Heterocyclic fused gamma-carbolines acting on the serotonin 5-HT2A receptor

Abstract

The present invention relates to certain substituted heterocyclic fused gamma-carbolines described herein in free, solid, pharmaceutically acceptable salt and / or substantially pure form, pharmaceutical compositions thereof, and compounds that inhibit serotonin (5-HT 2+ ) signaling, particularly those with biased agonism toward the beta-arrestin signaling pathway. 2A Such compounds are useful in the treatment of mood disorders, generalized anxiety disorder, social anxiety disorder, depression, anhedonia, and other neuropsychiatric disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to and the benefit of U.S. Provisional Application No. 63 / 478,010, filed December 30, 2022, and U.S. Provisional Application No. 63 / 603,617, filed November 28, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to certain substituted heterocyclic fused gamma-carbolines described herein in free, solid, pharmaceutically acceptable salt and / or substantially pure form, pharmaceutical compositions thereof, and compounds that inhibit serotonin (5-HT 2+ ) signaling, particularly those with biased agonism toward the beta-arrestin signaling pathway. 2A ) receptors, or as non-hallucinogenic biased agonists or antagonists at serotonin (5-HT 2A Such compounds may be useful in the treatment of mood disorders, generalized anxiety disorder, social anxiety disorder, depression, schizophrenia, anhedonia, and other neuropsychiatric disorders. [Background technology]

[0003] Serotonin, also known as 5-hydroxytryptamine (5-HT), is a neurotransmitter widely distributed in the brain. Dysregulation of serotonergic signaling in the brain has been implicated in the pathogenesis of several neuropsychiatric disorders. Drugs that directly or indirectly target 5-HT, such as 5-HT2 receptor agonists and selective serotonin reuptake inhibitors, are widely used in psychiatry and are utilized in the treatment of numerous mood disorders and psychoses. However, strong 5-HT2 agonists tend to induce hallucinations, a dangerous side effect. Hallucinogenic drugs, which induce serotonergic hallucinations, are potent psychoactive substances that alter both perception and mood, and they may be useful for restoring dysregulated serotonergic networks in the brain. Although research suggests that classical hallucinogenic serotonin agonists such as LSD (D-lysergic acid diethylamide) and psilocybin (via its active metabolite psilocin) may be highly effective in treating a number of neuropsychiatric disorders, particularly depression, these drugs are not practically viable due to their hallucinogenic side effects. Hallucinogenic hallucinogens can cause overwhelming distress (i.e., "bad trips") or prolonged or intermittent psychosis, can promote self-harm or harm to others, and are prone to abuse and dependence. In addition, 5-HT 2B It has been reported that serotonergic agents with agonist activity can cause valvular heart disease and / or pulmonary arterial hypertension. Therefore, efforts have been made to develop novel compounds with pharmacological profiles for the treatment of mood and other CNS disorders similar to those of hallucinogenic hallucinogens, but without the hallucinations, abuse liability, or risk of valvular heart disease.

[0004] [ka]

[0005] One well-known non-hallucinogenic hallucinogen analog is lisuride, developed in the 1970s and used to treat Parkinson's disease and migraine attacks. Recently, two non-hallucinogenic hallucinogen analogs have been described with antidepressant-like activity. Cameron et al. generated novel compounds, tabernantalogues, by modifying the backbone core of the natural hallucinogenic hallucinogen ibogaine. Nature, 589:474-79 (2021). Cell, 184:2779-92.e18 (2021). Similarly, based on the well-known hallucinogenic hallucinogen 5-methoxy-dimethyltryptamine, Dong et al. arrived at a novel analog, AAZ-A-154. However, neither of these groups developed structure-activity guidelines for these compounds, and therefore, methods for rationally designing non-hallucinogenic hallucinogen analogs remained unclear.

[0006] [ka]

[0007] There are seven families of serotonin receptors, numbered 5-HT1 through 5-HT7. It has long been known that all serotonin receptors, except for 5-HT3, a ligand-gated ion channel, are G protein-coupled receptors (GPCRs). GPCRs have an intracellular domain that binds to heterotrimeric G proteins. G proteins consist of alpha, beta, and gamma subunits in a complex. G protein heterotrimers are normally in an inactive state bound to guanosine diphosphate ligands. Agonist binding to a GPCR induces a conformational change in the protein's intracellular domain, allowing the GPCR to catalyze the exchange of bound GDP for a GTP molecule (guanosine triphosphate). This results in activation of the G protein and dissociation of the GPCR from its intracellular domain. In particular, the G protein alpha subunit (G-alpha) dissociates and diffuses into the cytoplasm. There are numerous types of G-alpha proteins with different functional effects. G i , G o , and G sSome G-alpha proteins, including the G-alpha-q variant (G), regulate the levels of the cytoplasmic second messenger cAMP (cyclic adenosine monophosphate) by activating or inactivating the adenylyl cyclase enzyme. q GPCRs operate by activating the enzyme phospholipase C, which cleaves phosphatidylinositol bisphosphate (PIP2) to form two second messengers: inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates calcium release from intracellular stores, leading to activation of various calcium-dependent kinases, and DAG stimulates protein kinase C (PKC) activation. Because G-proteins are abundant soluble cytosolic proteins, agonist-activated GPCRs that activate and release their G-proteins can bind to another GDP-bound heterotrimer, thus activating and releasing a second GTP-bound G-alpha subunit, and so on, until the receptor is deactivated.

[0008] GPCRs are inactivated 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-proteins. In the second step, beta-arrestin proteins can competitively bind to the phosphorylated GPCR's active site, resulting in complete inhibition of G-protein binding. The arrestin-GPCR complex then targets the inactivated receptor for intracellular recycling or degradation.

[0009] Beta-arrestin proteins were initially thought to play only a role in inactivating and directing inactivated GPCRs for recycling or degradation. However, in recent years, it has become increasingly clear that beta-arrestin proteins also play a novel role in G-protein-independent signaling mechanisms. The GPCR-arrestin complex created after agonist-induced receptor activation and inactivation appears to function as a scaffold that can attract many other proteins to form large multiprotein complexes. This complex can then trigger the activation of various kinases involved in cell signaling, including Src, ERK, and MAPK. For example, some signaling cascades, such as the MAPK cascade, require two kinase proteins to be in close proximity to each other so that one can phosphorylate the other. The arrestin complex can facilitate such phosphorylation by simultaneously binding to both kinase proteins. Thus, beta-arrestin signaling provides an alternative mechanism of GPCR signaling that does not rely on G-protein-induced signaling cascades and second messengers.

[0010] Signaling bias is the concept that some ligands bind to GPCRs in a way that biases the receptor toward or away from one of two signaling pathways: G-protein-mediated signaling and beta-arrestin-mediated signaling. Several examples of such biased GPCR ligands have been discovered, which creates the possibility of functionally selective receptor agonism. For example, the mu-opioid receptor (MOR) binds to G iMOR is a GPCR linked to the alpha subunit of the α-type receptor, and agonist binding results in inhibition of adenylate cyclase activity and a reduction in cytosolic cAMP levels. This G-protein-mediated pathway has been found to be responsible for the analgesic activity of morphine and other opioid drugs. However, the major opioid side effects, respiratory depression and inhibition of gastrointestinal motility, are due to the recruitment of beta-arrestin to the receptor. Various MOR ligands have been discovered that show a bias toward G-protein signaling and away from beta-arrestin signaling, resulting in enhanced analgesic efficacy with a reduced side effect profile. This can reflect either greater efficacy of agonism via one pathway or the other, or even agonism of one pathway and antagonism of the other.

[0011] The 5-HT1, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors are linked to cAMP-regulated G proteins, whereas the 5-HT2 family of receptors is linked to Gq proteins and thus is a GPCR that triggers the classical signaling cascade mediated by the phosphatidylinositol pathway. It has also been found that the 5-HT2 receptor can activate the beta-arrestin signaling cascade as well. Serotonin agonists can activate 5-HT to induce hallucinations. 2A Although both the G-protein signaling pathway and the beta-arrestin signaling pathway of the receptor must be agonized, agonists that selectively agonize the beta-arrestin pathway without agonizing the G-protein-coupled pathway could provide relief from mood disorders, anxiety, and other CNS disorders without hallucinogenic side effects.

[0012] For example, Cao et al. recently used high-resolution X-ray crystallography to demonstrate that 5-HT 2AThey studied the binding of a number of compounds, including serotonin, psilocin, LSD, the non-hallucinogenic hallucinogen analog lisuride, and lumateperone, to the receptor. Science, 375:403-11 (2022). They identified a novel binding mode for serotonin and psilocin. Traditionally, LSD, lisuride, serotonin, and psilocin were known to bind to the so-called "orthosteric binding pocket (OBP)." In this binding mode, the polycyclic cores of LSD and lisuride bind to the lower part of the OBP, while the side chains of LSD and lisuride protrude into the so-called "extended binding pocket (EBP)." In contrast, the indole cores of serotonin and psilocin are located near the upper part of the OBP, but do not protrude significantly into the EBP.

[0013] Surprisingly, Cao et al. discovered that serotonin and psilocin have a second binding mode in which the indole core is located in the EBP and flipped over so that it is minimally present in the upper portion 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 found that G q We also present evidence that β-mediated signaling is responsible for the hallucinogenic effects of traditional hallucinogens and that ligands biased toward beta-arrestin recruitment can confer the therapeutic benefits of hallucinogens, such as antidepressant activity, without the hallucinogenic side effects.

[0014] Substituted heterocyclic fused gamma-carbolines bind to 5-HT2 receptors, especially 5-HT 2AIt is known to be receptor agonist or antagonist, and is useful for treating central nervous system disorders.These compounds are generally disclosed in United States Patent No. 6,548,493; United States Patent No. 7,238,690; United States Patent No. 6,552,017; United States Patent No. 6,713,471; United States Patent No. 7,183,282; USRE39.680 and USRE39,679.United States Patent No. 8,309,722 and United States Patent No. 7,081,455 disclose the method for producing such substituted heterocyclic fused gamma-carbolines and the use of these gamma-carbolines as serotonin agonists and antagonists, which are useful for controlling and preventing central nervous system disorders such as addictive behavior and sleep disorders.

[0015] Additionally, U.S. Patent No. 8,598,119 discloses the use of certain substituted heterocycle-fused gamma-carbolines for the treatment of combined psychotic and depressive disorders, as well as sleep, depression, and / or mood disorders in patients with psychosis or Parkinson's disease. In addition to disorders related to psychosis and / or depression, this patent application discloses compounds that have no or minimal effect on dopamine D2 receptors, thereby eliminating the side effects associated with high occupancy of the dopamine D2 pathway and other pathways (e.g., GABA receptors) associated with traditional sedative-hypnotic agents (e.g., benzodiazepines). A 5-HT receptors) are useful for treating sleep disorders without side effects. 2A The use of these compounds at low doses to selectively antagonize receptors is disclosed and claimed. U.S. Patent No. 8,648,077 discloses a method for preparing crystalline toluenesulfonic acid addition salts of these substituted heterocyclic-fused gamma-carbolines.

[0016] U.S. Patent Application Publication No. 2021 / 006009 discloses evidence showing that the aforementioned substituted fused heterocyclic gamma-carbolines can act in part through glutamate (NMDA and AMPA receptor) receptor activation, leading to enhanced mTOR1 signaling in a manner similar to ketamine. Ketamine is a selective NMDA receptor antagonist. Ketamine acts through a system unrelated to common psychogenic monoamines (serotonin, norepinephrine, and dopamine), which may be the primary reason for its more rapid effects. Ketamine directly antagonizes extrasynaptic glutamatergic NMDA receptors, which also reduces GABAergic inhibition, resulting in indirect activation of AMPA-type glutamate receptors. Downstream effects of AMPA receptor activation include increased levels of brain-derived neurotrophic factor (BDNF) and activation of the mTORC1 kinase pathway. Like ketamine, recent evidence suggests that compounds related to those disclosed herein 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.

[0017] U.S. Patent No. 10,245,260 discloses novel oxo-metabolites of the substituted heterocyclic fused gamma-carbolines disclosed in the above-mentioned publications. These new oxo-metabolites retain many of the unique pharmacological activities of the parent compounds, including serotonin receptor inhibition, SERT inhibition, and dopamine receptor modulation. However, these oxo-metabolites have unexpectedly been found to also exhibit significant activity at the mu-opioid receptor. Analogs of these novel compounds are also disclosed, for example, in U.S. Patent Nos. 10,906,906 and 10,961,245.

[0018] One such substituted heterocyclic fused gamma-carboline of the aforementioned technology is lumateperone, shown below, which has the chemical name (4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)-l-(4-fluorophenyl)-l-butanone).

[0019] [ka] It is a very powerful serotonin receptor (5-HT 2A It is known to be a dopamine receptor (D1 and / or D2) signaling modulator and serotonin transporter (SERT) antagonist, which is useful for treating various central nervous system disorders. It is also known as ITI-007.

[0020] Lumateperone inhibits serotonin-2A (5-HT 2A Lumateperone acts by antagonizing 5-HT receptors and / or modulating dopamine receptor signaling at the level of key intracellular phosphoproteins. This compound is primarily known to be useful in treating the positive and negative symptoms of schizophrenia, depression (particularly acute depression and bipolar depression), anxiety and traumatic disorders (including acute anxiety and post-traumatic stress disorder), and dementia (including Alzheimer's disease and its associated conditions). The effects of lumateperone as an antidepressant are due to its shared pharmacological characteristics with the SARI class of antidepressants (serotonin antagonists and reuptake inhibitors), which include trazodone, nefazodone, lorpiprazole, and mepiprazole. 2A It is related to its antagonism at the receptor and its inhibition of the serotonin transporter (SERT).

[0021] At the dopamine D2 receptor, lumateperone possesses dual properties, acting as both a postsynaptic antagonist and a presynaptic partial agonist of the D2 receptor. It also stimulates the phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors in a mesolimbic-specific manner. This regional selectivity in brain regions thought to mediate the efficacy of antipsychotic drugs, along with serotonergic, glutamatergic, and dopaminergic interactions, may contribute to antipsychotic efficacy against the positive, negative, affective, and cognitive symptoms associated with schizophrenia. The compound also exhibits serotonin reuptake inhibition, resulting in antidepressant activity for the treatment of schizoaffective disorder, comorbid depression, and / or as a sole treatment for major depressive disorder. Lumateperone is also useful for the treatment of bipolar disorder and other psychiatric and neurodegenerative disorders, particularly behavioral disorders associated with dementia, autism, and other CNS diseases. These features may improve the quality of life of patients with schizophrenia and enhance social functioning, allowing patients to integrate more fully into their families and their workplaces.

[0022] Lumateperone tosylate (Caplyta®) is currently approved in the United States for the treatment of schizophrenia and bipolar depression. It is currently in clinical trials and development for additional indications, including major depressive disorder (MDD).

[0023] 5-HT 2A Receptor binding induces beta-arrestin recruitment and G q The functional effects of lumateperone on the β-arrestin and G-mediated signaling pathways have not been previously disclosed. q Both functional assays demonstrated that lumateperone inhibited 5-HT 2A It was found to be a potent antagonist of the receptor.

[0024] There remains a need for new compounds that have efficacy in treating neuropsychiatric disorders, particularly depression, anxiety, and schizophrenia. 5-HT is a compound that can be used to produce non-hallucinogenic antidepressant or anxiolytic effects. 2A It would be particularly beneficial to have compounds with strong biased agonism (eg, full agonism or partial agonism) toward beta-arrestin recruitment at the receptor. Summary of the Invention

[0025] In a first aspect, the present disclosure provides compounds of Formula I, in free or salt form (e.g., a pharmaceutically acceptable salt form):

[0026] [ka] (In the formula, X is S, S(O), S(O)2, O, CH2, CHR b , C(R b )2, NH, N(R a ) (e.g., N(CH3)), NC(O)-R a , NC(O)-OR a , NC(O)-O-CH2-OR a , N-CH2-OC(O)-R a , N + (=O - ), spiro-bonded C 3~6 cycloalkyl (e.g., cyclopropane), or spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-linked C 3~6 Cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 Alkyl (e.g. trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Y is CH2, CHR c, -C(O)-, C(R c )2, spiro bond C 3~6 cycloalkyl (e.g., cyclopropane), or spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-linked C 3~6 Cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 Alkyl (e.g. trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; Z is a bond, -S-, S(O), S(O)2, -O-, -NH, N(R d ), -C(O)-, -C(OH)-, -C(OC 1~6 alkyl), -C(=N-OH)-, -C(=N-OC 1~6 Alkyl)-, spiro bond C 3~6 Cycloalkyl (e.g., cyclopropane), spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane), or -O(CH2) p O-, where p is 2, 3, or 4 (e.g., p is 2), and the spiro bond C 3~6 Cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 Alkyl (e.g. trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 optionally substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; A is H, C 3~6cycloalkyl (e.g., cyclopropyl or cyclohexyl), aryl (e.g., phenyl), or heteroaryl, wherein said cycloalkyl, aryl, or heteroaryl is substituted by 0 to 5 groups R; Each R is independently selected from the group consisting of aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C 1~6 Alkyl (e.g., methyl, ethyl), haloC 1~6 Alkyl (e.g. trifluoromethyl), C 1~6 Alkyl sulfonyl (e.g., methyl sulfonyl), C 1~6 Alkoxy (e.g., methoxy, ethoxy), C 1~6 Alkylthio (e.g., methylthio), halo (e.g., F), cyano, C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 cycloalkoxy (e.g., cyclopropoxy), or hydroxy, wherein each of said aryl, heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl, or cycloalkoxy is selected from aryl (optionally substituted with halo), halo, C 1~6 Alkyl (e.g., methyl), haloC 1~6 Alkyl (e.g. trifluoromethyl), C 1~6 Alkyl sulfonyl (e.g., methyl sulfonyl), C 1~6 Alkoxy (e.g., methoxy), C 1~6 Alkylthio (e.g., methylthio), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Cycloalkoxy (e.g., cyclopropoxy), amino, C 1~6 Alkylamino (e.g., methylamino), di(C 1~6 alkyl)amino (e.g., dimethylamino), (C 1~6 Alkyl)(C 1~6 optionally further substituted with one or more groups selected from: alkyl, amino (e.g., methylethylamino), and hydroxy; R a and R d are each independently C1~20 alkyl (e.g., methyl or tert-butyl), and C 1~2 alkylaryl (e.g., benzyl or phenethyl); R b and R c are each independently C 1~6 Alkyl (e.g., methyl, ethyl, tert-butyl), C 1~6 Alkoxy, C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 cycloalkoxy (e.g., cyclopropoxy), and C 1~2 alkylaryl (e.g., benzyl or phenethyl); m is 1 or 2; n is 1, 2, 3, 4, or 5; with the proviso that when Z is -C(O)-, X is CH2 or O, and m is 2, then n is not 3; with the proviso that when Z is -C(O)-, X is CH2, and m is 1, then n is not 3; provided that Z is -C(O)- or -O- and X is NH or N(R a ) and if m is 1, then n is not 3; provided that when Z is O, X is NCH3, Y is -C(O)-, and m is 1, then n is not 3. (Compound I).

