Organic compounds

Abstract

The invention relates to particular substituted heterocycle fused gamma-carbolines, in free, solid, pharmaceutically acceptable salt and / or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use as agonists or antagonists of the serotonin (5-HT2A) receptor, preferably non-hallucinogenic biased agonists at the serotonin (5-HT2A) receptor, such as having agonism biased towards the beta-arrestin signaling pathway. Such compounds are useful for the treatment of mood disorders, general anxiety, social anxiety, depression, and other neuropsychiatric diseases.

Description

ORGANIC COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS The instant application is an international application which claims priority to, and the benefit of, U.S. Provisional Applications Ser. Nos. 63 / 667,496, 63 / 667,501, 63 / 667,503 and 63 / 667,508, each filed on July 3, 2024, the contents of each of which are hereby incorporated by reference in their entireties. TECHNICAL FIELD

[0001] The invention relates to particular substituted and unsubstituted heterocycle fused gamma-carbolines, in free, solid, pharmaceutically acceptable salt and / or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use as agonists or antagonists of the serotonin (5-HT2A) receptor, preferably non-hallucinogenic biased agonists at the serotonin (5-HT2A) receptor, in particularly having agonism biased towards the beta-arrestin signaling pathway, or as serotonin (5-HT2A) receptor antagonists. Such compounds may be useful for the treatment of mood disorders, general anxiety, social anxiety, depression, schizophrenia, and other neuropsychiatric diseases. BACKGROUND

[0002] 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 5-HT receptor agonists and selective serotonin reuptake inhibitors, are widely used in psychiatry, finding use in the treatment of numerous mood disorders as well as in the treatment of psychosis. However, strong 5-HT agonists tend to cause hallucinations, which is a dangerous side effect. There have been studies suggesting that the classic hallucinogenic psychedelic serotonin agonists, such as LSD (D-lysergic acid diethylamide) and psilocybin (via its active metabolite psilocin) could be very effective in the treatment of numerous neuropsychiatric disorders, especially depression, but these drugs are not feasible in practice because of their hallucinogenic side effects. Therefore, there has been an effort to develop novel compounds having a pharmacological profile similar to the hallucinogenic psychedelics, but without the hallucinations.ped in the 1970’s, which has been used for the treatment of Parkinson’s disease and migraine attacks. Two non-hallucinogenic psychedelic analogs have been recently described as having anti-depressant like behavior. Cameron et al. generated the novel compound tabernanthalog by modifying the skeletal core of the natural hallucinogenic psychedelic ibogaine. Nature, 589:474-79 (2021). Cell, 184:2779-92.e18 (2021). Similarly, based on the well-known hallucinogenic psychedelic 5- methoxy-dimethyltryptamine, Dong et al. arrived at the novel analog AAZ-A-154. However, neither of these groups developed any structure-activity guidance for these compounds, and it thus remained unclear how to rationally design non-hallucinogenic psychedelic analogs.. Except for 5-HT3, a ligand gated ion channel, all of the serotonin receptors have long been known to be G- protein coupled receptors (GPCRs). GPCRs have an intracellular domain which is bound to a heterotrimeric G protein. G proteins consist of alpha-, beta-, and gamma-subunits in a complex. The G-protein heterotrimer is normally in an inactive state, bound to a guanosine diphosphate ligand. Agonist binding to a GPCR causes a conformational change in the protein’s intracellular domain which allows it to catalyze the exchange of the bound GDP for a GTP molecule (guanosine triphosphate). This results in activation of the G-protein and its dissociation from the GPCR’s intracellular domain. In particular, the G-protein alpha subunit (G-alpha) dissociates and diffuse into the cytosol. There are numerous types of G-alpha proteins which differ in their functional effects. Some G-alpha proteins, including Gi, Go, and Gs, regulate levels of the cytosolic second messenger cAMP (cyclic adenosine monophosphate), by activating or inactivating adenylyl cyclase enzymes. The G-alpha-q variant (Gq) operates by activating phospholipase C enzyme, which cleaves phosphatidylinositol diphosphate (PIP2) to form the two second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates calcium release from intracellular storage locations, resulting in the activation of various calcium- dependent kinases, and DAG stimulates protein kinase C (PKC) activation. Because G-proteins are abundant soluble cytosolic proteins, an agonist-activated GPCR which has activated and released its G-protein may bind to another GDP-bound heterotrimer, thus activating and releasing a second GTP-bound G-alpha subunit, and so on, until the receptor deactivated.

[0005] GPCR are deactivated in a two-step process. First, they are phosphorylated by a family of enzymes called G receptor kinases (GRKs). This greatly reduces the affinity of the GPCR’s active site for G-protein. In the second step, beta-arrestin proteins can competitively bind to the active site of the phosphorylated GPCR, resulting in complete inhibition of G-proteinbinding. The arrestin-GPCR complex then targets the inactivated receptor for either recycling or degradation within the cell.

[0006] The beta-arrestin proteins were originally thought to only play a role in inactivating and targeting the inactivated GPCR for recycling or degradation. However, in the last few years, it has become increasingly apparent that beta-arrestin proteins also play a novel role in G-protein independent signaling mechanisms. Apparently, the GPCR-arrestin complex created following agonist-induced receptor activation and deactivation may serve as a scaffold which can attract many other proteins to form large multi-protein complexes. The complexes can then cause the activation of a variety of kinases involved in cell signaling, including Src, ERKs, MAPKs. For example, some signaling cascades, such as the MAPK cascade, require two kinase proteins to approach each other closely so that one may phosphorylate the other. Arrestin complexes may facilitate such phosphorylation by binding to both kinase proteins at the same time. Therefore, beta-arrestin signaling provides an alternative mechanism for GPCR signal transduction that does not rely on G-protein-induced signaling cascades and second messengers.

[0007] Signaling bias is the concept that some ligands will bind to a GPCR in such a manner as to bias the receptor towards or away from one of the two signaling pathway: G-protein mediated signaling and beta-arrestin mediated signaling. Several examples of such biased GPCR ligands have been discovered, and it creates the potential for functionally selective receptor agonism. For example, the mu-opioid receptor (MOR) is a GPCR coupled to the Gi-type alpha subunit, so that agonist binding results in inhibition of adenylate cyclase activity and a reduction in cytosolic cAMP levels. It is found that this G-protein mediated pathway is responsible for morphine and other opioid drugs’ analgesic activity. However, it is beta-arrestin recruitment to the receptor that is the cause of the major opioid side effects, respiratory depression and inhibition of gastrointestinal motility. Various MOR ligands have been discovered which show bias towards the G-protein signaling and away from the beta-arrestin signaling, resulting in enhanced analgesic efficacy with a reduced side effect profile. This can either reflect a higher efficacy for agonism via one pathway or the other, or even agonism of one pathway and antagonism of the other pathway.

[0008] While the 5-HT1, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors are coupled to the cAMP-regulating G proteins, the 5-HT2family of receptors are GPCRs coupled to Gq proteins, thus resulting in a classic signaling cascade mediated by the phosphatidylinositol pathway. It hasalso been found that the 5-HT2receptors are also capable of activating a beta-arrestin signaling cascade as well.

[0009] Signaling bias offers an exciting opportunity when it comes to 5-HT2A receptor agonists, because while 5-HT2Areceptor agonism can provide potent relief for mood disorders, such as depression and anxiety, strong 5-HT2A receptor agonists are well-known as potent hallucinogens. For example, LSD (D-lysergic acid diethylamide) and psilocybin (via its active metabolite psilocin) could be very effective in the treatment of numerous neuropsychiatric disorders, especially depression, but these drugs are not feasible in practice because of their strong hallucinogenic side effects. These hallucinogenic psychedelics can cause overwhelming distress (i.e., “bad trips”) or prolonged or intermittent psychoses, can promote self-harm or harm to others, and are prone to abuse and dependence. In addition, it has been reported that serotonergic agents having 5-HT2B agonist activity may cause valvular heart disease and / or pulmonary arterial hypertension. Therefore, there has been an effort to develop novel compounds having a pharmacological profile for treatment of mood and other CNS disorders, similar to the hallucinogenic psychedelics, but without the hallucinations, abuse liability, or valvular heart disease risk.

[0010] It is believed that serotonin agonists must agonize both the G-protein signaling pathway and the beta-arrestin signaling pathway of the 5-HT2A receptor in order to cause hallucinations, while agonists which selectively agonize the beta-arrestin pathway without agonizing the G-protein coupled pathway may provide relief of mood disorders, anxiety, and other CNS disorders without hallucinogenic side effects. Thus, biased agonists would be extremely beneficial.

[0011] Recently, Cao et al. studied the binding of numerous compounds, including serotonin, psilocin, LSD, the non-hallucinogenic psychedelic analog lisuride, and lumateperone, to the 5- HT2A receptor using high-resolution X-ray crystallography. Science, 375:403-11 (2022). They identified a new binding mode for serotonin and psilocin. Traditionally, LSD, lisuride, serotonin and psilocin were known to bind in the so-called “orthostatic binding pocket (OBP).” In this binding mode, the polycyclic core of LSD and lisuride binds low in the OBP, while the side chains of LSD and lisuride protrude into the so-called “extended-binding pocket (EBP).” In contrast, the indole core of serotonin and psilocin sit higher in the OBP, closer to the EBP, but without significant protrusion into the EBP.

[0012] Surprisingly, Cao et al. discovered that serotonin and psilocin have a second binding mode which is flipped so that the indole core sits in the EBP with only minimal presence in the upper part of the OBP. Cao further generated data suggesting that this second binding mode is responsible for increased beta-arrestin recruitment by the receptor, thus explaining the existence of biased serotonin receptor agonism. They also present evidence that the Gq-mediated signaling is responsible for the hallucinogenic effects of the traditional psychedelics, and that ligands which are biased towards beta-arrestin recruitment may provide the therapeutic benefits of the psychedelics, such as antidepressant action, without hallucinogenic side effects.

[0013] Substituted heterocycle fused gamma-carbolines are known to be agonists or antagonists of 5-HT2receptors, particularly 5-HT2Areceptors, and are useful in treating central nervous system disorders. These compounds have been generally disclosed in U.S. Pat. No. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. RE 39.680, and U.S. RE 39,679. U.S. Patent 8,309,722, and U.S. Patent 7,081,455, disclose methods of making such substituted heterocycle fused gamma-carbolines and uses of these gamma-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders. The following generic structure is typical of these disclosures: .

[0014] In addition, U.S.substituted heterocycle fused gamma-carbolines for the treatment of a combination of psychosis and depressive disorders as well as sleep, depressive and / or mood disorders in patients with psychosis or Parkinson's disease. In addition to disorders associated with psychosis and / or depression, this patent application discloses and claims use of these compounds at a low dose to selectivelyantagonize 5-HT2Areceptors without affecting or minimally affecting dopamine D2receptors, thereby useful for the treatment of sleep disorders without the side effects associated with high occupancy of the dopamine D2 pathways or side effects of other pathways (e.g., GABAA receptors) associated with conventional sedative-hypnotic agents (e.g., benzodiazepines). U.S. Patent 8,648,077 discloses methods of preparing toluenesulfonic acid addition salt crystals of these substituted heterocycle fused gamma-carbolines.

[0015] US 2021 / 006009 discloses evidence showing that the aforementioned substituted fused heterocycle gamma carbolines, particularly lumateperone, may operate, in part, through glutamate (NMDA and AMPA receptor) receptor activation leading to enhanced mTOR1 signaling, in a manner similar to that of ketamine. Ketamine is a selective NMDA receptor antagonist. Ketamine acts through a system that is unrelated to the common psychogenic monoamines (serotonin, norepinephrine and dopamine), and this may be a major reason for its much more rapid effects. Ketamine directly antagonizes extrasynaptic glutamatergic NMDA receptors, which also decreases GABAergic inhibition resulting in indirect activation of AMPA- type glutamate receptors. The downstream effects of AMPA receptor activation involve increase levels of brain-derived neurotrophic factor (BDNF) and activation of mTORC1 kinase pathways. Like ketamine, recent evidence suggests that compounds related to those of the present disclosure enhance both NMDA and AMPA-induced currents in rat medial prefrontal cortex pyramidal neurons via activation of D1 receptors, and that this is associated with increased mTORC1 signaling.

[0016] U.S. 10,245,260 discloses novel substituted heterocycle fused gamma-carboline lactams, which are oxo-metabolites of the substituted heterocycle fused gamma-carbolines disclosed in the above-mentioned publications. These new lactams (oxo-metabolites) retain much of the unique pharmacologic activity of the parent compounds, including serotonin receptor inhibition, SERT inhibition, and dopamine receptor modulation. However, these oxo- metabolites were found to unexpectedly also show significant activity at mu-opioid receptors. Analogs of these novel compounds have also been disclosed, for example, in publications U.S. 10,906,906 and U.S. 10,961,245.

[0017] Only one substituted fused gamma-carboline pharmaceutical has been brough to market, lumateperone, which is sold in the United States as CAPLYTA® (lumateperone tosylate). Lumateperone has the following structure:F Hwith the chemical name - lH-pyrido[3',4': 4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)-l-(4-fluorophenyl)-l-butanone). It is known to be an extremely potent serotonin receptor (5-HT2A) antagonist, as well as a modulator of dopamine receptor (D1 and / or D2) signaling, and a serotonin transporter (SERT) antagonist, and it is useful in treating a variety of central nervous system disorders. It has also been known as ITI-007.

[0018] Lumateperone is a unique therapeutic agent with potent (Ki=0.5nM) 5-HT2A receptor antagonism, activity as a mesolimbic / mesocortical-selective dopamine receptor protein phosphorylation modulator consistent with presynaptic D2 receptor partial agonism and postsynaptic D2 receptor antagonism (Ki=32nM) in vivo, high D1 receptor affinity (Ki=52nM), and inhibition of the serotonin transporter (SERT) (Ki=26-62nM, using different assays for SERT activity).

[0019] Lumateperone antagonizes the serotonin-2A (5-HT2A) receptor, and / or modulates dopamine receptor signaling at the level of key intracellular phosphoproteins. This compound is principally known to be useful for the treatment of positive and negative symptoms of schizophrenia, depression (especially acute depression and bipolar depression), anxiety and traumatic disorders (including acute anxiety and post-traumatic stress disorder), and dementias (including Alzheimer’s disease and the symptoms associated therewith). Lumateperone’s effect as an anti-depressant is tied to its antagonism at the 5-HT2A receptor and its inhibition of the serotonin transporter (SERT), pharmacological features which it shares with the SARI class of antidepressants (Serotonin Antagonist and Reuptake Inhibitor), which includes trazodone, nefazodone, lorpiprazole, and mepiprazole.

[0020] At dopamine D2 receptors, lumateperone has dual properties and acts as both a post- synaptic antagonist and a pre-synaptic partial agonist of the D2 receptor. It also stimulates phosphorylation of glutamatergic NMDA NR2B, or GluN2B, receptors in a mesolimbic specific manner. It is believed that this regional selectivity in the brain areas is thought to mediate the efficacy of antipsychotic drugs, together with the serotonergic, glutamatergic, and dopaminergicinteractions, may result in antipsychotic efficacy for positive, negative, affective and cognitive symptoms associated with schizophrenia. The compound also exhibits serotonin reuptake inhibition, providing antidepressant activity for the treatment of schizoaffective disorder, co- morbid depression, and / or as a stand-alone treatment for major depressive disorder. Lumateperone is also useful for the treatment of bipolar disorder and other psychiatric and neurodegenerative disorders, particularly behavioral disturbances associated with dementia, autism and other CNS diseases. These features may be able to improve the quality of life of patients with schizophrenia and enhance social function to allow them to more fully integrate into their families and their workplace.

[0021] WO 2023 / 225620 and US 2023 / 0372336 disclose that substituted heterocycle fused gamma-carbolines, particularly lumateperone, are effective in reducing aberrantly elevated levels of proinflammatory cytokines in both brain and serum, alters key pathways involved in tissue integrity and the maintenance of the blood-brain barrier (BBB), demonstrating anxiolytic and antianhedonic properties in rats, and reinforced BBB protection during inflammatory and stress challenges. This suggests that such compounds are effective in the treatment of psychiatric disorders caused by viral, bacterial, or autoimmune encephalitis, and for treatment of psychiatric symptoms of viral, bacterial, and autoimmune encephalitis. It is further disclosed that such compounds are effective in protecting or reinforcing the blood-brain barrier.

[0022] More recently, WO2024 / 145659, described a new series of substituted fused gamma- carbolines having biased agonism at the 5-HT2Areceptor. Lumateperone, however, is not a biased agonist. In fact, as described in PCT / US2023 / 86562, lumateperone is a potent antagonist of 5-HT2A receptors in both the beta-arrestin and Gq functional assays. Indeed, it may be observed that the side-chain of lumateperone, a 4-(4-fluorophenyl)-4-oxobutyl side chain, is the same side chain as present in the classical typical antipsychotic haloperidol, which also has 5- HT2A receptor antagonist activity.

[0023] Lumateperone tosylate (CAPLYTA®) is currently approved in the United States for the treatment of schizophrenia and the treatment of depressive episodes of bipolar disorder (bipolar depression). It is currently in clinical trials and development for additional indications, including major depressive disorder (MDD) and agitation in dementia, including Alzheimer’s Disease.

[0024] The functional effects of lumateperone on the beta-arrestin recruitment and Gq- mediated signaling pathways induced by binding to the 5-HT2A receptor have not been previously disclosed. The present inventors have found that lumateperone is a potent antagonist of 5-HT2Areceptors in both the beta-arrestin and Gqfunctional assays.

[0025] There remains a need for new compounds with efficacy in treating neuropsychiatric disorders, especially depression, anxiety, and schizophrenia. It would be particularly beneficial to have compounds with strong biased agonism (e.g., full agonism or partial agonism) towards beta-arrestin recruitment at the 5-HT2A receptor in order to provide a non-hallucinogenic anti- depressant or anxiolytic effect. BRIEF SUMMARY

[0026] In a first aspect, the present disclosure relates to a compound (Compound I) of Formula I:wherein: X is selected from S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N- C(O)-Ra, N-C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O–), a spiro- joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHRc, -C(O)-, C(Rc)2, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g.,trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(Rd), -C(O)-, -C(OH)-, -C(OC1-6alkyl), -C(=N- OH)-, -C(=N-OC1-6alkyl)-, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), a spiro- joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -O(CH2)pO- wherein p is 2, 3, or 4 (e.g., p is 2), wherein said spiro-joined C3-6cycloalkyl or 3-6- membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; A is H, C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), an aryl (e.g., phenyl), or heteroaryl ring, wherein said cycloalkyl, aryl, or heteroaryl is substituted by 0-5 groups R; each R is independently selected from aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C1-6alkyl (e.g., methyl, ethyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1- 6alkylthio (e.g., methylthio), halo (e.g., F), cyano, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is optionally further substituted by one or more aryl (optionally substituted with halo), halo, C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1-6alkylthio (e.g., methylthio), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), amino, C1- 6alkylamino (e.g., methylamino), di(C1-6alkyl)amino (e.g., dimethylamino), (C1-6alkyl)(C1-6alkyl)amino (e.g., methylethylamino), and hydroxy; R1and R2are each independently selected from H, halo (e.g., F), C1-3alkyl (e.g., methyl), C1-3alkoxy (e.g., methoxy), OH, and CN, provided that R1and R2are not both H; Raand Rd, are each independently selected from C1-20alkyl (e.g., methyl or tert-butyl), and C1-2alkylaryl (e.g., benzyl or phenethyl); Rband Rcare each independently selected from C1-6alkyl (e.g., methyl, ethyl, tert-butyl), C1-6alkoxy, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and C1-2alkylaryl (e.g., benzyl or phenethyl);m is 1 or 2; n is 1, 2, 3, 4, or 5; in free or salt form (e.g., pharmaceutically acceptable salt form); optionally wherein X is not NH or N(Ra) (e.g., N(CH3)), when Y is -C(O)- and m is 1; optionally, provided that: R1is not methyl, when m is 1, n is 3, X is N(CH3), Y is -CH2-, Z is -C(O)-, and A is 4- fluorophenyl; R1is not methyl, when m is 1, n is 3, X is N(CH3), Y is -C(O)-, Z is –(O)-, and A is 4- fluorophenyl; R1is not methyl or ethyl, when m is 1, n is 3, X is N(CH3), Y is -C(O)-, Z is -C(O)-, and A is 4-fluorophenyl; and / or R1is not methyl, when m is 1, n is 3, X is N(CH2CH3), Y is -C(O)-, Z is -C(O)-, and A is 4-fluorophenyl.

