision of a healthcare professional (e.g., the compound is self-administered by the subject (e.g., patient)); 3.54. Any of the preceding methods that do not include supervision or observation of the subject (e.g., patient) by a health care professional during or after administration (e.g., within 2 hours after administration) of a dose of the compound of Formula I or a deuterated analog thereof; 3.55. Any of the foregoing methods that do not expose a subject (e.g., a patient) to risk of sedation, dissociation, abuse, misuse, or suicidal ideation; 3.56. Any of the preceding methods, wherein administration of a dose of a compound of Formula I or a deuterated analog thereof does not result in hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours, e.g., an increase in systolic and / or diastolic blood pressure of more than 10 mmHg, or more than 20 mmHg, or more than 30 mmHg, or more than 40 mmHg within 30 minutes to 4 hours after said dosing; 3.57. Any of the preceding methods, which does not result in cognitive decline in a subject (e.g., a patient); 3.58. Any of the preceding methods, wherein the subject (e.g., patient) has been diagnosed with or is at risk for aneurysmal vascular disease (e.g., thoracic aortic, abdominal aortic, intracranial, or peripheral artery aneurysm), arteriovenous malformation, or intracerebral hemorrhage; 3.59. Any of the preceding methods, wherein the subject (e.g., patient) is receiving concomitant treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 3.60. Any of the preceding methods, wherein the subject (e.g., patient) is not receiving concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 3.61. Any of the preceding methods, wherein the subject (e.g., patient) is unresponsive to ketamine (e.g., S-ketamine) or cannot be treated with ketamine because, for example, ketamine is contraindicated in said subject (e.g., patient); 3.62. Enhanced neuritogenesis and / or enhanced neurite outgrowth is mediated by synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., an increase or decrease in such receptor or transporter density), e.g., serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B Any of the aforementioned methods, wherein the change is associated with changes in serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density.

[0074] In a second embodiment of the second aspect, the present disclosure provides a method (Method 4) for enhancing neuritogenesis and / or neurite outgrowth in the brain of a subject in need thereof, for example in the prefrontal cortex region of the brain, comprising administering an effective amount of a compound of formula II (Compound II):

[0075] [ka] [In the formula, X is S, S(O), S(O)2, O, CH2, CHR b , C(R b )2, NH, N(R a ) (e.g., N(CH3)), NC(O)-R a , NC(O)-OR a , NC(O)-O-CH2-OR a , N-CH2-OC(O)-R a , N + (=O - ), spiro-bonded C 3~6 cycloalkyl (e.g., cyclopropane), or spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-linked C 3~6 Cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHR c , -C(O)-, C(R c )2, spiro bond C 3~6 cycloalkyl (e.g., cyclopropane), or spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein the spiro-linked C 3~6 Cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(R d ), -C(O)-, -C(OH)-, -C(OC 1~6 alkyl), -C(=N-OH)-, -C(=N-OC 1~6 Alkyl)-, spiro bond C 3~6 Cycloalkyl (e.g., cyclopropane), spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -O(CH2) p O- (wherein p is 2, 3, or 4 (e.g., p is 2)), and the spiro bond C 3~6 Cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; A is H, C 3~6 cycloalkyl (e.g., cyclopropyl or cyclohexyl), aryl (e.g., phenyl), or heteroaryl, wherein said cycloalkyl, aryl, or heteroaryl is substituted with 0 to 5 R groups; Each R is independently selected from the group consisting of aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkyl sulfonyl (e.g., methyl sulfonyl), C 1~6 Alkoxy (e.g., methoxy, ethoxy), C 1~6 Alkylthio (e.g., methylthio), halo (e.g., F), cyano, C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is selected from aryl (optionally substituted with halo), halo, C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkyl sulfonyl (e.g., methyl sulfonyl), C 1~6 Alkoxy (e.g., methoxy), C 1~6 Alkylthio (e.g., methylthio), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Cycloalkoxy (e.g., cyclopropoxy), amino, C 1~6 Alkylamino (e.g., methylamino), di(C 1~6 alkyl)amino (e.g., dimethylamino), (C 1~6 Alkyl)(C 1~6optionally further substituted with one or more groups selected from: alkyl)amino (e.g., methylethylamino), and hydroxy; R a and R d are each independently 1~20 alkyl (e.g., methyl or tert-butyl), and C 1~2 alkylaryl (e.g., benzyl or phenethyl); R b and R c are each independently 1~6 Alkyl (e.g., methyl, ethyl, tert-butyl), C 1~6 Alkoxy, C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Cycloalkoxy (e.g., cyclopropoxy), and C 1~2 alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2, n is 1, 2, 3, 4, or 5; provided that when Z is -C(O)-, X is CH2 or O, and m is 2, then n is not 3; when Z is -C(O)-, X is CH2, and m is 1, then n is not 3; Z is -C(O)- or -O- and X is NH or N(R a ) and if m is 1, then n is not 3, When Z is O, X is NCH3, Y is -C(O)-, and m is 1, then n is not 3. in free form or in a salt form (e.g., a pharmaceutically acceptable salt form) to a subject.