[0027] The present disclosure provides: 1.1 Compound I, wherein X is S, S(O), or S(O)2; 1.2 Compound I, wherein X is O; 1.3 x CH2, CHR b , or C(R b )2, Compound I; 1.4 R b independently C 1~6 Compound 1.3, which is alkyl (e.g., methyl); 1.5 Compound I, where X is CH2; 1.6 Compound I, wherein X is NH; 1.7 X is N(R a ), Compound I; 1.8 X is NC(O)-R a Compound I; 1.9 X is NC(O)-OR a Compound I; 1.10 X is NC(O)-O-CH2-OR a Compound I; 1.11 X is N-CH2-OC(O)-R a Compound I; 1.12 R a C 1~2 Compound I, or any of 1.7-1.11, which is alkylaryl (e.g., benzyl or phenethyl); 1.13 R a C 1~20 alkyl (e.g., methyl or tert-butyl), compound I, or any of 1.7-1.11; 1.14 R a C 10~20 Any of compounds I or 1.7-1.11, which is alkyl (e.g., decyl or dodecyl); 1.15 R a C 1~15 Any of compounds I or 1.7-1.11, which is alkyl (e.g., hexyl or octyl); 1.16 R a C 7~15 alkyl (e.g., heptyl or nonyl), compound I, or any of 1.7-1.11; 1.17 R a C 1~6 alkyl (e.g., butyl or hexyl), compound I, or any of 1.7-1.11; 1.18 R a C 1~4 alkyl (e.g., n-butyl or tert-butyl), compound I, or any of 1.7-1.11; 1.19 R a C 1~3Compound I, or any of 1.7-1.11, which is alkyl (e.g., propyl or isopropyl); 1.20 R a C 1~2 alkyl (e.g., methyl or ethyl), compound I, or any of 1.7-1.11; 1.21 Compound I or any of 1.7-1.11, where X is N(CH3); 1.22 X is a spiro bond C 3~6 Compound I, which is a cycloalkyl (e.g., cyclopropane); 1.23 Spiro bond C 3~6 Compound 1.22, in which cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 1.24 Spiro bond C 3~6 Compound 1.22, where cycloalkyl is cyclopropane; 1.25 Compound I, wherein X is a spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane); 1.26 Compound 1.25, in which the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; 1.27 Compound 1.25, in which the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridines; 1.28 The spiro bond C 3~6 Compound I or any of 1.22 to 1.27, wherein cycloalkyl or 3- to 6-membered heterocycloalkyl is unsubstituted; 1.29 The spiro bond C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 Alkyl (e.g. trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6Compound I, or any of 1.22-1.27, substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; 1.30 Compound I or any of 1.1-1.29, where Y is CH2; 1.31 Compound I or any of 1.1 to 1.29, wherein Y is —C(O)—; 1.32 Y is CHR c or C(R c )2, compound I, or any of 1.1 to 1.29; 1.33 each R c independently C 1~6 alkyl, compound 1.32; 1.34 each R c are independently selected from methyl, ethyl, and propyl, compound 1.32; 1.35 Y is spiro bond C 3~6 Compound I, or any of 1.1-1.29, which is a cycloalkyl (e.g., cyclopropane); 1.36 Spiro bond C 3~6 Compound 1.35, in which cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 1.37 Spiro bond C 3~6 Compound 1.35, where cycloalkyl is cyclopropane; 1.38 Compound I, or any of 1.1-1.29, wherein Y is a spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane); 1.39 Compound 1.38, in which the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; 1.40 Spiro-linked 3- to 6-membered heterocycloalkyl is aziridine, compound 1.39; 1.41 The spiro bond C 3~6 Compound I, or any of 1.35 to 1.40, wherein cycloalkyl or 3- to 6-membered heterocycloalkyl is unsubstituted; 1.42 The spiro bond C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 Alkyl (e.g. trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Compound I, or any of 1.35-1.40, substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; 1.43 Compound I or any of 1.1 to 1.42, wherein Z is a bond; 1.44 Compound I or any of 1.1-1.42, wherein Z is S, S(O), or S(O)2; 1.45 Compound I or any of 1.1 to 1.42, wherein Z is O; 1.46 Compound I or any of 1.1-1.42, where Z is NH; 1.47 Z is N(R a ), e.g., N(CH3), compound I, or any of 1.1 to 1.42; 1.48 Compound I or any of 1.1 to 1.42, wherein Z is —C(O)—; 1.49 Z is -C(OH)-, -C(OC 1~6 alkyl), -C(=N-OH)-, -C(=N-OC 1~6 alkyl)-, and optionally, 1~6 Compound I, or any of 1.1-1.42, where alkyl is methyl; 1.50 Z is spiro bond C 3~6 Compound I, or any of 1.1-1.42, which is a cycloalkyl (e.g., cyclopropane); 1.51 Spiro bond C 3~6 Compound 1.50, in which cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; 1.52 Spiro bond C 3~6Compound 1.50, where cycloalkyl is cyclopropane 1.53 Compound I, or any of 1.1-1.42, wherein Z is a spiro-linked 3- to 6-membered heterocycloalkyl (e.g., aziridine or oxetane); 1.54 Compound 1.53, in which the spiro-linked 3- to 6-membered heterocycloalkyl is selected from aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine, and morpholine; 1.55 Compound 1.53, in which the spiro-linked 3- to 6-membered heterocycloalkyl is an aziridine; 1.56 The spiro bond C 3~6 Compound I, or any of 1.49 to 1.55, wherein cycloalkyl or 3- to 6-membered heterocycloalkyl is unsubstituted; 1.57 The spiro bond C 3~6 cycloalkyl or 3- to 6-membered heterocycloalkyl is C 1~6 Alkyl (e.g., methyl), haloC 1~6 Alkyl (e.g. trifluoromethyl), C 1~6 Alkoxy (e.g., methoxy), C 3~6 cycloalkyl (e.g., cyclopropyl), C 3~6 Compound I, or any of 1.49-1.55, substituted with one or more groups selected from cycloalkoxy (e.g., cyclopropoxy), and hydroxy; 1.58 Compound I, or any of 1.1-1.57, wherein A is a 6-10 membered aryl ring selected from, for example, phenyl and naphthyl, substituted by 0-5 groups R; 1.59 Compound I, or any of 1.1-1.57, wherein A is a 5-10 membered heteroaryl ring substituted with 0-5 groups R; 1.60 A is furan, thiophene (e.g., thiophen-2-yl), pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyridine (e.g., pyrid-4-yl), 2-oxopyridine (e.g., 2-oxopyridin-1(2H)-yl), pyrimidine, pyridazine, pyrazine, benzofuran (e.g., benzofuran-4-yl, or benzofuran-7-yl, or 2-methylbenzofuran-4-yl), dihydrobenzofuran (e.g., 2,3-dihydrobenzofuran-7-yl), benzothiophene, indole (e.g., indol-1-yl, indol-3-yl, or indol-5-yl), benzoxazole, benzothiazole, benzo Compound 1.59, selected from imidazole (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); 1.61 Compound 1.60, in which A is substituted by 0 groups R; 1.62 Compound 1.60, in which A is substituted by one group R; 1.63 Compound 1.60, in which A is substituted by two groups R; 1.64 Compound 1.58, in which A is a phenyl ring substituted with 0-5 groups R; 1.65 Compound 1.64, where one group R is present; 1.66 Compound 1.65, in which the group R is located in the para position of the phenyl ring; 1.67 Compound 1.65, in which the group R is located in the meta position of the phenyl ring; 1.68 Compound 1.65, in which the group R is located in the ortho position of the phenyl ring; 1.69 Compound 1.64, where two groups R are present; 1.70 Compound 1.69, in which the groups R are located in the ortho and para positions of the phenyl ring; 1.71 Compound 1.69, in which the groups R are located in the meta and para positions of the phenyl ring; 1.72 Compound 1.69, in which the groups R are located in the ortho and meta positions on the same side of the phenyl ring; 1.73 Compound 1.69, in which the groups R are located in the ortho and meta positions on both sides of the phenyl ring; 1.74 Compound 1.69, in which the groups R are located at the two ortho positions of the phenyl ring; 1.75 Compound 1.69, in which the groups R are located in the two meta positions of the phenyl ring; 1.76 Three groups R are present, compound 1.64; 1.77 Compound 1.76, in which the group R is located at the two ortho and para positions of the phenyl ring; 1.78 Compound 1.64, where four groups R are present; 1.79 Compound 1.64, where five groups R are present; 1.80 Compound I, or any of 1.1-1.79, wherein each group R is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, F, Cl, cyano, hydroxy, 2-methoxyethoxy, methylsulfonyl, methylthio, cyclopropoxy, cyclopropylmethoxy, methylamino, 4-fluorophenoxy, and (4-fluorobenzyl)oxy; 1.81 A is phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 3-chloro-4-fluorophenyl, 2-cyano-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-methyl-4-fluorophenyl, 3-methyl-4-fluorophenyl, 2-methoxy-4-fluorophenyl, 2-methoxy-5-fluorophenyl, 2-fluoro-4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, Compound I, or any of 1.1 to 1.80, selected from the group consisting of 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; 1.82 A is pyrid-4-yl, thiophen-2-yl, indol-1-yl, indol-3-yl, 5-fluoroindol-3-yl, indazol-1-yl, indazol-3-yl, indazol-7-yl, benzofuran-4-yl, benzofuran-7-yl, 2,3-dihydrobenzofuran-7-yl, 2-methylbenzofuran-7-yl, benzo[d]isoxazol-3-yl, benzo[d]isoxazol-4-yl, benzo[d ]isoxazol-7-yl, 6-fluorobenzo[d]isoxazol-3-yl, benzo[d]isothiazol-3-yl, benzo[d]imidazol-1-yl, benzo[d][1,2,3]triazol-1-yl, isoquinolin-7-yl, quinolin-8-yl, quinoxalin-5-yl, quinazolin-7-yl, and 2-oxopyridin-1(2H)-yl, Compound I, or any of 1.1 to 1.80; 1.83 Compound I, or any of 1.1-1.80, 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; 1.84 m is 1, compound I, or any of 1.1 to 1.83; 1.85 m is 2, compound I, or any of 1.1-1.83; 1.86 Compound I, or any of 1.1 to 1.85, where n is 2; 1.87 Compound I, or any of 1.1 to 1.85, where n is 3; 1.88 Compound I, or any of 1.1 to 1.85, where n is 4; 1.89 Compound I, or any of 1.1 to 1.85, where n is 5; 1.90 Compound I, or any of 1.1-1.89, wherein X is S, O, CH2, NH, N(CH3), or spiro-linked cyclopropyl; Y is CH2, C(O), or spiro-linked cyclopropyl; and Z is a bond, —O—, —C(O)—, —O(CH2)2O—, or —C(═NOCH3)—; 1.91 Compound I, or any of 1.1-1.89, wherein X is N(CH3) or spiro-linked cyclopropyl, Y is CH2, C(O), or spiro-linked cyclopropyl, and Z is a bond, -O-, or -C(O)-; 1.92 When the compound of formula I is a compound of formula Ia:

[0028] [ka] wherein n, Z, and A are defined as in any preceding embodiment. Compound I, or any of 1.1 to 1.91; 1.93 When the compound of formula I is a compound of formula Ib:

[0029] [ka] wherein n, Z, and A are defined as in any preceding embodiment. Compound I, or any of 1.1 to 1.91; 1.94 When the compound of formula I is a compound of formula Ic:

[0030] [ka] wherein n, Z, and A are defined as in any preceding embodiment. Compound I, or any of 1.1 to 1.91; 1.95 When the compound of formula I is a compound of formula Id:

[0031] [ka] wherein n, Z, and A are defined as in any preceding embodiment. Compound I, or any of 1.1 to 1.91; 1.96 When the compound of formula I is a compound of formula Ie:

[0032] [ka] wherein n, Z, and A are defined as in any preceding embodiment. Compound I, or any of 1.1 to 1.91; 1.97 Compound I, or any of 1.1 to 1.96, wherein n is 4 and Z is a bond; 1.98 Compound I or any of 1.1 to 1.96, wherein n is 3 and Z is -O- or -C(O)-; 1.99 Compound I, or any of 1.1 to 1.96, wherein n is 3 and Z is a bond; 1.100 Compound I or any of 1.1 to 1.96, wherein n is 2 and Z is -O- or -C(O)-; 1.101 Compound I, or any of 1.1 to 1.96, wherein n is 2 and Z is a bond; 1.102 Compound I or any of 1.1 to 1.96, wherein n is 1 and Z is -O- or -C(O)-; 1.103 Compound I, or any of 1.1 to 1.96, wherein n is 1 and Z is a bond; 1.104 A is H or C 3~6 Compound I or any of 1.1-1.103, wherein Z is a bond or -C(O)- and n is 1, 2, or 3; 1.105 each independently in free or pharmaceutically acceptable salt form

[0033] [ka] Compound I, or any of 1.1 to 1.103, selected from the group consisting of: 1.106 is a compound of any one of Examples 1-180, each independently in free or pharmaceutically acceptable salt form; or

[0034] [ka] wherein the variables are as follows:

[0035] [Table 1-1]

[0036] [Table 1-2]

[0037] [Table 1-3]

[0038] [Table 1-4]

[0039] [Table 1-5]

[0040] [Table 1-6]

[0041] [Table 1-7] (defined as being provided to either wherein Cyp refers to a spiro-linked cyclopropyl ring, or any of compounds I, 1.1 to 1.105; 1.107

[0042] [ka] wherein the variables are as follows:

[0043] [Table 2] (defined as being provided to either Compound I, or any of 1.1 to 1.105, selected from the group consisting of: 1.108 Compound I or any of 1.1 to 1.107 in free form; 1.109 Compound I, or any of 1.1 to 1.107, in salt form, for example a pharmaceutically acceptable salt form; 1.110 Compound I, or any of 1.1 to 1.107, in acid addition salt form, for example, in hydrochloride or toluenesulfonate form; 1.111 Compound I, or any of 1.1-1.10, in substantially pure diastereomeric form (i.e., substantially free of other diastereomers); 1.112 Compound I or any of 1.1-1.110 having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90%, most preferably greater than 95%; 1.113 Compound I or any of 1.1-1.112 in solid form, e.g., crystalline form; 1.114 Compound I or any of 1.1-1.113 in isolated or purified form (e.g., at least 90% pure, or at least 95% or at least 98% or at least 99%). 1.115 At least 60% at a concentration of 100 nM, 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% 5-HT at a concentration of 100 nM 2A any of Compounds I or 1.1-1.114, having receptor binding affinity; 1.116 5-HT less than 250 nM, or less than 100 nM, or less than 70 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, or less than 10 nM 2A Receptor dissociation constant (K d ) any of compounds I or 1.1 to 1.115; 1.117 5-HT 2A an agonist of receptor-mediated beta-arrestin signaling, e.g., any of compounds I or 1.1-1.116, which is a partial agonist or full agonist; 1.118 E for a full agonist (e.g., alpha-methylserotonin) 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% max Compound 1.116, a partial agonist of beta-arrestin signaling having 1.119 5-HT 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 2A EC for receptor beta-arrestin agonism 50 having compounds 1.117 or 1.118; 1.120 beta-arrestin signaling relative intrinsic activity (RA) of less than 1.0 compared to the reference compound alpha-methylserotonin i ), e.g., compounds 1.117, 1.118, or 1.119 having a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or between 0.1 and 0.8, or between 0.2 and 0.8, or between 0.4 and 0.8, or between 0.5 and 0.8, or between 0.2 and 0.6, or between 0.2 and 0.5, or between 0.2 and 0.4, or between 0.5 and 1.0, or between 0.5 and 0.9, or between 0.5 and 0.8, or between 0.6 and 0.9, or between 0.6 and 0.8; 1.121 Beta-arrestin signaling relative intrinsic activity (RA) of greater than 1.0 compared to the reference compound alpha-methylserotonin i ), e.g., compounds 1.117, 1.118, or 1.119, having relative intrinsic activities of 1.0 to 1.2, or 1.0 to 1.4, or 1.0 to 1.6; 1.122 5-HT 2A any of Compounds I or 1.1-1.116, which are antagonists of receptor-mediated beta-arrestin signaling; 1.123 5-HT 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 2A IC for receptor beta-arrestin antagonism 50 Compound 1.122 having 1.124 5-HT 2AEither Compound I or 1.1–1.116 is not an antagonist of receptor-mediated beta-arrestin signaling; 1.125 5-HT 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 2A IC for receptor beta-arrestin antagonism 50 having the compound 1.124; 1.126 5-HT 2A Either Compound I or 1.1–1.125, which are not or are weak agonists of receptor-mediated Gq signaling; 1.127 E of less than 90%, or less than 80%, or less than 70%, or less than 60%, or less than 50%, or less than 40%, or less than 30%, or less than 20%, or less than 10% relative to a full agonist (e.g., alpha-methylserotonin) max , preferably less than 50%, less than 30%, or less than 10% E max Compound 1.126, a partial agonist of Gq signaling having 1.128 5-HT 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 2A EC in response to receptor Gq agonism 50 having compounds 1.125 or 1.126; 1.129 Gq signaling relative intrinsic activity (RA) of less than 1.0 compared to the reference compound alpha-methylserotonin i), e.g., compounds 1.125, 1.126, or 1.127 having a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or between 0.1 and 0.8, or between 0.2 and 0.8, or between 0.4 and 0.8, or between 0.5 and 0.8, or between 0.2 and 0.6, or between 0.2 and 0.5, or between 0.2 and 0.4, or between 0.5 and 1.0, or between 0.5 and 0.9, or between 0.5 and 0.8, or between 0.6 and 0.9, or between 0.6 and 0.8; 1.130 5-HT 2A either Compound I or 1.1-1.129, which are antagonists of receptor-mediated Gq signaling; 1.131 5-HT 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 2A IC for receptor Gq antagonism 50 having the compound 1.130; 1.132 5-HT 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 indefinite (i.e., if the compound has any degree of beta-arrestin agonism and zero Gq agonism). 2A Either compound I or 1.1 to 1.131, with a bias ratio (beta-arrestin / Gq) for receptor agonism; 1.133 Compound I or any of 1.1-1.132, which is an antagonist or agonist of the D1 and / or D2 dopamine receptor (e.g., has at least 70% receptor affinity at a concentration of 100 nM or an IC50 of less than 100 nM); 1.134 Not active at D1 and / or D2 dopamine receptors (e.g., less than 50% receptor affinity at a concentration of 100 nM and / or an EC2 of greater than 500 nM) 50 Or IC50 ), any of compounds I or 1.1 to 1.132; 1.135 is an antagonist of the serotonin transporter (e.g., has a receptor binding affinity of at least 70% at a concentration of 100 nM or an IC of less than 100 nM) 50 ), any of compounds I or 1.1 to 1.134; 1.136 Not active at the serotonin transporter (e.g., receptor binding affinity less than 50% at a concentration of 100 nM and / or EC > 500 nM) 50 Or IC 50 ), any of compounds I or 1.1 to 1.134; 1.137 A mu-opioid receptor agonist, antagonist, or partial agonist (e.g., at least 70% receptor binding affinity at a concentration of 100 nM or an EC 50 Or IC 50 ), any of compounds I or 1.1 to 1.136; 1.138 Not active at the mu-opioid receptor (e.g., receptor binding affinity less than 50% at a concentration of 100 nM and / or EC2 greater than 500 nM) 50 Or IC 50 ), any of compounds I or 1.1 to 1.136; 1.139 Compound I, or any of 1.1-1.138, which is non-hallucinogenic at therapeutic doses for the treatment of, for example, a neuropsychiatric disorder described herein (e.g., depression, anxiety, etc.) and does not cause visual or auditory hallucinations, visual distortions (e.g., floating, morphing, flickering, or melting of objects and surfaces in the visual field), separation from reality, dissociation, delirium, or undesirable altered states of consciousness; 1.140 Compound I, or any of 1.1 to 1.139, which does not stimulate a head-shake response in an animal test model or is an antagonist of the DOI-induced head-shake response; 1.141 Compound I, or any of 1.1 to 1.140, which is effective in mouse models of depression (tail suspension or forced swim test); 1.142 Compound I, or any of 1.1 to 1.141, which is effective in animal models of social anxiety disorder or anhedonia; 1.143 5-HT 2B Compound I, or any of 1.1 to 1.142, which has no 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); 1.144 5-HT 2B Compound I, or any of 1.1-1.143, having antagonist activity (e.g., an IC50 of less than 1000 nM, or less than 500 nM, or less than 250 nM, or less than 100 nM, or less than 50 nM, or less than 25 nM, or less than 15 nM); 1.145 5-HT 2c Compound I, or any of 1.1 to 1.144, having agonist activity (e.g., an EC50 of less than 1000 nM, or less than 500 nM, or less than 250 nM, or less than 100 nM, or less than 50 nM, or less than 25 nM, or less than 15 nM); 1.146 5-HT 2C Compound I, or any of 1.1 to 1.144, which does not have antagonist 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); 1.147 Compound I, or any of 1.1-1.146, which binds to the alpha-1A adrenergic receptor (e.g., with a binding affinity K i 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); 1.148 Compound I or any of 1.1 to 1.147, which does not cause psychosis (e.g., long-term or intermittent psychosis); 1.149 Compound I or any of 1.1 to 1.148, which does not promote self-harm or harm to others in the patient; 1.150 Compound I, or any of 1.1 to 1.149, which does not cause valvular heart disease or pulmonary arterial hypertension and is safe to administer to patients with, for example, cardiac comorbidities; 1.151 Compound I, or any of 1.1 to 1.150, which does not cause abuse or dependence (e.g., physical or psychological dependence); 1.152 Receptors and ion channels for: adenosine A2A, alpha-1A adrenergic, alpha-2A adrenergic, beta-1 adrenergic, beta-2 adrenergic, GABA-A benzodiazepine sites (BZDs, central), CB1 cannabinoids, CB2 cannabinoids, cholecystokinin CCK1, endothelin-A (ETA), NMDA, histamine H1, histamine H2, MAO-A, mu Muscarinic M1, muscarinic M2, muscarinic M3, nicotinic acetylcholine (neuronal alpha-4-beta-2), delta opioid, kappa opioid, mu opioid, serotonin-1A, serotonin-1B, serotonin-3, glucocorticoid (GR), androgen (AR), vasopressin V1A, cardiac calcium channel (dihydropyridine site), hERG potassium channel, voltage-gated potassium channel K V , Compound I, or any of 1.1 to 1.151, which is functionally inactive at one or more of the sodium channel (site 2), the norepinephrine transporter, the dopamine transporter, and / or the serotonin transporter; 1.153 Compound 1.152, having an in vitro receptor activity (for agonism or antagonism) of less than 60% (e.g., at a test concentration of 100 nM), e.g., less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% inhibition of radioligand binding to any one or more of said receptors or ion channels; 1.154 Compound I or any of 1.1-1.153, which is orally bioavailable (e.g., at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40% oral bioavailability). Further provided are additional embodiments of the first aspect, including:

[0044] As used herein, the term "spiro bond" refers to a bond between two or more atoms as described above. 3~6 It is intended to clarify that a cycloalkyl group or a 3- to 6-membered heterocycloalkyl group is present in a spiro-linked state, meaning that one atom of the cyclic group is an atom of the ring to which the group is attached. For example, the following are examples of compounds of Formula I having spiro-linked cyclic groups within the scope of the present disclosure:

[0045] [ka] In each of the above examples, cyclopropane, cyclobutane, aziridine, azetidine, or oxetane may be substituted with any other C, including, but not limited to, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, or morpholine. 3~6 It may be replaced by cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0046] As used below, "compounds of the invention" refers to compounds of Formula I or any of 1.1-1.154.

[0047] In a second aspect, the present disclosure provides a pharmaceutical composition (Pharmaceutical Composition 1) comprising a compound of the present invention, e.g., mixed with a pharmaceutically acceptable diluent or carrier. In certain embodiments, the compound of the present invention is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition is in the form of, e.g., a tablet or capsule for gastrointestinal absorption (i.e., absorption through the stomach and / or the 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 fast-dissolving sublingual or buccal tablet, wafer, film, or gel. In some embodiments, the pharmaceutical composition is formulated for intranasal or pulmonary 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 or subcutaneous injection may be in the form of, e.g., a long-acting injectable composition or a depot composition, which provides sustained or delayed release of the compound of the present invention into the bloodstream and body tissues. Alternatively, particularly when formulated for intravenous, intrathecal, intraperitoneal, or subcutaneous injection, the composition may be, for example, a fast-acting composition that provides for immediate release of most or all of the dose into body fluids.

[0048] In a further embodiment, the pharmaceutical composition of the present disclosure is a sustained or delayed release formulation (Pharmaceutical Composition 1-A), e.g., a depot formulation. In some embodiments, the compound of the present invention is provided in the form of an injectable depot that provides sustained or delayed release of the compound, preferably in free or pharmaceutically acceptable salt form, mixed with a pharmaceutically acceptable diluent or carrier.

[0049] In certain embodiments, pharmaceutical composition 1-A comprises a compound of the present invention in free base or pharmaceutically acceptable salt form, optionally in crystalline form, where the compound has been milled into particles or crystals having a volumetric particle size (e.g., diameter or Dv50) of, for example, 0.5 to 100 microns, e.g., 5 to 30 microns, 10 to 20 microns, 20 to 100 microns, 20 to 50 microns, or 30 to 50 microns, or the compound has been so crystallized. Such particles or crystals may be combined with a suitable pharmaceutically acceptable diluent or carrier, e.g., water, to form a depot formulation for injection. For example, a depot formulation may be formulated for intramuscular or subcutaneous injection with a dose of drug appropriate for 4 to 6 weeks of treatment. In some embodiments, the particles or crystals have a size of 0.1 to 5 microns. 2 / g, e.g., 0.5 to 3.3 m 2 / g or 0.8~1.2m 2 / g of surface area.

[0050] In another embodiment, the present disclosure provides Pharmaceutical Composition 1-B, which is Pharmaceutical Composition 1 in which the compound of the present invention is in a polymer matrix. In one embodiment, the compound of the present disclosure is dispersed or dissolved within the polymer matrix. In a further embodiment, the polymer matrix comprises a standard polymer used in depot formulations, such as a polymer selected from polyesters of hydroxy fatty acids and their derivatives, or polymers of alkyl alpha-cyanoacrylates, polyalkylene oxalates, polyorthoesters, polycarbonates, polyorthocarbonates, polyamino acids, hyaluronic acid esters, and mixtures thereof. In a further embodiment, the polymer is selected from the group consisting of polylactide, poly d,l-lactide, polyglycolide, PLGA 50:50, PLGA 85:15, and PLGA 90:10 polymers. In another embodiment, the polymer is selected from poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(orthocarbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as glycerol mono- and distearate. In a preferred embodiment, the polymer matrix comprises poly(d,l-lactide-co-glycolide).

[0051] Pharmaceutical composition 1-B is particularly useful for sustained or delayed release, in which the compound of the present disclosure is released upon degradation of the polymer matrix. These compositions may be formulated (e.g., as a depot composition) for controlled and / or sustained release of the compound of the present disclosure over a period of up to 180 days, e.g., about 14 to about 30 to about 180 days. For example, the polymer matrix may degrade and release the compound of the present disclosure over a period of about 30, about 60, or about 90 days. In another example, the polymer matrix may degrade and release the compound of the present disclosure over a period of about 120 or about 180 days.

[0052] In yet another embodiment, Pharmaceutical Composition 1 or 1-A or 1-B may be formulated, for example, as a sterile solution, for administration by injection.

[0053] In another embodiment, the present disclosure provides a pharmaceutical composition (Pharmaceutical Composition 1-C) comprising a compound of the present invention described above in an osmotic controlled release oral delivery system (OROS) as described in U.S. Patent Application Publication Nos. 2001 / 0036472 and 2009 / 0202631, the contents of each of which are incorporated by reference in their entireties. Accordingly, in one embodiment, the present disclosure provides a pharmaceutical composition or device comprising: (a) a gelatin capsule containing a compound of Formula I or any of the compounds thereafter in free or pharmaceutically acceptable salt form, optionally mixed with a pharmaceutically acceptable diluent or carrier; (b) a multilayer wall superimposed on the gelatin capsule, comprising, in order from the capsule outward, (i) a barrier layer, (ii) an expansion layer, and (iii) a semipermeable layer; and (c) an orifice formed or formable through the wall (Pharmaceutical Composition P.1).

[0054] In another embodiment, the present invention provides a pharmaceutical composition comprising a gelatin capsule containing a liquid compound of the present invention in free or pharmaceutically acceptable salt form, optionally mixed with a pharmaceutically acceptable diluent or carrier, surrounded by a composite wall comprising a barrier layer in contact with the exterior surface of the gelatin capsule, an extension layer in contact with the barrier layer, a semipermeable layer surrounding the extension layer, and an exit orifice formed or formable in the wall (Pharmaceutical Composition P.2).

[0055] In yet another embodiment, the present invention provides a composition comprising a gelatin capsule containing a liquid compound of the present invention in free or pharmaceutically acceptable salt form, optionally mixed with a pharmaceutically acceptable diluent or carrier, the composition comprising a gelatin capsule surrounded by a composite wall comprising a barrier layer in contact with the exterior surface of the gelatin capsule, an extension layer in contact with the barrier layer, a semipermeable layer surrounding the extension layer, and an exit orifice formed or formable in the wall, the barrier layer providing an air gap between the extension layer and the periphery of the exit orifice (Pharmaceutical Composition P.3).

[0056] In yet another embodiment, the present invention provides a composition comprising a gelatin capsule containing a liquid compound of the present invention in free or pharmaceutically acceptable salt form, optionally mixed with a pharmaceutically acceptable diluent or carrier, the composition comprising a barrier layer in contact with the exterior surface of the gelatin capsule, an extension layer in contact with a portion of the barrier layer, a semipermeable layer surrounding at least the extension layer, and an exit orifice formed or formable in the dosage form, extending from the exterior surface of the gelatin capsule to the environment of use (Pharmaceutical Composition P.4). The extension layer may be formed in one or more separate sections, such as, for example, two sections on opposite sides or ends of the gelatin capsule.

[0057] In certain embodiments, the compounds of the invention in the osmotic-controlled release oral delivery systems (i.e., in compositions P.1-P.4) are in a liquid formulation, which may be a neat liquid active agent, a liquid active agent in a solution, a suspension, an emulsion, or a self-emulsifying composition, etc.

[0058] Further information about osmotically-controlled release oral delivery system compositions, including the characteristics of the gelatin capsule, barrier layer, expansion layer, semipermeable layer, and orifice, can be found in U.S. Patent Application Publication No. 2001 / 0036472, the contents of which are incorporated by reference in their entirety.

[0059] Other osmotic-controlled release oral delivery systems for compounds of Formula I and thereafter or pharmaceutical compositions of the present disclosure can be found in U.S. Patent Application Publication No. 2009 / 0202631, the contents of which are incorporated by reference in their entirety. Accordingly, in another embodiment, the present invention provides a composition or device comprising: (a) two or more layers, including a first layer and a second layer, wherein said first layer comprises a compound of the present invention in free or pharmaceutically acceptable salt form, optionally mixed with a pharmaceutically acceptable diluent or carrier, and 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).

[0060] Pharmaceutical composition P.5 preferably utilizes a semipermeable membrane surrounding a three-layer core: in these embodiments, the first layer, referred to as the first drug layer, contains a low amount of drug (e.g., a compound of the invention) and an osmotic agent such as a salt; the middle layer, referred to as the second drug layer, contains a higher amount of drug, excipients, and no salt; and the third layer, referred to as the push layer, contains an osmotic agent and no drug (Pharmaceutical composition P.6). At least one orifice is drilled through the membrane at the first drug layer end of the capsule-shaped tablet.

[0061] Pharmaceutical composition P.5 or P.6 may include a compartment-defining membrane surrounding an inner protective subcoating, with at least one exit orifice formed or formable therein, at least a portion of the membrane being semipermeable; an extension layer located within the compartment remote from the exit orifice and fluidly connected to the semipermeable portion of the membrane; a first drug layer adjacent to the exit orifice; and a second drug layer located within the compartment between the first drug layer and the extension layer, the drug layer comprising a compound of the invention in its free form or a pharmaceutically acceptable salt (Pharmaceutical composition P.7). Depending on the relative viscosities of the first and second drug layers, different release profiles can be obtained. It is essential to identify the optimal viscosity for each layer. In the present invention, viscosity is modulated by the addition of salt, sodium chloride. The delivery profile from the core depends on the weight, formulation, and thickness of each of the drug layers.

[0062] In certain embodiments, the present invention provides pharmaceutical composition P.7, wherein the first drug layer comprises a salt and the second drug layer does not contain a salt. Pharmaceutical compositions P.5-P.7 may optionally comprise a flux-promoting layer between the membrane and the drug layer.

[0063] Pharmaceutical compositions P.1-P.7 are collectively referred to as osmotic-controlled release oral delivery system compositions.