[0027] The present disclosure further provides additional embodiments of first aspect, including: 1.1 Compound 1, wherein R1is halo (e.g., F) and R2is H; 1.2 Compound 1, wherein R1is H and R2is halo (e.g., F); 1.3 Compound 1, wherein R1is C1-3alkyl (e.g., methyl) and R2is H; 1.4 Compound 1, wherein R1is H and R2is C1-3alkyl (e.g., methyl); 1.5 Compound 1, wherein R1is halo (e.g., F) and R2is halo (e.g., F); 1.6 Compound 1, wherein R1is C1-3alkyl (e.g., methyl) and R2is C1-3alkyl (e.g., methyl); 1.7 Compound 1, wherein R1is C1-3alkyl (e.g., methyl) and R2is halo (e.g., F); 1.8 Compound 1, wherein R1is halo (e.g., F) and R2is C1-3alkyl (e.g., methyl); 1.9 Compound 1, or any of 1.1-1.8, wherein X is S, S(O), or S(O)2; 1.10 Compound 1, or any of 1.1-1.8, wherein X is O; 1.11 Compound 1, or any of 1.1-1.8, wherein X is CH2, CHRb, or C(Rb)2; 1.12 Compound 1.11, wherein Rbis independently C1-6alkyl (e.g., methyl); 1.13 Compound 1, or any of 1.1-1.8, wherein X is CH2; 1.14 Compound 1, or any of 1.1-1.8, wherein X is NH;Compound 1, or any of 1.1-1.8, wherein X is N(Ra); Compound 1, or any of 1.1-1.8, wherein X is N-C(O)-Ra; Compound 1, or any of 1.1-1.8, wherein X is N-C(O)-O-Ra; Compound 1, or any of 1.1-1.8, wherein X is N-C(O)-O-CH2-O-Ra; Compound 1, or any of 1.1-1.8, wherein X is N-CH2-O-C(O)-Ra; Compound 1, or any of 1.15-1.19, wherein Rais C1-2alkylaryl (e.g., benzyl or phenethyl); Compound 1, or any of 1.15-1.19, wherein Rais C1-20alkyl (e.g., methyl or tert- butyl); Compound 1, or any of 1.15-1.19, wherein Rais C10-20alkyl (e.g., decyl or dodecyl); Compound 1, or any of 1.15-1.19, wherein Rais C1-15alkyl (e.g., hexyl or octyl); Compound 1, or any of 1.15-1.19, wherein Rais C7-15alkyl (e.g., heptyl or nonyl); Compound 1, or any of 1.15-1.198, wherein Rais C1-6alkyl (e.g., butyl or hexyl); Compound 1, or any of 1.15-1.19, wherein Rais C1-4alkyl (e.g., n-butyl or tert- butyl); Compound 1, or any of 1.15-1.19, wherein Rais C1-3alkyl (e.g., propyl or isopropyl); Compound 1, or any of 1.15-1.19, wherein Rais C1-2alkyl (e.g., methyl or ethyl); Compound 1, or any of 1.1-1.8, wherein X is N(CH3); Compound 1, or any of 1.1-1.8, wherein X is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane); Compound 1.30, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 1.31, wherein the spiro-joined C3-6cycloalkyl is cyclopropane; Compound 1, or any of 1.1-1.8, wherein X is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane); Compound 1.33, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine;Compound 1.34, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine; Compound 1, or any of 1.30-1.35, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 1, or any of 1.30-1.35, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 1, or any of 1.1-1.37, wherein Y is CH2; Compound 1, or any of 1.1-1.37, wherein Y is -C(O)-; Compound 1, or any of 1.1-1.37, wherein Y is CHRcor C(Rc)2; Compound 1.40, wherein Rcis C1-6alkyl; Compound 1.40, wherein Rcis selected from methyl, ethyl and propyl; Compound 1, or any of 1.1-1.37, wherein Y is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane); Compound 1.43, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 1.43, wherein the spiro-joined C3-6cycloalkyl is cyclopropane; Compound 1, or any of 1.1-1.37, wherein Y is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane); Compound 1.46, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 1.46, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine; Compound 1, or any of 1.43-1.48, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 1, or any of 1.43-1.48, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g.,methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 1, or any of 1.1-1.50, wherein m is 1; Compound 1, or any of 1.1-1.50, wherein m is 2; Compound 1, or any of 1.1-1.52, wherein the Compound of Formula I is a compound of Formula I-A: ; Compound 1.53, is a compound of FormulaI-A-i: ; Compound 1.53, whereinI is a compound of Formula I-A-ii: ; Compound 1.53, whereinI is a compound of Formula I-A-iii: ;Compound 1.53, wherein the Compound of Formula I is a compound of Formula I-A-iv: ; Compound 1.53, wherein I is a compound of FormulaI-A-v: ; Compound 1, or any of 1.1-of Formula I is a compound of Formula I-B: ; Compound 1.59, whereinI is a compound of Formula I-B-i: ; Compound 1, or any of 1.1-of Formula I is a compound of Formula I-C:; Compound 1.61, wherein th la I is a compound of Formula I-C-i: ; Compound 1, or any of 1.1-Compound 1, or any of 1.1-1.62, wherein Z is S, S(O), or S(O)2; Compound 1, or any of 1.1-1.62, wherein Z is O; Compound 1, or any of 1.1-1.62, wherein Z is NH; Compound 1, or any of 1.1-1.62, wherein Z is N(Ra), e.g., N(CH3); Compound 1, or any of 1.1-1.62, wherein Z is -C(O)-; Compound 1, or any of 1.1-1.62, wherein Z is -C(OH)-, -C(OC1-6alkyl), -C(=N- OH)-, -C(=N-OC1-6alkyl)-, optionally wherein said C1-6alkyl is methyl; Compound 1, or any of 1.1-1.62, wherein Z is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane); Compound 1.70, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 1.70, wherein the spiro-joined C3-6cycloalkyl is cyclopropane; Compound 1, or any of 1.1-1.62, wherein Z is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane); Compound 1.73, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 1.73, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine;Compound 1, or any of 1.70-1.75, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 1, or any of 1.70-1.75, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 1, or any of 1.1-1.77, wherein A is a 6-10 membered aryl ring, e.g., selected from phenyl and naphthyl, substituted by 0-5 groups R; Compound1, or any of 1.1-1.77, wherein A is a 5-10 membered heteroaryl ring, substituted by 0-5 groups R; Compound 1.79, wherein A is selected from 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, benzothiazole, benzimidazole (e.g., benzo[d]imidazol-1- yl), benzisoxazole (e.g., benzo[d]isoxazol-3-yl, or benzo[d]isoxazol-4-yl), benzisothiazole (e.g., benzo[d]isothiazol-3-yl), benzotriazole (e.g., benzo[d][1,2,3-triazol-1-yl), indazole (e.g., indazol-1-yl, indazol-3-yl, or indazol- 7-yl), quinoline (e.g., quinolin-8-yl), isoquinoline (e.g., isoquinolin-7-yl), quinazoline (e.g., quinazolin-7-yl), and quinoxaline (e.g., quinoxalin-5-yl); Compound 1.80, wherein A is substituted by 0 groups R; Compound 1.80, wherein A is substituted by 1 group R; Compound 1.80, wherein A is substituted by 2 groups R; Compound 1.78, wherein A is a phenyl ring, substituted by 0-5 groups R; Compound 1.84, wherein there is one group R; Compound 1.85, wherein the group R is positioned at the para position of the phenyl ring;Compound 1.85, wherein the group R is positioned at the meta position of the phenyl ring; Compound 1.85, wherein the group R is positioned at the ortho position of the phenyl ring; Compound 1.84, wherein there are two groups R; Compound 1.89, wherein the groups R are positioned at the ortho and para positions of the phenyl ring; Compound 1.89, wherein the groups R are positioned at the meta and para positions of the phenyl ring; Compound 1.89, wherein the groups R are positioned at the ortho and meta positions on the same side of the phenyl ring; Compound 1.89, wherein the groups R are positioned at the ortho and meta positions on opposite sides of the phenyl ring; Compound 1.89, wherein the groups R are positioned at the two ortho positions of the phenyl ring; Compound 1.89, wherein the groups R are positioned at the two meta positions of the phenyl ring; Compound 1.84, wherein there are three groups R; Compound 1.96, wherein the groups R are positioned at the two ortho positions and the para position of the phenyl ring; Compound 1.84, wherein there are four groups R; Compound 1.84, wherein there are five groups R; Compound I, or any of 1.1-1.99, wherein each group R is independently selected from methyl, trifluoromethyl, methoxy, F, Cl, cyano, hydroxy, 2-methoxyethoxy, and (4-fluorobenzyl)oxy; Compound 1, or any of 1.1-1.100, wherein A is selected from the group consisting of: 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, 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; Compound 1, or any of 1.1-1.100, wherein 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, benzo[d]isoxazol-7-yl, 6-fluorobenzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, benzo[d]imidazole-1-yl, benzo[d][1,2,3]triazol-1-yl, isoquinolin-7-yl, quinolin-8-yl, quinoxaline-5-yl, quinazolin-7-yl, and 2- oxopyridin-1(2H)-yl; Compound 1, or any of 1.1-1.100, wherein 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; Compound 1, or any of 1.1-1.103, wherein n is 2; Compound 1, or any of 1.1-1.103, wherein n is 3; Compound 1, or any of 1.1-1.103, wherein n is 4; Compound 1, or any of 1.1-1.103, wherein n is 5; Compound 1, or any of 1.1-1.107, wherein X is S, O, CH2, NH, N(CH3), or spiro- joined cyclopropyl; Y is CH2, C(O), or spiro-joined cyclopropyl, and Z is a bond, -O-, -C(O)-, -O(CH2)2O-, or -C(=NOCH3)-; Compound 1, or any of 1.1-1.107, wherein X is N(CH3) or spiro-joined cyclopropyl; Y is CH2, C(O), or spiro-joined cyclopropyl, and Z is a bond, -O-, or -C(O)-; Compound 1, or any of 1.1-1.109, wherein X is N(CH3), Y is CH2, and m is 1; Compound 1, or any of 1.1-1.109, wherein X is N(CH3), Y is C(O), and m is 1; Compound 1, or any of 1.1-1.109, wherein X is NH, Y is C(O), and m is 1;Compound 1, or any of 1.1-1.109, wherein X is spiro-joined cyclopropyl, Y is CH2, and m is 1; Compound 1, or any of 1.1-1.109, wherein X is N(CH3), Y is spiro-joined cyclopropyl, and m is 1; Compound 1, or any of 1.1-1.114, wherein n is 4 and Z is a bond; Compound 1, or any of 1.1-1.114, wherein n is 3 and Z is -O- or -C(O)-; Compound 1, or any of 1.1-1.114, wherein n is 3 and Z is a bond; Compound 1, or any of 1.1-1.114, wherein n is 2 and Z is -O- or -C(O)-; Compound 1, or any of 1.1-1.114, wherein n is 2 and Z is a bond; Compound 1, or any of 1.1-1.114, wherein n is 1 and Z is -O- or -C(O)-; Compound 1, or any of 1.1-1.114, wherein n is 1 and Z is a bond; Compound 1, or any of 1.1-1.121, wherein A is H or C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), Z is a bond or -C(O)-, and n is 1, 2, or 3; Compound 1, or any of 1.1-1.122, wherein the Compound is selected from the group consisting of: ,Compound 1, or any of 1.1-1.122, wherein the compound is selected from the group consisting of:, 1.125 Compound 1, or any of 1.1-1.122, wherein the compound is selected from the group consisting of: , ,;r form; Compound 1, or any of 1.1-1.122, wherein the compound is selected from the group consisting of: ,Compound 1, or any of 1.1-1.122, wherein the compound is selected from the group consisting of: ,;rm; Compound 1, or any of 1.1-1.122, wherein the compound is selected from the group consisting of: , ,Compound 1, or any of 1.1-1.122, wherein the compound is selected from the group consisting of: ,, , rm; Compound 1, or any of 1.1-1.129, in free form; Compound 1, or any of 1.1-1.129, in salt form, e.g., pharmaceutically acceptable salt form; Compound 1, or any of 1.1-1.129, wherein the compound is in acid addition salt form, for example, hydrochloric or toluenesulfonic acid salt form; Compound 1, or any of 1.1-1.132, in substantially pure diastereomeric form (i.e., substantially free from other diastereomers); Compound 1 or any of 1.1-1.132, having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%; Compound 1 or any of 1.1-1.134 in solid form, e.g., in crystal form; Compound 1 or any of 1.1-1.135, in isolated or purified form (e.g., in at least 90% pure form, or at least 95% or at least 98% or at least 99%); Compound 1 or any of 1.1-1.136, wherein the compound has 5-HT2A receptor binding affinity of at least 60% at 100 nM concentration, e.g., at least 70%, or atleast 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%, at 100 nM concentration; Compound 1 or any of 1.1-1.137, wherein the compound has a 5-HT2A receptor dissociation constant (Kd) 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; Compound 1 or any of 1.1-1.138, wherein the compound is an agonist of beta- arrestin signaling via the 5-HT2A receptor, e.g., a partial agonist or a full agonist; Compound 1.139, wherein the compound is a partial agonist of beta-arrestin signaling having an Emaxof 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%, relative to a full agonist (e.g., alpha-methylserotonin); Compound 1.139 or 1.140, wherein the compound has an EC50 for 5-HT2A receptor beta-arrestin agonism 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; Compound 1.139, 1.140 or 1.141, wherein the compound has a beta-arrestin signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., 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 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8; Compound 1.139, 1.140, or 1.141, wherein the compound has a beta-arrestin signaling relative intrinsic activity (RAi) of greater than 1.0 compared to the reference compound alpha-methylserotonin, e.g., a relative intrinsic activity of 1.0 to 1.2, or 1.0 to 1.4, or 1.0 to 1.6; Compound 1 or any of 1.1-1.138, wherein the compound is an antagonist of beta- arrestin signaling via the 5-HT2Areceptor;Compound 1.144, wherein the compound has an IC50for 5-HT2Areceptor beta- arrestin antagonism 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; Compound 1 or any of 1.1-1.138, wherein the compound is not an antagonist of beta-arrestin signaling via the 5-HT2A receptor; Compound 1.146, wherein the compound has an IC50for 5-HT2Areceptor beta- arrestin antagonism of 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; Compound 1 or any of 1.1-1.147, wherein the compound is not an agonist of G-q signaling via the 5-HT2A receptor, or is a weak agonist thereof; Compound 1.148, wherein the compound is a partial agonist of G-q signaling having an Emaxof 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%, relative to a full agonist (e.g., alpha-methylserotonin), preferably an Emaxof less than 50% or less than 30% or less than 10%; Compound 1.148 or 1.149, wherein the compound has an EC50 for 5-HT2A receptor G-q agonism of 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; Compound 1.148, 1.149 or 1.150, wherein the compound has a G-q signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., 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 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8; Compound 1 or any of 1.1-1.151, wherein the compound is an antagonist of G-q signaling via the 5-HT2Areceptor;Compound 1.152, wherein the compound has an IC50for 5-HT2Areceptor G-q antagonism 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; Compound 1 or any of 1.1-1.153, wherein the compound has a bias ratio (beta- arrestin / G-q) for agonism 5-HT2A receptor 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 undefined (i.e., where the compound has any degree of beta-arrestin agonism and zero G-q agonism); Compound 1 or any of 1.1-1.154, wherein the compound is an antagonist or agonist of the D1 and / or D2 dopamine receptor (e.g., having at least 70% receptor affinity at 100 nM concentration or an IC50 of less than 100 nM); Compound 1 or any of 1.1-1.154, wherein the compound is not active at the D1 and / or D2 dopamine receptor (e.g., having less than 50% receptor affinity at 100 nM concentration and / or an EC50or IC50of more than 500 nM); Compound 1 or any of 1.1-1.156, wherein the compound is an antagonist of the serotonin transporter (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an IC50of less than 100 nM); Compound 1 or any of 1.1-1.156, wherein the compound is not active at the serotonin transporter (e.g., having less than 50% receptor binding affinity at 100 nM concentration and / or an EC50or IC50of more than 500 nM); Compound 1 or any of 1.1-1.158, wherein the compound is an agonist, antagonist, or partial agonist of the mu-opioid receptor (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an EC50 or IC50 of less than 100 nM); Compound 1 or any of 1.1-1.158, wherein the compound is not active at the mu- opioid receptor (e.g., having at less than 50% receptor binding affinity at 100 nM concentration and / or an EC50 or IC50 of more than 500 nM); Compound 1, or any of 1.1-1.160, wherein the compound is non-hallucinogenic, e.g., at therapeutic doses 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 (such as drifting, morphing,breathing or melting of objects and surfaces in the field of view), detachment from reality, dissociation, delirium, undesired altered states of consciousness; Compound 1, or any of 1.1-1.161, wherein the compound does not stimulate head twitch response in an animal test model, or is antagonist of DOI-induced head twitch response. Compound 1, or any of 1.1-1.162, wherein the compound is effective in a murine model of depression (tail suspension or forced swim test;) Compound 1, or any of 1.1-1.163, wherein the compound is effective in an animal model of social anxiety disorder or anhedonia; Compound1, or any of 1.1-1.164, wherein the compound does not have 5-HT2Bagonist activity (e.g., an EC50 of greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); Compound 1, or any of 1.1-1.165, wherein the compound has 5-HT2B 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); Compound 1, or any of 1.1-1.166, wherein the compound has 5-HT2cagonist 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); Compound 1, or any of 1.1-1.166, wherein the compound does not have 5-HT2Cantagonist activity (e.g., an IC50 of greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); Compound 1, or any of 1.1-1.168, wherein the compound binds to the alpha-1A adrenergic receptor (e.g., with 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); Compound 1, or any of 1.1-1.169, wherein the compound does not cause psychoses (e.g., prolonged or intermittent psychoses); Compound 1, or any of 1.1-1.170, wherein the compound does not promote self- harm or harm to others in the patient;1.172 Compound 1, or any of 1.1-1.171, wherein the compound does not cause heart valvulopathy or pulmonary arterial hypertension, e.g., wherein the Compound is safe to administer to a patient having cardiac comorbidities; 1.173 Compound 1, or any of 1.1-1.172, wherein the compound does not cause abuse or dependence (e.g., physical or psychological dependence); 1.174 Compound 1, or any of 1.1-1.173, wherein the compound is functionally inactive at one or more of the following receptors and ion channels: 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, 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 KV, sodium channel (site 2), norepinephrine transporter, dopamine transporter, and / or serotonin transporter; 1.175 Compound 1.174, wherein the compound has an in vitro receptor activity (for agonism or antagonism) of less than 60% inhibition of radioligand binding (e.g., at 100 nM test concentration) for any one or more of said receptor or ion channels, e.g., less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%; 1.176 Compound 1, or any of 1.1-1.175, wherein the compound is orally bioavailable (e.g., oral bioavailability of at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40%).

[0028] In another embodiment of the first aspect, the present disclosure relates to a compound (Compound 2) of Formula II:wherein:X is selected from S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N- C(O)-Ra, N-C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O–), a spiro- joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHRc, -C(O)-, C(Rc)2, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(Rd), -C(O)-, -C(OH)-, -C(OC1-6alkyl), -C(=N- OH)-, -C(=N-OC1-6alkyl)-, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), a spiro- joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -O(CH2)pO- wherein p is 2, 3, or 4 (e.g., p is 2), wherein said spiro-joined C3-6cycloalkyl or 3-6- membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; A is H, C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), an aryl (e.g., phenyl), or heteroaryl ring, wherein said cycloalkyl, aryl, or heteroaryl is substituted by 0-5 groups R; each R is independently selected from aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C1-6alkyl (e.g., methyl, ethyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1-6alkylthio (e.g., methylthio), halo (e.g., F), cyano, C3-6cycloalkyl (e.g., cyclopropyl), C3- 6cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is optionally further substituted by one or more aryl (optionally substituted with halo), halo, C1-6alkyl(e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1-6alkylthio (e.g., methylthio), C3- 6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), amino, C1- 6alkylamino (e.g., methylamino), di(C1-6alkyl)amino (e.g., dimethylamino), (C1-6alkyl)(C1-6alkyl)amino (e.g., methylethylamino), and hydroxy; R1is selected from H, halo (e.g., F), C1-3alkyl (e.g., methyl), C1-3alkoxy (e.g., methoxy), OH, CN, NH2, haloC1-3alkyl (e.g., trifluoromethyl), C1-3alkylsulfonyl (e.g., methylsulfonyl), C1-3alkylthio (e.g., methylthio), C3-4cycloalkyl (e.g., cyclopropyl), C3- 4cycloalkoxy (e.g., cyclopropoxy), amino, C1-3alkylamino (e.g., methylamino), di(C1- 3alkyl)amino (e.g., dimethylamino), and (C1-3alkyl)(C1-3alkyl)amino (e.g., methylethylamino); Raand Rd, are each independently selected from C1-20alkyl (e.g., methyl or tert-butyl), and C1-2alkylaryl (e.g., benzyl or phenethyl); Rband Rcare each independently selected from C1-6alkyl (e.g., methyl, ethyl, tert-butyl), C1-6alkoxy, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and C1-2alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2; n is 1, 2, 3, 4, or 5; in free or salt form (e.g., pharmaceutically acceptable salt form); optionally wherein X is not NH or N(Ra) (e.g., N(CH3)), when Y is -C(O)- and m is 1; optionally provided that: n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is a bond, R1is H, and A is 4- fluorophenyl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is -O-, R1is H, and A is 4-fluorophenyl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is a bond, R1is H, and A is indol-3-yl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is a bond, R1is H, and A is indazol-3-yl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is -C(O)-, R1is H, and A is pyrid-4- yl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is -C(O)-, R1is H, and A is 2-aminophenyl; n is not 3, when m is 1, X is -N(H)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl;n is not 3, when m is 1, X is -O-, Y is CH2, Z is -C(O)-, R1is H, and A is 4-fluorophenyl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is -O-, R1is H, and A is 4- fluorophenyl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is a bond, R1is H, and A is benzisoxazol-3-yl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is a bond, R1is H, and A is 6-fluoroindol-3- yl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is a bond, R1is H, and A is 6-fluoroindazol- 3-yl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is -C(O)-, R1is H, and A is 2-amino-4- fluorophenyl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is -C(O)-, R1is H, and A is 4-fluoro-2- hydroxyphenyl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is a bond, R1is H, and A is 6- fluorobenzisoxazol-3-yl; n is not 3, when m is 1, X is -N(CH2CH3)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl; n is not 3, when m is 1, X is -N(CH(CH3)2)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl; and / or n is not 3, when m is 1, X is -N(CH2Ph)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl.

[0029] The present disclosure further provides additional embodiments of first aspect, including: 2.1. Compound 2, wherein R1is halo (e.g., F, Cl, Br, I); 2.2. Compound 2, wherein R1is H; 2.3. Compound 2, wherein R1is C1-3alkyl (e.g., methyl); 2.4. Compound 2, wherein R1is C1-3alkoxy (e.g., methoxy); 2.5. Compound 2, wherein R1is OH or NH2; 2.6. Compound 2, wherein R1is CN;Compound 2, wherein R1is haloC1-3alkyl (e.g., trifluoromethyl); Compound 2, wherein R1is F or methyl; Compound 2, or any of 2.1-2.8, wherein X is S, S(O), or S(O)2; Compound 2, or any of 2.1-2.8, wherein X is O; Compound 1, or any of 2.1-2.8, wherein X is CH2, CHRb, or C(Rb)2; Compound 2.11, wherein Rbis independently C1-6alkyl (e.g., methyl); Compound 2, or any of 2.1-2.8, wherein X is CH2; Compound 2, or any of 2.1-2.8, wherein X is NH; Compound 2, or any of 2.1-2.8, wherein X is N(Ra); Compound 2, or any of 2.1-2.8, wherein X is N-C(O)-Ra; Compound 2, or any of 2.1-2.8, wherein X is N-C(O)-O-Ra; Compound 2, or any of 2.1-2.8, wherein X is N-C(O)-O-CH2-O-Ra; Compound 2, or any of 2.1-2.8, wherein X is N-CH2-O-C(O)-Ra; Compound 2, or any of 2.15-2.19, wherein Rais C1-2alkylaryl (e.g., benzyl or phenethyl); Compound 2, or any of 2.15-2.19, wherein Rais C1-20alkyl (e.g., methyl or tert- butyl); Compound 2, or any of 2.15-2.19, wherein Rais C10-20alkyl (e.g., decyl or dodecyl); Compound 2, or any of 2.15-2.19, wherein Rais C1-15alkyl (e.g., hexyl or octyl); Compound 2, or any of 2.15-2.19, wherein Rais C7-15alkyl (e.g., heptyl or nonyl); Compound 2, or any of 2.15-2.19, wherein Rais C1-6alkyl (e.g., butyl or hexyl); Compound 2, or any of 2.15-2.19, wherein Rais C1-4alkyl (e.g., n-butyl or tert- butyl); Compound 2, or any of 2.15-2.19, wherein Rais C1-3alkyl (e.g., propyl or isopropyl); Compound 2, or any of 2.15-2.19, wherein Rais C1-2alkyl (e.g., methyl or ethyl); Compound 2, or any of 2.1-2.8, wherein X is N(CH3); Compound 2, or any of 2.1-2.8, wherein X is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane);Compound 2.30, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 2.31, wherein the spiro-joined C3-6cycloalkyl is cyclopropane; Compound 2, or any of 2.1-2.8, wherein X is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane); Compound 2.33, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 2.34, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine; Compound 2, or any of 2.30-2.35, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 2, or any of 2.30-2.35, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 2, or any of 2.1-2.37, wherein Y is CH2; Compound 2, or any of 2.1-2.37, wherein Y is -C(O)-; Compound 2, or any of 2.1-2.37, wherein Y is CHRcor C(Rc)2; Compound 2.40, wherein Rcis C1-6alkyl; Compound 2.40, wherein Rcis selected from methyl, ethyl and propyl; Compound 2, or any of 2.1-2.37, wherein Y is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane) Compound 2.43, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 2.43, wherein the spiro-joined C3-6cycloalkyl is cyclopropane Compound 2, or any of 2.1-2.37, wherein Y is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane);Compound 2.46, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 2.46, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine; Compound 2, or any of 2.43-2.48, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 2, or any of 2.43-2.48, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 2, or any of 2.1-2.50, wherein m is 1; Compound 2, or any of 2.1-2.50, wherein m is 2; Compound 2, or any of 2.1-2.52, wherein the Compound of Formula II is a compound of Formula II-A: , wherein R1is selected from F, methyl, OH, CN,and NH2; Compound 2.53, wherein the Compound of Formula II is a compound of Formula II-A-i: ; Compound 2.53, whereinII is a compound of Formula II-A-ii:; Compound 2.53, wherein th la II is a compound of Formula II-A-iii: ; Compound 2.53, whereinII is a compound of Formula II-A-iv: ; Compound 2.53, whereinII is a compound of Formula II-A-v: ; Compound 2, or any of 2.1-of Formula II is a compound of Formula II-B:, wherein R1is selected from F, methyl, OH, CN, and NH2; Compound 2.59, wherein the Compound of Formula II is a compound of Formula II-B- or II-B-ii: ; Compound 2, or Formula II is acompound of Formula II-C: , wherein R1is selected from F, methyl, OH, CN, andNH2; Compound 2.61, wherein the Compound of Formula II is a compound of Formula II-C- or II-C-ii: ; Compound 2, orCompound 2, or any of 2.1-2.62, wherein Z is S, S(O), or S(O)2; Compound 2, or any of 2.1-2.62, wherein Z is O; Compound 2, or any of 2.1-2.62, wherein Z is NH; Compound 2, or any of 2.1-2.62, wherein Z is N(Ra), e.g., N(CH3); Compound 2, or any of 2.1-2.62, wherein Z is -C(O)-;Compound 2, or any of 2.1-2.62, wherein Z is -C(OH)-, -C(OC1-6alkyl), -C(=N- OH)-, -C(=N-OC1-6alkyl)-, optionally wherein said C1-6alkyl is methyl; Compound 2, or any of 2.1-2.62, wherein Z is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane); Compound 2.70, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 2.70, wherein the spiro-joined C3-6cycloalkyl is cyclopropane; Compound 2, or any of 2.1-2.62, wherein Z is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane); Compound 2.73, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 2.73, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine; Compound 2, or any of 2.70-2.75, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 2, or any of 2.70-2.75, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 2, or any of 2.1-2.77, wherein A is a 6-10 membered aryl ring, e.g., selected from phenyl and naphthyl, substituted by 0-5 groups R; Compound 2, or any of 2.1-2.77, wherein A is a 5-10 membered heteroaryl ring, substituted by 0-5 groups R; Compound 2.79, wherein A is selected from 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, orindol-5-yl), benzoxazole, benzothiazole, benzimidazole (e.g., benzo[d]imidazol-1- yl), benzisoxazole (e.g., benzo[d]isoxazol-3-yl, or benzo[d]isoxazol-4-yl), benzisothiazole (e.g., benzo[d]isothiazol-3-yl), benzotriazole (e.g., benzo[d][1,2,3-triazol-1-yl), indazole (e.g., indazol-1-yl, indazol-3-yl, or indazol- 7-yl), quinoline (e.g., quinolin-8-yl), isoquinoline (e.g., isoquinolin-7-yl), quinazoline (e.g., quinazolin-7-yl), and quinoxaline (e.g., quinoxalin-5-yl); Compound 2.80, wherein A is substituted by 0 groups R; Compound 2.80, wherein A is substituted by 1 group R; Compound 2.80, wherein A is substituted by 2 groups R; Compound 2.78, wherein A is a phenyl ring, substituted by 0-5 groups R; Compound 2.84, wherein there is one group R; Compound 2.85, wherein the group R is positioned at the para position of the phenyl ring; Compound 2.85, wherein the group R is positioned at the meta position of the phenyl ring; Compound 2.85, wherein the group R is positioned at the ortho position of the phenyl ring; Compound 2.84, wherein there are two groups R; Compound 2.89, wherein the groups R are positioned at the ortho and para positions of the phenyl ring; Compound 2.89, wherein the groups R are positioned at the meta and para positions of the phenyl ring; Compound 2.89, wherein the groups R are positioned at the ortho and meta positions on the same side of the phenyl ring; Compound 2.89, wherein the groups R are positioned at the ortho and meta positions on opposite sides of the phenyl ring; Compound 2.89, wherein the groups R are positioned at the two ortho positions of the phenyl ring; Compound 2.89, wherein the groups R are positioned at the two meta positions of the phenyl ring; Compound 2.84, wherein there are three groups R;Compound 2.96, wherein the groups R are positioned at the two ortho positions and the para position of the phenyl ring; Compound 2.84, wherein there are four groups R; Compound 2.84, wherein there are five groups R; Compound 2, or any of 2.1-2.99, wherein each group R is independently selected from methyl, trifluoromethyl, methoxy, F, Cl, cyano, hydroxy, 2-methoxyethoxy, and (4-fluorobenzyl)oxy; Compound 2, or any of 2.1-2.100, wherein A is selected from the group consisting of: 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, 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; Compound 2, or any of 2.1-2.100, wherein 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, benzo[d]isoxazol-7-yl, 6-fluorobenzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, benzo[d]imidazole-1-yl, benzo[d][1,2,3]triazol-1-yl, isoquinolin-7-yl, quinolin-8-yl, quinoxaline-5-yl, quinazolin-7-yl, and 2- oxopyridin-1(2H)-yl; Compound 2, or any of 2.1-2.100, wherein 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;Compound 2, or any of 2.1-2.103, wherein n is 2; Compound 2, or any of 2.1-2.103, wherein n is 3; Compound 2, or any of 2.1-2.103, wherein n is 4; Compound 2, or any of 2.1-2.103, wherein n is 5; Compound 2, or any of 2.1-2.107, wherein X is S, O, CH2, NH, N(CH3), or spiro- joined cyclopropyl; Y is CH2, C(O), or spiro-joined cyclopropyl, and Z is a bond, -O-, -C(O)-, -O(CH2)2O-, or -C(=NOCH3)-; Compound 2, or any of 2.1-2.107, wherein X is N(CH3) or spiro-joined cyclopropyl; Y is CH2, C(O), or spiro-joined cyclopropyl, and Z is a bond, -O-, or -C(O)-; Compound 2, or any of 2.1-2.109, wherein X is N(CH3), Y is CH2, and m is 1; Compound 2, or any of 2.1-2.109, wherein X is N(CH3), Y is C(O), and m is 1; Compound 2, or any of 2.1-2.109, wherein X is NH, Y is C(O), and m is 1; Compound 2, or any of 2.1-2.109, wherein X is spiro-joined cyclopropyl, Y is CH2, and m is 1; Compound 2, or any of 2.1-2.109, wherein X is N(CH3), Y is spiro-joined cyclopropyl, and m is 1; Compound 2, or any of 2.1-2.114, wherein n is 4 and Z is a bond; Compound 2, or any of 2.1-2.114, wherein n is 3 and Z is -O- or -C(O)-; Compound 2, or any of 2.1-2.114, wherein n is 3 and Z is a bond; Compound 2, or any of 2.1-2.114, wherein n is 2 and Z is -O- or -C(O)-; Compound 2, or any of 2.1-2.114, wherein n is 2 and Z is a bond; Compound 2, or any of 2.1-2.114, wherein n is 1 and Z is -O- or -C(O)-; Compound 2, or any of 2.1-2.114, wherein n is 1 and Z is a bond; Compound 2, or any of 2.1-2.121, wherein A is H or C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), Z is a bond or -C(O)-, and n is 1, 2, or 3; Compound 2, or any of 2.1-2.122, wherein the compound is selected from the group consisting of: ,, Compound 2, or any of 2.1-2.122, wherein the compound is selected from the group consisting of: ,Compound 2, or any of 2.1-2.122, wherein the compound is selected from the group consisting of: ,, each independently in free or pharmaceutically acceptable salt or form; Compound 2, or any of 2.1-2.122, wherein the compound is selected from the group consisting of: ,Compound 2, or any of 2.1-2.122, wherein the compound is selected from the group consisting of: ,, 2.128. Compound 2, or any of 2.1-2.122, wherein the compound is selected from the group consisting of: , ,; le salt or form; 2.129. Compound 2, or any of 2.1-2.122, wherein the compound is selected from the group consisting of: , ,each independently in free or pharmaceutically acceptable salt or form; Compound 2, or any of 2.1-2.129, in free form; Compound 2, or any of 2.1-2.129, in salt form, e.g., pharmaceutically acceptable salt form; Compound 2, or any of 2.1-2.129, wherein the compound is in acid addition salt form, for example, hydrochloric or toluenesulfonic acid salt form; Compound 2, or any of 2.1-2.132, in substantially pure diastereomeric form (i.e., substantially free from other diastereomers); Compound 2 or any of 2.1-2.132, having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%; Compound 2 or any of 2.1-2.134 in solid form, e.g., in crystal form; Compound 2 or any of 2.1-2.135, in isolated or purified form (e.g., in at least 90% pure form, or at least 95% or at least 98% or at least 99%); Compound 2 or any of 2.1-2.136, wherein the compound has 5-HT2A receptor binding affinity of at least 60% at 100 nM concentration, e.g., 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%, at 100 nM concentration; Compound 2 or any of 2.1-2.137, wherein the compound has a 5-HT2A receptor dissociation constant (Kd) 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; Compound 2 or any of 2.1-2.138, wherein the compound is an agonist of beta- arrestin signaling via the 5-HT2Areceptor, e.g., a partial agonist or a full agonist; Compound 2.139, wherein the compound is a partial agonist of beta-arrestin signaling having an Emax 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%, relative to a full agonist (e.g., alpha-methylserotonin); Compound 2.139 or 2.140, wherein the compound has an EC50 for 5-HT2A receptor beta-arrestin agonism 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 lessthan 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM; Compound 2.139, 2.140 or 2.141, wherein the compound has a beta-arrestin signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., 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 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8; Compound 2.139, 2.140 or 2.141, wherein the compound has a beta-arrestin signaling relative intrinsic activity (RAi) of greater than 1.0 compared to the reference compound alpha-methylserotonin, e.g., a relative intrinsic activity of 1.0 to 1.2, or 1.0 to 1.4, or 1.0 to 1.6; Compound 2 or any of 2.1-2.138, wherein the compound is an antagonist of beta- arrestin signaling via the 5-HT2A receptor; Compound 2.144, wherein the compound has an IC50 for 5-HT2A receptor beta- arrestin antagonism 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; Compound 2 or any of 2.1-2.138, wherein the compound is not an antagonist of beta-arrestin signaling via the 5-HT2Areceptor; Compound 2.146, wherein the compound has an IC50 for 5-HT2A receptor beta- arrestin antagonism of 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; Compound 2 or any of 2.1-2.147, wherein the compound is not an agonist of G-q signaling via the 5-HT2Areceptor, or is a weak agonist thereof; Compound 2.148, wherein the compound is a partial agonist of G-q signaling having an Emax 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%, orless than 10%, relative to a full agonist (e.g., alpha-methylserotonin), preferably an Emax of less than 50% or less than 30% or less than 10%; Compound 2.148 or 2.149, wherein the compound has an EC50 for 5-HT2A receptor G-q agonism of 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; Compound 2.148, 2.149 or 2.150, wherein the compound has a G-q signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., 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 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8; Compound 2 or any of 2.1-2.151, wherein the compound is an antagonist of G-q signaling via the 5-HT2A receptor; Compound 2.152, wherein the compound has an IC50for 5-HT2Areceptor G-q antagonism 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; Compound 2 or any of 2.1-2.153, wherein the compound has a bias ratio (beta- arrestin / G-q) for agonism 5-HT2Areceptor 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 undefined (i.e., where the compound has any degree of beta-arrestin agonism and zero G-q agonism); Compound 2 or any of 2.1-2.154, wherein the compound is an antagonist or agonist of the D1 and / or D2 dopamine receptor (e.g., having at least 70% receptor affinity at 100 nM concentration or an IC50 of less than 100 nM); Compound 2 or any of 2.1-2.154, wherein the compound is not active at the D1 and / or D2 dopamine receptor (e.g., having less than 50% receptor affinity at 100 nM concentration and / or an EC50or IC50of more than 500 nM);Compound 2 or any of 2.1-2.156, wherein the compound is an antagonist of the serotonin transporter (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an IC50 of less than 100 nM); Compound 2 or any of 2.1-2.156, wherein the compound is not active at the serotonin transporter (e.g., having less than 50% receptor binding affinity at 100 nM concentration and / or an EC50 or IC50 of more than 500 nM); Compound 2 or any of 2.1-2.158, wherein the compound is an agonist, antagonist, or partial agonist of the mu-opioid receptor (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an EC50 or IC50 of less than 100 nM); Compound 2 or any of 2.1-2.158, wherein the compound is not active at the mu- opioid receptor (e.g., having at less than 50% receptor binding affinity at 100 nM concentration and / or an EC50 or IC50 of more than 500 nM); Compound 2, or any of 2.1-2.160, wherein the compound is non-hallucinogenic, e.g., at therapeutic doses 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 (such as drifting, morphing, breathing or melting of objects and surfaces in the field of view), detachment from reality, dissociation, delirium, undesired altered states of consciousness; Compound 2, or any of 2.1-2.161, wherein the compound does not stimulate head twitch response in an animal test model, or is antagonist of DOI-induced head twitch response; Compound 2, or any of 2.1-2.162, wherein the compound is effective in a murine model of depression (tail suspension or forced swim test); Compound 2, or any of 2.1-2.163, wherein the compound is effective in an animal model of social anxiety disorder or anhedonia; Compound 2, or any of 2.1-2.164, wherein the compound does not have 5-HT2B agonist activity (e.g., an EC50 of greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); Compound 2, or any of 2.1-2.165, wherein the compound has 5-HT2B antagonist activity (e.g., an IC50 of less than 1000 nM, or less than 500 nM, or less than 250nM, or less than 100 nM, or less than 50 nM, or less than 25 nM, or less than 15 nM); Compound 2, or any of 2.1-2.166, wherein the compound has 5-HT2c 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); Compound 2, or any of 2.1-2.166, wherein the compound does not have 5-HT2Cantagonist activity (e.g., an IC50 of greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); Compound 2, or any of 2.1-2.168, wherein the compound binds to the alpha-1A adrenergic receptor (e.g., with 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); Compound 2, or any of 2.1-2.169, wherein the compound does not cause psychoses (e.g., prolonged or intermittent psychoses); Compound 2, or any of 2.1-2.170, wherein the compound does not promote self- harm or harm to others in the patient; Compound 2, or any of 2.1-2.171, wherein the compound does not cause heart valvulopathy or pulmonary arterial hypertension, e.g., wherein the compound is safe to administer to a patient having cardiac comorbidities; Compound 2, or any of 2.1-2.172, wherein the compound does not cause abuse or dependence (e.g., physical or psychological dependence); Compound 2, or any of 2.1-2.173, wherein the compound is functionally inactive at one or more of the following receptors and ion channels: 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, 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), hERGpotassium channel, voltage-gated potassium channel KV, sodium channel (site 2), norepinephrine transporter, dopamine transporter, and / or serotonin transporter; 2.175. Compound 2.174, wherein the compound has an in vitro receptor activity (for agonism or antagonism) of less than 60% inhibition of radioligand binding (e.g., at 100 nM test concentration) for any one or more of said receptor or ion channels, e.g., less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%; Compound 2, or any of 2.1-2.175, wherein the compound is orally bioavailable (e.g., oral bioavailability of at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40%).