[0076] In a further embodiment of the second embodiment of the second aspect, the present disclosure provides: 4.1. Method 4, wherein in the compound of formula II, X is S, S(O), or S(O)2; 4.2. Method 4, wherein in the compound of formula II, X is O; 4.3. In compounds of formula II, X is CH2, CHR b , or C(R b )2, Method 4; 4.4.R b independently C 1~6 alkyl (e.g., methyl), Method 4.3; 4.5. Method 4, wherein in the compound of formula II, X is CH2; 4.6. Method 4, wherein in the compound of formula II, X is NH; 4.7. In compounds of formula II, X is N(R a ), Method 4; 4.8. In compounds of formula II, X is NC(O)-R a Method 4; 4.9. In the compound of formula II, X is NC(O)-OR a Method 4; 4.10. In the compound of formula II, X is NC(O)—O—CH—OR a Method 4; 4.11. In the compound of formula II, X is N—CH—OC(O)—R a Method 4; 4.12. In the compound of formula II, R a C 1~2 Method 4, or any of methods 4.4-4.11, wherein the alkylaryl is (e.g., benzyl or phenethyl); 4.13. In compounds of formula II, R a C 1~20 Method 4, or any of methods 4.4 to 4.11, wherein R is alkyl (e.g., methyl or tert-butyl); 4.14. In the compound of formula II, R a C 10~20 Method 4, or any of methods 4.4 to 4.11, wherein the aryl group is alkyl (e.g., decyl or dodecyl); 4.15. In compounds of formula II, R a C 1~15 Method 4 or any of methods 4.4 through 4.11, wherein the alkyl is alkyl (e.g., hexyl or octyl); 4.16. In compounds of formula II, R a C 7~15 Method 4, or any of methods 4.4 to 4.11, wherein R is alkyl (e.g., heptyl or nonyl); 4.17. In compounds of formula II, R a C 1~6 Method 4 or any of methods 4.4 through 4.11, wherein the alkyl group is alkyl (e.g., butyl or hexyl); 4.18. In compounds of formula II, R a C 1~4 Method 4, or any of methods 4.4 to 4.11, wherein aryl is alkyl (e.g., n-butyl or tert-butyl); 4.19. In the compound of formula II, R a C 1~3 Method 4, or any of methods 4.4 to 4.11, wherein R is alkyl (e.g., propyl or isopropyl); 4.20. In compounds of formula II, R a C 1~2 Method 4 or any of methods 4.4 to 4.11, wherein R is alkyl (e.g., methyl or ethyl); 4.21. Method 4 or any of methods 4.4-4.11, wherein in the compound of formula II, X is N(CH3); 4.22. In the compound of formula II, X is a spiro bond C 3~6 cycloalkyl (e.g., cyclopropane), Method 4; 4.23. In the compound of formula II, the spiro bond C 3~6 Method 4.22, wherein cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 4.24. In the compound of formula II, the spiro bond C 3~6 Method 4.22, where cycloalkyl is cyclopropane; 4.25. Method 4, wherein in the compound of formula II, X is a spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane); 4.26. Method 4.25, wherein in the compound of formula II, the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; 4.27. Method 4.25, wherein in the compound of formula II, the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridines; 4.28. The spiro bond C 3~6 Method 4 or any of methods 4.22-4.27, wherein cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted; 4.29. The spiro bond C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Method 4, or any of methods 4.22-4.27, substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; 4.30. Method 4 or any of methods 4.1-4.29, wherein in the compound of formula II, Y is CH2; 4.31. Method 4 or any of methods 4.1 to 4.29, wherein in the compound of formula II, Y is —C(O)—; 4.32. In the compound of formula II, Y is CHR c or C(R c )2, Method 4, or any of Methods 4.1 to 4.29; 4.33. In the compound of formula II, each R c But independently, C 1~6 alkyl, compound 4.32; 4.34. In the compound of formula II, each R c is independently selected from methyl, ethyl, and propyl, compound 4.32; 4.35. In the compound of formula II, Y is a spiro bond C3~6 Method 4, or any of methods 4.1-4.29, wherein the cycloalkyl (e.g., cyclopropane) is cycloalkyl; 4.36. In the compound of formula II, the spiro bond C 3~6 Method 4.35, wherein cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 4.37. In the compound of formula II, the spiro bond C 3~6 Method 4.35, where cycloalkyl is cyclopropane; 4.38. Method 4, or any of methods 4.1-4.29, wherein in the compound of Formula II, Y is a spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane); 4.39. Method 4.38, in which in the compound of formula II, the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; 4.40. Method 4.39, in which the spiro-linked 3- to 6-membered heterocycloalkyl in the compound of formula II is aziridine; 4.41. The spiro bond C 3~6 Method 4, or any of methods 4.35-4.40, wherein cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted; 4.42. The spiro bond C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Method 4, or any of methods 4.35-4.40, substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; 4.43. Method 4 or any of methods 4.1-4.42, wherein in the compound of formula II, Z is a bond; 4.44. Method 4 or any of methods 4.1-4.42, wherein in the compound of formula II, Z is S, S(O), or S(O)2; 4.45. Method 4 or any of methods 4.1 to 4.42, wherein in the compound of formula II, Z is O; 4.46. Method 4 or any of methods 4.1 to 4.42, wherein in the compound of formula II, Z is NH; 4.47. In compounds of formula II, Z is N(R a ), for example, N(CH3), Method 4 or any of Methods 4.1 to 4.42; 4.48. Method 4 or any of methods 4.1 to 4.42, wherein in the compound of formula II, Z is —C(O)—; 4.49. In the compound of formula II, Z is -C(OH)-, -C(OC 1~6 alkyl), -C(=N-OH)-, -C(=N-OC 1~6 alkyl)-, and optionally 1~6 Method 4 or any of methods 4.1-4.42, wherein alkyl is methyl; 4.50. In compounds of formula II, Z is a spiro bond C 3~6 Method 4, or any of methods 4.1-4.42, wherein the cycloalkyl (e.g., cyclopropane) is cycloalkyl; 4.51. In the compound of formula II, the spiro bond C 3~6 Method 4.50, wherein cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 4.52. In the compound of formula II, the spiro bond C 3~6 Method 4.50, in which the cycloalkyl is cyclopropane; 4.53. Method 4, or any of methods 4.1-4.42, wherein in the compound of formula II, Z is a spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane); 4.54. Method 4.53, wherein in the compound of formula II, the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; 4.55. Method 4.53, in which in the compound of formula II, the spiro-linked 3- to 6-membered heterocycloalkyl is aziridine; 4.56. The spiro bond C 3~6 Method 4, or any of methods 4.49-4.55, wherein cycloalkyl or 3- to 6-membered heterocycloalkyl is unsubstituted; 4.57. The spiro bond C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 alkyl (e.g., trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Method 4, or any of methods 4.49-4.55, substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; 4.58. Method 4, or any of methods 4.1-4.57, wherein in the compound of formula II, A is a 6-10 membered aryl ring, e.g., a 6-10 membered aryl ring selected from phenyl and naphthyl substituted with 0-5 R groups; 4.59. Method 4, or any of methods 4.1-4.57, wherein in the compound of Formula II, A is a 5-10 membered heteroaryl ring substituted with 0-5 R groups; 4.60. In compounds of formula II, A is furan, thiophene (e.g., thiophen-2-yl), pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyridine (e.g., pyrid-4-yl), 2-oxopyridine (e.g., 2-oxopyridin-1(2H)-yl), pyrimidine, pyridazine, pyrazine, benzofuran (e.g., benzofuran-4-yl, or benzofuran-7-yl, or 2-methylbenzofuran-4-yl), dihydrobenzofuran (e.g., 2,3-dihydrobenzofuran-7-yl), benzothiophene, indole (e.g., indol-1-yl, indol-3-yl, or indol-5-yl), benzoxazole, benzothiazoline, Method 4.59, wherein the benzotriazole is selected from an indazole, a benzimidazole (e.g., benzo[d]imidazol-1-yl), a benzisoxazole (e.g., benzo[d]isoxazol-3-yl, or benzo[d]isoxazol-4-yl), a benzisothiazole (e.g., benzo[d]isothiazol-3-yl), a benzotriazole (e.g., benzo[d][1,2,3-triazol-1-yl), an indazole (e.g., indazol-1-yl, indazol-3-yl, or indazol-7-yl), a quinoline (e.g., quinolin-8-yl), an isoquinoline (e.g., isoquinolin-7-yl), a quinazoline (e.g., quinazolin-7-yl), and a quinoxaline (e.g., quinoxalin-5-yl); 4.61. Method 4.60, in which in the compound of formula II, A is substituted with 0 R groups; 4.62. Method 4.60, in which in the compound of formula II, A is substituted with one R group; 4.63. Method 4.60, in which in the compound of formula II, A is substituted with two R groups; 4.64. Method 4.58, in which in the compound of formula II, A is a phenyl ring substituted with 0-5 R groups; 4.65. Method 4.64, in which one R group is present in the compound of formula II; 4.66. Method 4.64, in which in the compound of formula II the R group is located in the para position of the phenyl ring; 4.67. Method 4.64, in which in the compound of formula II the R group is located in the meta position of the phenyl ring; 4.68. Method 4.64, in which in the compound of formula II the R group is located in the ortho position of the phenyl ring; 4.69. In the compound of formula II, there are two R groups, Method 4.64; 4.70. Method 4.69, in which in the compound of formula II the R groups are located at the ortho and para positions of the phenyl ring; 4.71. Method 4.69, in which the R groups in the compound of formula II are located at the meta and para positions of the phenyl ring; 4.72. Method 4.69, in which in the compound of formula II, the R groups are located at the ortho and meta positions on the same side of the phenyl ring; 4.73. Method 4.69, in which in the compound of formula II, the R groups are located at the ortho and meta positions on opposite sides of the phenyl ring; 4.74. Method 4.69, in which in the compound of formula II the R groups are located at the two ortho positions of the phenyl ring; 4.75. Method 4.69, in which in the compound of formula II, the R groups are located at the two meta positions of the phenyl ring; 4.76. In the compound of formula II, there are three R groups, Method 4.64; 4.77. Method 4.76, in which in the compound of formula II, the R groups are located at the two ortho and para positions of the phenyl ring; 4.78. In the compound of formula II, there are four R groups, Method 4.64; 4.79. In the compound of formula II, there are five R groups, Method 4.64; 4.80. Method 4, or any of methods 4.1 through 4.79, wherein in the compound of Formula II, each R group is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, F, Cl, cyano, hydroxy, 2-methoxyethoxy, methylsulfonyl, methylthio, cyclopropoxy, cyclopropylmethoxy, methylamino, 4-fluorophenoxy, and (4-fluorobenzyl)oxy; 4.81. In the compound of formula II, A is phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 3-chloro-4-fluorophenyl, 2-cyano-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-methyl-4-fluorophenyl, 3-methyl-4-fluorophenyl, 2-methoxy-4-fluorophenyl, 2-methoxy-5-fluorophenyl, 2-fluoro-4-methylphenyl, 2-methoxyphenyl, 3-methyl ... Method 4, or any of methods 4.1 through 4.80, wherein the aryl group is selected from the group consisting of 4-(4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 2-hydroxyphenyl, 2,5-dimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 2-(methylsulfonyl)phenyl, 3-(methylthio)phenyl, 4-(methoxyethoxy)phenyl, 4-(4-fluorobenzyloxy)phenyl, 4-(4-fluorophenoxy)phenyl, 3-cyclopropoxyphenyl, 3-(cyclopropylmethoxy)phenyl, and 2-(methylamino)phenyl; 4.82. In the compound of formula II, A is selected from the group consisting of pyrid-4-yl, thiophen-2-yl, indol-1-yl, indol-3-yl, 5-fluoroindol-3-yl, indazol-1-yl, indazol-3-yl, indazol-7-yl, benzofuran-4-yl, benzofuran-7-yl, 2,3-dihydrobenzofuran-7-yl, 2-methylbenzofuran-7-yl, benzo[d]isoxazol-3-yl, benzo[d]isoxazol-4-yl, Method 4, or any of methods 4.1 through 4.80, wherein the benzo[d]isoxazol-7-yl, 6-fluorobenzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, benzo[d]imidazol-1-yl, benzo[d][1,2,3]triazol-1-yl, isoquinolin-7-yl, quinolin-8-yl, quinoxalin-5-yl, quinazolin-7-yl, and 2-oxopyridin-1(2H)-yl; 4.83. Method 4, or any of methods 4.1 through 4.80, wherein in the compound of Formula II, A is selected from the group consisting of phenyl, 2-ethylphenyl, 4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, benzofuran-7-yl, benzo[d]isoxazol-3-yl, and benzo[d]isothiazol-3-yl; 4.84. Method 4 or any of methods 4.1 to 4.83, wherein in the compound of formula II, m is 1; 4.85. Method 4 or any of methods 4.1 to 4.83, wherein in the compound of formula II, m is 2; 4.86. Method 4 or any of methods 4.1 to 4.85, wherein in the compound of formula II, n is 2; 4.87. Method 4 or any of methods 4.1 to 4.85, wherein in the compound of formula II, n is 3; 4.88. Method 4 or any of methods 4.1 to 4.85, wherein in the compound of formula II, n is 4; 4.89. Method 4 or any of methods 4.1 to 4.85, wherein in the compound of formula II, n is 5; 4.90. Method 4, or any of methods 4.1 through 4.89, wherein in the compound of Formula II, X is S, O, CH2, NH, N(CH3), or spiro-linked cyclopropyl, Y is CH2, C(O), or spiro-linked cyclopropyl, and Z is a bond, -O-, -C(O)-, -O(CH2)2O-, or -C(=NOCH3)-; 4.91. Method 4, or any of methods 4.1 through 4.89, wherein in the compound of Formula II, X is N(CH3) or spiro-linked cyclopropyl, Y is CH2, C(O), or spiro-linked cyclopropyl, and Z is a bond, -O-, or -C(O)-; 4.92. The compound of formula II is a compound of formula Ia:

[0077] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 4.93. The compound of formula II is a compound of formula Ib:

[0078] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 4.94. The compound of formula II is a compound of formula Ic:

[0079] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 4.95. The compound of formula II is a compound of formula Id:

[0080] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 4.96. The compound of formula II is a compound of formula Ie:

[0081] [ka] wherein n, Z, and A are as defined in any preceding embodiment; 4.97. Method 4 or any of methods 4.1 to 4.96, wherein in the compound of formula II, n is 4 and Z is a bond; 4.98. Method 4 or any of methods 4.1 to 4.96, wherein in the compound of formula II, n is 3 and Z is —O— or —C(O)—; 4.99. Method 4 or any of methods 4.1 to 4.96, wherein in the compound of formula II, n is 3 and Z is a bond; 4.100. Method 4 or any of methods 4.1 through 4.96, wherein in the compound of formula II, n is 2 and Z is —O— or —C(O)—; 4.101. Method 4 or any of methods 4.1 through 4.96, wherein in the compound of formula II, n is 2 and Z is a bond; 4.102. Method 4 or any of methods 4.1 through 4.96, wherein in the compound of formula II, n is 1 and Z is —O— or —C(O)—; 4.103. Method 4 or any of methods 4.1-4.96, wherein in the compound of formula II, n is 1 and Z is a bond; 4.104. In compounds of formula II, A is H or C 3~6 Method 4, or any of methods 4.1 through 4.103, wherein Z is a bond or -C(O)-, and n is 1, 2, or 3; 4.105. Compounds of formula II, each independently in free form or in the form of a pharmaceutically acceptable salt or

[0082] [ka] Method 4 or any of methods 4.1 to 4.104, selected from the group consisting of: 4.106. The compound of formula II is

[0083] [ka] and the variables are as follows:

[0084] [Table 3-1]

[0085] [Table 3-2]

[0086] [Table 3-3]

[0087] [Table 3-4]

[0088] [Table 3-5]

[0089] [Table 3-6] [wherein Cyp refers to a spiro-linked cyclopropyl ring], each independently in free form or a pharmaceutically acceptable salt or form; 4.107. The compound of formula II is

[0090] [ka] and the variables are as follows:

[0091] [Table 4] Method 2, or any of methods 2.1 through 2.105, as defined in any of the preceding paragraphs; 4.108. Method 4 or any of methods 4.1-4.107, wherein the compound of formula II is in free form; 4.109. Method 4, or any of methods 4.1-4.107, wherein the compound of formula II is in the form of a salt, e.g., a pharmaceutically acceptable salt; 4.110. Method 4 or any of methods 4.1 to 4.107, wherein the compound of formula II is in acid addition salt form, for example, hydrochloride or toluenesulfonate form; 4.111. Method 4, or any of methods 4.1-4.110, wherein the compound of formula II is in substantially pure diastereomeric form (i.e., substantially free from other diastereomers); 4.112. Method 4 or any of methods 4.1 to 4.110, wherein the compound of formula II has a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%; 4.113. Method 4 or any of methods 4.1-4.112, wherein the compound of formula II is in solid form, e.g., crystalline form; 4.114. Method 4, or any of methods 4.1-4.113, wherein the compound of formula II is in isolated or purified form (e.g., at least 90%, or at least 95%, or at least 98%, or at least 99% pure form). 4.115. A compound of formula II inhibits 5-HT at a concentration of 100 nM by at least 60%, for example, at a concentration of 100 nM by at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%. 2A Method 4 or any of methods 4.1 to 4.114, having receptor binding affinity; 4.116. The compound of formula II has a 5-HT activity of less than 250 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM. 2A Receptor dissociation constant (K d ) Method 4 or any of methods 4.1 to 4.115; 4.117. The compound of formula II is 5-HT 2AMethod 4, or any of methods 4.1-4.116, wherein the agonist is a partial agonist or a full agonist of receptor-mediated beta-arrestin signaling; 4.118. The compound of Formula II has an E of less than 90%, or less than 80%, or less than 70%, or less than 60%, or less than 50%, or less than 40%, or less than 30%, or less than 20%, or less than 10% compared to a full agonist (e.g., alpha-methylserotonin). max Method 4.117, which is a partial agonist of beta-arrestin signaling having 4.119. The compound of formula II is 5-HT 2A EC for beta-arrestin agonism of the receptor of less than 500 nM, or less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM 50 having method 4.117 or 4.118; 4.120. A compound of Formula II has a relative intrinsic activity (RA) of beta-arrestin signaling of less than 1.0 compared to the reference compound alpha-methylserotonin. i ), e.g., having a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or between 0.1 and 0.8, or between 0.2 and 0.8, or between 0.4 and 0.8, or between 0.5 and 0.8, or between 0.2 and 0.6, or between 0.2 and 0.5, or between 0.2 and 0.4, or between 0.5 and 1.0, or between 0.5 and 0.9, or between 0.5 and 0.8, or between 0.6 and 0.9, or between 0.6 and 0.8, Methods 4.117, 4.118, or 4.119; 4.121. A compound of Formula II has a relative intrinsic activity (RA) of beta-arrestin signaling greater than 1.0 compared to the reference compound alpha-methylserotonin. i ), e.g., methods 4.117, 4.118, or 4.119, having a relative intrinsic activity of 1.0 to 1.2, or 1.0 to 1.4, or 1.0 to 1.6; 4.122. The compound of formula II is 5-HT 2A Method 4 or any of methods 4.1 through 4.116, wherein the compound is an antagonist of receptor-mediated beta-arrestin signaling; 4.123. The compound of formula II is 5-HT 2A IC of less than 300 nM, or less than 200 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM for beta-arrestin antagonism of the receptor 50 having, Method 4.122; 4.124. The compound of formula II is 5-HT 2A Method 4, or any of methods 4.1 through 4.116, that is not an antagonist of receptor-mediated beta-arrestin signaling; 4.125. The compound of formula II is 5-HT 2A IC greater than 10 nM, or greater than 50 nM, or greater than 100 nM, or greater than 250 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 5000 nM, or greater than 10,000 nM for beta-arrestin antagonism of the receptor 50 having, Method 4.124; 4.126. The compound of formula II is 5-HT 2A Method 4 or any of methods 4.1 to 4.125, which are not or are weak agonists of receptor-mediated Gq signaling; 4.127. The compound of Formula II has an E of less than 90%, or less than 80%, or less than 70%, or less than 60%, or less than 50%, or less than 40%, or less than 30%, or less than 20%, or less than 10% of that of a full agonist (e.g., alpha-methylserotonin). max , preferably less than 50%, or less than 30%, or less than 10% E max Method 4.126, which is a partial agonist of Gq signaling having 4.128. The compound of formula II is 5-HT 2AEC for Gq agonism of the receptor greater than 10 nM, or greater than 25 nM, or greater than 50 nM, or greater than 100 nM, or greater than 150 nM, or greater than 200 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 2000 nM, or greater than 5000 nM, or greater than 10,000 nM 50 having method 4.126 or 4.127; 4.129. The compound of formula II has a Gq signaling relative intrinsic activity (RA) of less than 1.0 compared to the reference compound alpha-methylserotonin. i ), e.g., having a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or between 0.1 and 0.8, or between 0.2 and 0.8, or between 0.4 and 0.8, or between 0.5 and 0.8, or between 0.2 and 0.6, or between 0.2 and 0.5, or between 0.2 and 0.4, or between 0.5 and 1.0, or between 0.5 and 0.9, or between 0.5 and 0.8, or between 0.6 and 0.9, or between 0.6 and 0.8, Methods 4.126, 4.127, or 4.128; 4.130. The compound of formula II is 5-HT 2A Method 4 or any of methods 4.1 to 4.129, which is an antagonist of receptor-mediated Gq signaling; 4.131. The compound of formula II is 5-HT 2A IC of less than 10 nM, or less than 25 nM, or less than 50 nM, or less than 100 nM, or less than 150 nM, or less than 200 nM, or less than 500 nM for receptor Gq antagonism 50 having, method 4.130; 4.132. The compound of formula II is 5-HT 2AMethod 4, or any of methods 4.1 through 4.131, having a bias ratio (beta-arrestin / Gq) relative to receptor agonism of at least 2, or at least 5, or at least 10, or at least 25, or at least 50, or at least 100, or at least 150, or at least 200, or at least 500, or at least 1000, or at least 10,000, or the bias ratio is undetermined (i.e., the compound has any degree of beta-arrestin agonism and zero Gq agonism); 4.133. Method 4, or any of methods 4.1-4.132, wherein the compound of formula II is an antagonist or agonist of the D1 and / or D2 dopamine receptor (e.g., has at least 70% receptor affinity at 100 nM concentration or an IC50 of less than 100 nM); 4.134. Compounds of Formula II exhibit no activity at D1 and / or D2 dopamine receptors (e.g., less than 50% receptor affinity at 100 nM concentration and / or an EC2 of greater than 500 nM). 50 Or IC 50 ), method 4, or any of methods 4.1 to 4.132; 4.135. The compound of formula II is an antagonist of the serotonin transporter (e.g., has a receptor binding affinity of at least 70% at a concentration of 100 nM or an IC of less than 100 nM). 50 ), method 4, or any of methods 4.1 to 4.134; 4.136. Compounds of Formula II exhibit no activity at the serotonin transporter (e.g., less than 50% receptor binding affinity at 100 nM concentration and / or an EC2 of greater than 500 nM). 50 Or IC 50 ), method 4, or any of methods 4.1 to 4.134; 4.137. The compound of Formula II is an agonist, antagonist, or partial agonist of the mu opioid receptor (e.g., at a 100 nM concentration, has a receptor binding affinity of at least 70% or an EC of less than 100 nM). 50 Or IC50 ), method 4, or any of methods 4.1 to 4.136; 4.138. Compounds of Formula II exhibit no activity at the mu opioid receptor (e.g., a receptor binding affinity of less than 50% at 100 nM concentration and / or an EC2 of greater than 500 nM). 50 Or IC 50 ), method 4, or any of methods 4.1 to 4.136; 4.139. Method 4, or any of methods 4.1-4.138, wherein the compound of Formula II is non-hallucinogenic, e.g., when in therapeutic amounts for the treatment of a neuropsychiatric disorder described herein (e.g., depression, anxiety, etc.), the compound does not cause visual or auditory hallucinations, visual distortions (e.g., objects and surfaces appearing to drift, morph, flicker, or melt within the field of vision), escapism, dissociation, delirium, or unwanted altered states of consciousness; 4.140. Method 4 or any of methods 4.1-4.139, wherein the compound of formula II does not elicit a head-twitch response in an animal test model or is an antagonist of a DOI-induced head-twitch response; 4.141. Method 4, or any of methods 4.1-4.140, wherein the compound of formula II is effective in a murine model of depression (tail suspension test or forced swim test); 4.142. Method 4, or any of methods 4.1-4.141, wherein the compound of formula II is effective in an animal model of social anxiety disorder or anhedonia; 4.143. The compound of formula II is 5-HT 2B Method 4 or any of methods 4.1 to 4.142, which has no agonist activity (e.g., an EC50 greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); 4.144. The compound of formula II is 5-HT 2BMethod 4, or any of methods 4.1 to 4.143, having antagonist activity (e.g., an IC50 of less than 1000 nM, or less than 500 nM, or less than 250 nM, or less than 100 nM, or less than 50 nM, or less than 25 nM, or less than 15 nM); 4.145. The compound of formula II is 5-HT 2c Method 4, or any of methods 4.1 to 4.144, having agonist activity (e.g., an EC50 of less than 1000 nM, or less than 500 nM, or less than 250 nM, or less than 100 nM, or less than 50 nM, or less than 25 nM, or less than 15 nM); 4.146. The compound of formula II is 5-HT 2C Method 4 or any of methods 4.1 to 4.144, which does not have antagonist activity (e.g., IC50 greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); 4.147. Method 4, or any of methods 4.1-4.146, wherein the compound of Formula II binds to alpha-1A adrenergic receptors (e.g., has a binding affinity, Ki, of less than 1000 nM, or less than 500 nM, or less than 250 nM, or less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 50 nM, or less than 25 nM); 4.148. Method 4, or any of methods 4.1-4.147, wherein the compound of formula II does not cause psychosis (e.g., long-term or intermittent psychosis); 4.149. Method 4 or any of methods 4.1 through 4.148, wherein the compound of Formula II does not promote self-harm or harm to others in the patient; 4.150. Method 4, or any of methods 4.1 through 4.149, wherein the compound of formula II does not cause valvular heart disease or pulmonary arterial hypertension, e.g., the compound is safely administered to patients with cardiac comorbidities; 4.151. Method 4 or any of methods 4.1-4.150, wherein the compound of formula II does not cause abuse or dependence (e.g., physical or psychological dependence); 4.152. The compound of formula II is adenosine A2A, alpha-1A adrenergic, alpha-2A adrenergic, beta-1 adrenergic, beta-2 adrenergic, GABA-A benzodiazepine site (BZD, central), CB1 cannabinoid, CB2 cannabinoid, cholecystokinin CCK1, endothelin-A (ETA), NMDA, histamine H1, histamine H2, MAO-A, mus Muscarinic M1, Muscarinic M2, Muscarinic M3, Nicotinic acetylcholine (neuronal alpha-4-beta-2), Delta opioid, Kappa opioid, Mu opioid, Serotonin-1A, Serotonin-1B, Serotonin-3, Glucocorticoid (GR), Androgen (AR), Vasopressin V1A, Cardiac calcium channel (dihydropyridine site), hERG potassium channel, Voltage-gated potassium channel K V , the method of any of methods 4, or 4.1 to 4.151, wherein the receptor and ion channel are functionally inactive at one or more of the following receptors and ion channels: sodium channel (site 2), norepinephrine transporter, dopamine transporter, and / or serotonin transporter; 4.153. Method 4.152, wherein the compound of Formula II has in vitro receptor activity (vs. agonism or antagonism) for any one or more of said receptors or ion channels of less than 60% inhibition of radioligand binding (e.g., at a 100 nM test concentration), e.g., less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% inhibition; 4.154. Method 4, or any of methods 4.1-4.153, wherein the compound of formula II is orally bioavailable (e.g., at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40% oral bioavailability); 4.155.Any of the preceding methods providing enhanced neural growth within the subject's brain (e.g., in the prefrontal cortex region of the brain); 4.156. Any of the preceding methods, providing increased neural connectivity within the subject's brain (e.g., in the prefrontal cortex region of the brain); 4.157.Any of the preceding methods providing an increase in synaptic density in the subject's brain (e.g., in the prefrontal cortex region of the brain); 4.158. Any of the preceding methods, providing an increase in dendritic spine density in the subject's brain (e.g., in the prefrontal cortex region of the brain); 4.159. Any of the preceding methods, providing an increase in dendritic spine size (e.g., an increase in spine head width and / or an increase in spine process length) within the subject's brain (e.g., in the prefrontal cortex region of the brain); 4.160. Any of the preceding methods, providing increased excitatory neurotransmission (e.g., enhanced glutamatergic transmission or increased rate of mEPSCs) within the subject's brain (e.g., in a prefrontal cortex region of the brain); 4.161. Method 4, or any of methods 4.1-4.160, providing enhanced neuritogenesis, enhanced neurite outgrowth, enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the medial prefrontal cortex region of the brain) within less than 4 weeks of initiating administration of a compound of Formula II, e.g., within less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days after initiating treatment with a compound of Formula II; 4.162. Method 4, or any of methods 4.1-4.161, wherein at least 50% of the peak enhanced neuritogenesis, enhanced neurite outgrowth, enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the prefrontal cortex region of the brain) is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months after administration of the compound of Formula II has stopped; 4.163. Method 4, or any of methods 4.1-4.162, wherein at least 50% of the peak enhanced neuritogenesis, enhanced neurite outgrowth, enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months, after administration of a single dose of a compound of Formula II, as measured in the subject's brain (e.g., in the prefrontal cortex region of the brain), e.g., by in vivo imaging (e.g., MRI); 4.164. Enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission are caused by enhanced neuritogenesis and / or enhanced neurite outgrowth, and / or by increased or decreased synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., increased or decreased density of such receptors or transporters), e.g., serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B ), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density; 4.165. Method 4, or any of methods 4.1-4.164, wherein neuritogenesis is enhanced and / or neurite outgrowth is enhanced within less than 4 weeks of initiating administration of a compound of Formula II, e.g., within less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days after initiating treatment with a compound of Formula II; 4.166. Method 4, or any of methods 4.1-4.165, wherein the enhanced neuritogenesis or enhanced neurite outgrowth is characterized by an increase in one or more of the total number of neurites per neuron, neurite length (individual length and / or total neuron length), number of branch points on neurites, number of neurite bases, number of neurite nodes, total number of neurite terminals, total neuron length (with or without branching), and total amount of neurite dendritic branching (e.g., measured or predicted using Sholl analysis); 4.167. Any of the aforementioned methods that do not cause hallucinogenic side effects; 4.168. Any of the preceding methods, wherein the compound of formula II is administered in a daily dose equivalent to 1 to 100 mg of the free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 50 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg of the free base; 4.169. Any of the preceding methods, wherein the compound of formula II is administered at a dose equivalent to 1 to 100 mg of the free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 50 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg of the free base, at a frequency of every other day, or every two days, or every three days, or every four days, or every five days, or every six days, or every seven days; 4.170. Method 4, or any of methods 4.1-4.169, wherein the compound of formula II is administered as a unit dosage form for oral administration (e.g., enteral), e.g., as a tablet or capsule; 4.171. Method 4.170, wherein a unit dosage form, e.g., a tablet or capsule, for oral administration (e.g., enteral) comprises a compound of Formula II equivalent to 1 to 100 mg of free base, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of free base, and a pharmaceutically acceptable diluent or carrier; 4.172. Method 4, or any of methods 4.1 to 4.171, wherein the compound of formula II is administered as a unit dosage form for subcutaneous or transmucosal administration, e.g., an orally disintegrating tablet or film for sublingual or buccal administration; 4.173. Method 4.172, in which a unit dosage form for subcutaneous or transmucosal administration, e.g., an orally disintegrating tablet or film for sublingual or buccal administration, comprises a compound of formula II in an amount equivalent to 0.5 to 30 mg of free base, e.g., 1 to 10 mg of free base, and a pharmaceutically acceptable diluent or carrier; 4.174. Method 4, or any of methods 4.1-4.173, wherein the compound of formula II is administered as a long-acting injectable (LAI) composition, e.g., an LAI composition for intramuscular or subcutaneous injection; 4.175. Method 4.174, wherein the dose of the LAI composition is sufficient to provide the equivalent of a daily dose of 1 to 100 mg of free base of the compound of formula II, e.g., 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of free base, released over a period of time ranging from about 1 week to about 3 months, e.g., from about 1 week to about 8 weeks, or from about 1 week to about 6 weeks, or from about 1 week to about 4 weeks, or from about 1 week to about 3 weeks, or from about 1 week to about 2 weeks; 4.176. Method 4.174 or 4.175, wherein the LAI composition comprises a compound of formula II dissolved, dispersed, suspended, or encapsulated within a polymer matrix; 4.177. Method 4.176, wherein the polymer matrix comprises one or more biocompatible and biodegradable polymers, as defined herein, such as poly(hydroxycarboxylic acids), poly(amino acids), cellulose polymers, modified cellulose polymers, polyamides, and polyesters; 4.178. Method 4.177, wherein the one or more polymers comprise polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta-hydroxybutyric acid, poly(lactic acid-glycolic acid) copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, polyglycolic acid-polyethylene glycol copolymer, poly(alkyl alpha-cyanoacrylate), e.g., poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoester), polycarbonate, polyortho-carbonate, polyamino acids, (e.g., poly-gamma-L-alanine, poly-gamma-benzyl-L-glutamic acid, or poly-γ-methyl-L-glutamic acid), and / or hyaluronic acid ester; 4.179. Method 4.177, wherein the one or more polymers comprise polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic acid-glycolic acid) copolymer; 4.180. Method 4.177, wherein the one or more polymers include a poly(lactic acid-glycolic acid) copolymer, e.g., poly-d,l-lactide-co-glycolide; 4.181. Any of the foregoing methods in which the subject is an animal; 4.182.Any of the preceding methods, wherein the subject is a human (e.g., a patient suffering from a neuropsychiatric disorder); 4.183. Method 4.182, in which the subject is a patient suffering from anxiety or depression, e.g., bipolar depression, major depressive disorder (MDD), post-traumatic stress disorder, or treatment-resistant depression; 4.184. Method 4.183, wherein the subject is a patient suffering from treatment-resistant depression (e.g., depression that has not responded to treatment with an antidepressant selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof); 4.185. Method 4.184, in which the subject is a patient suffering from bipolar depression or major depressive disorder; 4.186. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate, or sequential administration, of an antidepressant (e.g., selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof); 4.187. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate or sequential administration, of an NMDA receptor antagonist, e.g., an NMDA receptor antagonist selected from ketamine (e.g., S-ketamine and / or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine, and agmatine, or any combination thereof; 4.188. Any of the preceding methods, further comprising co-administration, e.g., simultaneous, separate or sequential administration, of an NMDA receptor allosteric modulator, e.g., an NMDA receptor glycine site modulator, e.g., rapastinel, nebostinel, apimostinel, D-cycloserine, or any combination thereof; 4.189. Any of the preceding methods, wherein the subject has previously received treatment with, and has had an unresponsive or inadequate response to, or is suffering from undesirable side effects from, another antidepressant, e.g., a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), an SRI / NRI, an SRI / DRI, an NRI / DRI, an SRI / NRI / DRI (triple reuptake inhibitor), or a serotonin receptor antagonist; 4.190. Any of the preceding methods wherein the compound of Formula II is administered as monotherapy, e.g., the compound of Formula II is not administered concurrently or in conjunction with an antidepressant, antipsychotic, or anxiolytic; 4.191. Any of the preceding methods, wherein the compound of Formula II is administered without the direct supervision of a healthcare professional (e.g., the compound is self-administered by the subject (e.g., patient)); 4.192. Any of the preceding methods that do not include supervision or observation of the subject (e.g., patient) by a health care professional during or after administration (e.g., within 2 hours after administration) of a dose of the compound of Formula II; 4.193.Any of the foregoing methods that do not expose the subject (e.g., patient) to risk of sedation, dissociation, abuse, misuse, or suicidal ideation; 4.194. Any of the preceding methods, wherein the administration of a dose of a compound of Formula II does not result in hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours after administration, e.g., an increase in systolic and / or diastolic blood pressure of more than 10 mmHg, or more than 20 mmHg, or more than 30 mmHg, or more than 40 mmHg within 30 minutes to 4 hours after said administration; 4.195. Any of the preceding methods, which does not result in cognitive decline in a subject (e.g., a patient); 4.196. Any of the preceding methods, wherein the subject (e.g., patient) has been diagnosed with or is at risk for aneurysmal vascular disease (e.g., aneurysm of the thoracic aorta, abdominal aorta, intracranial, or peripheral artery), arteriovenous malformation, or intracerebral hemorrhage; 4.197. Any of the preceding methods, wherein the subject (e.g., patient) is receiving concomitant treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 4.198. Any of the preceding methods, wherein the subject (e.g., patient) is not receiving concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine; 4.199. Any of the preceding methods, wherein the subject (e.g., patient) is unresponsive to ketamine (e.g., S-ketamine) or cannot be treated with ketamine because, for example, ketamine is contraindicated in said subject (e.g., patient); 4.200. Enhanced neuritogenesis and / or enhanced neurite outgrowth is mediated by synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., an increase or decrease in such receptor or transporter density), e.g., serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B Any of the aforementioned methods, wherein the change is associated with changes in serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density.