[0064] In a third aspect, the present invention provides a method (Method 1) for the treatment or prevention of a central nervous system disorder or more than one central nervous system disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound of Formula I), wherein the compound of the present invention inhibits 5-HT 2A In a further embodiment of Method 1, the present disclosure provides a method comprising: 1.1 Method 1, wherein the compound of the invention is a compound of formula I in free form; 1.2 Method 1, wherein the compound of the invention is a compound of formula I in the form of a pharmaceutically acceptable salt; 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 a compound of the invention is administered in the form of a pharmaceutical composition (e.g., Pharmaceutical Composition I or 1-A, 1-B, 1-C, or any of P.1-P.7) comprising a compound of the invention in admixture with a pharmaceutically acceptable diluent or carrier; 1.5 Method 1.4, wherein the pharmaceutical composition is Pharmaceutical Composition 1-A, 1-B, or 1-C; 1.6 Method 1.4, wherein the pharmaceutical composition is any one of pharmaceutical compositions P.1 to P.7; 1.7 Central nervous system disorders caused by 5-HT 2A any of Method 1 or Methods 1.1-1.6, wherein the disorder is receptor-mediated and susceptible to treatment with agonism of the beta-arrestin signaling pathway and / or agonism or antagonism of the Gq signaling pathway; 1.8 Central nervous system disorders include serotonin 5-HT 2A any of Method 1 or Methods 1.1-1.7, wherein the disorder involves, is mediated by, or is affected (directly or indirectly) by the receptor, dopamine D1 receptor, and / or D2 receptor systems, and / or the serotonin reuptake transporter (SERT) pathway, and / or the mu-opioid receptor pathway; 1.9 Central nervous system disorders include serotonin 5-HT 2A A disorder involving, mediated by, or affected (directly or indirectly) by receptors, serotonin reuptake transporters (SERT), but not involving, mediated by, or affected (directly or indirectly) by the dopamine D1 or D2 receptor systems, or involving, mediated by, or affected (directly or indirectly) by the mu-opioid receptor pathway, as defined in Method 1 or any of 1.1 to 1.7; 1.10 Method 1, or any of 1.1-1.7, where the central nervous system disorder is a disorder that does not involve, is mediated by, or is affected (directly or indirectly) by one or more of the dopamine D1 receptor, dopamine D2 receptor, serotonin reuptake transporter (SERT), or mu-opioid receptor pathways; 1.11 Central nervous system disorders include serotonin 5-HT 2A A disorder involving, mediated by, or affected (directly or indirectly) by a receptor, as defined in method 1 or any of 1.1-1.7; 1.12 Central nervous system disorders include serotonin 5-HT 2A Any of methods 1 or 1.1-1.11, which is a disorder involving, mediated by, or affected (directly or indirectly) by signaling through the receptor beta-arrestin signaling pathway; 1.13 Method 1 or any of Methods 1.1-1.12, wherein the central nervous system disorder is a disorder selected from the group consisting of anxiety disorders (including generalized anxiety disorder, social anxiety disorder, and panic disorder), and depression (e.g., treatment-resistant depression and major depressive disorder, bipolar depression); 1.14 Method 1 or any of methods 1.1-1.13, where the central nervous system disorder is an anxiety disorder, such as generalized anxiety disorder, social anxiety disorder, and panic disorder; 1.15 Method 1 or any of Methods 1.1-1.13, wherein the central nervous system disorder is depression, such as treatment-refractory depression, major depressive disorder, and bipolar depression, and / or anhedonia; 1.16 Method 1, or any of 1.1-1.15, wherein the patient suffers from any combination of the disorders described in methods 1.7-1.15; 1.17 Method 1, or any of 1.1 to 1.15, which is a method for the treatment or prevention of any combination of the disorders described in Methods 1.7 to 1.15; 1.18 Method 1 or any of Methods 1.1-1.17, wherein the patient does not respond to or cannot tolerate the side effects of conventional antidepressants; 1.19 Method 1 or any of Methods 1.1-1.18, wherein the patient does not respond to or cannot tolerate the side effects of treatment with a selective serotonin reuptake inhibitor (SSRI), such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; 1.20 Method 1 or any of Methods 1.1-1.19, wherein the patient does not respond to or cannot tolerate the side effects of treatment with a serotonin-norepinephrine reuptake inhibitor (SNRI), such as venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran; 1.21 Method 1 or any of Methods 1.1-1.20, wherein the patient has not responded to or cannot tolerate the side effects of treatment with conventional anti-anxiety medications, such as lorazepam, diazepam, alprazolam, and buspirone; 1.22 Any of the foregoing methods, wherein the therapeutically effective amount of a compound of the invention (e.g., a compound of Formula I) is 1 mg to 1000 mg, preferably 2.5 mg to 50 mg, or for long-acting formulations, 25 mg to 1500 mg, e.g., 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; 1.23 Method 1.22, wherein the therapeutically effective amount is 1 mg to 100 mg per day, preferably 2.5 mg to 50 mg per day. 1.24 Method 1.22, wherein the therapeutically effective amount of the compound of the invention is 1 mg to 1000 mg, e.g., 2.5 mg to 50 mg, or for long-acting formulations, 25 mg to 1500 mg, e.g., 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; 1.25 Method 1.22, wherein the therapeutically effective amount of the compound of the invention is 1 mg to 100 mg per day, for example, 2.5 mg to 50 mg per day; 1.26 Method 1.22, wherein the therapeutically effective amount of the compound of the present invention is 1 mg to 5 mg, preferably 2.5 to 5 mg per day; 1.27 Method 1.22, wherein the therapeutically effective amount of the compound of the invention is 2.5 mg or 5 mg per day; 1.28 Any of Methods 1 or 1.1-1.27, wherein the pharmaceutical composition is a sustained or delayed release formulation, e.g., according to Pharmaceutical Composition 1-A described herein; 1.29 Any of Methods 1 or 1.1-1.28, wherein the pharmaceutical composition comprises a compound of the invention in a polymer matrix, e.g., according to Pharmaceutical Composition 1-B described herein; 1.30 Any of Methods 1 or 1.1-1.29, wherein the pharmaceutical composition is in the form of a tablet or capsule; 1.31 Any of Methods 1 or 1.1-1.30, wherein the pharmaceutical composition is formulated for oral, sublingual, or buccal administration; 1.32 Any of Methods 1 or 1.1-1.31, wherein the pharmaceutical composition is a fast-dissolving oral tablet (e.g., a fast-dissolving sublingual tablet); 1.33 Any of Methods 1 or 1.1-1.32, wherein the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (e.g., as an aerosol, mist, or powder for inhalation); 1.34 Any of Methods 1 or 1.1-1.33, wherein the pharmaceutical composition is formulated for administration by injection, e.g., as a sterile aqueous solution; 1.35 Method 1.34, wherein the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous, or intraperitoneal injection; 1.36 Any of Methods 1 or 1.1-1.35 further comprising co-administration of one or more other therapeutic agents, e.g., administered simultaneously, separately or sequentially; 1.37 Method 1.36, wherein the additional therapeutic agent is an antidepressant, optionally wherein the antidepressant 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; 1.38 Method 1.36, wherein the additional therapeutic agent is an anxiolytic agent optionally selected from lorazepam, diazepam, alprazolam, and buspirone; 1.39 Method 1 or any of 1.1-1.38, which does not cause psychosis (e.g., long-term or intermittent psychosis); 1.40 Method 1 or any of 1.1-1.39, which does not promote self-harm or harm to others in the patient; 1.41 Method 1 or any of 1.1 to 1.40, which does not cause valvular heart disease or pulmonary arterial hypertension and is safe for treating, for example, patients with cardiac comorbidities; 1.42 Method 1 or any of 1.1-1.41, which does not lead to abuse or dependence (e.g., physical or psychological dependence); 1.43 The patient has or has previously been diagnosed with hallucinogenic persistent perception disorder (HPPD), either Method 1 or 1.1–1.42; 1.44 The patient has or has previously been diagnosed with a psychosis (e.g., schizophrenia), either method 1 or any of 1.1–1.43 to provide.

[0065] In a fourth aspect, the present invention provides a method (Method 2) for the treatment or prevention of a central nervous system disorder or more than one central nervous system disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound of Formula I), wherein the compound of the present invention inhibits 5-HT 2A In certain embodiments, method 2 comprises: 2.1 Method 2, wherein the compound of the invention is a compound of formula I in free form; 2.2 Method 2, wherein the compound of the invention is a compound of formula I in the form of a pharmaceutically acceptable salt; 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 a compound of the invention is administered in the form of a pharmaceutical composition (e.g., Pharmaceutical Composition I or 1-A, 1-B, 1-C, or any of P.1-P.7) comprising a compound of the invention in admixture with a pharmaceutically acceptable diluent or carrier; 2.5 Method 2.4, wherein the pharmaceutical composition is Pharmaceutical Composition 1-A, 1-B, or 1-C; 2.6 Method 2.4, wherein the pharmaceutical composition is any of pharmaceutical compositions P.1 to P.7; 2.7 Central nervous system disorders caused by 5-HT 2A Receptor antagonism, e.g., 5-HT 2A any of Method 2 or Methods 2.1-2.6, wherein the disorder is amenable to treatment by antagonism of the beta-arrestin signaling pathway and antagonism of the Gq signaling pathway, which is receptor-mediated; 2.8 Central nervous system disorders include serotonin 5-HT 2Aany of Method 2 or Methods 2.1-2.7, wherein the disorder involves, is mediated by, or is affected (directly or indirectly) by the receptor, dopamine D1 receptor and / or D2 receptor system, and / or the serotonin reuptake transporter (SERT) pathway, and / or the mu-opioid receptor pathway; 2.9 Central nervous system disorders include serotonin 5-HT 2A Method 2, or any of 2.1-2.7, is a disorder involving, mediated by, or affected (directly or indirectly) by receptors or the serotonin reuptake transporter (SERT), but not involving, mediated by, or affected (directly or indirectly) by the dopamine D1 or D2 receptor systems, or involving, mediated by, or affected (directly or indirectly) by the mu-opioid receptor pathway; 2.10 Central nervous system disorders include serotonin 5-HT 2A Disorders involving, mediated by, or affected (directly or indirectly) by receptors or the serotonin reuptake transporter (SERT), but not involving, mediated by, or affected (directly or indirectly) by the mu-opioid receptor pathway, method 2, or any of 2.1-2.7; 2.11 Central nervous system disorders include serotonin 5-HT 2A A disorder involving, mediated by, or affected (directly or indirectly) by a receptor, method 2 or any of 2.1-2.7; 2.12 Method 2 or any of Methods 2.1-2.12, wherein the central nervous system disorder is a disorder selected from the group consisting of anxiety disorder, depression, psychosis, schizophrenia, sleep disorder, impulse control disorder, post-traumatic stress disorder, intermittent explosive disorder, and dementia; 2.13 Method 2 or any of methods 2.1-2.13, where the central nervous system disorder is an anxiety disorder, such as generalized anxiety disorder, social anxiety disorder, and panic disorder; 2.14 Method 2 or any of methods 2.1-2.13, in which the central nervous system disorder is depression, including treatment-refractory depression, major depressive disorder, and bipolar depression; 2.15 Method 2 or any of methods 2.1-2.13, wherein the central nervous system disorder is a psychosis, e.g., schizophrenia; 2.16 Method 2.16, which is effective in treating positive and / or negative symptoms of schizophrenia; 2.17 Method 2, or any of 2.1-2.16, in which the patient suffers from any combination of the disorders described in methods 2.7-2.16; 2.18 Method 2, or any of 2.1 to 2.46, which is a method for the treatment or prevention of any combination of the disorders described in Methods 2.7 to 2.16; 2.19 Method 2 or any of Methods 2.1-2.18, wherein the patient does not respond to or cannot tolerate side effects from conventional antipsychotic medications, such as 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; 2.20 Method 2 or any of Methods 2.1-2.19, wherein the patient does not respond to or cannot tolerate the side effects of conventional antidepressants; 2.21 Method 2 or any of Methods 2.1-2.20, wherein the patient does not respond to or cannot tolerate the side effects of treatment with a selective serotonin reuptake inhibitor (SSRI), such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; 2.22 Method 2 or any of Methods 2.1-2.21, wherein the patient does not respond to or cannot tolerate the side effects of treatment with a serotonin-norepinephrine reuptake inhibitor (SNRI), such as venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran; 2.23 Method 2 or any of Methods 2.1-2.22, wherein the patient has not responded to or cannot tolerate the side effects of treatment with conventional anxiolytics, such as lorazepam, diazepam, alprazolam, and buspirone; 2.24 Method 2 or any of Methods 2.1-2.23, wherein the patient does not respond to or cannot tolerate the side effects of treatment with antipsychotic drugs such as clomipramine, risperidone, quetiapine, and olanzapine; 2.25 Any of the foregoing methods, wherein the therapeutically effective amount of a compound of the invention (e.g., a compound of Formula I) is 1 mg to 1000 mg, preferably 2.5 mg to 50 mg, or for long-acting formulations, 25 mg to 1500 mg, e.g., 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; 2.26 Method 2.26, wherein the therapeutically effective amount is 1 mg to 100 mg per day, preferably 2.5 mg to 50 mg per day. 2.27 Method 2.26, wherein the therapeutically effective amount of the compound of the invention is 1 mg to 1000 mg, e.g., 2.5 mg to 50 mg, or for long-acting formulations, 25 mg to 1500 mg, e.g., 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg; 2.28 Method 2.26, wherein the therapeutically effective amount of the compound of the invention is 1 mg to 100 mg per day, for example, 2.5 mg to 50 mg per day; 2.29 Method 2.26, wherein the therapeutically effective amount of the compound of the present invention is 1 mg to 5 mg, preferably 2.5 to 5 mg per day; 2.30 Method 2.26, wherein the therapeutically effective amount of a compound of the invention is 2.5 mg or 5 mg per day; 2.31 Method 2 or any of Methods 2.1-2.30, wherein the pharmaceutical composition is a sustained or delayed release formulation, e.g., according to Pharmaceutical Composition 1-A described herein; 2.32 Method 2 or any of Methods 2.1-2.30, wherein the pharmaceutical composition comprises a compound of the invention in a polymer matrix, e.g., according to Pharmaceutical Composition 1-B described herein; 2.33 Method 2 or any of Methods 2.1-2.32, wherein the pharmaceutical composition is in the form of a tablet or capsule; 2.34 Method 2 or any of Methods 2.1-2.33, wherein the pharmaceutical composition is formulated for oral, sublingual, or buccal administration; 2.35 Method 2 or any of Methods 2.1-2.34, wherein the pharmaceutical composition is a fast-dissolving oral tablet (e.g., a fast-dissolving sublingual tablet); 2.36 Method 2 or any of Methods 2.1-2.35, wherein the pharmaceutical composition is formulated for intranasal or pulmonary administration (e.g., as an aerosol, mist, or powder for inhalation); 2.37 Method 2 or any of Methods 2.1-2.36, wherein the pharmaceutical composition is formulated for administration by injection, e.g., as a sterile aqueous solution; 2.38 Method 2.37, wherein the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous, or intraperitoneal injection; 2.39 Method 2 or any of Methods 2.1-2.38 further comprising co-administration of one or more other therapeutic agents, e.g., administered simultaneously, separately or sequentially; 2.40 Method 2.39, wherein the additional therapeutic agent is optionally an antipsychotic selected from the 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; 2.41 Method 2.39, wherein the additional therapeutic agent is optionally an antidepressant 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; 2.42 Method 2.39, wherein the additional therapeutic agent is optionally an atypical antipsychotic selected from the group consisting of brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone; 2.43 Method 2.39, wherein the additional therapeutic agent is an atypical stimulant optionally selected from modafinil, adrafinil, and armodafinil; 2.44 Method 2.39, wherein the additional therapeutic agent is optionally an antiparkinsonian agent selected from L-dopa, co-calerdopa, duodopa, stalevo, symmetrel, benztropine, biperiden, bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline, and tolcapone; 2.45 Method 2.39, wherein the additional therapeutic agent is an anxiolytic agent optionally selected from lorazepam, diazepam, alprazolam, and buspirone; 2.46 Does not cause psychosis (e.g., long-term or intermittent psychosis), method 2 or any of 2.1–2.45; 2.47 Method 2 or any of 2.1-2.46, which does not promote self-harm or harm to others in the patient; 2.48 Method 2 or any of 2.1 to 2.47, which does not cause valvular heart disease or pulmonary arterial hypertension and is safe for treating, for example, patients with cardiac comorbidities; 2.49 Method 2 or any of 2.1-2.48, which does not lead to abuse or dependence (e.g., physical or psychological dependence) This includes administering the following.

[0066] In some embodiments of the methods described below, pharmaceutical compositions comprising a compound of the invention may be administered for controlled and / or sustained release of a compound of the invention over a period of about 14 days, about 30 to about 180 days, preferably about 30, about 60, or about 90 days. Controlled and / or sustained release is particularly useful for avoiding premature discontinuation of treatment, especially with antipsychotic therapy, where non-compliance or non-adherence to dosing regimens is common.

[0067] In some embodiments of the methods described below, the pharmaceutical composition comprising a compound of the invention may be a depot composition of the present disclosure, administered for controlled and / or sustained release of the compound of the invention over a period of time.

[0068] The compounds of the present disclosure (i.e., compounds of the present invention) and pharmaceutical compositions of the present disclosure may be used in combination with a second therapeutic agent to enhance the therapeutic activity of the combined agent, particularly at lower dosages than when each agent is used as a monotherapy, without causing the undesirable side effects commonly associated with conventional monotherapy. Thus, the compounds of the present disclosure may be administered simultaneously, sequentially, or contemporaneously with other therapeutic agents described above, such as opiates, opioids, analgesics, antidepressants, antipsychotics, other hypnotics, and / or agents used to treat Parkinson's disease or mood disorders.

[0069] In any of the embodiments of Method 1 and later or Method 2 and later in which a compound of the present disclosure is administered in conjunction with one or more second therapeutic agents, the one or more second therapeutic agents may be administered as part of a pharmaceutical composition comprising a compound of the present disclosure. Alternatively, the one or more second therapeutic agents may be administered in separate pharmaceutical compositions (e.g., pills, tablets, capsules, and injections) that are administered sequentially or separately, simultaneously with the administration of the compound of the present disclosure.

[0070] 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, which is an opioid antagonist or inverse agonist (e.g., naloxone), to enhance the therapeutic activity of the combined agent without causing undesirable side effects, particularly at lower dosages than when the individual agents are used as monotherapy. The compounds of the present disclosure may be administered simultaneously, sequentially, or contemporaneously with such opioid antagonist or opioid inverse agonist.

[0071] In a fifth aspect, the disclosure provides use of a compound of the invention in the manufacture of a medicament for use by Method 1 or any of Methods 1.1-1.42, or Method 2 or any of Methods 2.1-2.49. In another embodiment, the disclosure provides a compound of the invention for use in treating a disease or disorder by Method 1 or any of Methods 1.1-1.42, or Method 2 or any of Methods 2.1-2.49. DETAILED DESCRIPTION OF THE INVENTION

[0072] The term "biased agonist," as used herein, refers to an agonist that has either partial or full agonism for beta-arrestin signaling through the receptor, but either antagonism or weak partial agonism for Gq-mediated signaling, and that inhibits serotonin 5-HT 2A It is used to refer to compounds that have activity at the receptor. A useful measure of bias is the relative intrinsic activity of beta-arrestin signaling (RA). i ) RA of Gq signaling iThe "bias ratio" is calculated as the ratio of the bias ratio to the bias ratio. A non-biased agonist has a bias ratio of 1.0. A biased agonist has a non-zero bias ratio. In some embodiments, the compounds of the present disclosure are preferably biased toward beta-arrestin signaling and therefore have a bias ratio greater than 1.0. More preferably, the bias ratio toward beta-arrestin signaling is greater than 10, or greater than 100, or greater than 1000, or greater than 10,000.

[0073] As used herein, the term "partial agonist" is understood to refer to a compound that has agonism to any degree less than a reference standard full agonist. For example, 5-HT 2A The reference compound for receptor agonism is alpha-methylserotonin. The maximum efficacy (E) is less than 100% of the maximum efficacy of alpha-methylserotonin. max ) are partial agonists.

[0074] The term "hallucinogenic drug" refers to a compound that causes hallucinations, which are any one or more symptoms selected from visual hallucinations, auditory hallucinations, visual distortions (e.g., floating, morphing, flickering, or melting objects and surfaces in the field of vision), detachment from reality, dissociation, delirium, and unwanted altered states of consciousness. A compound of the present disclosure is considered "non-hallucinogenic" if the compound does not cause hallucinations at doses therapeutically effective for treating the neuropsychiatric disorders described herein (e.g., depression, anxiety, etc.).

[0075] It is understood that the terms "opiate" and "opioid" differ in that "opiate" refers to natural products derived from the opium poppy, such as morphine, codeine, and heroin, while "opioid" refers to these natural compounds as well as their semi-synthetic and synthetic derivatives, e.g., fentanyl and its analogs.

[0076] "Alkyl," as used herein, unless otherwise indicated, refers to a saturated or unsaturated hydrocarbon moiety, e.g., from 1 to 21 carbon atoms in length, and unless otherwise specified, any such alkyl may be straight-chained or branched (e.g., n-butyl or tert-butyl), preferably straight-chained. For example, "C1 to 21 "Alkyl" refers to an alkyl having 1 to 21 carbon atoms. In one embodiment, alkyl is selected from the group consisting of one or more hydroxy or C 1~22 In another embodiment, for example, in some embodiments where R1 is an alkyl chain containing 1 to 21 carbon atoms, preferably 6 to 15 carbon atoms, 16 to 21 carbon atoms, the alkyl preferably contains 1 to 21 carbon atoms that is straight-chained and optionally saturated or unsaturated, e.g., so that, when cleaved from, for example, a compound of Formula I, it forms, together with the -C(O)- to which it is attached, the residue of a natural or unnatural saturated or unsaturated fatty acid.