[0030] In another embodiment of the first aspect, the present disclosure relates to a compound (Compound 3) of Formula III:wherein: X is selected from S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N- C(O)-Ra, N-C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O–), a spiro- joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHRc, -C(O)-, C(Rc)2, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3- 6cycloalkoxy (e.g., cyclopropoxy), and hydroxy;Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(Rd), -C(O)-, -C(OH)-, -C(OC1-6alkyl), -C(=N- OH)-, -C(=N-OC1-6alkyl)-, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), a spiro- joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -O(CH2)pO- wherein p is 2, 3, or 4 (e.g., p is 2), wherein said spiro-joined C3-6cycloalkyl or 3-6- membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; A is H, C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), an aryl (e.g., phenyl), or heteroaryl ring, wherein said cycloalkyl, aryl, or heteroaryl is substituted by 0-5 groups R; each R is independently selected from aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C1-6alkyl (e.g., methyl, ethyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1-6alkylthio (e.g., methylthio), halo (e.g., F), cyano, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is optionally further substituted by one or more aryl (optionally substituted with halo), halo, C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1-6alkylthio (e.g., methylthio), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), amino, C1-6alkylamino (e.g., methylamino), di(C1-6alkyl)amino (e.g., dimethylamino), (C1-6alkyl)(C1-6alkyl)amino (e.g., methylethylamino), and hydroxy; Raand Rd, are each independently selected from C1-20alkyl (e.g., methyl or tert-butyl), and C1-2alkylaryl (e.g., benzyl or phenethyl); Rband Rcare each independently selected from C1-6alkyl (e.g., methyl, ethyl, tert-butyl), C1-6alkoxy, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and C1-2alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2; n is 1, 2, 3, 4, or 5; in free or salt form (e.g., pharmaceutically acceptable salt form).

[0031] The present disclosure further provides additional embodiments of first aspect, including: 3.1. Compound 3, wherein X is S, S(O), or S(O)2; 3.2. Compound 3, wherein X is O; 3.3. Compound 3, wherein X is CH2, CHRb, or C(Rb)2; 3.4. Compound 3.3, wherein Rbis independently C1-6alkyl (e.g., methyl); 3.5. Compound 3, wherein X is CH2; 3.6. Compound 3, wherein X is NH; 3.7. Compound 3, wherein X is N(Ra); 3.8. Compound 3, wherein X is N-C(O)-Ra; 3.9. Compound 3, wherein X is N-C(O)-O-Ra; 3.10. Compound 3, wherein X is N-C(O)-O-CH2-O-Ra; 3.11. Compound 3, wherein X is N-CH2-O-C(O)-Ra; 3.12. Compound 3, or any of 3.7-3.11, wherein Rais C1-2alkylaryl (e.g., benzyl or phenethyl); 3.13. Compound 3, or any of 3.7-3.11, wherein Rais C1-20alkyl (e.g., methyl or tert- butyl); 3.14. Compound 3, or any of 3.7-3.11, wherein Rais C10-20alkyl (e.g., decyl or dodecyl); 3.15. Compound 3, or any of 3.7-3.11, wherein Rais C1-15alkyl (e.g., hexyl or octyl); 3.16. Compound 3, or any of 3.7-3.11, wherein Rais C7-15alkyl (e.g., heptyl or nonyl); 3.17. Compound 3, or any of 3.7-3.11, wherein Rais C1-6alkyl (e.g., butyl or hexyl); 3.18. Compound 3, or any of 3.7-3.11, wherein Rais C1-4alkyl (e.g., n-butyl or tert- butyl); 3.19. Compound 3, or any of 3.7-3.11, wherein Rais C1-3alkyl (e.g., propyl or isopropyl); 3.20. Compound 3, or any of 3.7-3.11, wherein Rais C1-2alkyl (e.g., methyl or ethyl); 3.21. Compound 3, wherein X is N(CH3); 3.22. Compound 3, wherein X is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane); 3.23. Compound 3.22, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 3.24. Compound 3.23, wherein the spiro-joined C3-6cycloalkyl is cyclopropane;Compound 3, wherein X is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane); Compound 3.25, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 3.26, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine; Compound 3, or any of 3.22-3.27, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 3, or any of 3.22-3.27, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 3, or any of 3.1-3.29, wherein Y is CH2; Compound 3, or any of 3.1-3.29, wherein Y is -C(O)-; Compound 3, or any of 3.1-3.29, wherein Y is CHRcor C(Rc)2; Compound 3.32, wherein Rcis C1-6alkyl; Compound 3.32, wherein Rcis selected from methyl, ethyl and propyl; Compound 3, or any of 3.1-3.29, wherein Y is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane) Compound 3.35, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 3.35, wherein the spiro-joined C3-6cycloalkyl is cyclopropane Compound 3, or any of 3.1-3.29, wherein Y is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane); Compound 3.38, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 3.39, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine;Compound 3, or any of 3.35-3.40, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 3, or any of 3.35-3.40, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 3, or any of 3.1-3.42, wherein m is 1; Compound 3, or any of 3.1-3.42, wherein m is 2; Compound 3, or any of 3.1-3.44, wherein the Compound of Formula III is a compound of Formula III-A: ; Compound 3, or any ofof Formula III is a compound of Formula III-B: ; Compound 3, or any ofof Formula III is a compound of Formula III-C: ; Compound 3, or any ofCompound 3, or any of 3.1-3.47, wherein Z is S, S(O), or S(O)2; Compound 3, or any of 3.1-3.47, wherein Z is O; Compound 3, or any of 3.1-3.47, wherein Z is NH; Compound 3, or any of 3.1-3.47, wherein Z is N(Ra), e.g., N(CH3); Compound 3, or any of 3.1-3.47, wherein Z is -C(O)-;Compound 3, or any of 3.1-3.47, wherein Z is -C(OH)-, -C(OC1-6alkyl), -C(=N- OH)-, -C(=N-OC1-6alkyl)-, optionally wherein said C1-6alkyl is methyl; Compound 3, or any of 3.1-3.47, wherein Z is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane); Compound 3.55, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 3.55, wherein the spiro-joined C3-6cycloalkyl is cyclopropane; Compound 3, or any of 3.1-3.47, wherein Z is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane); Compound 3.58, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 3.58, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine; Compound 3, or any of 3.55-3.60, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 3, or any of 3.55-3.60, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 3, or any of 3.1-3.62, wherein A is a 6-10 membered aryl ring, e.g., selected from phenyl and naphthyl, substituted by 0-5 groups R; Compound 3, or any of 3.1-3.62, wherein A is a 5-10 membered heteroaryl ring, substituted by 0-5 groups R; Compound 3.64, wherein A is selected from 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, orindol-5-yl), benzoxazole, benzothiazole, benzimidazole (e.g., benzo[d]imidazol-1- yl), benzisoxazole (e.g., benzo[d]isoxazol-3-yl, or benzo[d]isoxazol-4-yl), benzisothiazole (e.g., benzo[d]isothiazol-3-yl), benzotriazole (e.g., benzo[d][1,2,3-triazol-1-yl), indazole (e.g., indazol-1-yl, indazol-3-yl, or indazol- 7-yl), quinoline (e.g., quinolin-8-yl), isoquinoline (e.g., isoquinolin-7-yl), quinazoline (e.g., quinazolin-7-yl), and quinoxaline (e.g., quinoxalin-5-yl); Compound 3.65, wherein A is substituted by 0 groups R; Compound 3.65, wherein A is substituted by 1 group R; Compound 3.65, wherein A is substituted by 2 groups R; Compound 3.63, wherein A is a phenyl ring, substituted by 0-5 groups R; Compound 3.69, wherein there is one group R; Compound 3.70, wherein the group R is positioned at the para position of the phenyl ring; Compound 3.70, wherein the group R is positioned at the meta position of the phenyl ring; Compound 3.70, wherein the group R is positioned at the ortho position of the phenyl ring; Compound 3.69, wherein there are two groups R; Compound 3.74, wherein the groups R are positioned at the ortho and para positions of the phenyl ring; Compound 3.74, wherein the groups R are positioned at the meta and para positions of the phenyl ring; Compound 3.74, wherein the groups R are positioned at the ortho and meta positions on the same side of the phenyl ring; Compound 3.74, wherein the groups R are positioned at the ortho and meta positions on opposite sides of the phenyl ring; Compound 3.74, wherein the groups R are positioned at the two ortho positions of the phenyl ring; Compound 3.74, wherein the groups R are positioned at the two meta positions of the phenyl ring; Compound 3.69, wherein there are three groups R;Compound 3.81, wherein the groups R are positioned at the two ortho positions and the para position of the phenyl ring; Compound 3.69, wherein there are four groups R; Compound 3.69, wherein there are five groups R; Compound 3, or any of 3.1-3.84, wherein each group R is independently selected from methyl, trifluoromethyl, methoxy, F, Cl, cyano, hydroxy, 2-methoxyethoxy, and (4-fluorobenzyl)oxy; Compound 3, or any of 3.1-3.85, wherein A is selected from the group consisting of: 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, 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; Compound 3, or any of 3.1-3.85, wherein 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, benzo[d]isoxazol-7-yl, 6-fluorobenzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, benzo[d]imidazole-1-yl, benzo[d][1,2,3]triazol-1-yl, isoquinolin-7-yl, quinolin-8-yl, quinoxaline-5-yl, quinazolin-7-yl, and 2- oxopyridin-1(2H)-yl; Compound 3, or any of 3.1-3.85, wherein 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; Compound 3, or any of 3.1-3.88, wherein n is 2;Compound 3, or any of 3.1-3.88, wherein n is 3; Compound 3, or any of 3.1-3.88, wherein n is 4; Compound 3, or any of 3.1-3.88, wherein n is 5; Compound 3, or any of 3.1-3.92, wherein X is S, O, CH2, NH, N(CH3), or spiro- joined cyclopropyl; Y is CH2, C(O), or spiro-joined cyclopropyl, and Z is a bond, -O-, -C(O)-, -O(CH2)2O-, or -C(=NOCH3)-; Compound 3, or any of 3.1-3.92, wherein X is N(CH3) or spiro-joined cyclopropyl; Y is CH2, C(O), or spiro-joined cyclopropyl, and Z is a bond, -O-, or -C(O)-; Compound 3, or any of 3.1-3.92, wherein X is N(CH3), Y is CH2, and m is 1; Compound 3, or any of 3.1-3.92, wherein X is N(CH3), Y is C(O), and m is 1; Compound 3, or any of 3.1-3.92, wherein X is NH, Y is C(O), and m is 1; Compound 3, or any of 3.1-3.92, wherein X is spiro-joined cyclopropyl, Y is CH2, and m is 1; Compound 3, or any of 3.1-3.92, wherein X is N(CH3), Y is spiro-joined cyclopropyl, and m is 1; Compound 3, or any of 3.1-3.99, wherein n is 4 and Z is a bond; Compound 3, or any of 3.1-3.99, wherein n is 3 and Z is -O- or -C(O)-; Compound 3, or any of 3.1-3.99, wherein n is 3 and Z is a bond; Compound 3, or any of 3.1-3.99, wherein n is 2 and Z is -O- or -C(O)-; Compound 3, or any of 3.1-3.99, wherein n is 2 and Z is a bond; Compound 3, or any of 3.1-3.99, wherein n is 1 and Z is -O- or -C(O)-; Compound 3, or any of 3.1-3.99, wherein n is 1 and Z is a bond; Compound 3, or any of 3.1-3.106, wherein A is H or C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), Z is a bond or -C(O)-, and n is 1, 2, or 3; Compound 3, or any of 3.1-3.107, wherein the Compound is selected from the group consisting of: ,, Compound 3, or any of 3.1-3.107, wherein the compound is selected from the group consisting of: ,Compound 3, or any of 3.1-3.107, wherein the compound is selected from the group consisting of:, rm; Compound 3, or any of 3.1-3.110, in free form; Compound 3, or any of 3.1-3.110, in salt form, e.g., pharmaceutically acceptable salt form; Compound 3, or any of 3.1-3.110, wherein the compound is in acid addition salt form, for example, hydrochloric or toluenesulfonic acid salt form; Compound 3, or any of 3.1-3.113, in substantially pure diastereomeric form (i.e., substantially free from other diastereomers); Compound 3 or any of 3.1-3.114, having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%; Compound 3 or any of 3.1-3.115, in solid form, e.g., in crystal form; Compound 3 or any of 3.1-3.116, in isolated or purified form (e.g., in at least 90% pure form, or at least 95% or at least 98% or at least 99%). Compound 3 or any of 3.1-3.117, wherein the compound has 5-HT2A receptor binding affinity of at least 60% at 100 nM concentration, e.g., 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%, at 100 nM concentration; Compound 3 or any of 3.1-3.118, wherein the compound has a 5-HT2A receptor dissociation constant (Kd) 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;Compound 3 or any of 3.1-3.119, wherein the compound is an agonist of beta- arrestin signaling via the 5-HT2A receptor, e.g., a partial agonist or a full agonist; Compound 3.120, wherein the compound is a partial agonist of beta-arrestin signaling having an Emaxof 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%, relative to a full agonist (e.g., alpha-methylserotonin); Compound 3.120 or 3.121, wherein the compound has an EC50for 5-HT2Areceptor beta-arrestin agonism 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; Compound 3.120, 3.121 or 3.122, wherein the compound has a beta-arrestin signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., 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 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8; Compound 3.120, 3.121, or 3.122, wherein the compound has a beta-arrestin signaling relative intrinsic activity (RAi) of greater than 1.0 compared to the reference compound alpha-methylserotonin, e.g., a relative intrinsic activity of 1.0 to 1.2, or 1.0 to 1.4, or 1.0 to 1.6; Compound 3 or any of 3.1-3.119, wherein the compound is an antagonist of beta- arrestin signaling via the 5-HT2Areceptor; Compound 3.125, wherein the compound has an IC50 for 5-HT2A receptor beta- arrestin antagonism 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; Compound 3 or any of 3.1-3.119, wherein the compound is not an antagonist of beta-arrestin signaling via the 5-HT2Areceptor;Compound 3.127, wherein the compound has an IC50for 5-HT2Areceptor beta- arrestin antagonism of 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; Compound 3 or any of 3.1-3.128, wherein the compound is not an agonist of G-q signaling via the 5-HT2A receptor, or is a weak agonist thereof; Compound 3.129, wherein the compound is a partial agonist of G-q signaling having an Emax 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%, relative to a full agonist (e.g., alpha-methylserotonin), preferably an Emaxof less than 50% or less than 30% or less than 10%; Compound 3.129 or 3.130, wherein the compound has an EC50 for 5-HT2A receptor G-q agonism of 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; Compound 3.129, 3.130 or 3.131, wherein the compound has a G-q signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., 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 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8; Compound 3 or any of 3.1-3.132, wherein the compound is an antagonist of G-q signaling via the 5-HT2A receptor; Compound 3.133, wherein the compound has an IC50 for 5-HT2A receptor G-q antagonism 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; Compound 3 or any of 3.1-3.134, wherein the compound has a bias ratio (beta- arrestin / G-q) for agonism 5-HT2Areceptor 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 atleast 500, or at least 1000, or at least 10,000, or undefined (i.e., where the compound has any degree of beta-arrestin agonism and zero G-q agonism); Compound 3 or any of 3.1-3.135, wherein the compound is an antagonist or agonist of the D1 and / or D2 dopamine receptor (e.g., having at least 70% receptor affinity at 100 nM concentration or an IC50 of less than 100 nM); Compound 3 or any of 3.1-3.135, wherein the compound is not active at the D1 and / or D2 dopamine receptor (e.g., having less than 50% receptor affinity at 100 nM concentration and / or an EC50 or IC50 of more than 500 nM); Compound 3 or any of 3.1-3.137, wherein the compound is an antagonist of the serotonin transporter (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an IC50of less than 100 nM); Compound 3 or any of 3.1-3.137, wherein the compound is not active at the serotonin transporter (e.g., having less than 50% receptor binding affinity at 100 nM concentration and / or an EC50or IC50of more than 500 nM); Compound 3 or any of 3.1-3.139, wherein the compound is an agonist, antagonist, or partial agonist of the mu-opioid receptor (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an EC50or IC50of less than 100 nM); Compound 3 or any of 3.1-3.139, wherein the compound is not active at the mu- opioid receptor (e.g., having at less than 50% receptor binding affinity at 100 nM concentration and / or an EC50or IC50of more than 500 nM); Compound 3, or any of 3.1-3.141, wherein the compound is non-hallucinogenic, e.g., at therapeutic doses 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 (such as drifting, morphing, breathing or melting of objects and surfaces in the field of view), detachment from reality, dissociation, delirium, undesired altered states of consciousness; Compound 3, or any of 3.1-3.142, wherein the compound does not stimulate head twitch response in an animal test model, or is antagonist of DOI-induced head twitch response. Compound 3, or any of 3.1-3.143, wherein the compound is effective in a murine model of depression (tail suspension or forced swim test;)Compound 3, or any of 3.1-3.144, wherein the compound is effective in an animal model of social anxiety disorder or anhedonia; Compound 3, or any of 3.1-3.145, wherein the compound does not have 5-HT2B agonist activity (e.g., an EC50 of greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); Compound 3, or any of 3.1-3.146, wherein the compound has 5-HT2B 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); Compound 3, or any of 3.1-3.147, wherein the compound has 5-HT2cagonist 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); Compound 3, or any of 3.1-3.148, wherein the compound does not have 5-HT2Cantagonist activity (e.g., an IC50 of greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); Compound 3, or any of 3.1-3.149, wherein the compound binds to the alpha-1A adrenergic receptor (e.g., with 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); Compound 3, or any of 3.1-3.150, wherein the compound does not cause psychoses (e.g., prolonged or intermittent psychoses); Compound 3, or any of 3.1-3.151, wherein the compound does not promote self- harm or harm to others in the patient; Compound 3, or any of 3.1-3.152, wherein the compound does not cause heart valvulopathy or pulmonary arterial hypertension, e.g., wherein the compound is safe to administer to a patient having cardiac comorbidities; Compound 3, or any of 3.1-3.153, wherein the compound does not cause abuse or dependence (e.g., physical or psychological dependence); Compound 3, or any of 3.1-3.154, wherein the compound is functionally inactive at one or more of the following receptors and ion channels: 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, 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 KV, sodium channel (site 2), norepinephrine transporter, dopamine transporter, and / or serotonin transporter; 3.156. Compound 3.155, wherein the compound has an in vitro receptor activity (for agonism or antagonism) of less than 60% inhibition of radioligand binding (e.g., at 100 nM test concentration) for any one or more of said receptor or ion channels, e.g., less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%; 3.157. Compound 3, or any of 3.1-3.156, wherein the compound is orally bioavailable (e.g., oral bioavailability of at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40%).

[0032] In another embodiment of the first aspect, the present disclosure relates to a compound (Compound 4) of Formula IV or Formula IV-A:A wherein: X is S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N-C(O)-Ra, N- C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O–), a spiro-joined C3- 6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl(e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHRc, -C(O)-, C(Rc)2, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; R1and R2are each independently selected from H, halo (e.g., F), C1-3alkyl (e.g., methyl), C1-3alkoxy (e.g., methoxy), OH, and CN; Rais selected from C1-20alkyl (e.g., methyl or tert-butyl), and C1-2alkylaryl (e.g., benzyl or phenethyl); Rband Rcare each independently selected from C1-6alkyl (e.g., methyl, ethyl, tert-butyl), C1-6alkoxy, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and C1-2alkylaryl (e.g., benzyl or phenethyl); and m is 1 or 2; in free or salt form (e.g., pharmaceutically acceptable salt form); optionally provided that: X is not N(CH3), when Y is CH2, and m is 1; and / or X is not NH, when Y is CH2, and m is 1; and / or X is not O, when Y is CH2, and m is 1; and / or X is not S, when Y is CH2, and m is 1; and / or X is not N(CH3), when Y is -C(O)-, and m is 1; and / or X is not NH, when Y is -C(O)-, and m is 1; and / or X is not CH2, when Y is CH2, and m is 1; and / or X is not O, when Y is CH2, and m is 2; and / or X is not S, when Y is CH2, and m is 2; and / or X is not CH2, when Y is CH2, and m is 2.