[0092] In another aspect, the present disclosure provides a compound of formula I as previously described herein or a deuterated analog thereof, or a compound of formula II as previously described herein, each in free form or a pharmaceutically acceptable salt form, for use in enhancing neuritogenesis and / or neurite outgrowth in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, e.g., for use in any of methods 3 or 4 et seq.

[0093] In another aspect, the disclosure provides the use of a compound of formula I or a deuterated analog thereof, as previously described herein, or a compound of formula II as previously described herein, each in free form or in pharmaceutically acceptable salt form, in the manufacture of a medicament for enhancing neuritogenesis and / or neurite outgrowth in the brain of a subject in need thereof, e.g., for any of methods 3 or 4 et seq.

[0094] In a third aspect, the present disclosure provides a method (Method 5) for enhancing neural growth, enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in neural cells or neural tissue (e.g., cell culture), in vitro or in vivo, comprising contacting the neural cells or neural tissue with an effective amount of a compound of Formula I or a deuterated analog thereof, or a compound of Formula II, each in free form or in a pharmaceutically acceptable salt form.

[0095] In a further embodiment of the third aspect, the present disclosure provides: 5.1. Method 5, in which neuronal cells or neuronal tissue are contacted with an effective amount of a compound of formula I, or a deuterated analog thereof, as described in any of methods 1, or 1.1-1.16 herein above; 5.2. Method 5, in which neuronal cells or neuronal tissue are contacted with an effective amount of a compound of formula II as described in any of methods 2, or 2.1 to 2.154 herein above; 5.3. Any of the preceding methods providing enhanced nerve growth in nerve cells or nerve tissue; 5.4. Any of the preceding methods providing enhanced neural connectivity in neural cells or neural tissue; 5.5. Any of the preceding methods providing increased synaptic density in a neuronal cell or neuronal tissue; 5.6. Any of the preceding methods providing increased dendritic spine density in a neuronal cell or neuronal tissue; 5.7. Any of the preceding methods, providing an increase in dendritic spine size (e.g., an increase in spine head width and / or an increase in spine process length) in a neuronal cell or neuronal tissue; 5.8. Any of the preceding methods, which provide increased excitatory neurotransmission in a neuronal cell or neuronal tissue (e.g., enhanced glutamatergic transmission or increased rate of mEPSCs); 5.9. Method 5, or any of methods 5.1-5.8, providing enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in neural cells or neural tissue within less than 4 weeks of initiating administration of a compound of Formula I, or a deuterium analog thereof, or a compound of Formula II, e.g., within less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days after initiating treatment with a compound of Formula I, or a deuterium analog thereof, or a compound of Formula II; 5.10. Method 5, or any of methods 5.1-5.9, wherein at least 50% of the peak enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the prefrontal cortex region of the brain) is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months, after cessation of administration of the compound of Formula I or a deuterated analog thereof, or the compound of Formula II; 5.11. Method 5, or any of methods 5.1-5.10, wherein at least 50% of the peak enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission is maintained in the subject's brain (e.g., in the prefrontal cortex region of the brain), e.g., by in vivo imaging (e.g., MRI), for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months, after administration of a single dose of a compound of Formula I or a deuterated analog thereof; 5.12. Enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission are characterized or caused by enhanced neuritogenesis and / or enhanced neurite outgrowth, and / or increased synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., increased or decreased density of such receptor or transporter), e.g., serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density; 5.13. Method 5 or any of methods 5.1-5.12, providing enhanced neuritogenesis or enhanced neurite outgrowth in neuronal cells or tissue; 5.14. Method 5, or any of methods 5.1-5.13, wherein the method enhances neuritogenesis and / or enhances neurite outgrowth within less than 4 weeks of initiating administration of a compound of Formula I or a deuterium analog thereof or a compound of Formula II, e.g., within less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days after initiating treatment with a compound of Formula I or a deuterium analog thereof or a compound of Formula II; 5.15. Method 5, or any of methods 5.1-5.14, wherein the enhanced neuritogenesis or enhanced neurite outgrowth is characterized by an increase in one or more of the following: total number of neurites per neuron, neurite length (individual length and / or total neuron length), number of branch points on neurites, number of neurite bases, number of neurite nodes, total number of neurite terminals, total neuron length (with or without branching), and total amount of neurite dendritic branching (e.g., measured or predicted using Sholl analysis); 5.16. Synaptic neurotransmitter receptor or neurotransmitter transporter density (e.g., an increase or decrease in such receptor or transporter density), e.g., serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B), serotonin transporter (SERT), dopamine transporter (DAT), norepinephrine transporter (NET), glutamate transporter (e.g., EAAT or VGLUT), and / or GABA transporter (e.g., GAT1, GAT3) density; 5.17. Method 5 or any of methods 5.1-5.16, wherein the neural cells or neural tissue is a cell culture (e.g., a cell culture of pluripotent stem cells, neural progenitor cells, immature neurons, or mature neurons); 5.18. Method 5.17, wherein the neural cells or neural tissue are of human origin (e.g., an immortalized human cell line); 5.19. Method 5.17, wherein the neural cells or neural tissue are of animal origin (e.g., a murine cell line); 5.20. Method 5, or any of methods 5.1-5.16, in which neuronal cells or tissue are isolated from the animal after its death (e.g., a compound is administered to a living animal, and when the animal dies, a dissection is performed to obtain neuronal cells or tissue for postmortem analysis); 5.21. Method 5.20, wherein the compound does not cause findings comparable to hallucinogenic side effects in animals during administration of the compound; 5.22. Method 5, or any of methods 5.1 through 5.21, performed to determine whether the compound is effective in enhancing nerve growth, enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in an in vivo animal model, e.g., an animal model of a neuropsychiatric disorder; 5.23. Any of methods 5.19-5.22, wherein the animal is an animal model of a neuropsychiatric disorder, e.g., an animal model of anxiety, depression, psychosis, or a neurodegenerative disorder.

[0096] In another aspect, the disclosure provides a compound of Formula I, as previously described herein, or a deuterated analog thereof, or a compound of Formula II, as previously described herein, each in free form or a pharmaceutically acceptable salt form, for use in neuronal cells or neuronal tissue (e.g., cell culture), in vitro or in vivo, e.g., in any of Methods 5 et seq., for enhancing neural growth, enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission.

[0097] As used hereinafter, "compounds of the disclosure" refers to any compound described in Method I or 1.1 through 1.16 or Method 2, or any of Methods 2.1 through 2.154, e.g., lumateperone, its related analogs, its deuterated analogs, and other octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines, each in free form or a pharmaceutically acceptable salt form.

[0098] As used herein, the term "spiro bond" refers to the C 3~6 It is intended to define that a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group is at a spirojunction, meaning that one atom of the cyclic group is an atom of the ring to which the group is attached. For example, the following are examples of compounds of Formula II having spiro-linked cyclic groups within the scope of the present disclosure:

[0099] [ka]

[0100] In each of the above examples, cyclopropane, cyclobutane, aziridine, azetidine, or oxetane may be substituted with any other C 3~6It may be optionally substituted with a cycloalkyl or a 3- to 6-membered heterocycloalkyl, including, but not limited to, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, or morpholine.

[0101] The compound of formula II inhibits serotonin 5-HT 2A The term "biased agonist," as used herein, refers to a serotonin 5-HT receptor biased agonist. 2A It is used in reference to compounds that are active at the receptor and exhibit partial or full agonism for receptor-mediated beta-arrestin signaling, but antagonism or weak partial agonism for Gq-mediated signaling. A useful measure of bias is the "bias ratio," which is the ratio of the intrinsic relative activity (RA) for beta-arrestin signaling. i ) as a function of RA on Gq signaling i The bias ratio is calculated as a ratio of β-arrestin signaling to β-arrestin signaling. A non-biased agonist has a bias ratio of 1.0. A biased agonist has a non-zero bias ratio. In some embodiments, compounds of the present disclosure preferably exhibit a bias against beta-arrestin signaling and thus have a bias ratio greater than 1.0. More preferably, the bias ratio against beta-arrestin signaling is greater than 10, or greater than 100, or greater than 1000, or 10,000 or greater.

[0102] As used herein, the term "partial agonist" is intended to refer to a compound that has agonism to some extent narrower than that of a reference standard full agonist. For example, 5-HT 2A The reference compound for receptor agonism is alpha-methylserotonin. The maximum efficacy (E) for alpha-methylserotonin max ) Compounds with a maximal efficacy of less than 100% are partial agonists.

[0103] The term "hallucinogen" refers to a compound that causes hallucinogenic symptoms, which are any one or more symptoms selected from visual hallucinations, auditory hallucinations, visual distortions (e.g., objects and surfaces appearing to drift, morph, waver, or melt within the field of vision), escapism, dissociation, delirium, and unwanted altered states of consciousness. A compound of the present disclosure is considered to be "non-hallucinogenic" if the compound does not cause hallucinogenic symptoms at doses therapeutically effective for the treatment of neuropsychiatric disorders described herein (e.g., depression, anxiety, etc.).

[0104] "Alkyl," as used herein, unless otherwise indicated, is a saturated or unsaturated hydrocarbon moiety, e.g., from 1 to 21 carbon atoms in length. Any such alkyl may be straight-chained or branched (e.g., n-butyl or tert-butyl), preferably straight-chained, unless otherwise indicated. For example, "C 1~21 "Alkyl" refers to an alkyl having 1 to 21 carbon atoms. In one embodiment, alkyl is selected from the group consisting of one or more hydroxy or C 1~22 and optionally substituted with an alkoxy (e.g., ethoxy) group. In another embodiment, alkyl contains 1 to 21 carbon atoms, preferably straight chain and optionally saturated or unsaturated, e.g., in some embodiments, R1 is an alkyl chain containing 1 to 21 carbon atoms, preferably 6 to 15 carbon atoms, 16 to 21 carbon atoms, such that, for example, when cleaved from a compound of Formula II, together with the -C(O)- to which it is attached, it forms the residue of a natural or unnatural, saturated or unsaturated fatty acid.

[0105] Thus, the words "treatment" and "treating" should be understood to encompass prevention and treatment or amelioration of symptoms of disease, and / or treatment of the cause of disease. In certain embodiments, the words "treatment" and "treating" refer to prevention or amelioration of symptoms of disease.

[0106] As used herein, the term "brain" or "brain region" can refer to any structural or functional region of the brain, including, but not limited to, the prefrontal cortex (e.g., medial prefrontal cortex, lateral prefrontal cortex, dorsal medial prefrontal cortex, dorsolateral prefrontal cortex, ventromedial prefrontal cortex, ventral prefrontal cortex), amygdala, hippocampus, frontal cortex, orbitofrontal cortex, insular cortex, anterior insular cortex, anterior cingulate cortex, subcallosal cingulate cortex, ventral tegmental area, ventral palladium, nucleus accumbens, supramarginal gyrus, inferior temporal gyrus, and subcallosal cingulate area. Each of these brain regions is associated with one or more of emotion, cognition, depression, psychosis, bipolar disorder, anxiety, and other neuropsychiatric disorders. There is evidence that several neuropsychiatric disorders, including depression and bipolar disorder, may be associated with changes in tissue volume (indicating neuronal loss and / or synaptic "pruning") or changes in synaptic expression or activity of neurotransmitter receptors or transporters in one or more of these brain regions. In some embodiments, brain regions affected by the methods disclosed herein include subregions of the prefrontal cortex (e.g., mPFC), the amygdala, and / or the hippocampus.

[0107] The prefrontal cortex, an anterior region of the frontal lobe of the cerebral cortex, is the primary brain region responsible for the integrated control of thought and behavior. The prefrontal cortex is crucial for executive functions such as planning, decision-making, short-term memory, personality, social behavior, and some aspects of speech production and language. The prefrontal cortex (PFC) has several subregions. In humans, the PFC is generally divided into the ventromedial PFC (vmPFC, which includes the ventromedial prefrontal cortex, vPFC, and the medial prefrontal cortex, mPFC) and the lateral prefrontal cortex (LPFC, which includes the dorsolateral prefrontal cortex, dLPFC, and the ventrolateral prefrontal cortex, vLPFC). The mPFC includes the anterior cingulate cortex, which is important for many high-level functions. The dlPFC is thought to be particularly important in the pathogenesis of depression. In some lower mammals, including rats and mice, functions performed by the dlPFC in humans are more closely related to the mPFC.

[0108] In some embodiments of the present disclosure, the methods are directed to providing structural remodeling in any region of the PFC, including, for example, the mPFC or dLPFC.

[0109] The term "patient" may include human or non-human patients.

[0110] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ("DSM-5") defines "Major Depressive Disorder (MDD)" as a set of five or more symptoms occurring within the same two-week period that represent a change from the patient's previous functioning. These five symptoms are selected from the following: depressed mood, markedly diminished interest or pleasure in almost all activities, significant weight change, insomnia or hypersomnia, psychomotor agitation or slowness, fatigue, feelings of worthlessness or excessive guilt, impaired thinking or indecisiveness, and recurrent thoughts of death or suicidal ideation, each of which is present nearly every day. A diagnosis of MDD requires, at a minimum, at least depressed mood or loss of interest or pleasure as one of the five symptoms. MDD may also consist of one or more "major depressive episodes," which may occur weeks or months apart (with more than two weeks between episodes to qualify as separate episodes). The DSM-5 notes that there is always a risk of suicidal behavior during a major depressive episode.

[0111] MDD is acute in nature, as distinguished by the DSM-5 from "persistent depressive disorder." In persistent depressive disorder, patients have many of the same symptoms as MDD, but these symptoms persist for at least two years. In addition to MDD, the DSM-5 also defines "short-term persistent depressive episodes," which are characterized by the presence of depressed affect and at least four of the other symptoms defining MDD for at least four days but less than 14 days. The DSM further defines "recurrent brief depression" as the simultaneous presence of depressed mood and at least four other symptoms of depression for two to 13 days, occurring at least once a month, and persisting for at least 12 consecutive months. Thus, recurrent brief depression similarly consists of periodically recurring short-term depressive episodes.