[0077] The term "pharmaceutically acceptable diluent or carrier" is intended to mean diluents and carriers that are useful in pharmaceutical preparations and that do not contain allergenic, pyrogenic, or pathogenic substances, and substances known to potentially cause or promote disease. Thus, pharmaceutically acceptable diluents or carriers exclude, for example, bodily fluids such as blood, urine, spinal fluid, saliva, and the like, and their components, such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in several well-known treatises on pharmaceutical formulations, such as 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, 20037ybg; and others, all of which are incorporated herein by reference in their entirety. th Ed., Lippincott Williams & Wilkins, 2000; and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0078] The terms "purified," "in purified form," or "in isolated and purified form" with respect to a compound refer to the physical state of said compound after isolation from a synthetic process (e.g., from a reaction mixture) or from a natural source, or a combination thereof. Thus, the terms "purified," "in purified form," or "in isolated and purified form" with respect to a compound refer to the physical state of said compound after it has been obtained from one or more purification processes described herein or known to those of skill in the art (e.g., chromatography, recrystallization, LC-MS and LC-MS / MS techniques, etc.) with sufficient purity to be characterized by standard analytical techniques described herein or known to those of skill in the art.

[0079] Unless otherwise specified, the compounds of the present invention may exist in a salt form, such as a free base form or a pharmaceutically acceptable salt form, for example, as an acid addition salt.Sufficiently basic acid addition salts of the compounds of the present invention are, for example, acid addition salts with inorganic or organic acids, such as hydrochloric acid or toluenesulfonic acid.In addition, sufficiently acidic salts of the compounds of the present invention are alkali metal salts, such as sodium or potassium salts, or salts with organic bases that provide physiologically acceptable cations.In certain embodiments, the salts of the compounds of the present invention are toluenesulfonic acid addition salts or hydrochloric acid addition salts.

[0080] The compounds of the present invention are intended for use as pharmaceuticals, and therefore pharmaceutically acceptable salts are preferred. Salts that are not suitable for pharmaceutical use may be useful, for example, in the isolation or purification of free compounds of the present invention, and therefore are also included within the scope of the compounds of the present disclosure.

[0081] The compounds of the present invention may contain one or more chiral carbon atoms. Thus, the compounds exist in individual isomers, e.g., enantiomeric or diastereomeric forms, or as mixtures of individual forms, e.g., racemic / diastereomeric mixtures. Any isomer may exist in which the asymmetric center is in the (R)-, (S)-, or (R,S)-configuration. It is understood that the present invention encompasses both individual optically active isomers and mixtures thereof (e.g., racemic / diastereomeric mixtures). Thus, the compounds of the present invention may be racemic mixtures, or they may be predominantly in pure or substantially pure isomeric form, e.g., with an enantiomeric / diastereomeric excess ("ee") of greater than 70%, preferably greater than 80% ee, more preferably greater than 90% ee, and most preferably greater than 95% ee. Purification of the isomers and separation of the isomeric mixtures may be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed, etc.).

[0082] Geometric isomers by nature of the substituents around a double bond or a ring may exist in cis (Z) or trans (E) form and both isomeric forms are encompassed within the scope of the present invention.

[0083] The compounds of the present disclosure are also intended to encompass their stable and unstable isotopes. A stable isotope is a non-radioactive isotope that contains one additional neutron compared to the abundant nuclide of the same species (i.e., element). The activity of compounds containing such isotopes is expected to be maintained, and such compounds are also useful for measuring the pharmacokinetics of non-isotopic analogs. For example, a hydrogen atom at a certain position on a compound of the present disclosure may be replaced with deuterium (a stable isotope that is non-radioactive). An example of a known stable isotope is deuterium ( 2 H or D), 13 C. 15 N, 18Alternatively, unstable isotopes, which are radioactive isotopes that contain additional neutrons compared to the abundant nuclide of the same species (i.e., element), e.g., 123 I, 131 I, 125 I, 14 C. 18 F may replace the corresponding abundant species of I, C, and F. Other examples of useful isotopes of the compounds of the invention are: 14 C isotopes. These radioisotopes are useful for radioimaging and / or pharmacokinetic studies of the compounds of the present invention. In addition, substitution of atoms with natural isotopic distributions with heavier isotopes can result in desirable changes in pharmacokinetic rates when these substitutions are made at sites that are easily metabolized. For example, deuterium ( 2 Incorporation of H) can slow metabolic degradation if the hydrogen position is a site of enzymatic or metabolic activity.

[0084] The compounds of the present invention may be included in a depot formulation, e.g., by dispersing, dissolving, or encapsulating the compounds of the present invention in a polymer matrix as described above, so that the compound is released continuously as the polymer degrades over time. Release of the compounds of the present invention from the polymer matrix results in controlled and / or delayed and / or sustained release of the compound from, for example, a pharmaceutical depot composition to a subject, e.g., a warm-blooded animal such as a human, to whom the pharmaceutical depot is administered. Thus, the pharmaceutical depot delivers the compounds of the present invention to the subject at concentrations effective to treat a particular disease or medical condition for a sustained period, e.g., 14 to 180 days, preferably about 30, about 60, or about 90 days.

[0085] Polymers useful for the polymer matrix in the compositions of the invention (e.g., depot compositions of the invention) include polyesters or other agents of hydroxy fatty acids and their derivatives, such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, ε-caprolactone ring-opening polymers, lactic acid-glycolic acid copolymers, 2-hydroxybutyric acid-glycolic acid copolymers, polylactic acid-polyethylene glycol copolymers, or polyglycolic acid-polyethylene glycol copolymers, polymers of alkyl alpha-cyanoacrylates (e.g., poly( butyl 2-cyanoacrylate), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene-propylene carbonate), polyortho-carbonates, polyamino acids (e.g., poly-gamma-L-alanine, poly-gamma-benzyl-L-glutamic acid or poly-y-methyl-L-glutamic acid), hyaluronic acid esters, and the like, one or more of these polymers can be used.

[0086] When the polymer is a copolymer, it may be a random, block, and / or graft copolymer. When the above-mentioned alpha-hydroxycarboxylic acids, hydroxydicarboxylic acids, and hydroxytricarboxylic acids have optical activity in their molecules, any one of the D-isomer, L-isomer, and / or DL-isomer may be used. In particular, alpha-hydroxycarboxylic acid polymers (preferably lactic acid-glycolic acid polymers), their esters, poly-alpha-cyanoacrylates, etc. may be used, with lactic acid-glycolic acid copolymers (also referred to as poly(lactide-alpha-glycolide) or poly(lactic acid-co-glycolic acid), hereinafter referred to as PLGA) being preferred. Thus, in one embodiment, the polymer useful for the polymer 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 a biodegradable poly(d,l-lactide-co-glycolide) polymer.

[0087] In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymeric material. The term "biocompatible" is defined as a polymeric material that is not toxic, carcinogenic, or significantly inflammatory in body tissues. The matrix material should be biodegradable; that is, the polymeric material should break down through bodily processes into products that are easily disposed of by the body and should not accumulate within the body. To the extent that the polymeric matrix is ​​biocompatible with the body, the products of biodegradation should also be biocompatible with the body. Particularly 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(orthocarbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as glycerol mono- and distearate. A preferred polymer for use in the practice of the present invention is dl (polylactide-co-glycolide). The molar ratio of lactide to glycolide in such copolymers preferably ranges from about 75:25 to 50:50.

[0088] Useful PLGA polymers may have a weight-average molecular weight of about 5,000 to 500,000 daltons, preferably about 150,000 daltons. Polymers of different molecular weights may be used depending on the degradation rate to be achieved. For a diffusion mechanism of drug release, the polymer should remain intact until all of the drug is released from the polymer matrix and then degrade. The drug may also be released from the polymer matrix as the polymer excipient bioerodes. PLGA may be prepared by any conventional method or may be commercially available. For example, PLGA can be produced from cyclic lactide, glycolide, etc. by ring-opening polymerization using an appropriate catalyst. (See EP 0058481; Effects of polymerization variables on PLGA properties: molecular weight, composition, and chain structure.)

[0089] PLGA is considered biodegradable due to the breakdown of the entire solid polymer composition under biological conditions (e.g., in the presence of water and biological enzymes found in the tissues of warm-blooded animals such as humans) resulting from the rupture of hydrolytically and enzymatically cleavable ester bonds, forming lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism, which can further biodegrade to form carbon dioxide and water. In other words, PLGA is considered to degrade in the presence of water, for example, in the body of a warm-blooded animal such as a human, by hydrolysis of its ester groups to produce lactic acid and glycolic acid, creating an acidic microclimate. Lactic acid and glycolic acid are by-products of various metabolic pathways in the body of a warm-blooded animal such as a human under normal physiological conditions, and therefore are well tolerated and cause minimal systemic toxicity.

[0090] In another embodiment, the polymer matrix useful in the present invention may comprise a star polymer, in which the polyester structure is star-shaped. These polyesters have a single polyol residue as the central moiety surrounded by a chain of acid residues. The polyol moiety may be, for example, glucose or, for example, mannitol. These esters are known and are described in GB 2,145,422 and U.S. Pat. No. 5,538,739, the contents of which are incorporated by reference.

[0091] Star polymers may be prepared using a polyhydroxy compound, such as a polyol, e.g., glucose or mannitol, as an initiator. The polyol contains at least three hydroxy groups and has a molecular weight of up to about 20,000 daltons, and at least one, preferably at least two, e.g., an average of three, of the hydroxy groups of the polyol are in the form of an ester group containing a polylactide or co-polylactide chain. Branched polyesters, such as poly(d,l-lactide-co-glycolide), have a central glucose moiety with linear polylactide chain radiators.

[0092] The depot compositions of the present invention (long-acting injectable compositions having a compound of the present invention in a polymer matrix) described above may comprise a polymer in the form of microparticles or nanoparticles or in liquid form, in which the compound of the present invention is dispersed or encapsulated. "Microparticles" refers to solid particles containing a compound of the present invention, either in solution or in solid form, where such compound is dispersed or dissolved within a polymer that functions as the matrix of the particle. By appropriate selection of polymer materials, microparticle formulations can be produced in which the resulting microparticles exhibit both diffusional release and biodegradable release properties.

[0093] When the polymer is in the form of microparticles, the microparticles can be prepared by any suitable method, for example, by solvent evaporation or solvent extraction.For example, in solvent evaporation, the compound of the present invention and the polymer can be dissolved in a volatile organic solvent (for example, ketones such as acetone, halogenated hydrocarbons such as chloroform or methylene chloride, halogenated aromatic hydrocarbons, cyclic ethers such as dioxane, esters such as ethyl acetate, nitriles such as acetonitrile, or alcohols 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 obtain microparticles in which the compound of the present invention is encapsulated.In solvent extraction, the compound of the present invention and the polymer can be dissolved in a polar solvent (for example, acetonitrile, dichloromethane, methanol, ethyl acetate, or methyl formate), and then dispersed in an aqueous phase (for example, water / PVA solution).An emulsion is formed to obtain microparticles in which the compound of the present invention is encapsulated.Spray drying is an alternative manufacturing technique for preparing microparticles.

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

[0095] The microparticles of the present invention can be prepared by any method that can produce microparticles of a size range acceptable for use in injectable compositions.One preferred preparation method is that described in U.S. Patent No. 4,389,330.In this method, the active agent is dissolved or dispersed in a suitable solvent.To the drug-containing vehicle, a polymer matrix material is added in an amount relative to the active ingredient that will result in a product with the desired loading of the active agent.Optionally, all of the components of the microparticle product can be blended together in a solvent vehicle.

[0096] The solvent for preparing such compositions comprising the compound of the present invention and polymer matrix material that can be used in the practice of the present invention includes organic solvents such as acetone; halogenated hydrocarbons such as chloroform, methylene chloride, etc.; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols such as benzyl alcohol; ethyl acetate, etc. In one embodiment, the solvent for use in the practice of the present invention can be a mixture of benzyl alcohol and ethyl acetate.Further information about the preparation of microparticles useful in the present invention can be found in US Patent Publication No. 2008 / 0069885, the contents of which are incorporated herein by reference in their entirety.

[0097] The amount of the compound of the present disclosure incorporated into the microparticles is typically in the range of about 1 wt.% to about 90 wt.%, preferably 30 to 50 wt.%, and more preferably 35 to 40 wt.%. Wt.% refers to the portion of the compound of the present disclosure relative to the total weight of the microparticles.

[0098] The pharmaceutical depot composition 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 compositions can be found in EP 1539115 (U.S. Patent Application Publication No. 2009 / 0202631) and WO 2000 / 35419 (U.S. Patent Application Publication No. 2001 / 0036472), the contents of each of which are incorporated by reference in their entirety.

[0100] A "therapeutically effective amount" is an amount of any of the compounds of the invention (e.g., contained in a pharmaceutical depot) that, when administered to a subject suffering from a disease or disorder, is effective to cause a reduction, remission, or remission of the disease or disorder over the period of time intended for treatment.

[0101] Dosages used in the practice of this invention will, of course, vary depending, for example, on the particular disease or condition being treated, the particular compound of the invention being used, the mode of administration, and the desired therapy. Unless otherwise indicated, amounts of compounds of the invention for administration (whether administered as the free base or as a salt form) refer to or are based on the amount of compound of the invention in free base form (i.e., amount calculations are based on the amount of free base).

[0102] The compounds of the present invention may be administered by any satisfactory route, including orally, parenterally (intravenously, intramuscularly, intranasally, pulmonary, or subcutaneously), or transdermally. In certain embodiments, compounds of the present invention, for example in a depot formulation, are preferably administered parenterally, for example by injection, for example, intramuscularly or subcutaneously.

[0103] In general, satisfactory results for the methods of treatment disclosed herein or for the use of the compounds of the invention described above have been shown to be obtained with oral administration at dosages of about 1 mg to 100 mg once daily, preferably 2.5 mg to 50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg once daily orally.

[0104] For the treatment of some diseases, particularly for the treatment of sleep disorders, lower doses such as about 2.5 mg to 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, administered once daily, preferably orally, are sufficient.

[0105] Satisfactory results of treatment methods involving the co-administration of a second therapeutic agent may be obtained with a dose of less than 100 mg, preferably less than 50 mg, 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.

[0106] For the treatment of disorders disclosed herein in which depot compositions are used to achieve a longer duration of action, the dosage will be higher than that of shorter acting compositions, e.g., greater than 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greater than 1,000 mg. The duration of action of the compounds of the present disclosure may be controlled by manipulating the polymer composition, i.e., the polymer:drug ratio and microparticle size. When the composition of the present invention is a depot composition, administration by injection is preferred.

[0107] The pharmaceutically acceptable salt of the compound of the present disclosure can be synthesized from parent compound containing basic or acidic moiety by conventional chemical methods.Generally, this salt can be prepared by reacting the free base form of these compounds with stoichiometric amount of suitable acid in water or organic solvent or the mixture of the two, and generally non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.Further details about the preparation of these salts in amorphous or crystalline form, such as toluenesulfonic acid salt, can be found in U.S. Patent No. 8,309,722, U.S. Patent No. 8,648,077, U.S. Patent No. 9,199,995 and U.S. Patent No. 9,586,960.

[0108] Pharmaceutical compositions containing the compounds of the present disclosure may be prepared using conventional diluents or excipients (examples include, but are not limited to, sesame oil) and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, etc.

[0109] The term "combination," when referring to therapeutic use, means the administration of two or more active ingredients to a patient as part of a regimen for treating a disease or disorder, whether the two or more active agents are given at the same or different times, or by the same or different routes of administration. The combined administration of two or more active ingredients may be at different times on the same day, or on different days, or with different frequencies.

[0110] The term "concurrently" when referring to therapeutic use means administration of two or more active ingredients at or near the same time by the same route of administration.

[0111] The term "separately" when referring to therapeutic use means the administration of two or more active ingredients simultaneously or near simultaneously by different routes of administration.

[0112] Methods for preparing the compounds of the present invention: Compounds of Formula A and methods for their synthesis, including the synthesis of intermediates used in the synthetic schemes below, are disclosed, for example, in U.S. Pat. No. 10,245,260, U.S. Patent Application Publication No. 2022 / 0041600, and U.S. Patent Application Publication No. 2022 / 0064166, the contents of which are incorporated herein by reference in their entireties.

[0113] The synthesis of similar fused gamma-carbolines is disclosed, for example, in U.S. Pat. No. 8,309,722, U.S. Pat. No. 8,993,572, U.S. Patent Application Publication No. 2017 / 0183350, WO 2018 / 126140, and WO 2018 / 126143, the contents of each of which are incorporated by reference in their entirety. Compounds of the present disclosure can be prepared using similar procedures.

[0114] Other compounds of the present disclosure can be prepared by analogous procedures known to those skilled in the art.

[0115] Isolation or purification of diastereomers of compounds of the present invention may be achieved by conventional methods known in the art, such as column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving bed, and the like.

[0116] Salts of the compounds of the present disclosure may be prepared similarly as described in U.S. Patent Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; 8,648,077; 9,199,995; 9,586,860; USRE39680; and USRE39679, the contents of each of which are incorporated by reference in their entirety.

[0117] The diastereomers of the prepared compounds can be separated by HPLC using, for example, a CHIRALPAK® AY-H column (5μ, 30 x 250 mm) at room temperature, eluting with 10% ethanol / 90% hexane / 0.1% dimethylethylamine. Peaks detected at 230 nm yield diastereomers with 98-99.9% ee. [Example]

[0118] Methods for the synthesis of the compounds of the present disclosure are known in the art. In particular, methods have been published for the synthesis of the tetracyclic core structure, as well as for various modifications and variations of the pendant side chains on the piperidine ring. See, for example, Li, et al., Journal of Medicinal Chemistry 57:2670-2682 (2014), U.S. Patent Nos. 6,713,471, 6,552,017, 7,071,186, 8,309,722, 9,708,322, 10,245,260, 10,688,097, 10,961,245, 10,906,906, 11,427,587, 11,453,670, and U.S. Patent Application Publication No. 2022 / 0048910, the contents of each of which are incorporated herein by reference in their entirety.

[0119] Compounds of the present disclosure may be prepared according to the following general scheme:

[0120] [ka] Typical reagents and conditions: (a) ethylmagnesium bromide, titanium isopropoxide, THF, 25°C; (b) saturated KOH solution in 90% EtOH, 100°C; (c) RX, KI, DIPEA, DMF, 75°C.

[0121] [ka] Typical reagents and conditions: (a) 4-bromo-1-butene, DIPEA, KI, dioxane, 110°C; (b) DBU, Pd(OAc)2, tricyclohexylphosphine, DMF, 140°C; (c) ZnEt2, CHI2, CHCl2, 0°C; (d) saturated KOH solution in 90% EtOH, 100°C; (e) RX, KI, DIPEA, DMF, 75°C.