[0033] The present disclosure further provides additional embodiments of first aspect, including: 4.1. Compound 4, wherein X is S, S(O), or S(O)2;Compound 4, wherein X is O; Compound 4, wherein X is CH2, CHRb, or C(Rb)2; Compound 4.3, wherein Rbis independently C1-6alkyl (e.g., methyl); Compound 4, wherein X is CH2; Compound 4, wherein X is NH; Compound 4, wherein X is N(Ra); Compound 4, wherein X is N-C(O)-Ra; Compound 4, wherein X is N-C(O)-O-Ra; Compound 4, wherein X is N-C(O)-O-CH2-O-Ra; Compound 4, wherein X is N-CH2-O-C(O)-Ra; Compound 4, or any of 4.7-4.11, wherein Rais C1-2alkylaryl (e.g., benzyl or phenethyl); Compound 4, or any of 4.7-4.11, wherein Rais C1-20alkyl (e.g., methyl or tert- butyl); Compound 4, or any of 4.7-4.11, wherein Rais C10-20alkyl (e.g., decyl or dodecyl); Compound 4, or any of 4.7-4.11, wherein Rais C1-15alkyl (e.g., hexyl or octyl); Compound 4, or any of 4.7-4.11, wherein Rais C7-15alkyl (e.g., heptyl or nonyl); Compound 4, or any of 4.7-4.11, wherein Rais C1-6alkyl (e.g., butyl or hexyl); Compound 4, or any of 4.7-4.11, wherein Rais C1-4alkyl (e.g., n-butyl or tert- butyl); Compound 4, or any of 4.7-4.11, wherein Rais C1-3alkyl (e.g., propyl or isopropyl); Compound 4, or any of 4.7-4.11, wherein Rais C1-2alkyl (e.g., methyl or ethyl); Compound 4, or any of 4.7-4.11, wherein X is N(CH3); Compound 4, wherein X is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane); Compound 4.22, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 4.22, wherein the spiro-joined C3-6cycloalkyl is cyclopropane; Compound 4, wherein X is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane);Compound 4.25, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 4.25, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine; Compound 4, or any of 4.22-4.27, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 4, or any of 4.22-4.27, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 4, or any of 4.1-4.29, wherein Y is CH2; Compound 4, or any of 4.1-4.29, wherein Y is -C(O)-; Compound 4, or any of 4.1-4.29, wherein Y is CHRcor C(Rc)2; Compound 4.32, wherein each Rcis independently C1-6alkyl; Compound 4.32, wherein each Rcis independently selected from methyl, ethyl and propyl; Compound 4, or any of 4.1-4.29, wherein Y is a spiro-joined C3-6cycloalkyl (e.g., cyclopropane); Compound 4.35, wherein the spiro-joined C3-6cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; Compound 4.35, wherein the spiro-joined C3-6cycloalkyl is cyclopropane; Compound 4, or any of 4.1-4.29, wherein Y is spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane); Compound 4.38, wherein the spiro-joined 3-6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; Compound 4.39, wherein the spiro-joined 3-6-membered heterocycloalkyl is aziridine;Compound 4, or any of 4.35-4.40, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is unsubstituted; Compound 4, or any of 4.35-4.40, wherein said spiro-joined C3-6cycloalkyl or 3- 6-membered heterocycloalkyl is substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Compound 4, or any of 4.1-4.42, wherein m is 1; Compound 4, or any of 4.1-4.42, wherein m is 2; Compound 4, or any of 4.1-4.44, wherein X is S, O, CH2, NH, N(CH3), or spiro- joined cyclopropyl; and Y is CH2, C(O), or spiro-joined cyclopropyl; Compound 4, or any of 4.1-4.44, wherein X is N(CH3) or spiro-joined cyclopropyl; and Y is CH2, C(O), or spiro-joined cyclopropyl; Compound 4, or any of 4.1-4.46, wherein the compound is a compound of Formula IV; Compound 4, or any of 4.1-4.46, wherein the compound of Formula IV is a compound of Formula IVa: ; Compound 4, or any of 4.1-of Formula IV is a compound of Formula IVb: ; Compound 4, or any of 4.1-of Formula IV is a compound of Formula IVc:; Compound 4, or any of 4.1-4 pound of Formula IV is a compound of Formula IVd: ; Compound 4, or any of 4.1- of Formula IV is acompound of Formula IVe: ; Compound 4, or any of 4.1-of Formula IV is a compound selected from one or more of: ;Formula IV-A; Compound 4.54, wherein R1is halo (e.g., F) and R2is H; Compound 4.54, wherein R1is H and R2is halo (e.g., F);Compound 4.54, wherein R1is C1-3alkyl (e.g., methyl) and R2is H; Compound 4.54, wherein R1is H and R2is C1-3alkyl (e.g., methyl); Compound 4.54, wherein R1is halo (e.g., F) and R2is halo (e.g., F); Compound 4.54, wherein R1is C1-3alkyl (e.g., methyl) and R2is C1-3alkyl (e.g., methyl); Compound 4.54, wherein R1is C1-3alkyl (e.g., methyl) and R2is halo (e.g., F); Compound 4.54, wherein R1is halo (e.g., F) and R2is C1-3alkyl (e.g., methyl); Compound 4.54, wherein the compound of Formula IV-A is selected from: ;Compound 4, or any of 4.1-4.63, in salt form, e.g., pharmaceutically acceptable salt form; Compound 4, or any of 4.1-4.63, wherein the compound is in acid addition salt form, for example, hydrochloric or toluenesulfonic acid salt form; Compound 4, or any of 4.1-4.66, in substantially pure diastereomeric form (i.e., substantially free from other diastereomers); Compound 4 or any of 4.1-4.66, having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%; Compound 4 or any of 4.1-4.68, in solid form, e.g., in crystal form; Compound 4 or any of 4.1-4.69, in isolated or purified form (e.g., in at least 90% pure form, or at least 95% or at least 98% or at least 99%); Compound 4 or any of 4.1-4.70, wherein the compound has 5-HT2A receptor binding affinity of at least 60% at 100 nM concentration, e.g., 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%, at 100 nM concentration;Compound 4 or any of 4.1-4.71, wherein the compound has a 5-HT2Areceptor dissociation constant (Kd) 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; Compound 4 or any of 4.1-4.72, wherein the compound is an agonist of beta- arrestin signaling via the 5-HT2A receptor, e.g., a partial agonist or a full agonist; Compound 4.73, wherein the compound is a partial agonist of beta-arrestin signaling having an Emax 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%, relative to a full agonist (e.g., alpha-methylserotonin); Compound 4.73 or 4.74, wherein the compound has an EC50for 5-HT2Areceptor beta-arrestin agonism 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; Compound 4.73, 4.74, or 4.75, wherein the compound has a beta-arrestin signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., 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 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8; Compound 4.73, 4.74, or 4.75, wherein the compound has a beta-arrestin signaling relative intrinsic activity (RAi) of greater than 1.0 compared to the reference compound alpha-methylserotonin, e.g., a relative intrinsic activity of 1.0 to 1.2, or 1.0 to 1.4, or 1.0 to 1.6; Compound 4, or any of 4.1-4.72, wherein the compound is an antagonist of beta- arrestin signaling via the 5-HT2A receptor; Compound 4.78, wherein the compound has an IC50 for 5-HT2A receptor beta- arrestin antagonism of less than 300 nM, or less than 200 nM, or less than 100nM, 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; Compound 4 or any of 4.1-4.72, wherein the compound is not an antagonist of beta-arrestin signaling via the 5-HT2Areceptor; Compound 4.80, wherein the compound has an IC50 for 5-HT2A receptor beta- arrestin antagonism of 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; Compound 4 or any of 4.1-4.81, wherein the compound is not an agonist of G-q signaling via the 5-HT2Areceptor, or is a weak agonist thereof; Compound 4.82, wherein the compound is a partial agonist of G-q signaling having an Emax 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%, relative to a full agonist (e.g., alpha-methylserotonin), preferably an Emax of less than 50% or less than 30% or less than 10%; Compound 4.82 or 4.83, wherein the compound has an EC50 for 5-HT2A receptor G-q agonism of 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; Compound 4.82, 4.83 or 4.84, wherein the compound has a G-q signaling relative intrinsic activity (RAi) of less than 1.0 compared to the reference compound alpha-methylserotonin, e.g., 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 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8; Compound 4 or any of 4.1-4.81, wherein the compound is an antagonist of G-q signaling via the 5-HT2A receptor;Compound 4.86, wherein the compound has an IC50for 5-HT2Areceptor G-q antagonism 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; Compound 4 or any of 4.1-4.87, wherein the compound has a bias ratio (beta- arrestin / G-q) for agonism 5-HT2A receptor 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 undefined (i.e., where the compound has any degree of beta-arrestin agonism and zero G-q agonism); Compound 4 or any of 4.1-4.88, wherein the compound is an antagonist or agonist of the D1 and / or D2 dopamine receptor (e.g., having at least 70% receptor affinity at 100 nM concentration or an IC50 of less than 100 nM); Compound 4 or any of 4.1-4.88, wherein the compound is not active at the D1 and / or D2 dopamine receptor (e.g., having less than 50% receptor affinity at 100 nM concentration and / or an EC50or IC50of more than 500 nM); Compound 4 or any of 4.1-4.90, wherein the compound is an antagonist of the serotonin transporter (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an IC50of less than 100 nM); Compound 4 or any of 4.1-4.90, wherein the compound is not active at the serotonin transporter (e.g., having less than 50% receptor binding affinity at 100 nM concentration and / or an EC50or IC50of more than 500 nM); Compound 4 or any of 4.1-4.92, wherein the compound is an agonist, antagonist, or partial agonist of the mu-opioid receptor (e.g., having at least 70% receptor binding affinity at 100 nM concentration or an EC50 or IC50 of less than 100 nM); Compound 4 or any of 4.1-4.92, wherein the compound is not active at the mu- opioid receptor (e.g., having at less than 50% receptor binding affinity at 100 nM concentration and / or an EC50 or IC50 of more than 500 nM); Compound 4, or any of 4.1-4.94, wherein the compound is non-hallucinogenic, e.g., at therapeutic doses 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 (such as drifting, morphing,breathing or melting of objects and surfaces in the field of view), detachment from reality, dissociation, delirium, undesired altered states of consciousness; Compound 4, or any of 4.1-4.95, wherein the compound does not stimulate head twitch response in an animal test model, or is antagonist of DOI-induced head twitch response; Compound 4, or any of 4.1-4.96, wherein the compound is effective in a murine model of depression (tail suspension or forced swim test); Compound 4, or any of 4.1-4.97, wherein the compound is effective in an animal model of social anxiety disorder or anhedonia; Compound 4, or any of 4.1-4.98, wherein the compound does not have 5-HT2Bagonist activity (e.g., an EC50 of greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); Compound 4, or any of 4.1-4.99, wherein the compound has 5-HT2B 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); Compound 4, or any of 4.1-4.100, wherein the compound has 5-HT2cagonist 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); Compound 4, or any of 4.1-4.100, wherein the compound does not have 5-HT2Cantagonist activity (e.g., an IC50 of greater than 100 nM, or greater than 500 nM, or greater than 1000 nM, or greater than 10,000 nM); Compound 4, or any of 4.1-4.102, wherein the compound binds to the alpha-1A adrenergic receptor (e.g., with 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); Compound 4, or any of 4.1-4.103, wherein the compound does not cause psychoses (e.g., prolonged or intermittent psychoses); Compound 4, or any of 4.1-4.104, wherein the compound does not promote self- harm or harm to others in the patient;4.106. Compound 4, or any of 4.1-4.105, wherein the compound does not cause heart valvulopathy or pulmonary arterial hypertension, e.g., wherein the compound is safe to administer to a patient having cardiac comorbidities; 4.107. Compound 4, or any of 4.1-4.106, wherein the compound does not cause abuse or dependence (e.g., physical or psychological dependence); 4.108. Compound 4, or any of 4.1-4.107, wherein the compound is functionally inactive at one or more of the following receptors and ion channels: 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, 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 KV, sodium channel (site 2), norepinephrine transporter, dopamine transporter, and / or serotonin transporter; 4.109. Compound 4.108, wherein the compound has an in vitro receptor activity (for agonism or antagonism) of less than 60% inhibition of radioligand binding (e.g., at 100 nM test concentration) for any one or more of said receptor or ion channels, e.g., less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%; 4.110. Compound 4, or any of 4.1-4.109, wherein the compound is orally bioavailable (e.g., oral bioavailability of at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40%).

[0034] As used herein, the term “spiro-joined” is meant to clarify that the stated C3- 6cycloalkyl group or 3-6-membered heterocycloalkyl is present in a spiro-junction, meaning that one atom of said cyclic group is an atom of the ring to which the group is attached. For example, the following are examples of compounds of Formula I having spiro-joined cyclic groups within the scope of the present disclosure:, , , . , of Formula II having spiro- joined cyclic groups within the scope of the present disclosure:, , , . , of Formula III having spiro- joined cyclic groups within the scope of the present disclosure:, , , . , of Formula IV having spiro- joined cyclic groups within the scope of the present disclosure:of

[0038] In each of the above examples, the cyclopropane, cyclobutane, aziridine, azetidine, or oxetane, may be replaced by any other C3-6cycloalkyl or 3-6-membered heterocycloalkyl, including, but not limited to, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, or morpholine.

[0039] As used hereinbelow, the “Compound of the Invention” refers to a Compound of Formula I or any of 1.1-1.176, or a Compound of Formula II or any of 2.1-2.176, or Compound of Formula III or any of 3.1-3.157, or a Compound of Formula IV or IV-A or any of 4.1-4.110.

[0040] The present disclosure also embraces enantiomers and diastereomers of the each of the Compounds disclosed herein, e.g., Compound 1 or any of 1.1-1.176, or Compound 2 or any of 2.1-2.176, or Compound 3 or any of 3.1-3.157, or Compound 4 or any of 4.1-4.110, and the term the “Compound of the Invention” also embraces such compounds.

[0041] In particular, the present disclosure embraces enantiomers having the opposite stereochemistry across the tetracyclic ring fusion, but retaining the cis-geometry, as well as diastereomers having trans-geometry across the ring fusion, as well as mixtures thereof, including racemates, and compounds of unspecified stereochemistry across the ring junction. For example, in addition to the Compound of Formula I, compounds of the present disclosure also include:R1 R1 R1 N A A A n Z N n Z N n Z asII, compounds of the present disclosure also include: as

[0042] The present disclosure also embraces stereoisomers of the Compounds of Formula III having different orientations for the chiral hydrogen atoms of the tetracyclic core. The present disclosure embraces compounds having these stereocenters in any orientation, as well asmixtures thereof, including racemates, and compounds of unspecified stereochemistry across the tetracyclic ring core. For example, compounds of the present disclosure also include: Y,

[0043] In some embodiments, the Compound of the Invention is a biased agonist of the serotonin 5-HT2A receptor (e.g., biased towards beta-arrestin mediated agonism). Without being bound by theory, it is believed that biased agonism of this receptor will provide the benefits of rapid and / or potent anti-depressant activity comparable to or better than the hallucinogenic psychedelics, but without the hallucinogenic side effects of such compounds. Nevertheless, in some embodiments, the Compounds of the Invention may be slightly or mildly hallucinogenic and / or may be non-biased agonists, or antagonists, of the serotonin 5-HT2Areceptor. Preferably, the Compounds of the invention are non-hallucinogenic.

[0044] In a second aspect, the present disclosure provides a pharmaceutical composition (Pharmaceutical Composition 1) comprising a Compound of the Invention, e.g., in admixture with a pharmaceutically acceptable diluent or carrier. In a particular embodiment, the Compound of the Invention is in pharmaceutically acceptable salt form. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule, e.g., for gastroenteric absorption (i.e., absorption through the stomach and / or large and small intestines). In some embodiments, the pharmaceutical composition is an oral transmucosal composition, e.g., an orally dissolving tablet, wafer, film, gel or spray. For example, the composition may be a rapidly-dissolving sublingual or buccal tablet, wafer, film, or gel. In some embodiments, the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (e.g., as an aerosol, mist, or powder for inhalation). In some embodiments, the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous or intraperitoneal injection. In particular, pharmaceutical compositions for intramuscular orsubcutaneous injection may be in the form of long-acting injectable compositions or depot compositions, e.g., providing for sustained or delayed release of the Compound of the Invention into the blood stream and body tissues. Alternatively, particularly as formulated for intravenous, intrathecal, intraperitoneal, or subcutaneous injection, the composition may be an immediate- acting composition, e.g., providing immediate release into the body fluids of the majority or entirety of the dose.

[0045] In a further embodiment, the Pharmaceutical Compositions of the present disclosure, are for a sustained or delayed release formulation (Pharmaceutical Composition 1-A), e.g., a depot formulation. In some embodiments, the Compound of the Invention is provided, preferably in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier, in the form of an injectable depot, which provides sustained or delayed release of the compound.

[0046] In a particular embodiment, the Pharmaceutical Composition 1-A comprises a Compound of the Invention, in free base or pharmaceutically acceptable salt form, optionally in crystal form, wherein the compound has been milled to, or the compound crystallized to, microparticle or nanoparticle size, e.g., particles or crystals having a volume-based particle size (e.g., diameter or Dv50) of 0.5 to 100 microns, for example, for example, 5-30 microns, 10-20 microns, 20-100 microns, 20-50 microns or 30-50 microns. Such particles or crystals may be combined with a suitable pharmaceutically acceptable diluent or carrier, for example water, to form a depot formulation for injection. For example, the depot formulation may be formulated for intramuscular or subcutaneous injection with a dosage of drug suitable for 4 to 6 weeks of treatment. In some embodiments, the particles or crystals have a surface area of 0.1 to 5 m2 / g, for example, 0.5 to 3.3 m2 / g or from 0.8 to 1.2 m2 / g.

[0047] In another embodiment, the present disclosure provides a Pharmaceutical Composition 1-B, which is Pharmaceutical Composition 1, wherein Compound of the Invention, is in a polymeric matrix. In one embodiment, the Compound of the present disclosure is dispersed or dissolved within the polymeric matrix. In a further embodiment, the polymeric matrix comprises standard polymers used in depot formulations such as polymers selected from a polyester of a hydroxy fatty acid and derivatives thereof, or a polymer of an alkyl alpha- cyanoacrylate, a polyalkylene oxalate, a polyortho ester, a polycarbonate, a polyortho-carbonate, a polyamino acid, a hyaluronic acid ester, and mixtures thereof. In a further embodiment, thepolymer is selected from a group consisting of polylactide, poly d,l-lactide, poly glycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymer. In another embodiment, the polymer is selected form poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as, glycerol mono- and distearate, and the like. In a preferred embodiment, the polymeric matrix comprises poly(d,l-lactide-co-glycolide).

[0048] The Pharmaceutical Composition 1-B is particularly useful for sustained or delayed release, wherein the Compound of the present disclosure is released upon degradation of the polymeric matrix. These Compositions may be formulated for controlled- and / or sustained- release of the Compounds of the present disclosure (e.g., as a depot composition) over a period of up to 180 days, e.g., from about 14 to about 30 to about 180 days. For example, the polymeric matrix may degrade and release the Compounds of the present disclosure over a period of about 30, about 60 or about 90 days. In another example, the polymeric matrix may degrade and release the Compounds of the present disclosure over a period of about 120, or about 180 days.

[0049] In still another embodiment, the Pharmaceutical Composition 1 or 1-A or 1-B may be formulated for administration by injection, for example, as a sterile solution.

[0050] In another embodiment, the present disclosure provides a Pharmaceutical Composition (Pharmaceutical Composition 1-C) comprising a Compound of the Invention as hereinbefore described, in an osmotic controlled release oral delivery system (OROS), which is described in US 2001 / 0036472 and US 2009 / 0202631, the contents of each of which applications are incorporated by reference in their entirety. Therefore in one embodiment, the present disclosure provides a pharmaceutical composition or device comprising (a) a gelatin capsule containing a Compound of any of Formulae I et seq. in free or pharmaceutically acceptable salt form, optionally in admixture with a pharmaceutically acceptable diluent or carrier; (b) a multilayer wall superposed on the gelatin capsule comprising, in outward order from the capsule: (i) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer; and (c) and orifice formed or formable through the wall (Pharmaceutical Composition P.1).

[0051] In another embodiment, the invention provides a pharmaceutical composition comprising a gelatin capsule containing a liquid, the Compound of the Invention in free orpharmaceutically acceptable salt form, optionally in admixture with a pharmaceutically acceptable diluent or carrier, the gelatin capsule being surrounded by a composite wall comprising a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting the barrier layer, a semi-permeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall (Pharmaceutical Composition P.2).

[0052] In still another embodiment, the invention provides a composition comprising a gelatin capsule containing a liquid, the Compound of the Invention in free or pharmaceutically acceptable salt form, optionally in admixture with a pharmaceutically acceptable diluent or carrier , the gelatin capsule being surrounded by a composite wall comprising a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting the barrier layer, a semipermeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall, wherein the barrier layer forms a seal between the expandable layer and the environment at the exit orifice (Pharmaceutical Composition P.3).

[0053] In still another embodiment, the invention provides a composition comprising a gelatin capsule containing a liquid, the Compound of the Invention in free or pharmaceutically acceptable salt form, optionally in admixture with a pharmaceutically acceptable diluent or carrier, the gelatin capsule being surrounded by a barrier layer contacting the external surface of the gelatin capsule, an expandable layer contacting a portion of the barrier layer, a semi- permeable layer encompassing at least the expandable layer, and an exit orifice formed or formable in the dosage form extending from the external surface of the gelatin capsule to the environment of use (Pharmaceutical Composition P.4). The expandable layer may be formed in one or more discrete sections, such as for example, two sections located on opposing sides or ends of the gelatin capsule.

[0054] In a particular embodiment, the Compound of the Invention in the Osmotic-controlled Release Oral Delivery System (i.e., in Composition P.1-P.4) is in a liquid formulation, which formulation may be neat, liquid active agent, liquid active agent in a solution, suspension, emulsion or self-emulsifying composition or the like.

[0055] Further information on Osmotic-controlled Release Oral Delivery System composition including characteristics of the gelatin capsule, barrier layer, an expandable layer, a semi-permeable layer; and orifice may be found in US 2001 / 0036472, the contents of which are incorporated by reference in their entirety.

[0056] Other Osmotic-controlled Release Oral Delivery System for the Compound of Formulas I et seq. or the Pharmaceutical Composition of the present disclosure may be found in US 2009 / 0202631, the contents of which are incorporated by reference in their entirety. Therefore, in another embodiment, the invention provides a composition or device comprising (a) two or more layers, said two or more layers comprising a first layer and a second layer, said first layer comprises the Compound of the Invention in free or pharmaceutically acceptable salt form, optionally in admixture with a pharmaceutically acceptable diluent or carrier, said second layer comprises a polymer; (b) an outer wall surrounding said two or more layers; and (c) an orifice in said outer wall (Pharmaceutical Composition P.5).

[0057] Pharmaceutical Composition P.5 preferably utilizes a semi-permeable membrane surrounding a three-layer-core: in these embodiments, the first layer is referred to as a first drug layer and contains low amounts of drug (e.g., the Compound of the Invention) and an osmotic agent such as salt, the middle layer referred to as the second drug layer contains higher amounts of drug, excipients and no salt; and the third layer referred to as the push layer contains osmotic agents and no drug (Pharmaceutical Composition P.6). At least one orifice is drilled through the membrane on the first drug layer end of the capsule-shaped tablet.

[0058] Pharmaceutical Composition P.5 or P.6 may comprise a membrane defining a compartment, the membrane surrounding an inner protective subcoat, at least one exit orifice formed or formable therein and at least a portion of the membrane being semi-permeable; an expandable layer located within the compartment remote from the exit orifice and in fluid communication with the semi-permeable portion of the membrane; a first drug layer located adjacent the exit orifice; and a second drug layer located within the compartment between the first drug layer and the expandable layer, the drug layers comprising the Compound of the Invention in free or pharmaceutically acceptable salt thereof (Pharmaceutical Composition P.7). Depending upon the relative viscosity of the first drug layer and second drug layer, different release profiles are obtained. It is imperative to identify the optimum viscosity for each layer. In the present invention, viscosity is modulated by addition of salt, sodium chloride. The delivery profile from the core is dependent on the weight, formulation and thickness of each of the drug layers.

[0059] In a particular embodiment, the invention provides Pharmaceutical Composition P.7 wherein the first drug layer comprises salt and the second drug layer contains no salt.Pharmaceutical Composition P.5-P.7 may optionally comprise a flow-promoting layer between the membrane and the drug layers.

[0060] Pharmaceutical Compositions P.1-P.7 will generally be referred to as Osmotic- controlled Release Oral Delivery System Composition.

[0061] In a third aspect, the invention provides a method (Method 1) for the treatment or prophylaxis of a central nervous system disorder, or more than one central nervous system disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of the Invention (e.g., a Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV- A), wherein the Compound of the Invention is an agonist of the 5-HT2Areceptor, optionally wherein the Compound of the Invention is a biased agonist of the 5-HT2Areceptor. In further embodiments of Method 1, the present disclosure provides: 1.1 Method 1, wherein the Compound of the invention is a Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV-A, in free form; 1.2 Method 1, wherein the Compound of the invention is a Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV-A, in pharmaceutically acceptable salt form; 1.3 Method 1.2, wherein the pharmaceutically acceptable salt form is a toluenesulfonic acid addition salt; 1.4 Any of Methods 1, or 1.1-1.3, wherein the Compound of the Invention is administered in the form of a pharmaceutical composition comprising Compound of the Invention in admixture with a pharmaceutically acceptable diluent or carrier (e.g., Pharmaceutical Composition I or any of 1-A, 1-B, 1-C, or P.1 to P.7); 1.5 Method 1.4, wherein the pharmaceutical composition is a Pharmaceutical Composition 1-A, 1-B or 1-C; 1.6 Method 1.4, wherein the pharmaceutical composition is any of the Pharmaceutical Compositions P.1 to P.7; 1.7 Method 1, or any of Methods 1.1-1.6, wherein the central nervous system disorder is a disorder which is susceptible to treatment by agonism of the beta-arrestinsignaling pathway and / or agonism or antagonism of the G-q signaling pathway, mediated by the 5-HT2A receptor; Method 1, or any of Methods 1.1-1.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2A receptor, the dopamine D1 receptor, and / or D2 receptor systems, and / or the serotonin reuptake transporter (SERT) pathways, and / or the mu-opioid receptor pathway; Method 1, or any of 1.1-1.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2Areceptor, the serotonin reuptake transporter (SERT), but not the dopamine D1 receptor or D2 receptor systems, and not the mu-opioid receptor pathway; Method 1, or any of 1.1-1.7, wherein the central nervous system disorder is a disorder not involving, mediated by, or affected (directly or indirectly) by, one or more of the dopamine D1 receptor, dopamine D2 receptor, serotonin reuptake transporter (SERT), or mu-opioid receptor pathway; Method 1, or any of 1.1-1.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2A receptor; Method 1, or any of 1.1-1.11, wherein central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, signaling via the beta-arrestin signaling pathway of the serotonin 5-HT2A receptor; Method 1, or any of Methods 1.1-1.12, wherein the central nervous system disorder is a disorder selected from a group consisting of anxiety (including general anxiety, social anxiety, and panic disorders), and depression (for example refractory depression and major depressive disorder, bipolar depression); Method 1, or any of Methods 1.1-1.13, wherein the central nervous system disorder is anxiety, such as general anxiety, social anxiety, and panic disorders; Method 1, or any of Methods 1.1-1.13, wherein the central nervous system disorder is depression, such as refractory depression, major depressive disorder, and bipolar depression;Method 1, or any of 1.1-1.15, wherein the patient suffers from any combination of the disorders recited in Methods 1.7-1.15; Method 1, or any of 1.1-1.15, wherein the method is a method for the treatment or prophylaxis of any combination of the disorders recited in Methods 1.7-1.15; Method 1, or any of Methods 1.1-1.17, wherein said patient is not responsive to or is unable to tolerate the side effects of conventional anti-depressant agents; Method 1, or any of Methods 1.1-1.18, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with selective serotonin reuptake inhibitors (SSRIs), such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; Method 1, or any of Methods 1.1-1.19, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran; Method 1, or any of Methods 1.1-1.20, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with conventional anxiolytic agents, such as lorazepam, diazepam, alprazolam, and buspirone; Any of the foregoing methods, wherein the therapeutically effective amount of the Compound of the Invention (e.g., the Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV- A) is 1 mg-1000 mg, preferably 2.5 mg-50 mg, or for a long-acting formulation, 25 mg-1500 mg, for example, 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; Method 1.22, wherein the therapeutically effective amount is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day; Method 1.22, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-1000 mg, for example 2.5 mg-50 mg, or for a long-acting formulation, 25 mg-1500 mg, for example, 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; Method 1.22, where therapeutically in the effective amount of the Compound of the Invention is 1 mg-100 mg per day, for example 2.5 mg-50 mg per day;Method 1.22, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-5 mg, preferably 2.5-5 mg, per day; Method 1.22, wherein the therapeutically effective amount of the Compound of the Invention is 2.5 mg or 5 mg, per day; Method 1.22, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-1000 mg administered less than daily, e.g., every other day, every two days, every three days, every four days, every five days, every six days, once per week, once every two weeks, once every three weeks, once per month, once every two months, or once every three months, e.g., wherein the single administration of a dose of the compound provides therapeutic effectiveness for the duration of said period (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months); Method 1.28, wherein the therapeutically effective amount is 1 mg to 500 mg, or 10 mg to 500 mg, or 25 mg to 250 mg, or 50 mg to 100 mg, or 1 mg to 10 mg, or 1 mg or 50 mg, or 1 mg to 100 mg, or 100 mg to 200 mg, or 200 mg to 300 mg, or 300 mg to 400 mg, or 400 mg to 400 mg, or 500 mg to 1000 mg; Method 1, or any of 1.1-1.29, wherein the pharmaceutical composition is a sustained release or delayed release formulation, e.g., according to Pharmaceutical Composition 1-A as described herein; Method 1, or any of 1.1-1.30, wherein the pharmaceutical composition comprises the Compound of the Invention in a polymeric matrix, e.g., according to Pharmaceutical Composition 1-B as described herein; Method 1, or any of 1.1-1.31, wherein the pharmaceutical composition is in the form of a tablet or capsule; Method 1, or any of 1.1-1.32, wherein the pharmaceutical composition is formulated for oral, sublingual, or buccal administration; Method 1, or any of 1.1-1.33, wherein the pharmaceutical composition is a rapidly-dissolving oral tablet (e.g., a rapidly dissolving sublingual tablet); Method 1, or any of 1.1-1.34, wherein the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (e.g., as an aerosol, mist, or powder for inhalation);Method 1, or any of 1.1-1.35, wherein the pharmaceutical composition is formulated for administration by injection, for example, as a sterile aqueous solution; Method 1.36, wherein the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous or intraperitoneal injection Any of Method 1, or 1.1-1.37, wherein the method further comprises the concurrent administration of one or more other therapeutic agents, e.g., administered simultaneously, separately or sequentially; Method 1.38, wherein the additional therapeutic agent is an anti-depressant agent, optionally wherein the anti-depressant agent is selected from amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, ketamine, and esketamine; Method 1.38, wherein the additional therapeutic agent is an anxiolytic agent, optionally selected from lorazepam, diazepam, alprazolam, and buspirone; Method 1, or any of 1.1-1.40, wherein the method does not cause psychoses (e.g., prolonged or intermittent psychoses); Method 1, or any of 1.1-41, wherein the method does not promote self-harm or harm to others in the patient; Method 1, or any of 1.1-1.42, wherein the method does not cause heart valvulopathy or pulmonary arterial hypertension, e.g., wherein the method is safe for treatment of a patient having cardiac comorbidities; Method 1, or any of 1.1-1.43, wherein the method does not cause abuse or dependence (e.g., physical or psychological dependence); Method 1, or any of 1.1-1.44, wherein the patient suffers from or has previously diagnosed with hallucinogen persisting perception disorder (HPPD); Method 1, or any of 1.1-1.45, wherein the patient suffers from or has previously diagnosed with psychosis (e.g., schizophrenia).