[0112] The DSM-5 also includes a major depressive episode as one of the diagnostic criteria for patients with bipolar disorder, so patients with a major depressive episode may have either major depressive disorder or bipolar disorder.

[0113] There is clearly a particular need for effective depression treatments during the earliest stages of a major depressive episode. This is because each day of such an episode can have significant consequences for the patient, yet typical SSRI antidepressants take 2 to 4 weeks to produce beneficial effects. The same is true for the treatment of brief depressive episodes as well as individual episodes of recurrent brief depression.

[0114] DSM-5 classifies what has traditionally been called "postpartum depression" or "peripartum depression" simply as a subtype of depressive disorders recognized in the DSM, rather than as a separate depressive disorder. Thus, both major depressive disorder and acute depressive disorder may be diagnosed as "peripartum onset" (DSM-5 also does not distinguish between "peripartum" and "postpartum"). Thus, as used herein, any symptom of depression can be considered to include symptoms of such depression of perinatal or postpartum onset, and thus these symptoms encompass postpartum and perinatal depression.

[0115] DSM-5 defines various anxiety disorders, including generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. Similar to the depressive disorders discussed above, anxiety disorders can be characterized by short-term recurrent episodes, such as anxiety attacks, which may persist throughout the course of the chronic disorder. For example, DSM-5 defines generalized anxiety disorder as excessive anxiety and worry about some event or activity for at least six months, occurring more days than not. Anxiety attacks are defined as sudden surges of intense anxiety or intense discomfort that peak within minutes and may recur repeatedly in response to either expected or unexpected stimuli. Therefore, as with the depressive disorders described above, there is a need for fast-acting anxiolytics that can treat anxiety or panic symptoms. However, some of the most common treatments for anxiety disorders are SSRIs and other antidepressants, which take 2 to 4 weeks to provide relief.

[0116] Social avoidance can be a significant and debilitating symptom for patients with anxiety disorders, particularly those with social anxiety disorder and post-traumatic anxiety disorder. Social avoidance is often one of the major determinants of whether a person with severe anxiety disorder can maintain family or employment relationships. The compounds of the present disclosure have unexpectedly been found to be effective in treating emotional experience symptoms of psychiatric disorders (e.g., negative emotional symptoms of schizophrenia). Negative symptoms of schizophrenia can be divided into two categories: emotional experience (e.g., emotional withdrawal, passive social withdrawal, active social avoidance) and emotional expression (e.g., blunted affect, poor interpersonal relationships, lack of spontaneity, and slow motor skills). In two clinical studies of patients with acute exacerbation schizophrenia, administration of lumateperone (60 mg PO) once daily for up to 28 days resulted in significant and unexpected improvement in emotional experience symptoms compared to placebo. These are the symptoms most highly correlated with interpersonal functioning, and therefore the compounds of the present disclosure may be highly effective in treating the emotionally experiential symptoms of other psychiatric disorders such as social anxiety disorder, or any other psychiatric disorder in which social withdrawal and avoidance are manifestations.

[0117] Unless otherwise specified or otherwise clear from the context, the following terms used herein have the following meanings:

[0118] The compound of the present disclosure described herein can be in free form or pharmaceutically acceptable salt form.For the compound of formula I or II, pharmaceutically acceptable salt includes, for example, tosylate.The dosage or amount of salt is given by weight, for example, milligrams per day or milligrams per unit dose, and unless otherwise specified, the dosage of salt is given by the weight of corresponding free base.

[0119] The term "concurrently," when referring to therapeutic use, means administering two or more active ingredients to a patient as part of a regimen for treating a disease or disorder, regardless of whether the two or more active agents are given at the same or different times, or by the same or different routes of administration. Co-administration of two or more active ingredients may be at different times on the same day or on different days, or may be at different frequencies.

[0120] The term "concurrently," when referring to therapeutic use, means that two or more active ingredients are administered at or about the same time and by the same route of administration.

[0121] The term "separately," when referring to therapeutic use, means that two or more active ingredients are administered at or about the same time by different routes of administration.

[0122] With respect to simultaneous treatment with a compound of the present disclosure and an NMDA receptor antagonist (e.g., ketamine), without being bound by theory, it is believed that the combination of these agents allows for the desired effect to be achieved at lower doses of both agents according to the methods described herein, thereby maximizing synergistic effects while minimizing the dissociative effects caused by the NMDA receptor antagonist.

[0123] Dosages utilized in the practice of the present disclosure will naturally vary depending, for example, on the particular disease or condition being treated, the particular active compound used, the mode of administration, and the desired therapy. Unless otherwise indicated, the amount of active compound for administration refers to or is based on the amount of the compound in free form (whether administered as a free base or in salt form) (i.e., the amount calculation is based on the amount of the active moiety in free form, and in the case of salts, the weight of the counterion is not taken into account). The compounds of the present disclosure can be administered by any suitable route, including oral, parenteral, transdermal, or transmucosal, for example, in the form of tablets, capsules, subcutaneous injections, or oral, rapidly disintegrating tablets or films for sublingual or buccal administration.

[0124] As a reminder, any disclosure of a numerical range, e.g., an amount "up to X," is intended to include the upper numerical boundary X. Thus, a disclosure of "up to 60 mg" is intended to include 60 mg.

[0125] Pharmaceutical compositions containing the compounds of the present disclosure can be prepared using conventional diluents or excipients and techniques known in the pharmaceutical art. Thus, oral dosage forms can include tablets, capsules, solutions, suspensions, and the like.

[0126] The compounds of the present disclosure may be included in a depot formulation, for example, by dispersing, dissolving, suspending, or encapsulating the compounds of the present disclosure in a polymer matrix described herein, such that the compound is continuously released as the polymer degrades over time. The release of the compounds of the present disclosure from the polymer matrix provides, for example, controlled and / or delayed and / or sustained release of the compound from the pharmaceutical depot composition to a subject, for example, a warm-blooded animal, for example, a human, to whom the pharmaceutical depot is administered. Thus, the pharmaceutical depot delivers the compounds of the present disclosure to the subject over a sustained period, for example, for one week to three months, at concentrations effective to treat a particular disease or medical condition.

[0127] Useful polymers for the polymer matrix in the compositions of the present disclosure (e.g., depot compositions of the present disclosure) include polyesters of hydroxy fatty acids and their derivatives or other materials, such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta-hydroxybutyric acid, epsilon-caprolactone ring-opening polymers, lactic acid-glycolic acid copolymers, 2-hydroxybutyric acid-glycolic acid copolymers, polylactic acid-polyethylene glycol copolymers, or polyglycolic acid-polyethylene glycol copolymers), polymers of alkyl alpha-cyanoacrylates. (e.g., poly(butyl 2-cyanoacrylate)), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene propylene carbonate), polyortho-carbonates, polyamino acids (e.g., polygamma-L-alanine, polygamma-benzyl-L-glutamic acid or poly-γ-methyl-L-glutamic acid), hyaluronic acid esters, and the like, and one or more of these polymers can be used.

[0128] When the polymer is a copolymer, it may be any of random, block, and / or graft copolymers. When the above-mentioned alpha-hydroxycarboxylic acids, hydroxydicarboxylic acids, and hydroxytricarboxylic acids have optical activity in their molecules, any one of D-, L-, and / or DL-isomers can be used. Among them, alpha-hydroxycarboxylic acid polymers (preferably lactic acid-glycolic acid polymers), their esters, poly-alpha-cyanoacrylates, etc. can be used, and lactic acid-glycolic acid copolymers (also called poly(lactide-alpha-glycolide) or poly(lactic acid-co-glycolic acid), hereinafter referred to as PLGA) are preferred. Thus, in one embodiment, a useful polymer for the polymer matrix is ​​PLGA. As used herein, the term PLGA includes polymers of lactic acid (also called polylactic acid, poly(lactic acid), or PLA). Most preferably, the polymer is a biodegradable poly(d,l-lactide-co-glycolide) polymer, such as PLGA 50:50, PLGA 85:15, and PLGA 90:10.

[0129] In a preferred embodiment, the polymer matrix is ​​a biocompatible and biodegradable polymeric material. The term "biocompatible" is defined as a polymeric material that is non-toxic, non-carcinogenic, and does not induce significant inflammation in body tissues. The matrix material should be biodegradable such that the polymeric material is broken down by internal processes into products that can be easily disposed of by the body and should not accumulate within the body. The biodegradation products should also be biocompatible within the body in that the polymeric matrix is ​​also biocompatible with the body. Particularly useful examples of polymer matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, e.g., glycerol monostearate and glycerol distearate. A preferred polymer for use in the practice of the present invention is dl(polylactic acid-co-glycolide). The molar ratio of lactide to glycolide in such copolymers preferably ranges from about 75:25 to 50:50.

[0130] Useful PLGA polymers can have a weight-average molecular weight of about 5,000 to 500,000 daltons, preferably about 150,000 daltons. Polymers of different molecular weights can be used depending on the degradation rate to be achieved. For a diffusion mechanism of drug release, the polymer should remain intact until all the drug is released from the polymer matrix, after which it should degrade. Drugs may also be released from the polymer matrix as the polymeric excipient gradually erodes in vivo.

[0131] PLGA may be prepared by any conventional method or may be commercially available. For example, PLGA can be produced from cyclic lactide, glycolide, etc. by ring-opening polymerization using an appropriate catalyst (see EP 0058481; effect of polymerization variables on PLGA properties: molecular weight, composition, and chain structure).

[0132] PLGA is biodegradable by the breakdown of the entire solid polymer composition, and is believed to form lactic acid and glycolic acid by hydrolysis and the destruction of enzymatically cleavable ester bonds under in vivo conditions (e.g., in the presence of water and biological enzymes found in the tissues of warm-blooded animals such as humans). Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism and can be further biodegraded to form carbon dioxide and water. In other words, PLGA is believed to degrade in the presence of water, for example, in the body of a warm-blooded animal such as a human, by the hydrolysis of its ester groups to produce lactic acid and glycolic acid, creating an acidic microenvironment. Lactic acid and glycolic acid are by-products of various metabolic pathways under normal physiological conditions in the body of a warm-blooded animal such as a human, and are therefore well tolerated and produce minimal systemic toxicity.

[0133] The compounds of the present disclosure, and methods for their synthesis, including the synthesis of intermediates, are described, for example, in Li, et al., Journal of Medicinal Chemistry 57:2670-2682, the contents of which are incorporated herein by reference in their entirety. (2014), U.S. Patent No. 6,713,471, U.S. Patent No. 6,552,017, U.S. Patent No. 7,071,186, U.S. Patent No. 8,309,722, U.S. Patent No. 9,708,322, U.S. Patent No. 10,245,260, U.S. Patent No. 10,688,097, U.S. Patent No. 10,961,245, U.S. Patent No. 10,906,906, U.S. Patent No. 11,427,587, U.S. Patent No. 11,453,670, U.S. Patent Application Publication No. 2022 / 0048910, U.S. Patent Application Publication No. 2022 / 0041600, and U.S. Patent Application Publication No. 2022 / 0064166, and U.S. Provisional Application No. 63 / 478,010.