[0122] [ka] Typical reagents and conditions: (a) RX, DIPEA, KI, 18-crown-6, dioxane, 95° C., or RX, K2CO3, dioxane, 60° C. The tetracyclic starting material can be prepared according to known methods, for example, according to Scheme 3-A below.

[0123] [ka] Typical reagents and conditions: (a) N-methylchloroacetamide, DIPEA, KI, dioxane, reflux, 48 h; (b) CuI, K2CO3, DMEDA, dioxane, reflux, 24 h; (c) BH3-THF, THF, 60 °C, 20 h; (d) KOH, n-BuOH, 120 °C, 3 h.

[0124] [ka] Typical reagents and conditions: (a) ROH, Triton B, KOH, 18-crown-6, 150°C.

[0125] According to the above general scheme, the following compounds of Examples 1-180 have been or will be synthesized and characterized:

[0126] [Table 3-1]

[0127] [Table 3-2]

[0128] [Table 3-3]

[0129] [Table 3-4]

[0130] [Table 3-5]

[0131] [Table 3-6]

[0132] [Table 3-7]

[0133] Representative synthesis examples follow.

[0134] [Example 2] 1-(4-Fluorophenyl)-5-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)pentan-1-one

[0135] [ka] The synthesis method is similar to Example 71, except that 5-chloro-1-(4-fluorophenyl)-1-pentanone is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 17% isolated yield. 1 H NMR (500 MHz, DMSO) δ 8.10 - 8.01 (m, 2H), 7.40 - 7.28 (m, 2H), 6.53 - 6.46 (m, 1H), 6.43 - 6.38 (m, 1H), 6.32 (dd, J = 7.9, 1.0 Hz, 1H), 3.43 (ddd, J = 11.5, 9.7, 3.0 Hz, 1H), 3.26 (dt, J = 11.4, 2.9 Hz, 3H), 3.10 (ddd, J = 6.8, 4.3, 2.4 Hz, 1H), 3.02 (dd, J = 7.8, 6.7 Hz, 2H), 2.78 (s, 3H), 2.74 (ddd, J = 11.3, 6.2, 1.7 Hz, 1H), 2.68 (td, J = 9.9, 2.8 Hz, 1H), 2.54 (t, J = 11.5 Hz, 1H), 2.35 - 2.15 (m, 2H), 2.07 (td, J = HRMS (ESI) m / z C 25 H 30 FN3O [M+H] + Calculated value: 408.2446; Measured value: 408.2446.

[0136] [Example 3] 1-(4-Fluorophenyl)-3-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)propan-1-one.

[0137] [ka] To a degassed solution of 2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)ethan-1-ol hydrochloride (3.0 g, 11.3 mmol) in anhydrous dioxane (20 mL), N,N-diisopropylethylamine (3.0 g, 22.6 mmol), 3-chloro-1-(4-fluorophenyl)propan-1-one (2.3 g, 12.4 mmol), potassium iodide (2.3 g, 13.6 mmol), and a catalytic amount of 18-crown-6 were added under argon. The resulting mixture was heated to 95 °C and stirred for 6.5 h. After cooling to room temperature, the solvent is removed and the residue is suspended in ethyl acetate (50 mL) and water (50 mL). The aqueous phase is separated and extracted twice with ethyl acetate (30 mL). The combined organic phases are dried over MgSO4 and concentrated. The residue is purified by silica gel column chromatography using a 0-20% mixed solvent gradient [ethyl acetate / methanol / 7N NH3 in methanol (10:1:0.1 v / v)] in ethyl acetate to give the title product as a brown solid (0.8 g, 16% yield). MS (ESI) m / z 380.2 [M+1] + . 1H NMR (500 MHz, DMSO) δ 9.15 (s, 1H), 8.19 - 8.07 (m, 2H), 7.42 (t, J = 8.8 Hz, 2H), 6.62 (t, J = 7.7 Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 6.44 (d, J = 7.9 Hz, 1H), 3.68 - 3.57 (m, 3H), 3.53 - 3.41 (m, 5H), 3.35 (q, J = 2.6 Hz, 1H), 3.23 (d, J = 5.8 Hz, 1H), 3.14 (q, J = 13.1 Hz, 1H), 2.82 (s, 4H), 2.76 - 2.61 (m, 2H), 2.29 (d, J = 15.5 Hz, 1H), 2.07 (t, J = 14.8 Hz, 1H).

[0138] [Example 4] 1-(4-Fluorophenyl)-4-((6b'R,10a'S)-3'-methyl-6b',7',10',10a'-tetrahydrospiro[cyclopropane-1,2'-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline]-8'(1'H,3'H,9'H)-yl)butan-1-one.

[0139] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 4-chloro-1-(4-fluorophenyl)butan-1-one is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 13% isolated yield. MS (ESI) m / z 420.3 [M+1] + . 1H NMR (500 MHz, DMSO) δ 8.09 - 7.99 (m, 2H), 7.40 - 7.28 (m, 2H), 6.56 - 6.51 (m, 2H), 6.48 (dd, J = 6.6, 2.5 Hz, 1H), 3.11 (ddd, J = 6.8, 4.3, 2.6 Hz, 1H), 3.00 (t, J = 6.9 Hz, 2H), 2.91 (dt, J = 10.3, 6.3 Hz, 1H), 2.74 (dd, J = 11.4, 6.3 Hz, 1H), 2.69 (dd, J = 10.0, 2.0 Hz, 1H), 2.58 (s, 3H), 2.56 - 2.53 (m, 2H), 2.39 - 2.20 (m, 2H), 2.18 - 2.07 (m, 1H), 1.88 (t, J = 10.9 Hz, 1H), 1.83 - 1.74 (m, 3H), 1.70 - 1.56 (m, 1H), 1.24 (s, 1H), 1.11 - 1.00 (m, 1H), 0.79 - 0.62 (m, 1H), 0.41 (ddd, J = 9.8, 6.3, 4.1 Hz, 1H).

[0140] [Example 5] 1-(4-Fluorophenyl)-6-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)hexan-1-one

[0141] [ka] The synthesis method is similar to Example 71, with 6-chloro-1-(4-fluorophenyl)-1-hexanone being added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 11% isolated yield. 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 6.87 - 6.77 (m, 2H), 6.75 - 6.71 (m, 1H), 6.70 - 6.66 (m, 2H), 6.64 (dd, J = 7.9, 1.2 Hz, 1H), 3.99 (t, J = 5.8 Hz, 2H), 3.57 (dt, J = 12.1, 6.3 Hz, 1H), 3.45 (ddd, J = 11.9, 6.4, 2.0 Hz, 1H), 3.39 - 3.26 (m, 2H), 3.18 - 2.99 (m, 2H), 2.92 (dd, J = 9.9, 2.2 Hz, 1H), 2.90 - 2.79 (m, 1H), 2.71 (s, 3H), 2.54 (t, J = 11.7 Hz, 1H), 2.48 - 2.39 (m, 1H), 2.37 (d, J = 10.0 Hz, 1H), 2.32 - 2.23 (m, 2H), 2.18 (d, J = 3.4 Hz, 2H), 2.04 (dq, J = 15.5, 2.7 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 167.43, 157.18 (d, J = 240Hz), 152.75, 140.19, 136.76, 128.88, 120.84, 117.59 (d, J = 25.2Hz), 115.89, 115.07, 112.60 (d, J = 25.2Hz), 111.92(d, J = 10.1Hz), 66.07, 63.03, 54.93, 53.74, 48.58, 47.96, 41.94, 39.39, 38.17, 24.69, 22.63, 16.46, 14.55, 9.94. HRMS (ESI) m / z C 26 H 32 FN3O [M+H] + Calculated value: 422.2602; Measured value: 422.2602.

[0142] [Example 6] 1-(4-(2-methoxyethoxy)phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one.

[0143] [ka] A mixture of 2-methoxyethan-1-ol (1.5 mL), 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)butan-1-one (0.5 g, 1.3 mmol), N,N,N-trimethyl-1-phenylmethanaminium hydroxide (0.3 g, 1.7 mmol), and 85% KOH (0.1 g, 1.5 mmol) was heated in a microwave oven under argon at 150 °C for 3 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The residue was adjusted to pH 9 by adding aqueous NH4Cl with stirring, and the resulting suspension was then extracted three times with dichloromethane (3 × 10 mL). The combined organic phases are dried over MgSO4 and concentrated. The residue is purified by silica gel column chromatography using a 0-40% mixed solvent gradient [dichloromethane / methanol / 7N NH3 in methanol (10:1:0.1 v / v)] in dichloromethane. The title product is obtained as a brown solid (0.4 g, 35% yield). MS (ESI) m / z 450.3 [M+1] + . 1H NMR (500 MHz, MeOD) δ 8.05 - 7.95 (m, 2H), 7.09 - 6.99 (m, 2H), 6.61 (t, J = 7.7 Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 6.43 (dd, J = 8.0, 0.9 Hz, 1H), 4.27 - 4.17 (m, 2H), 3.81 - 3.75 (m, 2H), 3.52 (ddd, J = 11.8, 10.1, 3.2 Hz, 1H), 3.44 (s, 3H), 3.38 (t, J = 3.0 Hz, 1H), 3.31 (d, J = 3.0 Hz, 2H), 3.29 (t, J = 2.9 Hz, 1H), 3.15 (ddd, J = 6.5, 4.2, 2.2 Hz, 1H), 3.08 (dt, J = 10.8, 6.3 Hz, 1H), 2.85 (s, 4H), 2.77 (td, J = 10.0, 2.8 Hz, 2H), 2.51 - 2.37 (m, 2H), 2.32 (td, J = 11.9, 3.0 Hz, 1H), 2.04 - 1.86 (m, 5H).

[0144] [Example 7] 1-(4-Fluorophenyl)-4-((7a'S,11a'R)-5',6',8',9',11',11a'-hexahydrospiro[cyclopropane-1,4'-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline]-10'(7a'H)-yl)butan-1-one.

[0145] [ka] The synthesis method is similar to that of the compound of Example 8 according to Scheme 2, except that 4-chloro-1-(4-fluorophenyl)butan-1-one is added in place of 1-(3-chloropropoxy)-4-fluorobenzene in Step E. 21% isolated yield. MS (ESI) m / z 405.31 [M+H] + .

[0146] [Example 8] (7a'S,11a'R)-10'-(3-(4-fluorophenoxy)propyl)-5',6',7a',8',9',10',11',11a'-octahydrospiro[cyclopropane-1,4'-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline].

[0147] [ka] Step A: (4aS,9bR)-Ethyl 6-bromo-5-(but-3-en-1-yl)-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate. A mixture of ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (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) was heated at 110 °C for 48 h under an argon atmosphere. The reaction was cooled to room temperature, and the solvent was 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 K2CO3, and concentrated to give a brown oil. This oil is purified by silica gel column chromatography using a gradient of 0-70% ethyl acetate in hexane as eluent. The title compound is obtained as a brown oil (3.6 g, 48% yield). MS (ESI) m / z 379.16 [M+H] + .

[0148] Step B: 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. To a degassed solution of (4aS,9bR)-ethyl 6-bromo-5-(but-3-en-1-yl)-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (850 mg, 2.24 mmol), KCO (1.1 mg, 7.92 mmol), and tricyclohexylphosphine (59 mg, 0.21 mmol) in DMF (6 mL) was added Pd(OAc) (24 mg, 0.11 mmol) under an argon atmosphere. The resulting mixture is stirred at 140° C. for 3 hours. 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 eluent. The title compound is obtained as a beige solid (200 mg, 30% yield). MS (ESI) m / z 299.13 [M+H] + .

[0149] 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. CHCl (600 mg, 2.23 mmol) is added dropwise to a stirred solution of ZnEt (1.5 M in toluene, 0.7 mL, 1.1 mmol) in dichloromethane (0.5 mL) under argon at 0 °C, and the mixture is stirred at 0 °C for 50 min. A 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 (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 to 100% ethyl acetate:methanol:7N NH3 mixture (10:1:0.1 v / v / v) in ethyl acetate as the eluent. The title compound is obtained as a beige solid (75 mg, 43% yield). MS (ESI) m / z 313.14 [M+H] + .

[0150] 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]. (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 (70 g, 0.224 mmol) was suspended in 90% saturated KOH solution in EtOH (0.7 mL) at room temperature and heated with stirring in a microwave oven at 100 °C 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 under high vacuum to give the title compound as a beige solid (70 mg, >100% yield). This crude product is used directly in the next step without further purification. MS (ESI) m / z 241.17 [M+H] + .

[0151] Step E: (7a'S,11a'R)-10'-(3-(4-fluorophenoxy)propyl)-5',6',7a',8',9',10',11',11a'-octahydrospiro[cyclopropane-1,4'-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline]. A mixture of (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] (20 mg, 0.083 mmol), 1-(3-chloropropoxy)-4-fluorobenzene (30 mg, 0.16 mmol), and KI (32 mg, 0.2 mmol) in DMF (0.4 mL) was sparged with argon for 3 min, followed by the addition of DIPEA (0.35 mL, 0.2 mmol). The mixture was stirred at 75 °C for 2 h and then cooled to room temperature. The solvent was removed, and the residue was dissolved in DCM (5 mL) and washed with water (2 mL). The DCM phase was dried over K2CO3, filtered, and the filtrate was concentrated. The residue is purified by HPLC to give the final compound as a pale orange oil (8 mg, 25% yield). MS (ESI) m / z 393.29 [M+H] + .

[0152] [Example 12] (6bR,10aS)-8-(2-(2-(4-fluorophenoxy)ethoxy)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline.

[0153] [ka] The synthesis method is similar to that of the compound of Example 3 according to Scheme 3, with 1-(2-(2-chloroethoxy)ethoxy)-4-fluorobenzene added instead of 3-chloro-1-(4-fluorophenyl)propan-1-one. 19% isolated yield. MS (ESI) m / z 412.2 [M+1] + .

[0154] [Example 13] 1-(4-((4-fluorobenzyl)oxy)phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one.

[0155] [ka] The synthesis method is similar to that of the compound of Example 6 according to Scheme 4, with (4-fluorophenyl)methanol added instead of 2-methoxyethan-1-ol. 68% isolated yield. MS (ESI) m / z 500.3 [M+1] + . 1 H NMR (500 MHz, CDCl3) δ 8.03 - 7.95 (m, 2H), 7.47 - 7.39 (m, 2H), 7.15 - 7.07 (m, 2H), 7.04 - 6.98 (m, 2H), 6.67 (t, J = 7.6 Hz, 1H), 6.53 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 7.9, 0.9 Hz, 1H), 3.62 (ddd, J = 11.3, 9.8, 2.8 Hz, 1H), 3.31 (ddt, J = 18.9, 11.3, 2.9 Hz, 2H), 3.25 - 3.19 (m, 1H), 3.12 (s, 1H), 3.02 - 2.94 (m, 2H), 2.89 (s, 3H), 2.84 (td, J = 9.8, 2.7 Hz, 2H), 2.69 (s, 1H), 2.42 (s, 2H), 2.27 (s, 1H), 1.95 (d, J = 25.3 Hz, 6H), 1.28 (s, 1H), 0.93 - 0.83 (m, 1H).

[0156] [Example 14] 1-(4-Fluorophenyl)-3-((6b'R,10a'S)-3'-methyl-6b',7',10',10a'-tetrahydrospiro[cyclopropane-1,2'-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline]-8'(1'H,3'H,9'H)-yl)propan-1-one.

[0157] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 3-chloro-1-(4-fluorophenyl)propan-1-one is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 63% isolated yield. MS (ESI) m / z 406.32 [M + H] + . 1 H NMR (500 MHz, CDCl3) δ 7.99 (dd, J = 8.9, 5.4 Hz, 2H), 7.13 (dd, J = 8.6, 8.6 Hz, 2H), 6.67 (d, J = 5.9 Hz, 2H), 6.61 (dd, J = 5.8, 3.2 Hz, 1H), 3.35 - 3.26 (m, 1H), 3.17 (s, 3H), 2.90 (t, J = 5.7 Hz, 2H), 2.87 - 2.81 (m, 2H), 2.70 (s, 3H), 2.69 - 2.63 (m, 1H), 2.42 (d, J = 9.9 Hz, 2H), 2.21 (t, J = 11.1 Hz, 1H), 1.96 - 1.85 (m, 2H), 1.26 (t, J = 7.1 Hz, 1H), 1.14 - 1.05 (m, 1H), 0.89 - 0.81 (m, 1H), 0.75 - 0.67 (m, 1H), 0.55 - 0.46 (m, 1H).

[0158] [Example 15] (6b'R,10a'S)-8'-(2-(4-fluorophenoxy)ethyl)-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].

[0159] [ka] Step A: (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. Ethylmagnesium bromide (3.0 M in EtO, 13.6 mL, 10 mmol) was added dropwise to a vigorously stirred solution of (6bR,10aS)-ethyl 3-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate (4.29 g, 13.6 mmol) and titanium isopropoxide (6.1 mL, 20.6 mmol) in THF (40 mL). The solution was stirred at room temperature for 24 h and then quenched with saturated NH4Cl (15 mL). The solvent was removed under reduced pressure, and the residue was suspended in DCM (200 mL) and washed with water (100 mL). The DCM phase is separated, dried over K2CO3, and 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 eluent. The title compound is obtained as a light brown solid (3.12 g, 70% yield). MS (ESI) m / z 328.16 [M+H] + .

[0160] Step B: (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]. (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 (1.71 g, 5.22 mmol) is suspended in saturated KOH solution (17 mL) in 90% EtOH at room temperature, and the reaction is heated with stirring in a microwave at 100 °C for 4 h. The reaction is cooled to room temperature, and then 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 K2CO3, and concentrated. The residue is further dried under high vacuum to give the title compound as a beige solid (1.0 g, 72% yield). This crude product is used directly in the next step without further purification. MS(ESI) m / z 256.17 [M+H] + .