[0062] In a fourth aspect, the invention provides a method (Method 2) for the treatment or prophylaxis of a central nervous system disorder, or more than one central nervous system disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of the Invention (e.g., a Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV- A), wherein the Compound of the Invention is an antagonist of the 5-HT2A receptor. In particular embodiments, Method 2 comprises administering: 2.1 Method 2, wherein the Compound of the invention is a Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV-A, in free form; 2.2 Method 2, wherein the Compound of the invention is a Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV-A, in pharmaceutically acceptable salt form; 2.3 Method 2.2, wherein the pharmaceutically acceptable salt form is a toluenesulfonic acid addition salt; 2.4 Any of Methods 2, or 2.1-2.3, wherein the Compound of the Invention is administered in the form of a pharmaceutical composition comprising Compound of the Invention in admixture with a pharmaceutically acceptable diluent or carrier (e.g., Pharmaceutical Composition I or any of 1-A, 1-B, 1-C, or P.1 to P.7); 2.5 Method 2.4, wherein the pharmaceutical composition is a Pharmaceutical Composition 1-A, 1-B or 1-C; 2.6 Method 2.4, wherein the pharmaceutical composition is any of the Pharmaceutical Compositions P.1 to P.7; 2.7 Method 2, or any of Methods 2.1-2.6, wherein the central nervous system disorder is a disorder which is susceptible to treatment by antagonism of the 5-HT2A receptor, e.g., antagonism of the beta-arrestin signaling pathway and antagonism of the G-q signaling pathway, mediated by the 5-HT2A receptor; 2.8 Method 2, or any of Methods 2.1-2.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2Areceptor, dopamine D1 receptor, and / or D2 receptor systems,and / or the serotonin reuptake transporter (SERT) pathways, and / or the mu-opioid receptor pathway; Method 2, or any of 2.1-2.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2A receptor or serotonin reuptake transporter (SERT), but not the dopamine D1 receptor or D2 receptor systems, and not the mu-opioid receptor pathway; Method 2, or any of 2.1-2.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2Areceptor or serotonin reuptake transporter (SERT), but not the mu-opioid receptor pathway; Method 2, or any of 2.1-2.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2Areceptor; Method 2, or any of Methods 2.1-2.11, wherein the central nervous system disorder is a disorder selected from a group consisting of anxiety, depression, psychosis, schizophrenia, sleep disorders, impulse control disorder, post-traumatic stress disorder, intermittent explosive disorder, and dementia; Method 2, or any of Methods 2.1-2.12, wherein the central nervous system disorder is anxiety, such as general anxiety, social anxiety, and panic disorders; Method 2, or any of Methods 2.1-2.12, wherein the central nervous system disorder is depression, such as refractory depression, major depressive disorder, and bipolar depression; Method 2, or any of Methods 2.1-2.12, wherein the central nervous system disorder is psychosis, e.g., schizophrenia; Method 2.15, wherein the method is effective to treat the positive and / or negative symptoms of schizophrenia; Method 2, or any of 2.1-2.16, wherein the patient suffers from any combination of the disorders recited in Methods 2.7-2.16; Method 2, or any of 2.1-2.16, wherein the method is a method for the treatment or prophylaxis of any combination of the disorders recited in Methods 2.7-2.16;Method 2, or any of Methods 2.1-2.18, wherein said patient is not responsive to or is unable to tolerate the side effects of conventional antipsychotic drugs, e.g., chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molindone, perphenazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone; Method 2 or any of Methods 2.1-2.19, wherein said patient is not responsive to or is unable to tolerate the side effects of conventional anti-depressant agents; Method 2, or any of Methods 2.1-2.20, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with selective serotonin reuptake inhibitors (SSRIs), such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; Method 2, or any of Methods 2.1-2.21, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran; Method 2, or any of Methods 2.1-2.22, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with conventional anxiolytic agents, such as lorazepam, diazepam, alprazolam, and buspirone; Method 2, or any of Methods 2.1-2.23, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with antipsychotic agents, such as clomipramine, risperidone, quetiapine and olanzapine; Any of the foregoing methods, wherein the therapeutically effective amount of the Compound of the Invention (e.g., the Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV- A) is 1 mg-1000 mg, preferably 2.5 mg-50 mg, or for a long-acting formulation, 25 mg-1500 mg, for example, 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; Method 2.26, wherein the therapeutically effective amount is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day;Method 2.26, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-1000 mg, for example 2.5 mg-50 mg, or for a long-acting formulation, 25 mg-1500 mg, for example, 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; Method 2.26, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-100 mg per day, for example 2.5 mg-50 mg per day; Method 2.26, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-5 mg, preferably 2.5-5 mg, per day; Method 2.26, wherein the therapeutically effective amount of the Compound of the Invention is 2.5 mg or 5 mg, per day; Method 2.26, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-1000 mg administered less than daily, e.g., every other day, every two days, every three days, every four days, every five days, every six days, once per week, once every two weeks, once every three weeks, once per month, once every two months, or once every three months, e.g., wherein the single administration of a dose of the compound provides therapeutic effectiveness for the duration of said period (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months); Method 2.31, wherein the therapeutically effective amount is 1 mg to 500 mg, or 10 mg to 500 mg, or 25 mg to 250 mg, or 50 mg to 100 mg, or 1 mg to 10 mg, or 1 mg or 50 mg, or 1 mg to 100 mg, or 100 mg to 200 mg, or 200 mg to 300 mg, or 300 mg to 400 mg, or 400 mg to 400 mg, or 500 mg to 1000 mg; Method 2, or any of Methods 2.1-2.32, wherein the pharmaceutical composition is a sustained release or delayed release formulation, e.g., according to Pharmaceutical Composition 1-A as described herein; Method 2, or any of Methods 2.1-2.32, wherein the pharmaceutical composition comprises the Compound of the Invention in a polymeric matrix, e.g., according to Pharmaceutical Composition 1-B as described herein; Method 2, or any of Methods 2.1-2.34, wherein the pharmaceutical composition is in the form of a tablet or capsule;Method 2, or any of Methods 2.1-2.35, wherein the pharmaceutical composition is formulated for oral, sublingual, or buccal administration; Method 2, or any of Methods 2.1-2.36, wherein the pharmaceutical composition is a rapidly-dissolving oral tablet (e.g., a rapidly dissolving sublingual tablet); Method 2, or any of Methods 2.1-2.37, wherein the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (e.g., as an aerosol, mist, or powder for inhalation); Method 2, or any of Methods 2.1-2.38, wherein the pharmaceutical composition is formulated for administration by injection, for example, as a sterile aqueous solution; Method 2.39, wherein the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous or intraperitoneal injection Method 2, or any of Methods 2.1-2.40, wherein the method further comprises the concurrent administration of one or more other therapeutic agents, e.g., administered simultaneously, separately or sequentially; Method 2.41, wherein the additional therapeutic agent is an antipsychotic agent, optionally wherein the antipsychotic agent is selected from a group consisting of chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone; Method 2.42, wherein the additional therapeutic agent is an anti-depressant agent, optionally wherein the anti-depressant agent is selected from amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, ketamine, and esketamine; Method 2.43, wherein the additional therapeutic agent is an atypical antipsychotic agent, optionally wherein the agent is selected from a group consisting ofbrexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone; 2.45 Method 2.44, wherein the additional therapeutic agent is an atypical stimulant, optionally selected from modafinil, adrafinil, and armodafinil; 2.46 Method 2.44, wherein the additional therapeutic agent is an anti-Parkinson’s agent, optionally selected from L- dopa, co-careldopa, duodopa, stalevo, Symmetrel, benztropine, biperiden, bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline and tolcapone; 2.47 Method 2.44, wherein the additional therapeutic agent is an anxiolytic agent, optionally selected from lorazepam, diazepam, alprazolam, and buspirone; 2.48 Method 2, or any of 2.1-2.47, wherein the method does not cause psychoses (e.g., prolonged or intermittent psychoses); 2.49 Method 2, or any of 2.1-2.48, wherein the method does not promote self-harm or harm to others in the patient; 2.50 Method 2, or any of 2.1-2.49, wherein the method does not cause heart valvulopathy or pulmonary arterial hypertension, e.g., wherein the method is safe for treatment of a patient having cardiac comorbidities; 2.51 Method 2, or any of 2.1-2.50, wherein the method does not cause abuse or dependence (e.g., physical or psychological dependence).

[0063] In a fifth aspect, the invention provides a method (Method 3) of providing selective agonism of beta-arrestin signaling through the 5-HT2Areceptor (i.e., biased agonism), in subject in need thereof, or to a cell, comprising administering to the subject or contacting the cell with an effective amount (e.g., a therapeutically effective amount) of a Compound of the Invention (e.g., a Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV-A). In further embodiments of Method 3, the present disclosure provides: 3.1. Method 3, wherein the Compound of the invention is a Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV-A, in free form;Method 3, wherein the Compound of the invention is a Compound of Formula I, or a Compound of Formula II, or a Compound of Formula III, or a Compound of Formula IV or IV-A, in pharmaceutically acceptable salt form; Method 3.2, wherein the pharmaceutically acceptable salt form is a toluenesulfonic acid addition salt; Any of Methods 3 or 3.1-3.3, wherein the Compound of the Invention is administered in the form of a pharmaceutical composition comprising Compound of the Invention in admixture with a pharmaceutically acceptable diluent or carrier (e.g., Pharmaceutical Composition I or any of 1-A, 1-B, 1-C, or P.1 to P.7); Method 3.4, wherein the pharmaceutical composition is a Pharmaceutical Composition 1-A, 1-B or 1-C; Method 3.4, wherein the pharmaceutical composition is any of the Pharmaceutical Compositions P.1 to P.7; Method 3, or any of 3.1-3.6, wherein the method provides full agonism of beta- arrestin signaling via the 5-HT2A receptor; Method 3, or any of 3.1-3.6, wherein the method provides partial agonism of beta- arrestin signaling via the 5-HT2A receptor; Method 3, or any of 3.1-3.8, wherein the method provides full agonism of G-q signaling via the 5-HT2Areceptor, e.g., weaker G-q signaling than beta-arrestin signaling; Method 3, or any of 3.1-3.8, wherein the method provides partial agonism of G-q signaling via the 5-HT2A receptor, e.g., weaker G-q signaling than beta-arrestin signaling; Method 3, or any of 3.1-3.10, wherein the method provides inverse agonism of G- q signaling via the 5-HT2A receptor, e.g., weaker G-q signaling than beta-arrestin signaling; Method 3, or any of 3.1-3.10, wherein the method provides antagonism of G-q signaling via the 5-HT2A receptor, e.g., weaker G-q signaling than beta-arrestin signaling;Method 3, or any of 3.1-3.12, wherein the method provides antagonism or agonism of the D1 and / or D2 receptors; Method 3, or any of 3.1-3.12, wherein the method provides no effect on D1 and / or D2 receptors; Method 3, or any of 3.1-3.14, wherein the method provides antagonism or agonism of the serotonin transporter; Method 3, or any of 3.1-3.14, wherein the method provides no effect on the serotonin transporter; Method 3, or any of 3.1-3.16, wherein the method provides antagonism, partial agonism, or full agonism of the Mu-opioid receptor; Method 3, or any of 3.1-3.16, wherein the method provides no effect on the Mu- opioid receptor; Method 3, or any of 3.1-3.18, wherein the cell is isolated from a patient in need of treatment of a central nervous system disorder; Method 3, or any of 3.1-3.18, wherein the cell is a cell in an in vitro experimental system; Method 3, or any of 3.1-3.18, wherein the subject is an animal, e.g., an animal research model; Method 3, or any of 3.1-3.18, wherein the subject is a patient in need of treatment of a central nervous system disorder; Method 3, or any of 3.1-3.22, wherein the method does not cause hallucination; Method 3, or any of 3.1-3.23, wherein the method does not cause psychoses (e.g., prolonged or intermittent psychoses); Method 3, or any of 3.1-3.24, wherein the method does not promote self-harm or harm to others in the patient; Method 3, or any of 3.1-3.25, wherein the method does not cause heart valvulopathy or pulmonary arterial hypertension, e.g., wherein the method is safe for treatment of a patient having cardiac comorbidities; Method 3, or any of 3.1-3.26, wherein the method does not cause abuse or dependence (e.g., physical or psychological dependence);Method 3, or any of 3.1-3.27, wherein the patient suffers from or has previously diagnosed with hallucinogen persisting perception disorder (HPPD); Method 3, or any of 3.1-3.28, wherein the patient suffers from or has previously diagnosed with psychosis (e.g., schizophrenia); Method 3, or any of 3.1-3.29, wherein the central nervous system disorder is a disorder which is susceptible to treatment by agonism of the beta-arrestin signaling pathway and / or agonism or antagonism of the G-q signaling pathway, mediated by the 5-HT2A receptor; Method 3, or any of 3.1-3.30, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2Areceptor, the dopamine D1 receptor, and / or D2 receptor systems, and / or the serotonin reuptake transporter (SERT) pathways, and / or the mu-opioid receptor pathway; Method 3, or any of 3.1-3.30, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2A receptor, the serotonin reuptake transporter (SERT), but not the dopamine D1 receptor or D2 receptor systems, and not the mu-opioid receptor pathway; Method 3, or any of 3.1-3.30, wherein the central nervous system disorder is a disorder not involving, mediated by, or affected (directly or indirectly) by, one or more of the dopamine D1 receptor, dopamine D2 receptor, serotonin reuptake transporter (SERT), or mu-opioid receptor pathway; Method 3, or any of 3.1-3.30, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, the serotonin 5-HT2A receptor; Method 3, or any of 3.1-3.34, wherein central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by, signaling via the beta-arrestin signaling pathway of the serotonin 5-HT2A receptor; Method 3, or any of 3.1-3.35, wherein the central nervous system disorder is a disorder selected from a group consisting of anxiety (including general anxiety,social anxiety, and panic disorders), and depression (for example refractory depression and major depressive disorder, bipolar depression); Method 3, or any of 3.1-3.35, wherein the central nervous system disorder is anxiety, such as general anxiety, social anxiety, and panic disorders; Method 3, or any of 3.1-3.35, wherein the central nervous system disorder is depression, such as refractory depression, major depressive disorder, and bipolar depression, and / or anhedonia; Method 3, or any of 3.1-3.38, wherein the patient suffers from any combination of the disorders recited in Methods 3.30-3.38; Method 3, or any of 3.1-3.39, wherein said patient is not responsive to or is unable to tolerate the side effects of conventional anti-depressant agents; Method 3, or any of 3.1-3.40, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with selective serotonin reuptake inhibitors (SSRIs), such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; Method 3, or any of 3.1-3.41, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran; Method 3, or any of 3.1-3.42, wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with conventional anxiolytic agents, such as lorazepam, diazepam, alprazolam, and buspirone; Any of the foregoing methods, wherein the therapeutically effective amount of the Compound of the Invention (e.g., the Compound of Formula I) is 1 mg-1000 mg, preferably 2.5 mg-50 mg, or for a long-acting formulation, 25 mg-1500 mg, for example, 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; Method 3.44, wherein the therapeutically effective amount is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day; Method 3.44, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-1000 mg, for example 2.5 mg-50 mg, or for a long-actingformulation, 25 mg-1500 mg, for example, 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; Method 3.44, where therapeutically in the effective amount of the Compound of the Invention is 1 mg-100 mg per day, for example 2.5 mg-50 mg per day; Method 3.44, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-5 mg, preferably 2.5-5 mg, per day; Method 3.44, wherein the therapeutically effective amount of the Compound of the Invention is 2.5 mg or 5 mg, per day; Method 3.44, wherein the therapeutically effective amount of the Compound of the Invention is 1 mg-1000 mg administered less than daily, e.g., every other day, every two days, every three days, every four days, every five days, every six days, once per week, once every two weeks, once every three weeks, once per month, once every two months, or once every three months, e.g., wherein the single administration of a dose of the compound provides therapeutic effectiveness for the duration of said period (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months); Method 3.50, wherein the therapeutically effective amount is 1 mg to 500 mg, or 10 mg to 500 mg, or 25 mg to 250 mg, or 50 mg to 100 mg, or 1 mg to 10 mg, or 1 mg or 50 mg, or 1 mg to 100 mg, or 100 mg to 200 mg, or 200 mg to 300 mg, or 300 mg to 400 mg, or 400 mg to 400 mg, or 500 mg to 1000 mg; Method 3, or any of 3.1-3.51, wherein the pharmaceutical composition is a sustained release or delayed release formulation, e.g., according to Pharmaceutical Composition 1-A as described herein; Method 3, or any of 3.1-3.51, wherein the pharmaceutical composition comprises the Compound of the Invention in a polymeric matrix, e.g., according to Pharmaceutical Composition 1-B as described herein; Method 3, or any of 3.1-3.53, wherein the pharmaceutical composition is in the form of a tablet or capsule; Method 3, or any of 3.1-3.54, wherein the pharmaceutical composition is formulated for oral, sublingual, or buccal administration;Method 3, or any of 3.1-3.55, wherein the pharmaceutical composition is a rapidly-dissolving oral tablet (e.g., a rapidly dissolving sublingual tablet); Method 3, or any of 3.1-3.53, wherein the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (e.g., as an aerosol, mist, or powder for inhalation); Method 3, or any of 3.1-3.53, wherein the pharmaceutical composition is formulated for administration by injection, for example, as a sterile aqueous solution; Method 3.58, wherein the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous or intraperitoneal injection Method 3, or any of 3.1-3.59, wherein the method further comprises the concurrent administration of one or more other therapeutic agents, e.g., administered simultaneously, separately or sequentially; Method 3.60, wherein the additional therapeutic agent is an anti-depressant agent, optionally wherein the anti-depressant agent is selected from amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, ketamine, and esketamine; Method 3.60, wherein the additional therapeutic agent is an anxiolytic agent, optionally selected from lorazepam, diazepam, alprazolam, and buspirone; Method 3, or any of 3.1-3.62, wherein the method does not cause psychoses (e.g., prolonged or intermittent psychoses); Method 3, or any of 3.1-3.63, wherein the method does not promote self-harm or harm to others in the patient; Method 3, or any of 3.1-3.64, wherein the method does not cause heart valvulopathy or pulmonary arterial hypertension, e.g., wherein the method is safe for treatment of a patient having cardiac comorbidities; Method 3, or any of 3.1-3.65, wherein the method does not cause abuse or dependence (e.g., physical or psychological dependence);3.67. Method 3, or any of 3.1-3.66, wherein the patient suffers from or has previously diagnosed with hallucinogen persisting perception disorder (HPPD); 3.68. Method 3, or any of 3.1-3.67, wherein the patient suffers from or has previously diagnosed with psychosis (e.g., schizophrenia).

[0064] In some embodiments of the methods described hereinbelow, the Pharmaceutical Composition comprising a Compound of the Invention may be administered for controlled- and / or sustained-release of the Compounds of the Invention over a period of from about 14 days, about 30 to about 180 days, preferably over the period of about 30, about 60 or about 90 days. Controlled- and / or sustained-release is particularly useful for circumventing premature discontinuation of therapy, particularly for antipsychotic drug therapy where non-compliance or non-adherence to medication regimes is a common occurrence.

[0065] In some embodiments of the methods described hereinbelow, the Pharmaceutical Composition comprising a Compound of the Invention may be a Depot Composition of the present disclosure which is administered for controlled- and / or sustained-release of the Compounds of the Invention over a period of time.

[0066] The Compounds of the present disclosure (i.e., Compounds of the Invention) and the Pharmaceutical Compositions of the present disclosure may be used in combination with a second therapeutic agent, particularly at lower dosages than when the individual agents are used as a monotherapy so as to enhance the therapeutic activities of the combined agents without causing the undesirable side effects commonly occur in conventional monotherapy. Therefore, the Compounds of the present disclosure may be simultaneously, sequentially, or contemporaneously administered with other therapeutic agents as described hereinabove, such as opiate, opioid, analgesic, anti-depressant, anti-psychotic, other hypnotic agents, and / or agents use to treat Parkinson's disease or mood disorders.

[0067] In any of the embodiments of Method 1 et seq. or Method 2 et seq. wherein the Compound of the present disclosure is administered along with one or more second therapeutic agents, the one or more second therapeutic agents may be administered as a part of the pharmaceutical composition comprising the Compound of the present disclosure. Alternatively, the one or more second therapeutic agents may be administered in separate pharmaceutical compositions (such as pills, tablets, capsules and injections) administered simultaneously, sequentially or separately from the administration of the Compound of the present disclosure.

[0068] In some further embodiments of the present disclosure, the Pharmaceutical Compositions of the present disclosure may be used in combination with a second therapeutic agent, particularly at lower dosages than when the individual agents are used as a monotherapy so as to enhance the therapeutic activities of the combined agents without causing the undesirable side effects, wherein the second therapeutic agent is an opioid antagonist or inverse agonist (e.g., naloxone). The Compounds of the present disclosure may be simultaneously, sequentially, or contemporaneously administered with such opioid antagonists or opioid inverse agonists.

[0069] In a sixth aspect, the present disclosure provides use of a Compound of the Invention, in the manufacture of a medicament for use according to Method 1 or any of Methods 1.1-1.46 or Method 2 or any of Methods 2.1-2.51, or Method 3 or any of Methods 3.1-3.68. In another embodiment, the present disclosure provides a Compound of the Invention, for use in the treatment of a disease or disorder according to Method 1 or any of Methods 1.1-1.46 or Method 2 or any of Methods 2.1-2.51, or Method 3 or any of Methods 3.1-3.68. DETAILED DESCRIPTION

[0070] The term “biased agonist” as used herein, is used in reference to a compound having activity at the serotonin 5-HT2A receptor with either partial or full agonism for beta-arrestin signaling via the receptor, but with either antagonism or weak partial agonism for G-q mediated signaling. A useful measure of bias is the “bias ratio”, which is calculated as the ratio of the intrinsic relative activity (RAi) for beta-arrestin signaling over the RAifor G-q 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 are preferably biased towards beta-arrestin signaling, and thus have a bias ratio greater than 1.0. More preferably, the bias ratio towards beta-arrestin signaling is greater than 10, or greater than 100, or greater than 1000, or 10,000 or more.

[0071] As used herein, the term “partial agonist” is understood to refer to a compound having agonism to any extent that is lesser than that of a reference standard full agonist. For example, the reference compound for 5-HT2A receptor agonism is alpha-methylserotonin. A compound which has a maximum efficacy (Emax) that is less than 100% of the maximum efficacy for alpha-methylserotonin is a partial agonist.

[0072] The term “hallucinogen” refers to a compound which causes hallucinogenic symptoms, which are any one or more symptoms selected from visual hallucinations, auditory hallucinations, visual distortions (such as drifting, morphing, breathing or melting of objects and surfaces in the field of view), detachment from reality, dissociation, delirium, and undesired altered states of consciousness. A compound of the present disclosure is considered “non- hallucinogenic” if at doses which are therapeutically effective for the treatment of neuropsychiatric disorders described herein (e.g., depression, anxiety, etc.) the compound does not cause hallucinogenic symptoms.

[0073] It is understood that the terms “opiate” and “opioid” are distinct, in that “opiate” refers to natural products derived from the opium poppy, such as morphine, codeine and heroin, but “opioid” refers to these natural compounds as well as semi-synthetic and synthetic derivatives thereof, such as fentanyl and its analogs.

[0074] “Alkyl” as used herein is a saturated or unsaturated hydrocarbon moiety, e.g., one to twenty-one carbon atoms in length, unless indicated otherwise; any such alkyl may be linear or branched (e.g., n-butyl or tert-butyl), preferably linear, unless otherwise specified. For example, "C1-21 alkyl" denotes alkyl having 1 to 21 carbon atoms. In one embodiment, alkyl is optionally substituted with one or more hydroxy or C1-22alkoxy (e.g., ethoxy) groups. In another embodiment, alkyl contains 1 to 21 carbon atoms, preferably straight chain and optionally saturated or unsaturated, for example in some embodiments wherein R1 is an alkyl chain containing 1 to 21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, e.g., so that together with the -C(O)- to which it attaches, e.g., when cleaved from the compound of Formula I, forms the residue of a natural or unnatural, saturated or unsaturated fatty acid.

[0075] The term “pharmaceutically acceptable diluent or carrier” is intended to mean diluents and carriers that are useful in pharmaceutical preparations, and that are free of substances that are allergenic, pyrogenic or pathogenic, and that are known to potentially cause or promote illness. Pharmaceutically acceptable diluents or carriers thus exclude bodily fluids such as example blood, urine, spinal fluid, saliva, and the like, as well as their constituent components such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in any of several well-known treatises on pharmaceutical formulations, for example Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds.,Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

[0076] The terms “purified,” “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g., from a reaction mixture), or natural source or combination thereof. Thus, the term “purified,” “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization, LC-MS and LC-MS / MS techniques and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

[0077] Unless otherwise indicated, the Compounds of the Invention may exist in free base form or in salt form, such as a pharmaceutically acceptable salt form, e.g., as acid addition salts. An acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric acid or toluenesulfonic acid. In addition, a salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, or a salt with an organic base which affords a physiologically-acceptable cation. In a particular embodiment, the salt of a Compound of the Invention is a toluenesulfonic acid addition salt.

[0078] The Compounds of the Invention are intended for use as pharmaceutical compounds, therefore, pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Invention, and are therefore also included within the scope of the compounds of the present disclosure.

[0079] The Compounds of the Invention may comprise one or more chiral carbon atoms. The compounds thus exist in individual isomeric, e.g., enantiomeric or diastereomeric form or as mixtures of individual forms, e.g., racemic / diastereomeric mixtures. Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R,S)- configuration. The invention is to beunderstood as embracing both individual optically active isomers as well as mixtures (e.g., racemic / diastereomeric mixtures) thereof. Accordingly, the Compounds of the Invention may be a racemic mixture or it may be predominantly, e.g., in pure, or substantially pure, isomeric form, e.g., greater than 70% enantiomeric / diastereomeric excess (“ee”), preferably greater than 80% ee, more preferably greater than 90% ee, most preferably greater than 95% ee. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed and the like).

[0080] Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (Z) or trans (E) form, and both isomeric forms are encompassed within the scope of this invention.

[0081] It is also intended that the compounds of the present disclosure encompass their stable and unstable isotopes. Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non-isotopic analogs. For example, the hydrogen atom at a certain position on the compounds of the disclosure may be replaced with deuterium (a stable isotope which is non-radioactive). Examples of known stable isotopes include, but not limited to, deuterium (2H or D),13C,15N,18O. Alternatively, unstable isotopes, which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g.,123I,131I,125I,14C,18F, may replace the corresponding abundant species of I, C and F. Another example of useful isotope of the compound of the invention is the14C isotope. These radio isotopes are useful for radio-imaging and / or pharmacokinetic studies of the compounds of the invention. In addition, the substitution of atoms of having the natural isotopic distributing with heavier isotopes can result in desirable change in pharmacokinetic rates when these substitutions are made at metabolically liable sites. For example, the incorporation of deuterium (2H) in place of hydrogen can slow metabolic degradation when the position of the hydrogen is a site of enzymatic or metabolic activity.

[0082] Compounds of the Invention may be included as a depot formulation, e.g., by dispersing, dissolving or encapsulating the Compounds of the Invention in a polymeric matrix as described hereinbefore, such that the Compound is continually released as the polymer degradesover time. The release of the Compounds of the Invention from the polymeric matrix provides for the controlled- and / or delayed- and / or sustained-release of the Compounds, e.g., from the pharmaceutical depot composition, into a subject, for example a warm-blooded animal such as man, to which the pharmaceutical depot is administered. Thus, the pharmaceutical depot delivers the Compounds of the Invention to the subject at concentrations effective for treatment of the particular disease or medical condition over a sustained period of time, e.g., 14-180 days, preferably about 30, about 60 or about 90 days.

[0083] Polymers useful for the polymeric matrix in the Composition of the Invention (e.g., Depot composition of the Invention) may include a polyester of a hydroxyfatty acid and derivatives thereof or other agents such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactone ring opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethyleneglycol copolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymer of an alkyl alpha-cyanoacrylate (for example poly(butyl 2-cyanoacrylate)), a polyalkylene oxalate (for example polytrimethylene oxalate or polytetramethylene oxalate), a polyortho ester, a polycarbonate (for example polyethylene carbonate or polyethylenepropylene carbonate), a polyortho-carbonate, a polyamino acid (for example poly-gamma.-L-alanine, poly- .gamma.-benzyl-L-glutamic acid or poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and the like, and one or more of these polymers can be used.

[0084] If the polymers are copolymers, they may be any of random, block and / or graft copolymers. When the above alpha-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity in their molecules, any one of D-isomers, L- isomers and / or DL-isomers may be used. Among others, alpha-hydroxycarboxylic acid polymer (preferably lactic acid-glycolic acid polymer), its ester, poly-alpha-cyanoacrylic acid esters, etc. may be used, and lactic acid-glycolic acid copolymer (also referred to as poly(lactide-alpha- glycolide) or poly(lactic-co-glycolic acid), and hereinafter referred to as PLGA) are preferred. Thus, in one aspect the polymer useful for the polymeric matrix is PLGA. As used herein, the term PLGA includes polymers of lactic acid (also referred to as polylactide, poly(lactic acid), or PLA). Most preferably, the polymer is the biodegradable poly(d,l-lactide-co-glycolide) polymer.

[0085] In a preferred embodiment, the polymeric matrix of the invention is a biocompatible and biodegradable polymeric material. The term “biocompatible” is defined as a polymericmaterial that is not toxic, is not carcinogenic, and does not significantly induce inflammation in body tissues. The matrix material should be biodegradable wherein the polymeric material should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. The products of the biodegradation should also be biocompatible with the body in that the polymeric matrix is biocompatible with the body. Particular useful examples of polymeric 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(ortho carbonates), poly(acetals), poly(lactic acid- caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as, glycerol mono- and distearate, and the like. The preferred polymer for use in the practice of this invention is dl(polylactide-co- glycolide). It is preferred that the molar ratio of lactide to glycolide in such a copolymer be in the range of from about 75:25 to 50:50.

[0086] Useful PLGA polymers may have a weight-average molecular weight of from about 5,000 to 500,000 Daltons, preferably about 150,000 Daltons. Dependent on the rate of degradation to be achieved, different molecular weight of polymers may be used. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the polymeric matrix and then degrade. The drug can also be released from the polymeric matrix as the polymeric excipient bioerodes.

[0087] The PLGA may be prepared by any conventional method, or may be commercially available. For example, PLGA can be produced by ring-opening polymerization with a suitable catalyst from cyclic lactide, glycolide, etc. (see EP-0058481B2; Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

[0088] It is believed that PLGA is biodegradable by means of the degradation of the entire solid polymer composition, due to the break-down of hydrolysable and enzymatically cleavable ester linkages under biological conditions (for example in the presence of water and biological enzymes found in tissues of warm-blooded animals such as humans) to form lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism, which may further biodegrade to form carbon dioxide and water. In other words, PLGA is believed to degrade by means of hydrolysis of its ester groups in the presence of water, for example in the body of a warm-blooded animal such as man, to produce lactic acid andglycolic acid and create the acidic microclimate. Lactic and glycolic acid are by-products of various metabolic pathways in the body of a warm-blooded animal such as man under normal physiological conditions and therefore are well tolerated and produce minimal systemic toxicity.

[0089] In another embodiment, the polymeric matrix useful for the invention may comprise a star polymer wherein the structure of the polyester is star-shaped. These polyesters have a single polyol residue as a central moiety surrounded by acid residue chains. The polyol moiety may be, e. g., glucose or, e. g., mannitol. These esters are known and described in GB 2,145,422 and in U. S. Patent No. 5,538,739, the contents of which are incorporated by reference.