[0134] The synthesis of similar fused gamma-carbolines is disclosed, for example, in U.S. Pat. No. 8,309,722, U.S. Pat. No. 8,993,572, U.S. Patent Application Publication No. 2017 / 0183350, WO 2018 / 126140, and WO 2018 / 126143, the contents of each of which are incorporated by reference in their entirety. Compounds of the present disclosure can be prepared using similar procedures.

[0135] Salts of compounds of the present disclosure can be similarly prepared as described in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; 8,648,077; 9,199,995; 9,586,860; U.S. Reissue Patent No. RE39680; and U.S. Reissue Patent No. RE39679, the contents of each of which are incorporated by reference in their entirety.

[0136] The compounds of formula II described herein are disclosed and their synthesis provided in International Application No. PCT / US2023 / 86562, which is incorporated herein by reference in its entirety. [Example]

[0137] [Example 1] 1-(4-Fluorophenyl)-3-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)propan-1-one [ka]

[0138] To a degassed solution of (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline hydrochloride (3.0 g, 11.3 mmol) in anhydrous dioxane (20 mL) was added N,N-diisopropylethylamine (3.0 g, 22.6 mmol), 3-chloro-1-(4-fluorophenyl)propan-1-one (2.3 g, 12.4 mmol), potassium iodide (2.3 g, 13.6 mmol), and a catalytic amount of 18-crown-6 under argon. The resulting mixture was heated to 95 °C and stirred for 6.5 h. After cooling to room temperature, the solvent was removed and the residue was suspended in ethyl acetate (50 mL) and water (50 mL). The aqueous phase is separated and extracted twice with ethyl acetate (30 mL). The combined organic phases are dried over MgSO4 and concentrated. The residue is purified by silica gel column chromatography using a 0-20% mixed solvent gradient in ethyl acetate [ethyl acetate / methanol / 7N NH3 in methanol (10:1:0.1 v / v)] to give the title product as a brown solid (0.8 g, 16% yield). MS (ESI) m / z 380.2 [M+1] + . 1H NMR (500 MHz, DMSO) δ 9.15 (s, 1H), 8.19 - 8.07 (m, 2H), 7.42 (t, J = 8.8 Hz, 2H), 6.62 (t, J = 7.7 Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 6.44 (d, J = 7.9 Hz, 1H), 3.68 - 3.57 (m, 3H), 3.53 - 3.41 (m, 5H), 3.35 (q, J = 2.6 Hz, 1H), 3.23 (d, J = 5.8 Hz, 1H), 3.14 (q, J = 13.1 Hz, 1H), 2.82 (s, 4H), 2.76 - 2.61 (m, 2H), 2.29 (d, J = 15.5 Hz, 1H), 2.07 (t, J = 14.8 Hz, 1H).

[0139] [Example 2] Assessment of the effects of compounds of formula I and / or formula II on dendritic spine turnover in mice One or more compounds of Formula I or II ("compounds"), e.g., the compound of Example 1, are evaluated using procedures more fully described in Shao et al., Neuron, 109(16):2535-2544 (2021). The purpose of the experiment is to evaluate dendritic spine turnover (new spine formation and spine loss) in mice as a function of treatment with compound(s). The experiment analyzes the effects of acute and chronic compound administration on longitudinal analysis of spines in the mPFC using two-photon imaging technology (see below) in anesthetized mice. Because Shao et al. found that the effects of psilocybin differed between males and females, the effects of compound(s) on spine formation will also be measured in female mice.

[0140] Briefly, male and female transgenic mice Thy1 GFPMice (M strain) were obtained from the Jackson Laboratory and received at 4-8 weeks of age. These mice will be used for imaging approximately 2 weeks later. Mice are group-housed (2-5 mice per cage) under controlled temperature, a 12-hour light / dark cycle, and provided with food and water ad libitum.

[0141] Compound(s) are formulated in a vehicle consisting of 5% DMSO, 5% Tween-20, 15% PEG-400, and 75% water for acute injection approximately 30 minutes before use. Compound and vehicle are administered intraperitoneally (ip) or subcutaneously (sc). Psilocybin is administered in a saline vehicle either ip or sc.

[0142] Mice are divided into at least four groups: (1) unstressed, vehicle-treated; (2) stressed, vehicle-treated; (3) stressed, compound-treated (10 mg / kg, ip or sc); and (4) stressed, psilocybin-treated (1 mg / kg, ip). There are 4-6 animals per group. If more than one compound is to be tested, additional group (3) can be utilized. Additionally, additional groups can be utilized to evaluate either more compounds or psilocybin after both acute (single injection) or chronic (daily injections over a period of several days or long-acting single injection) treatments.

[0143] Drug injections (vehicle, compound(s), or psilocybin) are given once daily starting on either day -15, day -7, or day 0. Alternatively, a single drug injection (vehicle, compound, or psilocybin) is given once on either day -15, day -7, or day 0. Imaging is performed, for example, on days -15, -3, -1, 1, 8, 15, and 22 (+ / - 1 day) until 22 days have elapsed.

[0144] Restraint stress is a model of chronic stress-induced depression, and has been reported to cause significant morphological and neurochemical brain changes, as well as behavioral and cognitive impairments. Stress is administered according to standard procedures as chronic restraint stress from -21 to -1 or 0 days (e.g., Buynitsky et al. 2009, PMID: 19463853; Chiba et al. 2012, PMID: 22664354; Jaggi et al. 2011, PMID: 21927881; O'Mahony et al., 2011, PMID: 21110995; Ju et al. 2022, PMID: 35291971; Codeluppi et al., 2021. PMID: 34346493). Briefly, restraint stress is administered using one of two methods. In one method, mice are individually placed head-first into a well-ventilated 50 ml Falcon polypropylene conical tube with small holes drilled at each end (bottom and cap). The mouse's nose is positioned closest to the bottom hole, thus ensuring adequate ventilation. Within this device, mice cannot move back and forth and are maintained in restraining tubes placed on a secure surface at room temperature under the hood of a biological safety cabinet. Alternatively, restraint stress can be administered in a mouse restraint device (e.g., Stoelting Ref# 51338 cylindrical restrainer or tapered plastic Decapicone). Pilot experiments will be conducted to test the compatibility of these two alternative configurations with the imaging headplate. After the restraint period, mice are returned to their home cages in the animal facility with free access to food and water until the next restraint cycle.

[0145] Spine density is assessed from pre-stress baseline to days -21 to 22. Rates of spine formation and disappearance are assessed during stress on days -3 and -1, and on day 1 after treatment.

[0146] Before surgery, each mouse was injected with carprofen (5 mg / kg, sc) and dexamethasone (3 mg / kg, im). During surgery, each mouse was anesthetized with isoflurane (3-4% for induction, then 1-1.5% during surgery) and secured in a stereotaxic apparatus (David Kopf Instruments). The mouse's body was placed on a water-circulating heating pad set at 38°C. Prior to the procedure, the head was shaved and then disinfected with an ethanol pad and betadine. An incision was made to remove the skin and remove connective tissue from the skull. Next, a dental drill was used to create a circular craniotomy approximately 3 mm in diameter over the right medial frontal cortex (centered at +1.5 mm anteroposterior, AP; +0.4 mm medial-lateral, ML; relative to bregma). Artificial cerebrospinal fluid (ACSF: 135 NaCl, 5 HEPES, 5 KCl, 1.8 CaCl2, 1 MgCl2; pH 7.3, in mM) was used to perfuse the exposed dura mater over the brain. Two 3 mm diameter, #1 thickness circular glass cover slips were bonded with UV-curable optical adhesive to create a double-layered glass window. The glass window was carefully placed over the craniotomy, and while maintaining slight pressure, the glass window was secured to the skull periphery using adhesive (Henkel Loctite 454). A stainless steel head plate was attached to the skull with C&B Metabond (Parkell), centered over the glass window. Mice were given carprofen (5 mg / kg, sc) immediately after surgery and daily thereafter for 3 days. Mice were allowed to recover for at least 20 days after surgery before the start of imaging experiments.

[0147] The two-photon microscope (Movable Objective Microscope, Sutter Instrument) is controlled by ScanImage 2020 software. Laser excitation is provided by a tunable Ti:sapphire femtosecond laser (Chameleon Ultra II, Coherent) and focused onto the mouse brain using a water-immersion 20X objective (XLUMPLFLN, 20X / 0.95NA, Olympus Corporation). The laser power measured at the objective is ≤40 mW. During imaging sessions, mice are head-fixed and anesthetized with 1–1.5% isoflurane. Body temperature is controlled using a heating pad and a DC temperature controller with rectal thermistor probe feedback. Each imaging session lasts no longer than 2 hours. Apical tuft dendrites are imaged 0–200 μm below the dura. Multiple fields of view are imaged in the same mouse. For each field of view, a 10-40 μm thick image stack is collected at a resolution of 1024 × 1024 pixels, with 1 μm steps and 0.11 μm per pixel.

[0148] For longitudinal imaging, the field of view was returned to the same throughout the imaging session by triangulation and positioning from a landmark on the left edge of the glass window. Control mice received an equal volume of preformed vehicle solution via sc injection.

[0149] Structural parameters, such as spine head width and spine protrusion length, were quantified using a standardized protocol. Briefly, dendritic spines were counted if the protrusion extended more than 0.4 μm from the dendritic shaft. Dendritic spine head width was measured as the width at the widest part of the spine head. Dendritic spine protrusion length refers to the distance from the base of the shaft to the tip of the head. Distances were measured using the line segment tool in ImageJ. Changes in spine density, spine head width, and spine protrusion length across imaging sessions are shown as fold differences relative to the values ​​measured in the first imaging session (day -3) for each dendritic segment. Spine formation rates were calculated by dividing the number of newly formed dendritic spines between two consecutive imaging sessions by the total number of dendritic spines observed in the first imaging session. The spine loss rate was calculated by dividing the number of dendritic spines lost between two consecutive imaging sessions by the total number of dendritic spines observed in the first imaging session. To quantify the persistence of newly formed spines, the number of newly formed dendritic spines on day 1 that were still present on days 15 and 22 was calculated and divided by the total number of newly formed dendritic spines on day 1.

[0150] These results of the experiment indicate that the test compound, and psilocybin, both promote the formation of new dendritic spines, or promote dendritic growth and neuritogenesis.

[0151] [Example 3] Evaluating the effects of compounds of formula I and / or formula II on mTOR signaling in the prefrontal cortex (PFC) in the brain Male adult mice were SC-injected with test compound (1 mg / kg and / or 3 mg / kg and / or 10 mg / kg) or vehicle. 24 hours after injection, brain samples (e.g., prefrontal cortex (PFC) region or amygdala) were collected, and synaptoneurosome-enriched fractions were collected and prepared for Western blotting. Quantitative analysis of phospho(p)protein immunoblots was performed relative to the total protein levels. Changes in the amounts of phosphorylated ERK, Akt, mTOR, and P70S6K proteins in the tested brain regions compared to vehicle-treated mice were determined as previously described (Dutheil, et al., J. Neuroscience, 43(5):863-77, 2023).

[0152] Test compounds were found to stimulate mTOR signaling in a dose-dependent manner in the mouse medial PFC, as evidenced by increases in one or more of p-ERK, p-mTOR, and p-P70s6k in the brain regions tested. The mTOR signaling pathway has been shown to contribute to enhanced neuroplasticity and cognitive function, which is altered in brain regions associated with major depressive disorder. Fast-acting antidepressants have been reported to stimulate this pathway in the prefrontal cortex. Similar results have been obtained using samples from the amygdala. Further experiments are being conducted using hippocampal brain samples.