[0161] Step C: (6b'R,10a'S)-8'-(2-(4-fluorophenoxy)ethyl)-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]. A mixture of (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] (300 mg, 1.18 mmol), 1-(2-bromoethoxy)-4-fluorobenzene (309 mg, 1.41 mmol), and KI (195 mg, 1.18 mmol) in DMF (3 mL) was sparged with argon for 3 min, followed by the addition of DIPEA (0.41 mL, 2.35 mmol). The mixture was stirred at 75 °C for 2 h and then cooled to room temperature. The solvent was removed, and the residue was dissolved in DCM (30 mL) and washed with water (20 mL). The DCM phase is dried over K2CO3, filtered, and the filtrate is concentrated. The resulting product is purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate in hexane as the eluent. The final compound is obtained as a light brown oil (338 mg, 73% yield). MS (ESI) m / z 394.25 [M + H] + . 1H NMR (500 MHz, CDCl3) δ 6.96 (dd, J = 9.2, 8.2 Hz, 2H), 6.89 - 6.82 (m, 2H), 6.70 - 6.65 (m, 2H), 6.64 - 6.59 (m, 1H), 4.08 (s, 2H), 3.34 - 3.27 (m, 1H), 3.22 (s, 1H), 2.96 (s, 1H), 2.89 - 2.82 (m, 1H), 2.79 (s, 3H), 2.70 (s, 3H), 2.42 (d, J = 9.9 Hz, 2H), 2.25 (t, J = 10.3 Hz, 1H), 2.01 - 1.86 (m, 2H), 1.61 (s, 1H), 1.16 - 1.05 (m, 1H), 0.90 - 0.83 (m, 1H), 0.76 - 0.67 (m, 1H), 0.56 - 0.47 (m, 1H).

[0162] [Example 16] 1-(4-Fluoro-2-methylphenyl)-3-((6b'R,10a'S)-3'-methyl-6b',9',10',10a'-tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline]-8'(7'H)-yl)propan-1-one.

[0163] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 3-chloro-1-(o-tolyl)propan-1-one is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 30% isolated yield. MS (ESI) m / z 394.28 [M+H] + .

[0164] [Example 17] (6b'R,10a'S)-8'-(2-(4-fluoro-2-methylphenoxy)ethyl)-3'-methyl-6b',7',8',9',10',10a'-hexahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline].

[0165] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 1-(2-chloroethoxy)-2-methylbenzene is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 33% isolated yield. MS (ESI) m / z 408.33 [M+H] + .

[0166] [Example 19] (6b'R,10a'S)-8'-(3-(3-chlorophenyl)propyl)-3'-methyl-6b',7',8',9',10',10a'-hexahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline].

[0167] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 1-(3-bromopropyl)-3-chlorobenzene is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 70% isolated yield. MS (ESI) m / z 408.29 [M+H] + .

[0168] [Example 20] (6b'R,10a'S)-8'-(3-(3-methoxyphenyl)propyl)-3'-methyl-6b',7',8',9',10',10a'-hexahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline].

[0169] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 1-(3-bromopropyl)-3-methoxybenzene is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 70% isolated yield. MS (ESI) m / z 404.35 [M+H] + .

[0170] [Example 21] (6b'R,10a'S)-3'-Methyl-8'-(3-(3-(trifluoromethyl)phenyl)propyl)-6b',7',8',9',10',10a'-hexahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline].

[0171] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 1-(3-bromopropyl)-3-(trifluoromethyl)benzene is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 58% isolated yield. MS (ESI) m / z 442.28 [M+H] + .

[0172] [Example 22] (6b'R,10a'S)-8'-(3-(2-chlorophenyl)propyl)-3'-methyl-6b',7',8',9',10',10a'-hexahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline].

[0173] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 1-(3-bromopropyl)-2-chlorobenzene is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 80% isolated yield. MS (ESI) m / z 408.29 [M+H] + .

[0174] [Example 23] (6b'R,10a'S)-3'-Methyl-8'-(3-(o-tolyl)propyl)-6b',7',8',9',10',10a'-hexahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline].

[0175] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 1-(3-bromopropyl)-2-methylbenzene is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 79% isolated yield. MS (ESI) m / z 388.35 [M+H] + .

[0176] [Example 24] (6b'R,10a'S)-8'-(2-chlorophenethyl)-3'-methyl-6b',7',8',9',10',10a'-hexahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline].

[0177] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 1-(2-bromoethyl)-2-chlorobenzene is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 39% isolated yield. MS (ESI) m / z 394.27 [M+H] + .

[0178] [Example 25] (6b'R,10a'S)-8'-(2-methoxyphenethyl)-3'-methyl-6b',7',8',9',10',10a'-hexahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline].

[0179] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 1-(2-bromoethyl)-2-methoxybenzene is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 66% isolated yield. MS (ESI) m / z 390.32 [M+H] + .

[0180] [Example 26] (6bR,10aS)-8-(2-(4-fluorophenoxy)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0181] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethoxy)-4-fluorobenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 75% isolated yield. 1H NMR (500 MHz, CDCl3) δ 7.03 - 6.92 (m, 2H), 6.89 - 6.79 (m, 2H), 6.66 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 4.07 (td, J = 6.0, 1.2 Hz, 2H), 3.61 (ddd, J = 11.2, 9.9, 3.0 Hz, 1H), 3.32 (dt, J = 9.9, 2.9 Hz, 1H), 3.27 (dt, J = 11.3, 2.9 Hz, 1H), 3.25 - 3.16 (m, 2H), 2.95 (ddd, J = 11.3, 6.0, 1.9 Hz, 1H), 2.87 (s, 3H), 2.85 - 2.81 (m, 1H), 2.81 - 2.69 (m, 3H), 2.41 (dt, J = 11.2, 7.9 Hz, 1H), 2.12 (t, J = 11.0 Hz, 1H), 1.96 (dt, J = 7.3, 4.0 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ157.4 (d, J = 239.4 Hz), 155.1, 138.1, 135.1, 130.1, 120.5, 115.9 (d, J = 37.8Hz), 115.8, 112.8, 109.1, 66.8, 64.5, 57.5, 57.0, 50.8, 49.6, 44.5, 41.8, 37.7, 25.1. HRMS (ESI) m / z C 22 H 26 N3OF [M+H] + Calculated value: 368.2133; Measured value: 368.2138.

[0182] [Example 27] (6bR,10aS)-8-(2-(4-フルオロ-2-メチルフェノキシ)エチル)-3-メチル-2,3,6b,7 ,8,9,10,10a-オクタヒドロ-1H-ピリド[3',4':4,5]ピロロ[1,2,3-de]キノキサリン

[0183] [ka] The synthetic method is similar to Example 71, except that 1-(2-chloroethoxy)-4-fluoro-2-methylbenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 50% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 6.92 - 6.82 (m, 1H), 6.73 (dd, J = 8.9, 4.6 Hz, 1H), 6.66 (t, J = 7.6 Hz, 1H), 6.52 (dd, J = 7.4, 0.9 Hz, 1H), 6.41 (dd, J = 7.9, 0.9 Hz, 1H), 4.08 (td, J = 5.9, 1.2 Hz, 2H), 3.62 (ddd, J = 11.3, 10.0, 3.0 Hz, 1H), 3.32 (dt, J = 10.0, 2.9 Hz, 1H), 3.27 (dt, J = 11.3, 2.9 Hz, 1H), 3.25 - 3.14 (m, 2H), 3.03 - 2.95 (m, 1H), 2.87 (s, 2H), 2.86 - 2.74 (m, 3H), 2.56 - 2.36 (m, 1H), 2.20 (s, 2H), 2.16 (t, J = 11.1 Hz, 1H), 2.01 - 1.85 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 157.1 (d, J = 239.4 Hz), 153.3, 138.1, 135.1, 130.1, 128.9 (d, J = 2.5 Hz), 120.5, 117.4 (d, J = 25.2 Hz), 112.8, 112.4 (d, J = 25.2 Hz), 112.2 (d, J = 12.6 Hz), 109.0, 67.4, 64.4, 57.6, 57.1, 50.8, 49.7, 44.5, 41.9, 37.7, 25.2, 16.6. HRMS (ESI) m / z C 23 H 28 N3OF [M+H] + Calculated value: 382.2289; Measured value: 382.2292.

[0184] [Example 28] (6bR,10aS)-8-(3-(2-methoxyphenyl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0185] [ka] The synthetic method is similar to Example 71, except that 1-(3-chloropropyl)-2-methoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 69% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.21 - 7.07 (m, 2H), 6.94 - 6.78 (m, 2H), 6.65 (t, J = 7.6 Hz, 1H), 6.52 (dd, J = 7.5, 0.9 Hz, 1H), 6.40 (dd, J = 8.1, 0.9 Hz, 1H), 3.81 (s, 3H), 3.60 (ddd, J = 11.2, 9.9, 3.0 Hz, 1H), 3.31 (dt, J = 10.0, 2.9 Hz, 1H), 3.26 (dt, J = 11.3, 2.9 Hz, 1H), 3.24 - 3.21 (m, 1H), 3.20 - 3.13 (m, 1H), 2.96 - 2.88 (m, 1H), 2.87 (s, 3H), 2.83 (td, J = 9.9, 2.9 Hz, 1H), 2.75 - 2.66 (m, 1H), 2.65 - 2.56 (m, 2H), 2.51 - 2.32 (m, 2H), 2.28 - 2.19 (m, 1H), 2.09 - 1.89 (m, 3H), 1.86 - 1.69 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 157.6, 138.2, 135.1, 130.8, 130.3, 129.9, 127.1, 120.4, 120.4, 112.8, 110.3, 109.0, 64.8, 58.7, 56.5, 55.3, 50.8, 49.2, 44.5, 41.9, 37.7, 28.4, 27.2, 25.2. HRMS (ESI) m / z C 24 H 31 NO [M+H] + Calculated value: 378.2540; Measured value: 378.2533.

[0186] [Example 29] (6bR,10aS)-8-(3-(3-methoxyphenyl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0187] [ka] The synthetic method is similar to Example 71, except that 1-(3-bromopropyl)-3-methoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 73% isolated yield. 1H NMR (500 MHz, CDCl3) δ 7.19 (td, J = 7.7, 0.7 Hz, 1H), 6.78 (d, J = 1.2 Hz, 1H), 6.76 - 6.70 (m, 2H), 6.65 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 1.0 Hz, 1H), 6.40 (dd, J = 7.9, 0.9 Hz, 1H), 3.80 (s, 3H), 3.69 - 3.48 (m, 1H), 3.31 (dt, J = 9.9, 2.9 Hz, 1H), 3.26 (dt, J = 11.3, 2.9Hz, 1H), 3.26 - 3.19 (m, 1H), 3.20 - 3.13 (m, 1H), 2.90 - 2.87 (m, 1H), 2.87 (s, 3H), 2.82 (td, J = 9.9, 2.8 Hz, 1H), 2.73 - 2.64 (m, 1H), 2.61 (t, J = 6.8 Hz, 2H), 2.48 - 2.29 (m, 2H), 2.28 - 2.18 (m, 1H), 2.14 - 1.91 (m, 3H), 1.85 - 1.74 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 159.7, 144.1, 138.1, 135.1, 130.3, 129.4, 121.0, 120.4, 114.3, 112.8, 111.2, 109.0, 64.7, 58.4, 56.5, 55.3, 50.8, 49.2, 44.5, 41.9, 37.7, 34.0, 28.7, 25.2. HRMS (ESI) m / z C 24 H 31 Calculated for NO [M+H]: 378.2540; Found: 378.2529.

[0188] [Example 30] (6bR,10aS)-8-(3-(3-chlorophenyl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0189] [ka] The synthetic method is similar to Example 71, except that 1-(3-bromopropyl)-3-chlorobenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 72% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.24 - 7.17 (m, 2H), 7.17 - 7.12 (m, 1H), 7.10 - 7.01 (m, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.52 (dd, J = 7.4, 0.9 Hz, 1H), 6.41 (dd, J = 7.9, 0.9 Hz, 1H), 3.68 - 3.53 (m, 1H), 3.31 (dt, J = 9.9, 2.9 Hz, 1H), 3.27 (dt, J = 11.3, 2.9 Hz, 1H), 3.25 - 3.21 (m, 1H), 3.20 - 3.12 (m, 1H), 2.87 (s, 3H), 2.86 - 2.75 (m, 1H), 2.72 - 2.52 (m, 3H), 2.42 - 2.27 (m, 2H), 2.28 - 2.17 (m, 1H), 2.15 - 1.88 (m, 3H), 1.85 - 1.75 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 144.5, 138.1, 135.1, 134.2, 130.2, 129.7, 128.7, 126.7, 126.0, 120.4, 112.8, 109.0, 64.7, 58.1, 56.5, 50.8, 49.2, 44.5, 41.9, 37.7, 33.6, 28.6, 25.2. HRMS (ESI) m / z C 23 H 28 ClN3[M+H] + Calculated value: 382.2045; Measured value: 382.2037.

[0190] [Example 31] (6bR,10aS)-8-(3-(2-chlorophenyl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0191] [ka] The synthetic method is similar to Example 71, except that 1-(3-bromopropyl)-2-chlorobenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 75% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.33 (dd, J = 7.8, 1.4 Hz, 1H), 7.22 (dd, J = 7.5, 1.9 Hz, 1H), 7.17 (td, J = 7.4, 1.4 Hz, 1H), 7.12 (td, J = 7.6, 1.9 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.52 (dd, J = 7.4, 0.9 Hz, 1H), 6.40 (dd, J = 7.9, 1.0 Hz, 1H), 3.66 - 3.54 (m, 1H), 3.31 (dt, J = 9.9, 2.9Hz, 1H), 3.27 (dt, J = 11.3, 2.9 Hz, 1H), 3.25 - 3.20 (m, 1H), 3.20 - 3.12 (m, 1H), 2.92 - 2.88 (m, 1H), 2.87 (s, 3H), 2.83 (td, J = 9.9, 2.9 Hz, 1H), 2.79 - 2.71 (m, 2H), 2.71 - 2.63 (m, 1H), 2.53 - 2.31 (m, 2H), 2.30 - 2.17 (m, 1H), 2.12 - 1.91 (m, 3H), 1.88 - 1.75 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 140.0, 138.1, 135.1, 134.1, 130.5, 130.3, 129.6, 127.4, 126.8, 120.4, 112.8, 109.0, 64.8, 58.3, 56.5, 50.8, 49.2, 44.5, 41.9, 37.7, 31.7, 27.2, 25.2. HRMS (ESI) m / z C 23 H 28 ClN3[M+H] + Calculated value: 382.2045; Measured value: 382.2038.

[0192] [Example 32] (6bR,10aS)-3-Methyl-8-(3-(3-(trifluoromethyl)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0193] [ka] The synthetic method is similar to Example 71, except that 1-(3-bromopropyl)-3-(trifluoromethyl)benzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 88% isolated yield. 1H NMR (500 MHz, CDCl3) δ 7.52 - 7.41 (m, 2H), 7.41 - 7.30 (m, 2H), 6.65 (t, J = 7.6 Hz, 1H), 6.52 (dd, J = 7.3, 0.9 Hz, 1H), 6.41 (dd, J = 8.0, 0.9 Hz, 1H), 3.67 - 3.54 (m, 1H), 3.31 (dt, J = 9.9, 3.0 Hz, 1H), 3.27 (dt, J = 11.3, 2.9 Hz, 1H), 3.25 - 3.20 (m, 1H), 3.20 - 3.12 (m, 1H), 2.87 (s, 3H), 2.86 - 2.79 (m, 2H), 2.70 (t, J = 6.8 Hz, 2H), 2.67 - 2.61 (m, 1H), 2.44 - 2.30 (m, 2H), 2.24 (td, J = 10.9, 4.5 Hz, 1H), 2.11 - 1.90 (m, 3H), 1.85 (p, J = 7.6 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 143.3, 138.1, 135.1, 132.0, 130.7 (q, J = 32.8), 130.2, 128.8, 125.3 (q, J = 3.8 Hz), 124.4 (q, J = 277.2 Hz), HRMS (ESI) m / z C 24 H 28 F3N3[M+H] + Calculated value: 416.2308; Measured value: 416.2298.

[0194] [Example 33] (6bR,10aS)-8-(2-クロロフェネチル)-3-メチル-2,3,6b,7,8,9,10 ,10a-オクタヒドロ-1H-ピリド[3',4':4,5]ピロロ[1,2,3-de]キノキサリン

[0195] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-2-chlorobenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 46% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.32 (dd, J = 7.7, 1.5 Hz, 1H), 7.23 (dd, J = 7.5, 1.9 Hz, 1H), 7.18 (td, J = 7.4, 1.5 Hz, 1H), 7.13 (td, J = 7.5, 1.9 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.55 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 8.0, 0.9 Hz, 1H), 3.68 - 3.55 (m, 1H), 3.33 (dt, J = 10.0, 3.0Hz, 1H), 3.30 - 3.15 (m, 3H), 3.10 - 2.91 (m, 3H), 2.87 (s, 3H), 2.84 (td, J = 10.0, 2.9 Hz, 1H), 2.80 - 2.73 (m, 1H), 2.69 - 2.49 (m, 2H), 2.44 - 2.30 (m, 1H), 2.10 (t, J = 11.1 Hz, 1H), 2.04 - 1.92 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 138.2, 138.2, 135.1, 134.2, 131.0, 130.2, 129.6, 127.6, 127.0, 120.4, 112.9, 109.1, 64.7, 58.7, 56.4, 50.8, 49.1, 44.5, 42.0, 37.7, 31.4, 25.2. HRMS (ESI) m / z C 22 H 26 ClN3[M+H] + Calculated value: 368.1888; Measured value: 368.1879.

[0196] [Example 34] (6bR,10aS)-8-(2-methoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0197] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-2-methoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 88% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.18 (td, J = 7.8, 1.7 Hz, 1H), 7.14 (dd, J = 7.4, 1.8 Hz, 1H), 6.87 (td, J = 7.4, 1.1 Hz, 1H), 6.83 (dd, J = 8.2, 1.1 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.56 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 8.0, 0.9 Hz, 1H), 3.80 (s, 3H), 3.71 - 3.53 (m, 1H), 3.33 (dt, J = 10.0, 2.9 Hz, 1H), 3.31 - 3.15 (m, 3H), 3.11 - 2.98 (m, 1H), 2.88 (s, 3H), 2.87 - 2.71 (m, 4H), 2.71 - 2.48 (m, 2H), 2.44 - 2.29 (m, 1H), 2.06 (t, J = 10.7 Hz, 1H), 2.02 - 1.92 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 157.7, 138.2, 135.1, 130.4, 130.4, 129.0, 127.4, 120.5, 120.4, 112.9, 110.4, 109.0, 64.8, 59.1, 56.4, 55.4, 50.8, 49.1, 44.5, 42.0, 37.7, 28.1, 25.3. HRMS (ESI) m / z C 23 H 29NO [M+H] + Calculated value: 364.2383; Measured value: 364.2375.