[0090] In preferred embodiments, the Pharmaceutical Compositions according to the present disclosure may take the form of a long-acting injectable (LAI) composition, comprising the compound of the Disclosure dissolved or suspended in a polymeric vehicle comprising a polymer and a non-aqueous, water-miscible, inorganic solvent. In some embodiments, the polymer is a polymer selected from poly(lactic acid) (PLA), poly(glycolic acid) (PLG), or poly(lactide-co-glycolide) (PLGA), for example poly-(L-lactic acid), poly-(DL-lactic acid), poly(L-lactide-co-glycolide), or poly(DL-lactide-co-glycolide). Such polymers may have carboxylic acid or carboxylic ester end groups, e.g., C1-6 alkyl ester end groups. In some embodiments, the solvent is selected from N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), dimethyl formamide (DMF), dimethylacetamide (DMA), 2-pyrrolidone, propylene carbonate, caprolactam, N-methylcaprolactam, and triacetin. In some embodiments, the solvent is a pharmacologically safe triglyceride oil, such as peanut oil, soybean oil, sesame oil, or castor oil. If the polymer is PLGA polymer, it may have wherein a lactic to glycolic molar ratio of about 99:1 to 50:50, e.g., about 99:1 to 80:20, or about 99:1 to 90:10, or about 90:10 to 75:25, or about 90:10 to 80:20, or about 80:20 to 75:25, or about 75:25 to 50:50, or about 85:15 to 75:25, or about 70:30 to 60:40. Preferably the PLA, PLG, and / or PLGA polymer has an inherent viscosity of 0.1 to 0.9 dL / g, and / or an average molecular weight of 5,000 to 150,000 Daltons. The injectable composition may comprise the polymer in an amount of about 10 to 60% by weight, and / or may comprise the solvent in an amount of about 30 to 70% by weight, and / or may comprise the compound of the Disclosure in an amount of 10 to 50% by weight. In some embodiments, the composition has a viscosity of 1 to 100 centiPoise (cP), or a viscosity of 50 to 2000 cP. The composition may comprise the compound if the disclosure at a concentration of 50 to 1000 mg / mL. The compositions may be designed for, and intended for, intramuscular orsubcutaneous injection. The compositions may be formulated as two-component composition for use in two-chamber mixing syringes, for example, wherein the one component comprises the compound of the invention and the polymer and the other component comprises the solvent, or wherein one component comprises the compound of the invention and the solvent, and the other component comprises the polymer.

[0091] The star polymers may be prepared using polyhydroxy compounds, e. g., polyol, e.g., glucose or mannitol as the initiator. The polyol contains at least 3 hydroxy groups and has a molecular weight of up to about 20,000 Daltons, with at least 1, preferably at least 2, e.g., as a mean 3 of the hydroxy groups of the polyol being in the form of ester groups, which contain polylactide or co-polylactide chains. The branched polyesters, e.g., poly (d, l-lactide-co- glycolide) have a central glucose moiety having rays of linear polylactide chains.

[0092] The depot compositions of the invention (long-acting injectable compositions having a Compound of the Invention in a polymeric matrix) as hereinbefore described may comprise the polymer in the form of microparticles or nanoparticles, or in a liquid form, with the Compounds of the Invention dispersed or encapsulated therein. “Microparticles” is meant solid particles that contain the Compounds of the Invention either in solution or in solid form wherein such compound is dispersed or dissolved within the polymer that serves as the matrix of the particle. By an appropriate selection of polymeric materials, a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties.

[0093] When the polymer is in the form of microparticles, the microparticles may be prepared using any appropriate method, such as by a solvent evaporation or solvent extraction method. For example, in the solvent evaporation method, the Compounds of the Invention and the polymer may be dissolved in a volatile organic solvent (for example a ketone such as acetone, a halogenated hydrocarbon such as chloroform or methylene chloride, a halogenated aromatic hydrocarbon, a cyclic ether such as dioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile, or an alcohol such as ethanol) and dispersed in an aqueous phase containing a suitable emulsion stabilizer (for example polyvinyl alcohol, PVA). The organic solvent is then evaporated to provide microparticles with the Compounds of the Invention encapsulated therein. In the solvent extraction method, the Compounds of the Invention and polymer may be dissolved in a polar solvent (such as acetonitrile, dichloromethane, methanol, ethyl acetate or methylformate) and then dispersed in an aqueous phase (such as a water / PVA solution). An emulsion is produced to provide microparticles with the Compounds of the Invention encapsulated therein. Spray drying is an alternative manufacturing technique for preparing the microparticles.

[0094] Another method for preparing the microparticles of the invention is also described in both U.S. Pat. No. 4,389,330 and U.S. Pat. No. 4,530,840.

[0095] The microparticle of the present invention can be prepared by any method capable of producing microparticles in a size range acceptable for use in an injectable composition. One preferred method of preparation is that described in U.S. Pat. No. 4,389,330. In this method the active agent is dissolved or dispersed in an appropriate solvent. To the agent-containing medium is added the polymeric matrix material in an amount relative to the active ingredient that provides a product having the desired loading of active agent. Optionally, all of the ingredients of the microparticle product can be blended in the solvent medium together.

[0096] Solvents for making such compositions comprising the Compounds of the Invention and the polymeric matrix material that can be employed in the practice of the present invention include organic solvents, such as acetone; halogenated hydrocarbons, such as chloroform, methylene chloride, and the like; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols, such as, benzyl alcohol; ethyl acetate; and the like. In one embodiment, the solvent for use in the practice of the present invention may be a mixture of benzyl alcohol and ethyl acetate. Further information for the preparation of microparticles useful for the invention can be found in U.S. Patent Publication Number 2008 / 0069885, the contents of which are incorporated herein by reference in their entirety.

[0097] The amount of the Compounds of the present disclosure incorporated in the microparticles usually ranges from about 1 wt. % to about 90 wt. %, preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. By weight % is meant parts of the Compounds of the present disclosure per total weight of microparticle.

[0098] The pharmaceutical depot compositions may comprise a pharmaceutically-acceptable diluent or carrier, such as a water miscible diluent or carrier.