[0153] These results support the prediction that compounds of the present disclosure will provide enhanced nerve growth, enhanced neuritogenesis, enhanced neurite outgrowth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission, and other effects described herein, in human or animal brains, or in neuronal cells or tissues, in vivo or in vitro, via their effects on the mTOR signaling pathway.

[0154] In further studies, compounds of the present disclosure can also be tested using in vivo or in vitro examination of synaptic strength of fluorescently tagged neurotransmitter receptors or transporters, such as GFP (green fluorescent protein)-tagged or SEP (superecliptic pH fluorescent)-tagged receptors or transporters, e.g., AMPA-type glutamate receptors. Various methods of fluorescence microscopy, optionally with instrumental learning-enhanced analysis, can be utilized, e.g., the analysis described in Xu et al., "Cross-modality supervised image restoration enables nanoscale tracking of synaptic plasticity in living mice," Nature Methods 20:935-944 (June 2023; published online May 2023). Such methods can be used to identify numerous synaptic receptors and transporters, e.g., intrasynaptic serotonin receptors (e.g., 5-HT 2A , or 5-HT 2C ), dopamine receptors (e.g., D1 or D2), norepinephrine receptors, glutamate receptors (e.g., NMDA-type, AMPA-type, or mGluR-type), GABA receptors (e.g., GABA A or GABA B It can be applied to analyze the function, activity, and distribution of serotonin transporters (SERTs), dopamine transporters (DATs), norepinephrine transporters (NETs), glutamate transporters (e.g., EAATs or VGLUTs), and / or GABA transporter (e.g., GAT1, GAT3) density.

[0155] The examples provided herein are merely illustrative and are in no way intended to be limiting of the various aspects and embodiments of the invention described herein.

Claims

1. 1. A method for enhancing neuronal growth, enhancing neuronal connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, for example in the prefrontal cortex region of the brain, comprising administering to the subject an effective amount of a compound of Formula I. 【Chemistry 1】 [wherein X is —O—, —S—, —N(H), and —N(CH ３ )—, and Y is selected from —O—, —C(O)—, —CH(OH)—, and —CH(OCH ３ ) are selected. or a deuterated analog thereof in free form or in pharmaceutically acceptable salt form; or Compound of Formula II: 【Chemistry 2】 [In the formula, X is S, S(O), S(O) ２ , O, C.H. ２ , CHR ｂ , C(R ｂ ) ２ , NH, N(R ａ ) (e.g., N(CH ３ )), N-C(O)-R ａ , N-C(O)-OR ａ , N-C(O)-O-CH ２ -O-R ａ , N-CH ２ —O—C(O)—R ａ , N ＋ (=O － ), spiro bond C ３～６ cycloalkyl (e.g., cyclopropane), or spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-linked C ３～６ Cycloalkyl or 3- to 6-membered heterocycloalkyl is C １～６ Alkyl (e.g., methyl), haloC １～６ alkyl (e.g., trifluoromethyl), C １～６ Alkoxy (e.g., methoxy), C ３～６ cycloalkyl (e.g., cyclopropyl), C ３～６ optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH ２ , CHR ｃ , -C(O)-,C(R ｃ ) ２ , spiro bond C ３～６ cycloalkyl (e.g., cyclopropane), or spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-linked C ３～６ Cycloalkyl or 3- to 6-membered heterocycloalkyl is C １～６ Alkyl (e.g., methyl), haloC １～６ alkyl (e.g., trifluoromethyl), C １～６ Alkoxy (e.g., methoxy), C ３～６ cycloalkyl (e.g., cyclopropyl), C ３～６ optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Z is a bond, -S-, S(O), S(O) ２ , -O-, -NH, N(R ｄ ), -C(O)-, -C(OH)-, -C(OC １～６ alkyl), -C(=N-OH)-, -C(=N-OC １～６ alkyl)-, spiro bond C ３～６ cycloalkyl (e.g., cyclopropane), spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), or —O(CH ２ ) ｐ O- (wherein p is 2, 3, or 4 (e.g., p is 2)), and the spiro bond C ３～６ Cycloalkyl or 3- to 6-membered heterocycloalkyl is C １～６ Alkyl (e.g., methyl), haloC １～６ alkyl (e.g., trifluoromethyl), C １～６ Alkoxy (e.g., methoxy), C ３～６ cycloalkyl (e.g., cyclopropyl), C ３～６ optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; A is H, C ３～６ cycloalkyl (e.g., cyclopropyl or cyclohexyl), aryl (e.g., phenyl), or heteroaryl, wherein said cycloalkyl, aryl, or heteroaryl is substituted with 0-5 R groups; Each R is independently aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C １～６ Alkyl (e.g., methyl), haloC １～６ alkyl (e.g., trifluoromethyl), C １～６ Alkyl sulfonyl (e.g., methyl sulfonyl), C １～６ Alkoxy (e.g., methoxy, ethoxy), C １～６ Alkylthio (e.g., methylthio), halo (e.g., F), cyano, C ３～６ cycloalkyl (e.g., cyclopropyl), C ３～６ cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is selected from aryl (optionally substituted with halo), halo, C １～６ Alkyl (e.g., methyl), haloC １～６ alkyl (e.g., trifluoromethyl), C １～６ Alkyl sulfonyl (e.g., methyl sulfonyl), C １～６ Alkoxy (e.g., methoxy), C １～６ alkylthio (e.g., methylthio), C ３～６ cycloalkyl (e.g., cyclopropyl), C ３～６ Cycloalkoxy (e.g., cyclopropoxy), amino, C １～６ Alkylamino (e.g., methylamino), di(C １～６ alkyl)amino (e.g., dimethylamino), (C １～６ alkyl) (C １～６ optionally further substituted with one or more groups selected from: alkyl)amino (e.g., methylethylamino), and hydroxy; R ａ and R ｄ are each independently C １～２０ alkyl (e.g., methyl or tert-butyl), and C １～２ alkylaryl (e.g., benzyl or phenethyl); R ｂ and R ｃ are each independently C １～６ Alkyl (e.g., methyl, ethyl, tert-butyl), C １～６ Alkoxy, C ３～６ cycloalkyl (e.g., cyclopropyl), C ３～６ cycloalkoxy (e.g., cyclopropoxy), and C １～２ alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2; n is 1, 2, 3, 4, or 5; provided that Z is —C(O)— and X is CH ２ or O, and when m is 2, n is not 3; Z is —C(O)— and X is CH ２ and when m is 1, n is not 3; Z is —C(O)— or —O—, and X is NH or N(R ａ ) and when m is 1, n is not 3; Z is O and X is NCH ３ and when Y is —C(O)— and m is 1, then n is not 3. to said subject in free form or in a salt form (e.g., a pharmaceutically acceptable salt form).

2. 1. A method for enhancing neuritogenesis and / or neurite outgrowth in the brain of a subject in need thereof, e.g., in the prefrontal cortex region of the brain, comprising administering to the subject an effective amount of a compound of formula I, or a deuterium analog thereof, as described in claim 1, or an effective amount of a compound of formula II, each in free form or in salt form (e.g., a pharmaceutically acceptable salt form).

3. The compound of formula I or a deuterium analog thereof is non-deuterated lumateperone, i.e., has the following structure: 【Transformation 3】 and in free form or in salt form (e.g., a pharmaceutically acceptable salt form).

4. The compound of formula II is 【Chemistry 4】 3. The method of claim 1 or 2, wherein the compound is in free form or in a salt form (e.g., a pharmaceutically acceptable salt form).

5. 5. The method of any of claims 1 to 4, wherein the compound of formula I or a deuterated analog thereof, or the compound of formula II, is in the form of a pharmaceutically acceptable salt.

6. The method of claim 5, wherein the pharmaceutically acceptable salt is a toluenesulfonic acid addition salt (e.g., mono-tosylate or bis-tosylate).

7. 7. The method of claim 1, wherein the method provides enhanced neural growth in the subject's brain (e.g., in the prefrontal cortex region of the brain).

8. 7. The method of any one of claims 1 to 6, wherein the method provides increased neural connectivity within the subject's brain (e.g., in the prefrontal cortex region of the brain).

9. 7. The method of any one of claims 1 to 6, which provides an increase in synaptic density in the subject's brain (e.g., in the prefrontal cortex region of the brain).

10. 7. The method of any one of claims 1 to 6, wherein the method provides an increase in dendritic spine density in the subject's brain (e.g., in the prefrontal cortex region of the brain).

11. 7. The method of any one of claims 1 to 6, wherein the method provides an increase in dendritic spine size (e.g., an increase in spine head width and / or an increase in spine process length) in the subject's brain (e.g., in the prefrontal cortex region of the brain).

12. 7. The method of any one of claims 1 to 6, wherein the method provides an increase in excitatory neurotransmission (e.g., enhanced glutamatergic transmission or an increase in the rate of mEPSCs) in the subject's brain (e.g., in the prefrontal cortex region of the brain).

13. 13. The method of any one of claims 7 to 12, wherein the enhanced neural growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission is characterized or caused by enhanced neuritogenesis and / or enhanced neurite outgrowth.

14. 13. The method of any one of claims 1 to 12, which enhances neuritogenesis and / or enhances neurite outgrowth.

15. 15. The method of any one of claims 1 to 14, wherein the enhanced neuritogenesis, enhanced neurite outgrowth, enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission is provided in the subject's brain (e.g., in the prefrontal cortex region of the brain) within less than 4 weeks of initiating administration of the compound, e.g., within less than 3 weeks, less than 2 weeks, less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days after initiating treatment with the compound.

16. 15. The method of any one of claims 1 to 14, wherein at least 50% of the peak of the enhanced neuritogenesis, enhanced neurite outgrowth, enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission is maintained in the subject's brain (e.g., in the prefrontal cortex region of the brain) for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months after administration of the compound has stopped.

17. 15. The method of any one of claims 1 to 14, wherein at least 50% of the peak of the enhanced neuritogenesis, enhanced neurite outgrowth, enhanced nerve growth, enhanced neural connectivity, increased synaptic density, increased dendritic spine density, increased dendritic spine size, and / or increased excitatory neurotransmission in the subject's brain (e.g., in the prefrontal cortex region of the brain) is maintained for at least 2 weeks, e.g., at least 3 weeks, or at least 4 weeks, or at least 2 months, or at least 3 months, after administration of a single dose of the compound.

18. 18. The method of any one of claims 1 to 17, which does not cause hallucinogenic side effects.

19. 1. A method for enhancing neural growth, enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in neural cells or neural tissue (e.g., cell culture), in vitro or in vivo, comprising contacting the neural cells or neural tissue with an effective amount of a compound of Formula I or a deuterated analog thereof, or a compound of Formula II, each in free form or in a pharmaceutically acceptable salt form, as described in claim 1.

20. 10. The compound of formula I or a deuterated analogue thereof according to claim 1, or the compound of formula II, in free form or a pharmaceutically acceptable salt form, for use in enhancing neuritogenesis, enhancing neurite outgrowth, enhancing neural connectivity, increasing synaptic density, increasing dendritic spine density, increasing dendritic spine size, and / or increasing excitatory neurotransmission in the brain of a subject in need thereof, for example in the prefrontal cortex region of the brain.

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