[0099] Details of Osmotic-controlled Release Oral Delivery System composition may be found in EP 1539115 (U.S. Pub. No. 2009 / 0202631) and WO 2000 / 35419 (US 2001 / 0036472), the contents of each of which are incorporated by reference in their entirety.[000100] A “therapeutically effective amount” is any amount of the Compounds of the invention (for example as contained in the pharmaceutical depot) which, when administered to a subject suffering from a disease or disorder, is effective to cause a reduction, remission, or regression of the disease or disorder over the period of time as intended for the treatment. [000101] Dosages employed in practicing the present invention will of course vary depending, e.g., on the particular disease or condition to be treated, the particular Compound of the Invention used, the mode of administration, and the therapy desired. Unless otherwise indicated, an amount of the Compound of the Invention for administration (whether administered as a free base or as a salt form) refers to or is based on the amount of the Compound of the Invention in free base form (i.e., the calculation of the amount is based on the free base amount). [000102] Compounds of the Invention may be administered by any satisfactory route, including orally, parenterally (intravenously, intramuscular, intranasal, pulmonary or subcutaneous) or transdermally. In certain embodiments, the Compounds of the Invention, e.g., in depot formulation, is preferably administered parenterally, e.g., by injection, for example, intramuscular or subcutaneous injection. [000103] In general, satisfactory results for the methods of treatment disclosed herein, or use of the Compounds of the Invention as hereinbefore described, as set forth above are indicated to be obtained on oral administration at dosages of the order from about 1 mg to 100 mg once daily, preferably 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg, once daily, preferably via oral administration. [000104] For some disease treatments, lower doses are satisfactory, particularly for sleep disorder treatment, such as from about 2.5 mg-5 mg, e.g., 2.5 mg, 3 mg, 4 mg or 5 mg, of a Compound of the Invention, in free or pharmaceutically acceptable salt form, once daily, preferably via oral administration. [000105] In some embodiments, Compounds of the Invention may have a long-acting duration after single dose administration. For example, administration of an oral dose of a Compound in an amount of 1 mg-1000 mg may provide therapeutic effect when administered less than daily, e.g., every other day, every two days, every three days, every four days, every five days, every six days, once per week, once every two weeks, once every three weeks, once per month, once every two months, or once every three months. Thus, a single dose may provide therapeutic efficacy for a period of 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3weeks, 1 month, 2 months, or 3 months. In some embodiments, the therapeutically effective amount for such an effect may be from 1 mg to 500 mg, or 10 mg to 500 mg, or 25 mg to 250 mg, or 50 mg to 100 mg, or 1 mg to 10 mg, or 1 mg or 50 mg, or 1 mg to 100 mg, or 100 mg to 200 mg, or 200 mg to 300 mg, or 300 mg to 400 mg, or 400 mg to 400 mg, or 500 mg to 1000 mg. [000106] Satisfactory results for methods of treatment involving co-administration of a second therapeutic agent may be obtained at doses of less than 100 mg, preferably less than 5 0mg, e.g., less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg, less than 2.5 mg, once daily. [000107] For treatment of the disorders disclosed herein wherein the depot composition is used to achieve longer duration of action, the dosages will be higher relative to the shorter action composition, e.g., higher than 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greater than 1000 mg. Duration of action of the Compounds of the present disclosure may be controlled by manipulation of the polymer composition, i.e., the polymer:drug ratio and microparticle size. Wherein the composition of the invention is a depot composition, administration by injection is preferred. [000108] The pharmaceutically acceptable salts of the Compounds of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Further details for the preparation of these salts, e.g., toluenesulfonic salt in amorphous or crystal form, may be found in U.S. 8,309,722, 8.648,077, 9,199,995, and 9,586,960. [000109] Pharmaceutical compositions comprising Compounds of the present disclosure may be prepared using conventional diluents or excipients (an example include, but is not limited to sesame oil) and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions and the like. [000110] The term “concurrently” when referring to a therapeutic use means administration of two or more active ingredients to a patient as part of a regimen for the treatment of a disease or disorder, whether the two or more active agents are given at the same or different times orwhether given by the same or different routes of administrations. Concurrent administration of the two or more active ingredients may be at different times on the same day, or on different dates or at different frequencies. [000111] The term “simultaneously” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by the same route of administration. [000112] The term “separately” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by different route of administration Methods of Making the Compounds of the Invention: [000113] The Compound of Formula A, and methods for its synthesis, including the synthesis of intermediates used in the synthetic schemes described below, have been disclosed in, for example, U.S. 10,245,260, and US 2022 / 0041600, and US 2022 / 0064166, the contents of which are hereby incorporated by reference in their entireties. [000114] The synthesis of similar fused gamma-carbolines has been disclosed in, for example, U.S. 8,309,722, U.S. 8,993,572, US 2017 / 0183350, WO 2018 / 126140, WO 2018 / 126143, U.S. 10,245,260, US 2022 / 0041600, the contents of each of which are incorporated by reference in their entireties. Compounds of the present disclosure can be prepared using similar procedures. [000115] Other Compounds of the present disclosure came be made by analogous procedures known to those skilled in the art. [000116] Isolation or purification of the diastereomers of the Compounds of the Invention may be achieved by conventional methods known in the art, e.g., column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving beds and the like. [000117] Salts of the Compounds of the present disclosure may be prepared as similarly described in U.S. Pat. No. 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. RE39,680; and U.S. RE39,679, the contents of each of which are incorporated by reference in their entirety. [000118] Diastereomers of prepared compounds can be separated by, for example, HPLC using CHIRALPAK® AY-H, 5μ, 30x250mm at room temperature and eluted with 10% ethanol / 90% hexane / 0.1% dimethylethylamine. Peaks can be detected at 230 nm to produce 98- 99.9%ee of the diastereomer. [000119] The disclosure is further illustrated in the following examples, which are meant to be exemplary and not limiting. EXAMPLES [000120] Method for the synthesis of the compounds of the present disclosure are known in the art. In particular, methods for synthesis of the tetracyclic core structure, and for various modifications and variations of the pendant side chain on the piperidine ring have been published. For example, see WO 2000 / 077001, WO 2000 / 077002, WO2000 / 077010, U.S. 4,219,550, US 2004 / 0209864, US 2004 / 0220178; as well as in Lee et al., Bioorg. & Med. Chem. Lett. 13(4):767-770 (2003), Li, et al., Journal of Medicinal Chemistry 57:2670-2682 (2014), U.S. 6,713,471, U.S. 6,552,017, U.S. 7,071,186, U.S. 8,309,722, U.S., 9,708,322, U.S. 10,245,260, U.S. 10,688,097, U.S. 10,961,245, U.S. 10,906,906, U.S. 11,427,587, U.S. 11,453,670, and US 2022 / 0048910, the contents of each of which are hereby incorporated by reference in their entireties. [000121] Compounds of the present disclosure may be prepared according to the following general schemes: [000122] Scheme 1aNObNH2HCl N RLiAlH4, THF, 0-5 °C, (ii) HCl, ether, 29% yield for two steps; (c) IPA, 110 °C, 26% yield; (d) K2CO3, MeOH, 87% yield; (e) RX, KI, DIPEA, DMF, 76oC, 15 - 20% yield. [000123] Scheme 2aNObNH N2HCl R Typical(i) LiAlH4, THF, 0-5 °C, (ii) HCl, ether, 22% yield for two steps; (c) IPA, 110 °C, 61% yield; (d) K2CO3, MeOH, 82% yield; (e) RX, KI, DIPEA, DMF, 76oC, 17% yield. [000124] According to the above general schemes, the following compounds of Examples 1 to 5 are, or will be, synthesized and characterized: Example 1Example 3Representative synthetic Examples follow. [000125] Example 1. 10-(2-(4-fluorophenoxy)ethyl)-11a-methyl-5,6,7a,8,9,10,11,11a- octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline. Step A: 1-nitroso-1,2,3,4- (102, 10.0 g,75.2 mmol) amide is dissolved in 100ml acetic acid (100mL) and water (50 mL). The solution ss cooled with ice to 0-5oC. Under stirring, sodium nitrite (5.5 g, 78.9 mmol), which is dissolved in water (15 mL), is dropped in slowly to maintain the reaction mixture temperature at less than 5 °C. The mixture is then stirred at room temperature for 1 hour and LC-MS confirms the completion of the reaction. Ethyl acetate (100 mL) is added to the reaction mixture and the aqueous phase is isolated and extracted with additional ethyl acetate (100 mL x 2). The organic phase is dried over MgSO4 and concentrated to give a brown oil. This crude oil is purified by silica gel column chromatography using a gradient of 0 – 30% ethyl acetate in hexane as an eluent. The title compound 103 is obtained as a light brown oil (9.9 g, 82% yield). MS (ESI) m / z 163.10 [M + H]+. [000126] Step B: 3,4-dihydroquinolin-1(2H)-amine hydrochloride (104). Purified 1-nitroso- 1,2,3,4-tetrahydroquinoline (103, 5.0g, 30.8 mmol) is dissolved in THF (10 mL) and the solution is cooled with ice. Under stirring, LiAlH4(17 mL, 2M in THF, 34.0 mmol) is dropped in slowly and carefully. The reaction took place suddenly within 5 minutes, elevating the temperature to 40-50oC. The solution is stirred for an additional 0.5 hours and LC-MS confirms the completion of the reaction. Saturated NH4Cl solution (2 mL) is added to quench the reaction. A white solid precipitates. DCM (20 mL) is added and the solid is filtered. The filtrate is dried over MgSO4 and concentrated to give a crude product as a brown oil. The crude product is further purified by silica gel column chromatography using a gradient of 0 – 30% ethyl acetate in hexane as an eluent. 1.54g free base of the title compound 104 is obtained. The free base is dissolved in ether (20 mL) and under stirring, HCl (11mL, 1M in ether, 11mmol) is dropped in to provide compound 104 as a white solid (1.65 g, 22% yield in two steps). MS (ESI) m / z 149.23 [M + H]+.[000127] Step C: 2,2,2-trifluoro-1-(11a-methyl-5,6,8,9,11,11a-hexahydro-4H- pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)ethan-1-one (106). 3-Methyl-1-(2,2,2- trifluoroacetyl) piperidin-4-one (105, 105 mg, 0.5 mmol) and 3,4-dihydroquinolin-1(2H)-amine hydrochloride (104, 93 mg, 0.5 mmol) are mixed in isopropanol (4 mL) and the reaction mixture is heated to 110oC and stirred at this temperature overnight. After cooling to room temperature, the solvent is removed, and the residue is purified with silica gel column chromatography using a gradient of 0 – 85% ethyl acetate in hexane as an eluent. The title compound 106 is obtained as a yellow solid (42 mg, 26% yield). MS (ESI) m / z 325.09 [M + H]+. [000128] Step D: 11a-methyl-5,6,7a,8,9,10,11,11a-octahydro-4H- pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (107). 2,2,2-Trifluoro-1-(11a-methyl-5,6,8,9,11,11a- hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)ethan-1-one (106, 36 mg, 0.11 mmol) is dissolved in MeOH (2.2 mL) and K2CO3 (31 mg, 0.22 mmol) is added. The reaction mixture is heated to 80oC and stirred at this temperature for 2 h. After cooling to room temperature, the solvent is removed. The residue is suspended in DCM (10mL) and the solid is filtered. The DCM solution is concentrated to afford the crude product 107 as a yellow solid. It is used directly for next step without any further purification. MS (ESI) m / z 229.17 [M + H]+.[000129] Step E: 10-(2-(4-fluorophenoxy)ethyl)-11a-methyl-5,6,7a,8,9,10,11,11a- octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (108). A mixture of compound 107 (20 mg, 0.08 mmol), 1-(2-bromoethoxy)-4-fluorobenzene (29 mg, 0.12 mmol), and KI (29 mg, 0.16 mmol) in DMF (0.5 mL) is bubbled with argon for 3 minutes, and then DIPEA (30 µL, 0.16 mmol) is added. The mixture is stirred at 76oC for 2 h, and then cooled to room temperature. The solvent is removed, and the residue is dissolved in DCM (10 mL) and washed with water (5 mL). The DCM phase is dried over K2CO3, and concentrated. The crude product is purified with silica gel column chromatography using a gradient of 0 – 45% ethyl acetate in hexanes as eluent. The compound of Example 1 (compound 108) is obtained as a yellow oil (11 mg, 34 % yield). MS (ESI) m / z 367.21 [M + H]+. [000130] Example 2. 3-(2-(11a-methyl-5,6,8,9,11,11a-hexahydro-4H- pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)ethyl)benzo[d]isoxazole.[000131] The synthesis m esis of compound of Example 1 according to Scheme 1, wherein 3-(2-bromoethyl)benzo[d]isoxazole is added in step E instead of 1-(2-bromoethoxy)-4-fluorobenzene. The title product is obtained as a yellow oil, 17% isolated yield. MS (ESI) m / z 374.28 [M + H]+. [000132] Example 3. 8-(2-(4-fluorophenoxyl)ethyl)-6b-methyl-1,2,6b,7,8,9,10,10a- octahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole. Step A: 4-nitroso-3,4-3,4-dihydro-2H- benzo[b][1,4]oxazine (110, 10.2 g, 75.2 mmol) amide is dissolved in 100ml acetic acid (100mL) and water (30 mL). The solution is cooled with ice to 0-5oC. Under stirring, sodium nitrite (5.5 g, 78.9 mmol), which is dissolved in water (15 mL), is dropped in slowly to maintain the reaction mixture temperature at less than 5 °C. The mixture is then stirred at room temperature for 1 hour and LC-MS confirms the completion of the reaction. Ice water 2100 mL) is added to the reaction mixture and the product precipitates as a yellow solid. The solid is filtered and dried over vacuum to afford the title compound 111 which was used directly in the next step without further purification. 10.6 g, 86% yield. MS (ESI) m / z 165.06 [M + H]+. [000133] Step B: 2,3-dihydrobenzo[b][1,4]oxazin-4-amine hydrochloride (112). Purified 4- nitroso-3,4-dihydro-2H-benzo[b][1,4]oxazine (111, 5.0g, 30.4 mmol) is dissolved in THF (20 mL) and the solution is cooled with ice. Under stirring, LiAlH4(17 mL, 2M in THF, 34.0 mmol) is dropped in slowly and carefully. The reaction took place suddenly within 5 minutes, elevating the temperature to 40-50oC. The solution is stirred for an additional 0.5 hours and LC-MS confirms the completion of the reaction. Saturated NH4Cl solution (2 mL) is added to quench the reaction. A white solid precipitates. DCM (20 mL) is added and the solid is filtered. The filtrate is dried over MgSO4 and concentrated to give a crude product as a brown oil. The crude product is further purified by silica gel column chromatography using a gradient of 0 – 30% ethyl acetatein hexane as an eluent. 1.11g free base of the title compound 112 is obtained. The free base is dissolved in ethyl acetate (2 mL) and under stirring, HCl (3.7mL, 2M in ether, 7.4 mmol) is dropped in to provide compound 112 as a white solid (1.25 g, 22% yield in two steps). MS (ESI) m / z 151.13 [M + H]+. [000134] Step C: 2,2,2-trifluoro-1-(6b-methyl-1,2,6b,9,10,10a-hexahydro- [1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)-yl)ethan-1-one (113). 3-Methyl-1-(2,2,2- trifluoroacetyl) piperidin-4-one (105, 640 mg, 3.1 mmol) and 2,3-dihydrobenzo[b][1,4]oxazin-4- amine hydrochloride (112, 560 mg, 2.9 mmol) are mixed in isopropanol (20 mL) and the reaction mixture is heated to 110oC and stirred at this temperature overnight. After cooling to room temperature, the solvent is removed, and the residue is purified with silica gel column chromatography using a gradient of 0 – 50% ethyl acetate in hexane as an eluent. The title compound 113 is obtained as a yellow solid (600 mg, 59% yield). MS (ESI) m / z 327.10 [M + H]+. [000135] Step D: 6b-methyl-1,2,6b,7,8,9,10,10a-octahydro-[1,4]oxazino[2,3,4- hi]pyrido[4,3-b]indole (114). 2,2,2-trifluoro-1-(6b-methyl-1,2,6b,9,10,10a-hexahydro- [1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)-yl)ethan-1-one (113, 190 mg, 0.58 mmol) is dissolved in MeOH (2.0 mL) and K2CO3(158 mg, 1.16 mmol) is added. The reaction mixture is heated to 80oC and stirred at this temperature for 2 h. After cooling to room temperature, the solvent is removed. The residue is suspended in DCM (10mL) and the solid is filtered. The DCM solution is concentrated to afford the crude product 114 as a yellow solid. It is used directly for next step without any further purification. MS (ESI) m / z 231.16 [M + H]+. [000136] Step E: 8-(2-(4-fluorophenoxyl)ethyl)-6b-methyl-1,2,6b,7,8,9,10,10a-octahydro- [1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (115). A mixture of compound 114 (67 mg, 0.29 mmol), 1-(2-bromoethoxy)-4-fluorobenzene (79 mg, 0.35 mmol), and KI (100 mg, 0.58 mmol) in DMF (2.0 mL) is bubbled with argon for 3 minutes, and then DIPEA (100 µL, 0.58 mmol) is added. The mixture is stirred at 76oC for 2 h, and then cooled to room temperature. The solvent is removed, and the residue is dissolved in DCM (10 mL) and washed with water (5 mL). The DCM phase is dried over K2CO3, and concentrated. The crude product is purified with silica gel column chromatography using a gradient of 0 – 65% ethyl acetate in hexanes as eluent. The compound of Example 3 (compound 115) is obtained as a yellow oil (11 mg, 34 % yield). MS (ESI) m / z 367.21 [M + H]+.[000137] The Compounds of Examples 4 and 5 are prepared according to analogous procedures as described above. The racemic compound of Example 5 is further resolved by chiral chromatography to afford the enantiomers, the compounds 5A and 5B. [000138] The Compounds of Examples 6, 7, 8, and 9 are prepared according to analogous procedures as described above, each of these racemic compounds is further resolved by chiral chromatography to provide the following stereoisomers: Example 6AExample 7B[000139] Example 6: 5-fluoro-2-(3-(6b-methyl-1,2,6b,9,10,10a-hexahydro- [1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)-yl)propoxy)benzonitrile. The title product is obtained as a colorless oil (60 mg, 17% yield).1H NMR (500 MHz, DMSO) δ 7.73 (dd, J = 8.2, 3.2 Hz, 1H), 7.55 (ddd, J = 9.4, 8.3, 3.2 Hz, 1H), 7.28 (dd, J = 9.4, 4.2 Hz, 1H), 6.64 – 6.54 (m, 2H), 6.50 (dd, J = 7.5, 1.6 Hz, 1H), 4.41 (dt, J = 11.1, 2.6 Hz, 1H), 4.34 – 4.23 (m, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.36 (dt, J = 11.0, 2.2 Hz, 1H), 2.79 (dd, J = 4.2, 2.1 Hz, 1H), 2.66 – 2.56 (m, 2H), 2.53 (dd, J = 11.1, 1.8 Hz, 1H), 2.45 (dt, J = 12.3, 7.0 Hz, 1H), 2.34 (dt, J = 12.7, 6.8 Hz, 1H), 2.24 – 2.14 (m, 1H), 1.98 – 1.83 (m, 4H), 1.78 (ddt, J = 12.3, 9.6, 4.5 Hz, 1H), 1.33 (s, 3H).13C NMR (126 MHz, DMSO) δ 157.18, 155 (J = 238.1 Hz), 142.83, 137.18, 136.90, 122.23 (J = 23.9 Hz), 119.81, 119.79 (J = 3.3 Hz), 115.28, 114.83 (J = 7.6 Hz), 113.76, 112.49, 101.17 (J = 10.1 Hz), 71.64, 67.67, 66.18, 61.14, 53.93, 49.02, 44.30, 43.76, 26.02, 22.99, 20.94. MS (ESI) [M+H]⁺: 408.3. [000140] Examples 6A and 6B: 5-fluoro-2-(3-((6bR)-6b-methyl-1,2,6b,9,10,10a- hexahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)-yl)propoxy)benzonitrile (6A) and 5-fluoro-2-(3-((6bS)-6b-methyl-1,2,6b,9,10,10a-hexahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)-yl)propoxy)benzonitrile (6B). These compounds are the two enantiomers of the compound of Example 6. They are obtained by chiral separation on a ChiralPak AD-H column (particle size, 5µm, 20 mm I.D.× 250 mm L) using 0.5% triethyl amine in EtOH as the eluent. Each product is given as a colorless oil. The first peak corresponds to 5-fluoro-2-(3-((6bR)-6b- methyl-1,2,6b,9,10,10a-hexahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)- yl)propoxy)benzonitrile (6A).1H NMR (500 MHz, DMSO) δ 7.73 (dd, J = 8.2, 3.2 Hz, 1H), 7.55 (ddd, J = 9.4, 8.3, 3.2 Hz, 1H), 7.28 (dd, J = 9.4, 4.2 Hz, 1H), 6.62 – 6.55 (m, 2H), 6.50 (dd, J = 7.5, 1.5 Hz, 1H), 4.41 (ddd, J = 11.2, 2.8, 1.9 Hz, 1H), 4.29 (ddd, J = 11.2, 10.3, 2.3 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.36 (dt, J = 11.1, 2.2 Hz, 1H), 2.79 (dd, J = 4.0, 2.0 Hz, 1H), 2.67 – 2.56 (m, 2H), 2.53 (dd, J = 11.1, 1.8 Hz, 1H), 2.44 (dt, J = 12.3, 7.0 Hz, 1H), 2.34 (dt, J = 12.4, 6.8 Hz, 1H), 2.19 (ddd, J = 12.5, 11.0, 2.9 Hz, 1H), 1.94 – 1.83 (m, 4H), 1.77 (ddt, J = 14.2, 12.6, 4.6 Hz, 1H), 1.33 (s, 3H).13C NMR (126 MHz, DMSO) δ 156.84, 155.0 (J = 238.1 Hz), 142.49, 136.84, 136.57, 121.81(J = 22.6 Hz),119.47, 119.45 (J = 26.46 Hz), 114.94, 114.49 (J = 7.56 Hz), 113.42, 112.15, 100.81(J = 7.56 Hz), 71.31, 67.33, 65.84, 60.80, 53.60, 48.69, 43.97, 43.42, 25.68, 22.66, 20.60. MS (ESI) [M+H]⁺: 408.3. The second peak corresponds to 5-fluoro- 2-(3-((6bS)-6b-methyl-1,2,6b,9,10,10a-hexahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol- 8(7H)-yl)propoxy)benzonitrile (6B).1H NMR (500 MHz, DMSO) δ 7.73 (dd, J = 8.2, 3.2 Hz, 1H), 7.55 (ddd, J = 9.4, 8.3, 3.2 Hz, 1H), 7.28 (dd, J = 9.3, 4.2 Hz, 1H), 6.62 – 6.54 (m, 3H), 6.50 (dd, J = 7.5, 1.5 Hz, 1H), 4.41 (ddd, J = 11.2, 2.8, 1.9 Hz, 1H), 4.29 (ddd, J = 11.2, 10.3, 2.3 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.37 (dt, J = 11.0, 2.2 Hz, 1H), 2.79 (dd, J = 4.1, 2.1 Hz, 1H), 2.67 – 2.56 (m, 2H), 2.56 – 2.50 (m, 1H), 2.45 (dt, J = 12.4, 6.9 Hz, 1H), 2.34 (dd, J = 12.4, 6.7 Hz, 1H), 2.19 (ddd, J = 12.5, 11.0, 2.9 Hz, 1H), 1.93 – 1.85 (m, 4H), 1.83 – 1.71 (m, 1H), 1.33 (s, 3H).13C NMR (126 MHz, DMSO) δ 157.18, 155.22 (J = 238.14 Hz), 142.83, 137.18, 136.91, 122.14 (J = 22.68 Hz), 119.81, 119.79 (J = 26.46 Hz), 115.28, 114.83 (J =7.56 Hz), 113.76, 112.49, 101.17 (J = 10.08 Hz), 71.64, 67.67, 66.18, 61.14, 53.93, 49.03, 44.30, 43.76, 26.02, 22.99, 20.94. MS (ESI) [M+H]⁺: 408.3. [000141] Example 7: 1-(4-fluorophenyl)-4-(6b-methyl-1,2,6b,9,10,10a-hexahydro- [1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)-yl)butan-1-one. The title product is obtained as a brown oil (26 mg, 7.5% yield).1H NMR (500 MHz, DMSO) δ 8.28 – 7.81 (m, 2H), 7.65 – 7.00 (m, 2H), 6.62 – 6.53 (m, 2H), 6.50 (dd, J = 7.5, 1.5 Hz, 1H), 4.49 – 4.37 (m, 1H), 4.28 (ddd, J = 11.2, 10.3, 2.3 Hz, 1H), 3.35 (dt, J = 11.1, 2.2 Hz, 1H), 3.02 (td, J = 7.0, 1.3 Hz, 2H), 2.77(dd, J = 4.2, 2.1 Hz, 1H), 2.59 (td, J = 10.7, 3.0 Hz, 2H), 2.47 (d, J = 1.7 Hz, 1H), 2.31 (dt, J = 12.2, 6.9 Hz, 1H), 2.21 (dt, J = 12.2, 6.9 Hz, 1H), 2.17 – 2.08 (m, 1H), 1.93 – 1.83 (m, 3H), 1.83 – 1.65 (m, 2H), 1.29 (s, 3H).13C NMR (126 MHz, DMSO) δ 198.66, 165.04 (J = 126 Hz), 142.98, 137.41, 137.06, 133.81, 130.96 (J = 8.82 Hz), 119.96, 115.81 (J = 21.42 Hz), 113.91, 112.63, 71.84, 66.34, 61.34, 57.28, 49.04, 44.02, 35.72, 23.08, 21.50, 21.10. MS (ESI) [M+H]+395.3. [000142] Examples 7A and 7B: 1-(4-fluorophenyl)-4-((6bR)-6b-methyl-1,2,6b,9,10,10a- hexahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)-yl)butan-1-one (7A) and 1-(4- fluorophenyl)-4-((6bS)-6b-methyl-1,2,6b,9,10,10a-hexahydro-[1,4]oxazino[2,3,4- hi]pyrido[4,3-b]indol-8(7H)-yl)butan-1-one (7B). These compounds are the two enantiomers of the compound of Example 7. They are obtained by chiral separation on a ChiralPak AD-H column (particle size, 5µm, 20 mm I.D.× 250 mm L) using 0.5% triethyl amine in EtOH as the eluent. Each product is given as a colorless oil. The first peak corresponds to 1-(4-fluorophenyl)- 4-((6bR)-6b-methyl-1,2,6b,9,10,10a-hexahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)- yl)butan-1-one (7A).1H NMR (500 MHz, DMSO) δ 8.11 – 8.00 (m, 2H), 7.40 – 7.30 (m, 2H), 6.61 – 6.53 (m, 2H), 6.50 (dd, J = 7.5, 1.5 Hz, 1H), 4.41 (ddd, J = 11.2, 2.8, 1.9 Hz, 1H), 4.28 (ddd, J = 11.2, 10.3, 2.3 Hz, 1H), 3.35 (dt, J = 11.1, 2.2 Hz, 1H), 3.02 (td, J = 7.0, 1.2 Hz, 2H), 2.76 (dd, J = 4.2, 2.1 Hz, 1H), 2.59 (td, J = 10.7, 2.9 Hz, 2H), 2.47 (d, J = 1.8 Hz, 1H), 2.31 (dt, J = 12.2, 7.0 Hz, 1H), 2.25 – 2.17 (m, 1H), 2.13 (ddd, J = 13.7, 11.2, 2.8 Hz, 1H), 1.94 – 1.83 (m, 2H), 1.79 – 1.68 (m, 2H), 1.29 (s, 3H).13C NMR (126 MHz, DMSO) δ 197.99, 164.37 (J = 252 Hz), 142.30, 136.74, 136.39, 133.14, 133.11, 130.28 (J = 8.82 Hz), 119.29, 115.14 (J = 21.42 Hz), 111.96, 71.17, 65.67, 60.66, 56.61, 48.37, 43.79, 43.20, 35.05, 22.41, 20.82, 20.43. MS (ESI) [M+H]+395.3. The second peak corresponds to 1-(4-fluorophenyl)-4-((6bS)-6b- methyl-1,2,6b,9,10,10a-hexahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indol-8(7H)-yl)butan-1- one (7B).1H NMR (500 MHz, DMSO) δ 8.10 – 7.99 (m, 2H), 7.39 – 7.31 (m, 2H), 6.61 – 6.53 (m, 2H), 6.50 (dd, J = 7.5, 1.5 Hz, 1H), 4.41 (ddd, J = 11.2, 2.9, 2.0 Hz, 1H), 4.28 (ddd, J = 11.2, 10.3, 2.3 Hz, 1H), 3.35 (dt, J = 11.0, 2.2 Hz, 1H), 3.02 (td, J = 7.0, 1.2 Hz, 2H), 2.76 (dd, J = 4.1, 2.1 Hz, 1H), 2.59 (td, J = 10.7, 3.0 Hz, 2H), 2.47 (d, J = 1.7 Hz, 1H), 2.31 (dt, J = 12.3, 6.9 Hz, 1H), 2.21 (dt, J = 12.3, 6.8 Hz, 1H), 2.13 (td, J = 11.8, 2.8 Hz, 1H), 1.93 – 1.84 (m, 2H), 1.82 – 1.71 (m, 3H), 1.29 (s, 3H).13C NMR (126 MHz, DMSO) δ 198.49, 164.87 (J = 252 Hz), 142.81, 137.24, 136.89, 133.63 (J = 1.26 Hz), 130.78 (J = 8.82 Hz), 119.79, 115.63 (J = 21.42 Hz),113.74, 112.46, 71.67, 66.17, 61.17, 57.12, 48.87, 44.29, 43.71, 35.55, 22.91, 21.33, 20.93. MS (ESI) [M+H] + 395.3. [000143] Example 8: 1-(4-fluorophenyl)-4-(11a-methyl-5,6,8,9,11,11a-hexahydro-4H- pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)butan-1-one. The title compound is obtained as a brown oil (120 mg, 51% yield).1H NMR (500 MHz, DMSO) δ 8.10 – 7.98 (m, 2H), 7.46 – 7.26 (m, 2H), 6.85 – 6.66 (m, 2H), 6.55 (t, J = 7.4 Hz, 1H), 3.25 (dt, J = 10.3, 3.8 Hz, 1H), 3.01 (td, J = 7.0, 1.1 Hz, 2H), 2.74 (dd, J = 4.2, 2.3 Hz, 1H), 2.61 (dd, J = 8.7, 4.5 Hz, 2H), 2.57 – 2.51 (m, 1H), 2.46 – 2.36 (m, 2H), 2.28 (dt, J = 12.2, 7.0 Hz, 1H), 2.18 (dt, J = 12.2, 6.9 Hz, 1H), 2.08 (ddd, J = 13.5, 11.1, 2.8 Hz, 1H), 2.05 – 1.90 (m, 2H), 1.86 (dq, J = 14.4, 2.6 Hz, 1H), 1.83 – 1.63 (m, 4H), 1.28 (s, 3H).13C NMR (126 MHz, DMSO) δ 198.99, 166.37, 164.37, 148.97, 135.94, 134.13(J = 1.3 Hz),131.28 (J = 8.8 Hz), 126.67, 120.11, 119.37, 118.69, 116.21, 116.04, 70.91, 61.87, 57.63, 49.32, 44.67, 43.43, 36.05, 24.13, 23.35, 22.92, 21.84, 21.55. MS (ESI) [M+H]⁺: 393.3. [000144] Examples 8A and 8B: 1-(4-fluorophenyl)-4-((11aR)-11a-methyl- 5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)butan-1- one (8A) and 1-(4-fluorophenyl)-4-((11aS)-11a-methyl-5,6,8,9,11,11a-hexahydro-4H pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)butan-1-one (8B). These compounds are the two enantiomers of the Compound of Example 8. They are obtained by chiral separation on a ChiralPak AD-H column (particle size, 5µm, 20 mm I.D.× 250 mm L) using 0.5% triethyl amine in EtOH as the eluent. Each product is given as a colorless oil. The first peak corresponds to 1-(4-fluorophenyl)-4-((11aR)-11a-methyl-5,6,8,9,11,11a-hexahydro-4H- pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)butan-1-one (8A).1H NMR (500 MHz, DMSO) δ 8.08 – 8.00 (m, 2H), 7.37 – 7.31 (m, 2H), 6.77 (ddd, J = 13.4, 7.4, 1.1 Hz, 2H), 6.55 (t, J = 7.4 Hz, 1H), 3.29 – 3.22 (m, 1H), 3.01 (td, J = 7.0, 1.1 Hz, 2H), 2.74 (dd, J = 4.2, 2.2 Hz, 1H), 2.61 (dd, J = 8.7, 4.5 Hz, 2H), 2.57 – 2.51 (m, 1H), 2.41 (ddd, J = 10.9, 8.8, 2.2 Hz, 2H), 2.28 (dt, J = 12.2, 7.0 Hz, 1H), 2.23 – 2.14 (m, 1H), 2.08 (ddd, J = 13.4, 11.1, 2.7 Hz, 1H), 2.03 – 1.92 (m, 1H), 1.90 – 1.82 (m, 1H), 1.82 – 1.65 (m, 4H), 1.28 (s, 3H).13C NMR (126 MHz, DMSO) δ 198.66, 165.03 (J = 252 Hz), 148.63, 135.61, 133.80 (J = 2.52Hz), 130.95 (J = 10.08Hz), 126.33, 119.77, 119.04, 118.35, 115.79 (J = 21.42Hz), 70.58, 61.54, 57.30, 48.99, 44.34, 43.09, 35.72, 23.79, 23.02, 22.59, 21.51, 21.22. MS (ESI) [M+H]⁺: 393.3. The second peak corresponds to (4-fluorophenyl)-4-((11aS)-11a-methyl-5,6,8,9,11,11a-hexahydro-4H -pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)butan-1-one (8B).1H NMR (500 MHz, DMSO) δ 8.08 – 8.00 (m, 2H), 7.38 – 7.30 (m, 2H), 6.80 – 6.72 (m, 2H), 6.54 (t, J = 7.4 Hz,1H), 3.29 – 3.21 (m, 1H), 3.01 (td, J = 7.0, 1.1 Hz, 2H), 2.74 (dd, J = 2.2 Hz, 1H), 2.61 (dd, J = 8.7, 4.5 Hz, 2H), 2.57 – 2.50 (m, 1H), 2.40 (ddd, J = 11.2, 9.5, 2.1 Hz, 2H), 2.27 (dt, J = 12.2, 7.0 Hz, 1H), 2.22 – 2.13 (m, 1H), 2.12 – 1.91 (m, 3H), 1.90 – 1.82 (m, 1H), 1.82 – 1.63 (m, 4H), 1.28 (s, 3H).13C NMR (126 MHz, DMSO) δ 198.16, 164.53 (J = 252 Hz), 148.13, 135.11, 133.30 (J = 3.78Hz), 130.45 (J = 8.82 Hz), 125.83, 119.27, 118.53, 117.85, 115.30 (J = 21.42 Hz), 70.08, 61.04, 56.80, 48.49, 43.84, 42.59, 35.21, 23.29, 22.52, 22.09, 21.01, 20.72. MS (ESI) [M+H]⁺: 393.3. [000145] Example 9: 5-fluoro-2-(3-(11a-methyl-5,6,8,9,11,11a-hexahydro-4H- pyrido[3',4':4,5] pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)propoxy)benzonitrile. The title product is obtained as a brown oil (65 mg, 40% yield).1H NMR (500 MHz, DMSO) δ 7.73 (ddd, J = 8.2, 3.2, 1.2 Hz, 1H), 7.55 (dddd, J = 9.2, 8.3, 3.3, 0.8 Hz, 1H), 7.28 (dd, J = 9.4, 4.2 Hz, 1H), 6.82 – 6.73 (m, 2H), 6.55 (t, J = 7.4 Hz, 1H), 4.18 (td, J = 6.3, 2.8 Hz, 3H), 3.27 (dt, J = 10.3, 3.7 Hz, 1H), 2.77 (dd, J = 4.1, 2.2 Hz, 1H), 2.62 (dd, J = 8.6, 4.5 Hz, 1H), 2.57 (dt, J = 10.8, 2.3 Hz, 1H), 2.50 (p, J = 1.9 Hz, 1H), 2.48 – 2.38 (m, 3H), 2.31 (dt, J = 12.3, 6.8 Hz, 1H), 2.14 (ddd, J = 12.5, 11.1, 2.9 Hz, 1H), 2.07 – 1.93 (m, 2H), 1.92 – 1.80 (m, 3H), 1.75 (ddt, J = 12.4, 9.8, 6.3 Hz, 1H), 1.32 (s, 3H).13C NMR (126 MHz, DMSO) δ 157.52, 155.50 (J = 238.1 Hz), 148.81, 135.72, 126.53, 122.46 (J = 22.7 Hz), 120.23, 120.00 (J = 6.3 Hz), 119.22, 118.54, 115.61, 115.16 (J = 7.6 Hz), 101.50 (J = 10.1 Hz), 70.72, 68.01, 61.68, 54.28, 49.32, 44.52, 43.31, 26.35, 23.96, 23.27, 22.76, 21.40. MS (ESI) [M+H]⁺: 406.3. [000146] Examples 9A and 9B: 5-fluoro-2-(3-((11aR)-11a-methyl-5,6,8,9,11,11a- hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)propoxy)benzonitrile (9A) and 5-fluoro-2-(3-((11aS)-11a-methyl-5,6,8,9,11,11a-hexahydro-4H - pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)propoxy)benzonitrile (9B). These compounds are the two enantiomers of the compound of Example 9. They are obtained by chiral separation on a ChiralPak AD-H column (particle size, 5µm, 20 mm I.D.× 250 mm L) using 0.5% triethyl amine in EtOH as the eluent. Each product is given as a colorless oil. The first peak corresponds to 5-fluoro-2-(3-((11aR)-11a-methyl-5,6,8,9,11,11a-hexahydro-4H- pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)propoxy)benzonitrile (9A).1H NMR (500 MHz, DMSO) δ 7.73 (dd, J = 8.2, 3.2 Hz, 1H), 7.55 (ddd, J = 9.4, 8.3, 3.2 Hz, 1H), 7.28 (dd, J =9.4, 4.2 Hz, 1H), 6.77 (ddd, J = 12.9, 7.4, 1.1 Hz, 2H), 6.55 (t, J = 7.4 Hz, 1H), 4.17 (t, J = 6.3 Hz, 2H), 3.27 (dt, J = 10.3, 3.7 Hz, 1H), 2.77 (dd, J = 4.1, 2.2 Hz, 1H), 2.62 (dd, J = 8.6, 4.6 Hz, 2H), 2.57 (dq, J = 8.9, 2.2 Hz, 1H), 2.48 – 2.38 (m, 3H), 2.31 (dt, J = 12.3, 6.7 Hz, 1H), 2.19 – 2.08 (m, 1H), 2.07 – 1.93 (m, 2H), 1.93 – 1.80 (m, 4H), 1.75 (ddt, J = 14.4, 12.5, 4.5 Hz, 1H), 1.32 (s, 3H).13C NMR (126 MHz, DMSO) δ 156.85, 155.87 (J = 238.14Hz), 148.14, 135.05, 125.86, 121.79 (J = 23.94 Hz), 119.56, 119.33 (J = 6.3 Hz), 118.55, 117.87, 114.94, 114.49 (J = 7.56 Hz), 100.83 (J = 10.08Hz), 70.05, 67.34, 61.00, 53.61, 48.65, 43.85, 42.64, 25.68, 23.29, 22.60, 22.09, 20.73. MS (ESI) [M+H]⁺: 406.3. The second peak corresponds to 5-fluoro-2-(3- ((11aS)-11a-methyl-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin- 10(7aH)-yl)propoxy)benzonitrile (9B).1H NMR (500 MHz, DMSO) δ 7.73 (dd, J = 8.2, 3.2 Hz, 1H), 7.55 (ddd, J = 9.4, 8.3, 3.2 Hz, 1H), 7.28 (dd, J = 9.4, 4.2 Hz, 1H), 6.77 (ddd, J = 13.1, 7.4, 1.1 Hz, 2H), 6.55 (t, J = 7.4 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.27 (dt, J = 10.3, 3.7 Hz, 1H), 2.77 (dd, J = 4.1, 2.2 Hz, 1H), 2.62 (dd, J = 8.6, 4.5 Hz, 2H), 2.60 – 2.53 (m, 1H), 2.49 – 2.37 (m, 3H), 2.36 – 2.26 (m, 1H), 2.20 – 2.09 (m, 1H), 2.08 – 1.93 (m, 2H), 1.93 – 1.80 (m, 4H), 1.75 (ddt, J = 14.3, 12.5, 4.5 Hz, 1H), 1.32 (s, 3H).13C NMR (126 MHz, DMSO) δ 157.02, 155.01 (J = 238.14Hz), 148.31, 135.21, 126.03, 121.96 (J = 23.94Hz), 119.73, 119.50 (J = 6.3Hz), 118.72, 118.04, 115.11, 114.66 (J = 7.56 Hz), 101.00 (J = 10.08Hz), 70.21, 67.50, 61.17, 53.78, 48.82, 44.02, 42.81, 25.85, 23.46, 22.77, 22.25, 20.90. MS (ESI) [M+H]⁺: 406.3. [000147] The following additional compounds may be prepared according to related synthetic methods: Example 11Example 13[000148] The following additional compounds may be prepared according to related synthetic methods: Example 21Example 24[000149] The tetracyclic moieties of the Compounds according to the present disclosure, as well as the Compounds of Formula IV and IV-A themselves, may be prepared according to the following general schemes and procedures using intermediates and reagents disclosed in the aforementioned references. [000150] Scheme A:[000151] Reagents and conditions: (a) NaH, MeI, THF, 49% yield; (b) ethylmagnesium bromide, titanium isopropoxide, THF, 25 °C, 70% yield; or ethylmagnesium bromide (3M inEt2O), methyl titanium triisopropoxide, THF, 25 °C, 39% yield; (c) sat. KOH in 90% EtOH solution, 100 °C, 72% yield. [000152] Scheme B: [000153]110 °C, 48% yield; (b) DBU, Pd(OAc)2, tricyclohexylphosphine, DMF, 140 °C, 30% yield; (c) ZnEt2, CH2I2, CH2Cl2, 0 °C, 43% yield; (d) sat. KOH in 90% EtOH solution, 100 °C, 100 % yield. [000154] Scheme C: [000155]hexahydro-1'H,3'H- spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline[000156] Step a: ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H- pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (6) [000157] Sodium hydride (3.18 g, 60% dispersion in mineral oil, 0.08 mol) is added slowly to a stirred solution of ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H- pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (8.0 g, 0.027 mol) in anhydrous THF (80 mL) at 0oC under nitrogen atmosphere, and the reaction mixture is stirred for 40 minutes. Iodomethane (2.15 ml, 0.035 mol) is added. The reaction mixture is warmed up to rt and continued to stir for 5 hours. The reaction mixture is quenched with sat. NH4Cl and extracted with DCM (30 ml x3). The DCM phase is dried over Na2SO4 and then concentrated; The residue is purified by column chromatography using a gradient of 0 – 100% ethyl acetate in hexane as an eluent. The title compound is obtained as a pale white solid (4.1 g, 49% yield). [000158] Step b: (6b'R,10a'S)-ethyl 3'-methyl-3',6b',7',9',10',10a'- hexahydrospiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline]-8'(1'H)- carboxylate (7). [000159] Ethylmagnesium bromide (3.0 M in Et2O, 13.6 mL, 10 mmol) is added dropwise to a vigorously stirred solution of Compound 6, 4.29 g, 13.6 mmol) and titanium isopropoxide (6.1 mL, 20.6 mmol) in THF (40 mL). The solution is stirred at room temperature for 1 to 3 days until no starting material is detected and then the reaction is quenched with saturated NH4Cl (15 mL). The solvent is removed under reduced pressure and the residue is suspended in DCM (200 mL) and washed with water (100 mL). The DCM phase is separated, dried over K2CO3and concentrated to give a brown oil. This crude oil is purified by silica gel column chromatography using a gradient of 0 – 100% ethyl acetate in hexane as an eluent. The title compound is obtained as a light brown solid (3.12 g, 70% yield). MS (ESI) m / z 328.16 [M + H]+.1H NMR (500 MHz, CDCl3) δ 6.73 – 6.65 (m, 2H), 6.61 (dd, J = 7.1, 1.9 Hz, 1H), 4.26 – 4.03 (m, 3H), 3.84 (s, 1H), 3.55 – 3.34 (m, 1H), 3.19 (dt, J = 13.9, 7.5 Hz, 2H), 2.86 (dd, J = 9.9, 2.2 Hz, 1H), 2.70 (s, 3H), 2.46 (d, J = 10.0 Hz, 1H), 1.85 (dt, J = 6.8, 3.7 Hz, 2H), 1.66 – 1.47 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.10 (dt, J = 10.0, 6.0 Hz, 1H), 0.97 – 0.80 (m, 1H), 0.78 – 0.62 (m, 1H), 0.58 – 0.33 (m, 1H).13C NMR (126 MHz, CDCl3) δ 155.69, 141.12, 136.25, 129.88, 119.89, 115.90, 115.43, 64.60, 61.37, 47.82, 45.57, 41.94, 41.25, 39.80, 38.82, 24.69, 14.91, 14.23, 10.33. [000160] Step c: (6b'R,10a'S)-3'-methyl-1',3',6b',7',8',9',10',10a'- octahydrospiro[cyclopropane-1,2'-pyrido- [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline] (8).[000161] Compound 7 (1.71 g, 5.22 mmol) is suspended in sat. KOH in 90% EtOH solution (17 mL) at room temperature and microwave heated at 100 °C with stirring for 4 h. The reaction is cooled to room temperature and ethyl acetate (200 mL) is added. The mixture is washed with water (100 mL), followed by brine (100 mL). The ethyl acetate phase is separated, dried over K2CO3and concentrated. The residue is further dried over high vacuum to give the title compound as a beige solid (1.0 g, 72% yield). MS (ESI) m / z 256.17 [M + H]+.1H NMR (500 MHz, CDCl3) δ 6.72 – 6.64 (m, 2H), 6.64 – 6.58 (m, 1H), 3.41 – 3.31 (m, 1H), 3.20 – 3.00 (m, 2H), 2.95 – 2.85 (m, 1H), 2.86 – 2.75 (m, 3H), 2.70 (s, 3H), 2.51 (d, J = 9.9 Hz, 1H), 1.93 – 1.72 (m, 2H), 1.71 – 1.65 (m, 1H), 1.16 – 1.04 (m, 1H), 0.94 – 0.82 (m, 1H), 0.76 – 0.63 (m, 1H), 0.60 – 0.46 (m, 1H).13C NMR (126 MHz, CDCl3) δ 141.25, 136.24, 131.21, 119.54, 115.79, 115.14, 64.52, 48.80, 47.41, 41.97, 41.89, 41.85, 39.14, 25.94, 14.07, 10.55. [000162] Example 32. (7a'S,11a'R)-5',6',7a',8',9',10',11',11a'- octahydrospiro[cyclopropane-1,4'-pyrido[3',4':4,5]pyrolo [3,2,1-ij]quinoline [000163] Step a: (4aS,9bR)-ethyl3-en-1-yl)-3,4,4a,5-tetrahydro-1H- pyrido[4,3-b]indole-2(9bH)-carboxylate (47). [000164] A mixture of ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3- b]indole-2-carboxylate (compound 46, 6.51 g, 20.0 mmol), 4-bromo-1-butene (4.05 g, 30.0 mmol), DIPEA (5.17 g, 40.0 mmol), and KI (4.98 g, 30.0 mmol) in anhydrous dioxane (17 mL) is heated under argon atmosphere at 110 °C for 48 h. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is suspended in DCM (200 mL) and washed with water (100 mL). The DCM phase is separated, dried over K2CO3and concentrated to give a brown oil. This oil is purified with silica gel column chromatography using a gradient of 0 – 70% ethyl acetate in hexane as an eluent. The title compound is obtained as a brown oil (3.6 g, 48% yield). MS (ESI) m / z 379.16 [M + H]+. [000165] Step b: ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H- pyrido[3',4':4,5]pyrrolo[1,2,3]dequinoxaline-8(7H)-carboxylate (48). [000166] To a degassed solution of Compound 47 (850 mg, 2.24 mmol), K2CO3 (1.1 mg, 7.92 mmol), and tricyclohexylphosphine (59 mg, 0.21 mmol) in DMF (6 mL) is added Pd(OAc)2(24 mg, 0.11 mmol) under Ar. The resulting mixture is stirred at 140 °C for 3 h. After evaporation of the reaction solvent, the residue is purified by flash column chromatography on silica gel using a gradient of 0 – 30% ethyl acetate in hexane as an eluent. The title compound is obtained as a beige solid (200 mg, 30% yield). MS (ESI) m / z 299.13 [M + H]+.1H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 8.0, 1.1 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.69 (dd, J = 8.0, 7.1 Hz, 1H), 5.44 (d, J = 2.2 Hz, 1H), 4.91 – 4.86 (m, 1H), 4.22 – 4.07 (m, 3H), 3.81 (s, 1H), 3.42 – 3.36 (m, 1H), 3.36 – 3.28 (m, 1H), 3.28 – 3.15 (m, 2H), 3.00 – 2.82 (m, 2H), 2.76 – 2.70 (m, 1H), 2.70 – 2.60 (m, 1H), 1.96 – 1.90 (m, 1H), 1.90 – 1.81 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H). [000167] Step c: (7a'S,11a'R)-ethyl 5',6',8',9',11',11a'-hexahydrospiro[cyclopropane-1,4'- pyrido[3',4':4,5]pyrrolo [3,2,1-ij]quinoline]-10'(7a'H)-carboxylate (49). [000168] Diiodomethane (600 mg, 2.23 mmol) is added dropwise to a stirred solution of ZnEt2(1.5 M in toluene, 0.7 mL, 1.1 mmol) in dichloromethane (0.5 mL) at 0 °C under argon, and the mixture is stirred at 0 °C for 50 min. A solution of compound 48 (165 mg, 0.553 mmol) in dichloromethane (0.5 mL) is added, and the resulting mixture is stirred at 0 °C for 4 h. The reaction is then quenched with saturated NH4Cl (0.5 mL) and neutralized with saturated NaHCO3(10 mL). The resulting solution is extracted with dichloromethane (20 mL) and the organic layer is evaporated to dryness. The residue is purified by silica gel column chromatography using a gradient of 0 – 100% a mixture of ethyl acetate: methanol: 7 N NH3in methanol (10 : 1 : 0.1 v / v / v) in ethyl acetate as an eluent. The title compound is obtained as a beige solid (75 mg, 43% yield). MS (ESI) m / z 313.14 [M + H]+. [000169] Step d: (7a'S,11a'R)-5',6',7a',8',9',10',11',11a'-octahydrospiro[cyclopropane-1,4'- pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline] (50). [000170] Compound 49 (70 g, 0.224 mmol) is suspended in sat. KOH in 90% EtOH solution (0.7 mL) at room temperature and microwave heated at 100 °C with stirring for 4 h. The reaction is cooled to room temperature and ethyl acetate (20 mL) is added. The mixture is washed with water (10 mL), followed by brine (10 mL). The ethyl acetate phase is separated, dried over K2CO3 and concentrated. The residue is further dried over high vacuum to provide the title compound as a beige solid (70 mg, yield > 100%). MS (ESI) m / z 241.17 [M + H]+. [000171] Example 33. (6bR,10aS)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H- pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one[000172] Ethyl (6bR,10aS)-3-meth 6b,9,10,10a-hexahydro-1H- pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate (0.8g, 2.5 mmol) is suspended in HBr solution (5.5 mL, 33% w in acetic acid) at room temperature. The reaction mixture is heated to 55oC and stirred at same overnight with strong stirring. After the completion of reaction, the mixture is cooled to room temperature and ethyl acetate (20 mL) is added. The resulting suspension is then filtered, and the filter cake is washed with ethyl acetate (2 mL) and dried under vacuum to afford the title compound as an HBr salt. This HBr salt is then added in small batches into a cold ammonia solution in methanol (15 mL, 7.0 N) and the resulting mixture is stirred for 10 min. The solvents are removed, and the residue is suspended in ethyl acetate (5 mL). The precipitate is filtered, and the filter cake is further dried under high vacuum to afford the title compound as a tan solid, (550 mg, yield 89%. MS (ESI) m / z 244.12 [M + H]+.1H NMR (500 MHz, CDCl3) δ 6.85 (dd, J = 7.4, 1.1 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.74 (dd, J = 7.9, 1.1 Hz, 1H), 4.03 (d, J = 14.3 Hz, 1H), 3.41 – 3.34 (m, 2H), 3.33 (s, 3H), 3.23 (dt, J = 10.8, 6.5 Hz, 1H), 3.14 (ddd, J = 12.4, 6.6, 1.3 Hz, 1H), 2.94 (ddd, J = 12.2, 5.6, 3.5 Hz, 1H), 2.85 (ddd, J = 12.3, 11.2, 4.0 Hz, 1H), 2.47 (dd, J = 12.4, 10.8 Hz, 1H), 2.27 (s, 1H), 1.92 – 1.79 (m, 2H).13C NMR (126 MHz, CDCl3) δ 165.60, 139.19, 130.97, 126.94, 121.09, 119.07, 112.20, 67.00, 53.08, 49.51, 41.86, 41.71, 28.44, 25.66. [000173] The following additional compounds, are prepared according to literature procedures and tested as described hereinbelow:[000174] The f pared according to the following schemes (wherein X is O or CH2): (a)℃, 2 h; then (2) HCl solution in ether, 22 – 86% yield; (c) 3-methyl-1-(2,2,2-trifluoroacetyl)piperidin-4-one, isopropanol, 110 ℃, overnight, 26 – 63% yield; (d) K₂CO₃, methanol, 80 ℃, 3 h, 88 – 91% yield.Example 10-A: Receptor Binding Profile [000175] Standard receptor binding to the serotonin, dopamine, and mu-opioid receptors, and to the serotonin transporter, is determined according to literature procedures. For example, the following literature procedures may be used, each of which reference is incorporated herein by reference in their entireties: 5-HT2A: Bryant, H.U. et al. (1996), Life Sci., 15:1259-1268; D2: Hall, D.A. and Strange, P.G. (1997), Brit. J. Pharmacol., 121:731-736; D1: Zhou, Q.Y. et al. (1990), Nature, 347:76-80; SERT: Park, Y.M. et al. (1999), Anal. Biochem., 269:94-104; Mu opioid receptor: Wang, J.B. et al. (1994), FEBS Lett., 338:217-222. [000176] In general, the results are expressed as a percent of control specific binding: measured specific binding x 100 control specific binding and as a percent inhibition of control specific binding: measured specific binding 100 -x 100control specific bindingobtained in the presence of the test compounds. [000177] The IC50values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) are determined by non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation curve fitting A-D where Y = specific binding, A =D = right asymptote of the curve, C = compound concentration, C50 = IC50, and nH = slope factor. This analysis was performed using in –house software and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc.). The inhibition constants (Ki) were calculated using the Cheng Prusoff equation: IC50where L = concentration ofKD = affinity of the radioligand for the receptor. A Scatchard plot is used to determine the KD.[000178] The compound of Formula A (ITI-007, lumateperone) is used as a comparison in the assays.Formula A (Lumateperone) [000179] The following receptor affinity results are obtained (with the Compound of Formula A for comparison): Receptor Kd (nM) or maximum binding affinity (%, at 100 nM) 09 98% 0.7 68% 22 39% 64 36% 80 28% 9A 99% 74% 49% 35% 22% [0001, ptor selectivity than the reference compound of Formula A. For example, the compounds of Examples 1, 2, and 3 show little D1, D2, or Mu receptor affinity, but retain strong affinity at the serotonin 2A receptor. [000181] Additional results are shown in the following table: Receptor Ki (nM) or maximum binding affinity (%, at 100 nM) E D1 D1 D2 D2 ERT ERT M M 0[000182] As shown above, the compound of Example 31 has high activity binding to the 5- HT2A receptor, but little to no activity binding to the D1 or D2 receptors, or SERT transporter.The compound shows significantly more receptor selectivity than the reference compound of Formula A. [000183] Selected compounds may also be tested in receptor binding assays for the 5-HT2B, and / or 5-HT2Creceptors. Some results are shown in the following table: Ex. 5-HT2A5-HT2A5-HT2B5-HT2B5-HT2C5-HT2C(%) Ki(%) Ki(%) Ki[000184]p y p ays for the 5- HT2B and 5-HT2C receptors as agonists (EC50) or antagonists (IC50). Some results are shown in the following table: Ex. 5-HT2B 5-HT2C[000185] Some compounds may additionally be tested in a receptor profiling panel consisting of agonist and / or antagonist radioligand binding assays. Assays are conducted using a 100 nM concentration of the test compound. Compound binding is calculated as a percent inhibition of the binding of the specific radioligand for the receptor (or ion channel) tested, which can be an agonist or antagonist. The following receptors and ion channels are included in the panel: Receptor or Ion Channel Reference Ligandcholecystokinin CCK1 CCK-8s (agonist) dopamine D1 SCH 23390 (antagonist)[000186] It is unexpectedly found that the compounds of the present disclosure have high selectivity with few off-target interactions. [000187] Example 10-B: Biased Agonism / Antagonism [000188] G-q Signaling Agonism / Antagonism at the 5-HT2A Receptor. Selected compounds are submitted to 5-HT2A agonist and antagonist assays for G-q recruitment. Alpha- methylserotonin is used as the reference control for agonist assays, and altanserin is used as the control for antagonist assays. [000189] Agonist Assay: CHO-K1 cells expressing human 5-HT2A (ES-313-AF) are obtained from PerkinElmer and used according to the supplier’s recommendations. Frozen cells are thawed in a water bath at 37 °C, and then are resuspended in 10 mL Ham’s F-12 medium containing 10% FBS. Cells are recovered by centrifugation at 150g for 5 minutes and are then resuspended in pre-warmed assay buffer (DMEM / HAM’s F-12 with HEPES) at 3x105cells / L in a Falcon tube. Under sterile conditions, Coelenterazine H is added to a final concentration of 5 µM to the cell suspension. The Falcon tube is wrapped in aluminum foil and placed on a rotating wheel (about 45° angle and 7 rpm / min speed) for 4 hours at room temperature. Cells are then diluted to 1x105cells / mL in assay buffer and transferred to a beaker wrapped in aluminum foil on a magnetic stirrer. After 1 hour of incubation, 50 µL of cells (5,000 cells / well) are injected into 50 µL of the test compound at increasing concentrations in the wells of a 96-well white plate. Light emission is recorded for 20 seconds immediately with FLUOstar Omega luminescence detector (BMG LABTECH). Digitonin at a final concentration of 50 µM in assay buffer is used as a positive control to measure the receptor independent cellular calcium response. Curve fitting was performed using GraphPad Prism and EC50 values are determined using a 4-parameter logistic fit, and maximum response (Emax) values are calculated by subtracting the bottom value from the top value of the dose-response curve. [000190] Antagonist Assay: 50 µL of cells (5,000 cells / well) are mixed with 50 µL of the test compound at increasing concentrations in the wells of a 96-well white plate, and then the plates are incubated 15 minutes at room temperature. Thereafter, 50 µL of alpha- methylserotonin (final assay concentration corresponding to its measured EC80) is injected and the light emission is recorded for 20 seconds immediately with FLUOstar Omega luminescence detector (BMG LABTECH). Curve fitting is performed using Prism and IC50values aredetermined using a 4-parameter logistic fit. For the antagonists, the apparent dissociation constants (KB) are calculated using the modified Cheng Prusoff equation—KB = IC50 / (1+(A / EC50A)) – where A is the concentration of the reference agonist alpha-methylserotonin, and EC50Ais the EC50value of the reference agonist alpha-methylserotonin. [000191] Beta-arrestin Signaling Agonism / Antagonism at the 5-HT2A Receptor. Selected compounds are submitted to 5-HT2A agonist and antagonist assays for beta-arrestin recruitment. Alpha-methylserotonin is used as the reference control for agonist assays, and altanserin is used as the control for antagonist assays. [000192] Agonist Assay: U2OS cells expressing human 5-HT2A receptor (93- 0401E3CP19L) are obtained from Eurofins DiscoverX and used according to the supplier’s recommendations. Frozen cells are thawed in a water bath at 37 °C, and then mixed with 0.5 mL of pre-warmed Cell Plating Reagent. Cells are pipetted up and down gently several times to ensure even distribution before transfer to 11.5 mL of pre-warmed Cell Plating Reagent and poured into a disposable reagent reservoir. 100 µL of cells are plated into each well of the 96- well tissue culture plate, and the plates are incubated for 24 hours at 37 °C (5% CO2). 10 µL of the test compound at increasing concentrations is added into the cells in the 96-well plate, and then the plates are incubated for 3 hours at room temperature. After addition of 55 µL of prepared detection reagent and a further 1-hour incubation, the samples are read on an Envision luminescence plate reader. All assay points are determined in duplicate and the data is presented as average values. Curve fitting is performed using Prism software (Graphpad), EC50values are determined using a 4-parameter logistic fit, and maximum response (Emax) values are calculated by subtracting the bottom value from the top value of the dose-response curve. [000193] Antagonist Assay: 5 µL of the test compound at increasing concentrations is added into the cells in the 96-well plate, and the plates are incubated for 30 minutes at 37 °C (5% CO2). Thereafter 5 µL of α-methylserotonin (final assay concentration Thereafter, 50 µL of alpha-methylserotonin (final assay concentration corresponding to its measured EC80) is added and the plates are incubated for 3 hours at room temperature. After addition of 55 µL of prepared detection reagent and a further 1-hour incubation, the samples are read on an Envision luminescence plate reader. All assay points are determined in duplicate and the data is presented as average values. Curve fitting is performed using Prism software (Graphpad), EC50values are determined using a 4-parameter logistic fit. For the antagonists, the apparent dissociationconstants (KB) are calculated using the modified Cheng Prusoff equation—KB= IC50 / (1+(A / EC50A)) – where A is the concentration of the reference agonist alpha-methylserotonin, and EC50A is the EC50 value of the reference agonist alpha-methylserotonin. [000194] For both the G-q signaling agonism assay and the beta-arrestin signaling agonism assay, the EC50 (effective concentration for 50% activation), and the Emax (maximum activation) are determined. [000195] The maximum efficacy (Emax) for the compound is calculated as a percentage of the maximal signaling activity induced by the compound compared to that induced by the full agonist alpha-methylserotonin. This is an indication of the compound’s intrinsic activity. Any degree of maximal activity less than that of the full agonist reference indicates that the test compound is a partial agonist. [000196] Like intrinsic activity (Emax), intrinsic relative activity (RAi) is another way to quantify the partial versus full agonism of receptor activity, but it also takes into account the efficacy of the compound. It is calculated using the following formula: [000197] Bias Score. Biasof the intrinsic relative activity (RAi) for agonism of beta-arrestin signaling over the intrinsic relative activity (RAi) for agonism of G-q signaling. [000198] The results are shown in the table below (RAi = Intrinsic Relative Activity, compared to the positive controls methylserotonin or altanserin): Beta-Arrestin Signaling G-q Signaling Bias re5A > 10,000 0% 816 5B > 10000 0% 558e to weak antagonists of both the G-q signaling pathway, and the beta-arrestin signaling pathway. Without being bound by theory, it is believed that for non-hallucinogenic activity, compounds should have either antagonistic activity at the G-q signaling pathway, or partial agonist activity with low intrinsic efficacy. Full agonist activity at the G-q signaling pathway (i.e., high intrinsic activity) is believed to cause hallucinogenic side effects. The present compounds are therefore expected to be non-hallucinogenic. [000200] Additional results are shown in the following table: Beta-Arrestin Signaling G-q Signaling Bias re[000201] The results show that the compounds of Examples 31, 32, and 33 are each biased agonists of beta-arrestin signaling, the compounds of Examples 31 and 33 being somewhat weakbiased agonists, and the compound of Example 32 being a stronger biased agonist. Interestingly, the compound of Example 32 is a partial agonist for both beta-arrestin and G-q signaling, while the compound of Example 31 is nearly a full agonist for beta-arrestin signaling and is a full agonist for G-q signaling, while the compound of Example 33 is partial agonist for beta-arrestin signaling but a full agonist for G-q signaling. In contrast, the compounds of Example 34A to 34G are unexpectedly found to be mildly biased towards G-q signaling, with full agonism for G-q signaling and partial to full agonism for beta-arrestin signaling. [000202] Preferably, without being bound by theory, it is believed that for non- hallucinogenic activity, compounds should have either antagonistic activity at the G-q signaling pathway, or partial agonist activity with low intrinsic efficacy. Full agonist activity at the G-q signaling pathway (i.e., high intrinsic activity) is believed to cause hallucinogenic side effects. [000203] For maximum effectiveness, the compounds of the present disclosure are preferably agonists of beta-arrestin mediated signaling, either as partial agonists or as full agonists. [000204] While the compounds of the present disclosure provide a range of related receptor binding activities, it should be noted that the desirable antidepressant, anxiolytic, and other CNS therapeutic properties of the hallucinogenic psychedelics is presently believed to be associated with beta-arrestin signaling at the 5-HT2A receptor, it cannot yet be ruled that some degree of Gq signaling is also desirable. While strong Gq signaling results in hallucinogenic effects, it remains possible that there is a degree of Gq signaling that may be beneficial to the therapeutic use of the present compounds without causing an undue risk of hallucinatory behavior. Indeed, in patients without a history of psychosis or hallucinogen persisting perception disorder (HPPD), higher levels of Gq signaling may be permissible, whereas in patients with such history, a compound that is more completely devoid of Gq signaling may be optimal. [000205] Furthermore, due to the various receptor binding activities and functional activities shown for compounds disclosed herein, there may be therapeutically useful and desirable compounds which combine receptor activities in an unexpected way, including compounds without 5-HT2A biased agonism or compounds with 5-HT2A antagonism, each optionally with or without activity at one or more of the D1 receptor, D2 receptor, SERT or mu- opiate receptor. [000206] Example 10-C: In Vivo Characterization[000207] Selected compounds (test compounds) may be submitted to rodent functional model assays to determine in vivo efficacy. [000208] Head Twitch Assay. The stereotyped head twitch response induced by 5-HT2A agonists is used as a behavioral proxy for hallucinations. See Halberstadt, et al., Neuropharmacology, 167, 107933 (2020). The head-twitch response is an indicator of hallucinogenic potency of a compound in humans and occurs nearly immediately after the administration of a classical psychedelic in rodents. By definition, a head-twitch is a rapid movement of the head from one side to the other. Head twitch is used to evaluate the potential hallucinogenic liability of compounds (at up to 10 mg / kg) relative to the positive control DOI (2.5 mg / kg). Male C57bl / 6 mice (9 weeks of age) are administered test compounds and vehicle via subcutaneous (SC) injection. Mice receiving the positive control DOI receive an intraperitoneal (IP) injection. At 30 minutes post-treatment, the number of head twitch responses is recorded by a blinded observer for 5 minutes.[000209] Open Field Test of Anxiety-Like Behaviors. Adult mice are habituated to the testroom for one hour, and then administered a SC injection of test compound (1, 3, or 10 mg / kg) or methylcellulose vehicle, in the hind flank. For testing, animals are placed in one of four arenas in a square apparatus measuring 500 cm x 500 cm for 15 minutes. Sessions are filmed using Anymaze software (Stoelting Co, IL), using a camera mounted to the ceiling. Locomotor activity is measured by the software within the pre-defined arena. An additional center arena is pre- defined for each zone, all with an area of 100 cm x 100 cm. [000210] Rat Social Interaction Test. Test compound (0.3, 1.0, 3 and 3.0 mg / kg, or alternatively, 1, 3, and 10 mg / kg) or vehicle (0.5% aqueous CMC) is injected SC 30 minutes before behavioral testing. During the testing phase, a pair of rats (Sprague-Dawley males) receiving the same treatment are placed in a white Plexiglass open field arena and are allowed to interact for 6 minutes. Social interactions include sniffing the other rat, grooming the other rat, climbing over, under or around the other rat, following the other rat, and exploring the ano- genital area of the other rat. The time the rats spend interacting with each other during the 6- minute test is recorded by a trained observer. Chlordiazepoxide (IP, 5 mg / kg) is used as a positive control. [000211] mTOR signaling in the pre-frontal cortex (PFC). Male adult mice are injected SC with either test compound (1 mg / kg) or vehicle. At 24 hours post-injection, samples from thePFC region of the brain are collected, and a synaptoneurosome-enriched fraction is collected and prepared for Western blotting., Quantitative analysis of phospho (p) protein immunoblots are determined relative to total levels of each protein. Change in the amount of phosphorylated ERK, Akt, mTOR, and P70S6K proteins, in the PFC are determined relative to vehicle-treated mice, as previously described (Dutheil, et al., J. Neuroscience, 43(5):863-77, 2023). [000212] Example 10-D: Pharmacokinetic evaluation [000213] Compounds according to the present disclosure may be submitted to a standard testing protocol for oral pharmacokinetics in Sprague-Dawley rats (males, 200-400 g). Test compounds are administered to rats either IV at 1 mg / kg or PO at 10 mg / kg, using a 0.05M citrate phosphate buffer as vehicle. Other potential vehicles include PEG-400 and aqueous 10% Trapposol / 1% Tween 80, depending on compound solubility. In some studies, a third arm may utilize subcutaneous dosing (e.g., SC at 1 mg / kg). Plasma samples are collected at 2, 5, 15, and 30 minutes, and 1, 2, 4, 8, and 24 hours, post-dosing. After processing, plasma samples are analyzed for the presence of the test compound, and for some cases, for the presence of major expected metabolites (e.g., N-des-methyl metabolite). Time to maximum concentration (Tmax), maximal plasma concentration (Cmax), and area-under-the-curve (AUC) are calculated from the data. Comparison between the AUC values for oral versus IV dosing provides the oral bioavailability of the test compound. [000214] The forgoing examples are merely exemplary and are not meant to limit the scope of the present disclosure in any way.

Claims

CLAIMS What is claimed:

1. A compound of a Formula Iwherein: X is selected from S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N- C(O)-Ra, N-C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O–), a spiro- joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHRc, -C(O)-, C(Rc)2, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(Rd), -C(O)-, -C(OH)-, -C(OC1-6alkyl), -C(=N- OH)-, -C(=N-OC1-6alkyl)-, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), a spiro- joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -O(CH2)pO- wherein p is 2, 3, or 4 (e.g., p is 2), wherein said spiro-joined C3-6cycloalkyl or 3-6- membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy;A is H, C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), an aryl (e.g., phenyl), or heteroaryl ring, wherein said cycloalkyl, aryl, or heteroaryl is substituted by 0-5 groups R; each R is independently selected from aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C1-6alkyl (e.g., methyl, ethyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1- 6alkylthio (e.g., methylthio), halo (e.g., F), cyano, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is optionally further substituted by one or more aryl (optionally substituted with halo), halo, C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1-6alkylthio (e.g., methylthio), C3- 6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), amino, C1- 6alkylamino (e.g., methylamino), di(C1-6alkyl)amino (e.g., dimethylamino), (C1-6alkyl)(C1-6alkyl)amino (e.g., methylethylamino), and hydroxy; R1and R2are each independently selected from H, halo (e.g., F), C1-3alkyl (e.g., methyl), C1-3alkoxy (e.g., methoxy), OH, and CN, provided that R1and R2are not both H; Raand Rd, are each independently selected from C1-20alkyl (e.g., methyl or tert-butyl), and C1-2alkylaryl (e.g., benzyl or phenethyl); Rband Rcare each independently selected from C1-6alkyl (e.g., methyl, ethyl, tert-butyl), C1-6alkoxy, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and C1-2alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2; n is 1, 2, 3, 4, or 5; in free or salt form (e.g., pharmaceutically acceptable salt form); provided that: R1is not methyl, when m is 1, n is 3, X is N(CH3), Y is -CH2-, Z is -C(O)-, and A is 4- fluorophenyl; R1is not methyl, when m is 1, n is 3, X is N(CH3), Y is -C(O)-, Z is –(O)-, and A is 4- fluorophenyl;R1is not methyl or ethyl, when m is 1, n is 3, X is N(CH3), Y is -C(O)-, Z is -C(O)-, and A is 4-fluorophenyl; and R1is not methyl, when m is 1, n is 3, X is N(CH2CH3), Y is -C(O)-, Z is -C(O)-, and A is 4-fluorophenyl.

2. The compound according to claim 1, wherein R1is halo (e.g., F) and R2is H.

3. The compound according to claim 1, wherein R1is H and R2is halo (e.g., F).

4. The compound according to claim 1, wherein R1is C1-3alkyl (e.g., methyl) and R2is H.

5. The compound according to claim 1, wherein R1is H and R2is C1-3alkyl (e.g., methyl).

6. The compound according to claim 1, wherein R1is halo (e.g., F) and R2is halo (e.g., F).

7. The compound according to claim 1, wherein R1is C1-3alkyl (e.g., methyl) and R2is C1-3alkyl (e.g., methyl).

8. The compound according to claim 1, wherein R1is C1-3alkyl (e.g., methyl) and R2is halo (e.g., F).

9. The compound according to claim 1, wherein R1is halo (e.g., F) and R2is C1-3alkyl (e.g., methyl).

10. The compound according to any one of claims 1-9, wherein X is NH or N(Ra) (e.g., N(CH3)).

11. The compound according to any one of claims 1-9, wherein X is O.

12. The compound according to any one of claims 1-9, wherein X is CH2.

13. The compound according to any of claims 1-12, wherein Y is CH2or -C(O)-.

14. The compound according to claim 1, wherein the Compound of Formula I is selected from Formula I-A, Formula I-B, or Formula I-C: Formula I-A:Formula I-C: .

15. The 1, wherein the Compound of Formula I is selectedfrom the following: , 16. The-C(O)-, or - O-.

17. The compound according to any of claims 1-16, wherein A is a 6-10 membered aryl ring, e.g., selected from phenyl and naphthyl, substituted by 0-5 groups R.

18. The compound according to any of claims 1-16, wherein A is a 5-10 membered heteroaryl ring, substituted by 0-5 groups R, optionally wherein A is selected from furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyridine, pyrimidine, pyridazine, pyrazine, benzofuran, benzothiophene, indole,benzoxazole, benzothiazole, benzimidazole, benzisoxazole, benzisothiazole, indazole, quinoline, isoquinoline, quinazoline, and quinoxaline, each substituted by 0-5 groups R.

19. The compound according to any of claims 1-18, wherein the compound is selected from the group consisting of: , ,,;salt or form.

20. A compound of a Formula II:wherein: X is selected from S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N- C(O)-Ra, N-C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O–), a spiro- joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHRc, -C(O)-, C(Rc)2, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3- 6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(Rd), -C(O)-, -C(OH)-, -C(OC1-6alkyl), -C(=N- OH)-, -C(=N-OC1-6alkyl)-, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), a spiro- joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -O(CH2)pO- wherein p is 2, 3, or 4 (e.g., p is 2), wherein said spiro-joined C3-6cycloalkyl or 3-6- membered heterocycloalkyl is optionally substituted by one or more groups selected fromC1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; A is H, C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), an aryl (e.g., phenyl), or heteroaryl ring, wherein said cycloalkyl, aryl, or heteroaryl is substituted by 0-5 groups R; each R is independently selected from aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C1-6alkyl (e.g., methyl, ethyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1- 6alkylthio (e.g., methylthio), halo (e.g., F), cyano, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is optionally further substituted by one or more aryl (optionally substituted with halo), halo, C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1-6alkylthio (e.g., methylthio), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), amino, C1- 6alkylamino (e.g., methylamino), di(C1-6alkyl)amino (e.g., dimethylamino), (C1-6alkyl)(C1-6alkyl)amino (e.g., methylethylamino), and hydroxy; R1is selected from H, halo (e.g., F), C1-3alkyl (e.g., methyl), C1-3alkoxy (e.g., methoxy), OH, CN, NH2, haloC1-3alkyl (e.g., trifluoromethyl), C1-3alkylsulfonyl (e.g., methylsulfonyl), C1-3alkylthio (e.g., methylthio), C3-4cycloalkyl (e.g., cyclopropyl), C3-4cycloalkoxy (e.g., cyclopropoxy), amino, C1-3alkylamino (e.g., methylamino), di(C1-3alkyl)amino (e.g., dimethylamino), and (C1-3alkyl)(C1-3alkyl)amino (e.g., methylethylamino); Raand Rd, are each independently selected from C1-20alkyl (e.g., methyl or tert-butyl), and C1-2alkylaryl (e.g., benzyl or phenethyl); Rband Rcare each independently selected from C1-6alkyl (e.g., methyl, ethyl, tert-butyl), C1-6alkoxy, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and C1-2alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2; n is 1, 2, 3, 4, or 5; in free or salt form (e.g., pharmaceutically acceptable salt form);provided that: n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is a bond, R1is H, and A is 4- fluorophenyl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is -O-, R1is H, and A is 4-fluorophenyl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is a bond, R1is H, and A is indol-3-yl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is a bond, R1is H, and A is indazol-3-yl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is -C(O)-, R1is H, and A is pyrid-4- yl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is -C(O)-, R1is H, and A is 2-aminophenyl; n is not 3, when m is 1, X is -N(H)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is -C(O)-, R1is H, and A is 4-fluorophenyl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is -O-, R1is H, and A is 4- fluorophenyl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is a bond, R1is H, and A is benzisoxazol-3-yl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is a bond, R1is H, and A is 6-fluoroindol-3- yl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is a bond, R1is H, and A is 6-fluoroindazol- 3-yl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is -C(O)-, R1is H, and A is 2-amino-4- fluorophenyl; n is not 3, when m is 1, X is -O-, Y is CH2, Z is -C(O)-, R1is H, and A is 4-fluoro-2- hydroxyphenyl; n is not 3, when m is 1, X is -N(CH3)-, Y is CH2, Z is a bond, R1is H, and A is 6- fluorobenzisoxazol-3-yl; n is not 3, when m is 1, X is -N(CH2CH3)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl;n is not 3, when m is 1, X is -N(CH(CH3)2)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl; and n is not 3, when m is 1, X is -N(CH2Ph)-, Y is CH2, Z is -C(O)-, R1is H, and A is 4- fluorophenyl; or a Compound of Formula III:wherein: X is selected from S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N- C(O)-Ra, N-C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O–), a spiro- joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHRc, -C(O)-, C(Rc)2, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3- 6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(Rd), -C(O)-, -C(OH)-, -C(OC1-6alkyl), -C(=N- OH)-, -C(=N-OC1-6alkyl)-, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), a spiro- joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -O(CH2)pO- wherein p is 2, 3, or 4 (e.g., p is 2), wherein said spiro-joined C3-6cycloalkyl or 3-6- membered heterocycloalkyl is optionally substituted by one or more groups selected fromC1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; A is H, C3-6cycloalkyl (e.g., cyclopropyl or cyclohexyl), an aryl (e.g., phenyl), or heteroaryl ring, wherein said cycloalkyl, aryl, or heteroaryl is substituted by 0-5 groups R; each R is independently selected from aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C1-6alkyl (e.g., methyl, ethyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1- 6alkylthio (e.g., methylthio), halo (e.g., F), cyano, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is optionally further substituted by one or more aryl (optionally substituted with halo), halo, C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkylsulfonyl (e.g., methylsulfonyl), C1-6alkoxy (e.g., methoxy), C1-6alkylthio (e.g., methylthio), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), amino, C1- 6alkylamino (e.g., methylamino), di(C1-6alkyl)amino (e.g., dimethylamino), (C1-6alkyl)(C1-6alkyl)amino (e.g., methylethylamino), and hydroxy; Raand Rd, are each independently selected from C1-20alkyl (e.g., methyl or tert-butyl), and C1-2alkylaryl (e.g., benzyl or phenethyl); Rband Rcare each independently selected from C1-6alkyl (e.g., methyl, ethyl, tert-butyl), C1-6alkoxy, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and C1-2alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2; n is 1, 2, 3, 4, or 5; in free or salt form (e.g., pharmaceutically acceptable salt form); or a Compound of Formula IV or IV-A.Formula IV Formula IV-A wherein: X is S, S(O), S(O)2, O, CH2, CHRb, C(Rb)2, NH, N(Ra) (e.g., N(CH3)), N-C(O)-Ra, N- C(O)-O-Ra, N-C(O)-O-CH2-O-Ra, N-CH2-O-C(O)-Ra, N+(=O–), a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3- 6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHRc, -C(O)-, C(Rc)2, a spiro-joined C3-6cycloalkyl (e.g., cyclopropane), or a spiro-joined 3-6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-joined C3-6cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted by one or more groups selected from C1-6alkyl (e.g., methyl), haloC1-6alkyl (e.g., trifluoromethyl), C1-6alkoxy (e.g., methoxy), C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and hydroxy; R1and R2are each independently selected from H, halo (e.g., F), C1-3alkyl (e.g., methyl), C1-3alkoxy (e.g., methoxy), OH, and CN; Rais selected from C1-20alkyl (e.g., methyl or tert-butyl), and C1-2alkylaryl (e.g., benzyl or phenethyl); Rband Rcare each independently selected from C1-6alkyl (e.g., methyl, ethyl, tert-butyl), C1-6alkoxy, C3-6cycloalkyl (e.g., cyclopropyl), C3-6cycloalkoxy (e.g., cyclopropoxy), and C1-2alkylaryl (e.g., benzyl or phenethyl); and m is 1 or 2; in free or salt form (e.g., pharmaceutically acceptable salt form); optionally provided that: X is not N(CH3), when Y is CH2, and m is 1; and / or X is not NH, when Y is CH2, and m is 1; and / or X is not O, when Y is CH2, and m is 1; and / or X is not S, when Y is CH2, and m is 1; and / or X is not N(CH3), when Y is -C(O)-, and m is 1; and / or X is not NH, when Y is -C(O)-, and m is 1; and / orX is not CH2, when Y is CH2, and m is 1; and / or X is not O, when Y is CH2, and m is 2; and / or X is not S, when Y is CH2, and m is 2; and / or X is not CH2, when Y is CH2, and m is 2.

21. The compound according to claim 20, wherein the Compound of Formula II is selected from Formula II-A, Formula II-B, or Formula II-C: Formula II-A: , is selected from F, methyl, OH, CN, and NH2; orIII is selected from Formula III-A, Formula III-B, or Formula III-C: Formula III-A:.

22. A phar n comprising a compound according to any one of claims 1- 20, in free or pharmaceutically acceptable salt form (e.g., pharmaceutically acceptable salt form), in admixture with a pharmaceutically acceptable diluent or carrier.

23. A method for the treatment or prophylaxis of a central nervous system disorder, comprising administering to a patient in need thereof a compound according to any one of claims 1-20, in free or pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 21.

24. Use of a compound according to any of claims 1-19, in free or pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 20, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for the treatment or prophylaxis of a central nervous system disorder.

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