[0198] [Example 35] (6bR,10aS)-3-Methyl-8-(3-(o-tolyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0199] [ka] The synthesis method is similar to Example 71, except that 1-(3-bromopropyl)-2-methylbenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 81% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.18 - 7.01 (m, 4H), 6.65 (t, J = 7.6 Hz, 1H), 6.52 (dd, J = 7.3, 0.9 Hz, 1H), 6.41 (dd, J = 7.9, 0.9 Hz, 1H), 3.68 - 3.51 (m, 1H), 3.32 (dt, J = 9.9, 2.9 Hz, 1H), 3.27 (dt, J = 11.3, 2.9 Hz, 1H), 3.25 - 3.21 (m, 1H), 3.20 - 3.13 (m, 1H), 2.96 - 2.88 (m, 1H), 2.87 (s, 3H), 2.83 (td, J = 9.9, 2.8 Hz, 1H), 2.73 - 2.66 (m, 1H), 2.68 - 2.57 (m, 2H), 2.51 - 2.34 (m, 2H), 2.31 (s, 3H), 2.28 - 2.19 (m, 1H), 2.07 - 1.90 (m, 3H), 1.85 - 1.70 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 140.6, 138.1, 136.0, 135.1, 130.3, 128.9, 126.0, 126.0, 120.4, 112.8, 109.0, 64.7, 58.7, 56.6, 50.8, 49.2, 44.5, 41.9, 37.7, 31.2, 27.7, 25.2, 19.4. HRMS (ESI) m / z C 24 H 31 N3[M+H] + Calculated value: 362.2591; Measured value: 362.2582.

[0200] [Example 36] 1-(4-Fluorophenyl)-3-((8aS,12aR)-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indol-11(8aH)-yl)propan-1-one

[0201] [ka] The synthetic method is similar to Example 71, using 3-chloro-1-(4-fluorophenyl)propan-1-one and (8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole in Step D. 46% isolated yield. 1H NMR (500 MHz, CDCl3) δ 8.18 - 7.86 (m, 1H), 7.19 - 7.05 (m, 1H), 6.92 (ddd, J = 12.4, 7.4, 1.3 Hz, 1H), 6.68 (t, J = 7.4 Hz, 0H), 3.32 - 3.22 (m, 2H), 3.21 - 3.18 (m, 1H), 3.17 - 3.10 (m, 1H), 2.94 - 2.87 (m, 1H), 2.86 - 2.73 (m, 3H), 2.73 - 2.61 (m, 2H), 2.49 (td, J = 12.1, 2.0 Hz, 1H), 2.37 (td, J = 11.8, 2.9 Hz, 1H), 2.15 - 1.95 (m, 3H), 1.94 - 1.84 (m, 2H), 1.81 - 1.71 (m, 1H), 1.67 - 1.49 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 197.8, 165.9 (d, J = 252 Hz), 152.9, 133.6 (d, J = 2.5 Hz), 133.4, 130.9 (d, J = 12.6 Hz), 129.7, 127.4, 121.1, 119.4, 115.8 (d, J = 25.2 Hz), 64.1, 57.4, 53.5, 52.0, 49.4, 41.1, 36.4, 35.4, 30.2, 27.3, 26.0. HRMS (ESI) m / z C 24 H 27 FN2O [M+H] + Calculated value: 379.2180; Measured value: 379.2170.

[0202] [Example 37] (8aS,12aR)-11-(2-(4-フルオロフェノキシ)エチル)-4,5,6,7,8a,9 ,10,11,12,12a-デカヒドロアゼピノ[3,2,1-hi]ピリド[4,3-b]インドール

[0203]

change

[0204] [Example 38] (8aS,12aR)-11-(2-Methoxyphenethyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole

[0205] [ka] The synthetic method is similar to Example 71, using 1-(2-bromoethyl)-2-methoxybenzene and (8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole in Step D. 83% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.18 (td, J = 7.7, 1.8 Hz, 1H), 7.13 (dd, J = 7.4, 1.8 Hz, 1H), 6.97 (dd, J = 7.3, 1.3 Hz, 1H), 6.92 (dd, J = 7.5, 1.2 Hz, 1H), 6.87 (td, J = 7.4, 1.1 Hz, 1H), 6.83 (dd, J = 8.2, 1.1 Hz, 1H), 6.70 (t, J = 7.4 Hz, 1H), 3.80 (s, 3H), 3.46 - 3.25 (m, 2H), 3.24 - 3.16 (m, 1H), 3.06 - 2.88 (m, 2H), 2.86 - 2.74 (m, 3H), 2.73 - 2.62 (m, 1H), 2.59 - 2.44 (m, 3H), 2.35 (td, J = 11.7, 3.2 Hz, 1H), 2.17 - 1.93 (m, 4H), 1.85 (t, J = 11.2 Hz, 1H), 1.82 - 1.71 (m, 1H), 1.65 - 1.48 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 157.7, 153.0, 133.7, 130.4, 129.6, 129.0, 127.4, 127.3, 121.2, 120.5, 119.4, 110.4, 64.3, 59.1, 57.4, 55.4, 52.0, 49.4, 41.2, 35.4, 30.2, 28.2, 27.3, 26.0. HRMS (ESI) m / z C 24 H 30 NO [M+H] +Calculated value: 363.2431; Measured value: 363.2421.

[0206] [Example 39] (6b'R,10a'S)-8'-(3-(2-methoxyphenyl)propyl)-3'-methyl-6b',7',8',9',10',10a'-hexahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline].

[0207] [ka] The synthesis method is similar to that of the compound of Example 15 according to Scheme 1, except that 1-(3-chloropropyl)-2-methoxybenzene is added in place of 1-(2-bromoethoxy)-4-fluorobenzene in Step C. 76% isolated yield. MS (ESI) m / z 404.36 [M+H] + .

[0208] [Example 41] 1-(4-Fluoro-2-methylphenyl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propan-1-one

[0209] [ka] The synthesis method is similar to Example 71, except that 3-chloro-1-(4-fluoro-2-methylphenyl)propan-1-one is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 27% isolated yield. 1H NMR (500 MHz, CDCl3) δ 7.78 - 7.60 (m, 1H), 7.05 - 6.82 (m, 2H), 6.76 - 6.58 (m, 1H), 6.50 (dd, J = 7.4, 0.9 Hz, 1H), 6.40 (dd, J = 8.0, 0.9 Hz, 1H), 3.60 (ddd, J = 11.3, 9.9, 2.9 Hz, 1H), 3.43 - 3.24 (m, 2H), 3.23 - 3.17 (m, 1H), 3.17 - 2.99 (m, 3H), 2.87 (s, 3H), 2.86 - 2.70 (m, 4H), 2.69 - 2.61 (m, 1H), 2.50 (s, 3H), 2.33 (td, J = 11.6, 3.4 Hz, 1H), 2.04 (t, J = 11.1 Hz, 1H), 1.99 - 1.80 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 202.2, 164.0 (d, J = 253.3 Hz), 142.2 (d, J = 8.8 Hz), 138.1, 135.1, 134.3 (d, J = 3.8 Hz), 131.0 (d, J = 8.8 Hz), 130.0, 120.5, 118.8 (d, J = 21.4 Hz), 112.8, 112.6 (d, J = 21.4 Hz), 109.1, 64.6, 56.4, 53.8, 50.8, 49.1, 44.5, 41.9, 39.3, 37.7, 25.2, 21.7. HRMS (ESI) m / z C 24 H 28 FN3O [M+H] + Calculated value: 394.2289; Measured value: 394.2284.

[0210] [Example 42] (8aS,12aR)-11-(2-(4-フルオロフェノキシ)エチル)-6,7,8a,9,10,11,1 2,12a-オクタヒドロ-5H-[1,4]オキサゼピノ[2,3,4-hi]ピリド[4,3-b]インドール

[0211] [ka] The synthetic method is similar to Example 71, using 1-(2-bromoethoxy)-4-fluorobenzene and (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-[1,4]oxazepino[2,3,4-hi]pyrido[4,3-b]indole in Step D. 45% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.01 - 6.92 (m, 2H), 6.90 - 6.83 (m, 2H), 6.81 - 6.75 (m, 2H), 6.75 - 6.66 (m, 1H), 4.56 - 4.35 (m, 1H), 4.06 (t, J = 5.9 Hz, 1H), 3.94 - 3.69 (m, 1H), 3.44 - 3.34 (m, 0H), 3.34 - 3.28 (m, 1H), 3.27 - 3.22 (m, 1H), 3.03 - 2.84 (m, 1H), 2.84 - 2.64 (m, 3H), 2.62 - 2.49 (m, 1H), 2.40 (td, J = 11.6, 3.3 Hz, 1H), 2.24 - 1.78 (m, 5H). 13 C NMR (126 MHz, CDCl3) δ 157.5 (d, J = 239.4 Hz), 155.1, 146.7, 142.9, 135.5, 120.6, 119.6, 117.7, 115.9 (d, J = 37.8 Hz), 115.8, 72.0, 66.8, 64.1, 57.7, 57.5, 50.3, 49.7, 41.5, 31.1, 25.5. HRMS (ESI) m / z C 22 H 25 N2O2F [M+H] + Calculated value: 369.1973; Measured value: 369.1965.

[0212] [Example 43] 1-(4-Fluorophenyl)-3-((8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-[1,4]oxazepino[2,3,4-hi]pyrido[4,3-b]indol-11(8aH)-yl)propan-1-one

[0213] [ka] The synthetic method is similar to Example 71, using 3-chloro-1-(4-fluorophenyl)propan-1-one and (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-[1,4]oxazepino[2,3,4-hi]pyrido[4,3-b]indole in Step D. 44% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 8.09 - 7.90 (m, 1H), 7.20 - 7.02 (m, 1H), 6.88 - 6.73 (m, 1H), 6.73 - 6.60 (m, 1H), 4.59 - 4.29 (m, 1H), 3.97 - 3.65 (m, 1H), 3.49 - 3.31 (m, 1H), 3.33 - 3.20 (m, 2H), 3.20 - 3.06 (m, 2H), 2.93 - 2.73 (m, 3H), 2.72 - 2.64 (m, 1H), 2.61 - 2.48 (m, 1H), 2.46 - 2.31 (m, 1H), 2.18 - 2.00 (m, 3H), 1.95 - 1.81 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 197.7, 165.9 (d, J = 252 Hz), 146.8, 142.9, 135.5, 133.6 (d, J = 3.8 Hz), 130.9 (d, J = 12.6 Hz), 120.6, 119.6, 117.7, 115.9 (d, J = 12.6 Hz), 72.0, 64.2, 57.1, 53.4, 50.3, 49.2, 41.6, 36.3, 31.1, 25.6.HRMS (ESI) m / z 23 H 25N2O2F [M+H] + Calculated value: 381.1973; Measured value: 381.1967.

[0214] [Example 44] 1-(4-Fluorophenyl)-3-((8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indol-11(8aH)-yl)propan-1-one

[0215] [ka] The synthetic method is similar to Example 71, using 3-chloro-1-(4-fluorophenyl)propan-1-one and (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole in Step D. 25% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 8.08 - 7.91 (m, 2H), 7.18 - 7.04 (m, 2H), 6.95 (dd, J = 7.8, 1.2 Hz, 1H), 6.89 - 6.82 (m, 1H), 6.68 - 6.52 (m, 1H), 3.88 - 3.73 (m, 1H), 3.67 - 3.48 (m, 1H), 3.33 - 3.24 (m, 1H), 3.20 - 3.11 (m, 3H), 3.09 - 3.03 (m, 1H), 3.00 - 2.90 (m, 1H), 2.87 - 2.73 (m, 3H), 2.69 - 2.63 (m, 1H), 2.37 (td, J = 11.4, 3.3 Hz, 1H), 2.23 - 2.07 (m, 1H), 2.06 - 1.96 (m, 2H), 1.94 - 1.79 (m, 2H). 13C NMR (126 MHz, CDCl3) δ197.7, 165.9 (d, J = 252 Hz), 152.3, 133.7, 133.6 (d, J = 2.5 Hz), 130.9 (d, J = 12.6 Hz), 129.0, 121.3, 119.9, 119.8, 115.9 (d, J = 12.6 Hz), 63.9, 56.7, 53.5, 49.3, 47.3, 41.0, 36.4, 32.1, 30.6, 25.8. HRMS (ESI) m / z C 23 H 25 N2OFS [M+H] + Calculated value: 397.1744; Measured value: 397.1738.

[0216] [Example 45] 1-(4-Fluorophenyl)-3-((7aS,11aR)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinolin-10(7aH)-yl)propan-1-one

[0217] [ka] The synthetic method is similar to Example 71, using 3-chloro-1-(4-fluorophenyl)propan-1-one and (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline in Step D. 30% isolated yield. 1H NMR (500 MHz, CDCl3) δ 8.12 - 7.84 (m, 2H), 7.19 - 7.05 (m, 2H), 7.01 - 6.80 (m, 2H), 6.63 (t, J = 7.4 Hz, 1H), 3.43 - 3.23 (m, 2H), 3.21 - 3.09 (m, 3H), 3.01 - 2.75 (m, 3H), 2.75 - 2.61 (m, 3H), 2.53 (td, J = 10.2, 3.6 Hz, 1H), 2.38 (td, J = 11.7, 3.2 Hz, 1H), 2.24 - 2.04 (m, 3H), 2.03 - 1.96 (m, 1H), 1.95 - 1.85 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 197.8, 165.9 (d, J= 252 Hz), 149.8,133.6 (d, J = 25.2 Hz), 131.0, 130.9 (d, J = 12.6 Hz), 126.9, 121.0, 120.6, 118.7, 115.8 (d, J = 25.2 Hz), 64.0, 56.3, 53.5, 49.1, 44.7, 41.1, 36.4, 25.1, 24.3, 23.2. HRMS (ESI) m / z C 23 H 25 N2OF [M+H] + Calculated value: 365.2024; Measured value: 365.2019.

[0218] [Example 46] 1-(4-Fluorophenyl)-3-((6bR,10aS)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indol-8(7H)-yl)propan-1-one

[0219] [ka] The synthetic method is similar to Example 71, using 3-chloro-1-(4-fluorophenyl)propan-1-one and (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole in Step D. 29% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 8.06 - 7.93 (m, 2H), 7.19 - 7.06 (m, 2H), 6.96 - 6.75 (m, 2H), 6.64 (t, J = 7.5 Hz, 1H), 3.68 - 3.54 (m, 1H), 3.53 - 3.44 (m, 1H), 3.38 - 3.32 (m, 1H), 3.23 - 3.12 (m, 3H), 3.09 - 3.03 (m, 1H), 3.01 - 2.90 (m, 1H), 2.89 - 2.74 (m, 3H), 2.71 - 2.57 (m, 1H), 2.33 (td, J = 11.4, 3.3 Hz, 1H), 2.06 (t, J = 11.0 Hz, 1H), 2.01 - 1.88 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 197.7, 165.9 (d, J = 252 Hz), 145.1, 133.6 (d, J = 12.6 Hz), 131.7, 130.9 (d, J = 12.6 Hz), 124.4 (d, J = 12.6 Hz), 119.9, 119.7, 116.3, 115.9 (d. 22 H 23 N2OFS [M+H] + Calculated value: 383.1588; Measured value: 383.1582.

[0220] [Example 71] (6bR,10aS)-8-(3-methoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0221] [ka] Step A: (6bR,10aS)-Ethyl 3-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate. A suspension of ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (25 g, 76.9 mmol), N-methylchloroacetamide (12.4 g, 115.3 mmol, 1.5 eq.), potassium iodide (19.2 g, 116 mmol), and diisopropylethylamine (26.6 mL, 153.1 mmol, 2.0 eq.) in dioxane (63 mL) is refluxed for 48 h. The reaction mixture is then cooled to approximately 80 °C, at which point copper iodide (2.92 g, 15.4 mmol, 0.2 eq.), potassium carbonate (23.3 g, 168.2 mmol, 2.2 eq.), dimethylethylenediamine (4.96 mL, 46.1 mmol, 0.6 eq.), and additional dioxane (38 mL) are added. The resulting mixture is reheated to reflux for 24 h, and then it is cooled to 40 °C. The cooled mixture is poured onto a plug of flash-grade silica gel (63 g) and eluted under vacuum with 6.25 L of ethyl acetate. The eluent is concentrated to a solid residue (320 g) and then redissolved in hot ethanol (80 mL). The mixture is cooled to ambient temperature and stirred overnight, then cooled to 0-5 °C, aged for 1 h, and filtered. The filter cake is washed with cold ethanol (15 ml) and air dried to give the title compound (17.0 g, 70% yield) as a white solid. 1HNMR (300MHz, CDCl3) 1.28(t, J = 6.9Hz, 3H), 1.86-1.96(m, 2H), 2.72(br, 1H), 3.09-3.48(m, 7H), 3.86-4.21(m, 5H), 6.75(dd, J = 1.2, MS (ESI) m / z 316.2 [M + H] + .

[0222] Step B: (6bR,10aS)-ethyl 3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxaline-8(9H)-carboxylate. To a suspension of (6bR,10aS)-ethyl 3-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate (21.8 g, 69.13 mmol) in 50 mL of THF was slowly added a 1 M solution of BH3-THF complex in THF (196 mL, 196.2 mmol, 2.8 eq.) through an addition funnel at room temperature under argon. The resulting clear solution is stirred at 60°C for 20 hours, then it is cooled to about 10°C in an ice bath. MeOH (33 mL) is slowly added to the cooled mixture through an addition funnel, maintaining the internal temperature below 25°C. The resulting mixture is stirred in an ice bath for about 30 minutes, then it is concentrated in vacuo to give a yellow paste. The crude paste is then partitioned between EtOAc (218 mL) and water (218 mL). The separated organic layer is dried (NaSO), filtered, and concentrated under reduced pressure to give the title compound (20.76 g, 99% yield) as a yellow liquid. 1HNMR (CDCI3, 300 MHz) δ 1.28 (t, J = 7.0Hz, 3H), 1.79-1.95 (m, 2H), 2.74-2.92 (m, 5H), 3.02-3.22 (m, 2H), 3.22-3.38 (m, 3H), 3.54-3.64 (m, 1H), 3.78-4.24 (m, 4H), 6.41(d, J = 7.8Hz, 1H), 6.54 (d, J = 7.2Hz, 1H), 6.66 (t, J = 7.7Hz, 1H); 13 CNMR (CDCl3, 75 MHz) δ 14.9, 24.7, 37.7, 39.9, 41.4, 44.4, 45.8, 50.7, 61.4, 65.0, 109.3, 113.3, 120.6, 128.8, 135.1, 138.2, 155.6.

[0223] Step C: (6bR,10aS)-3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxaline: (6bR,10aS)-Ethyl 3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxaline-8(9H)-carboxylate (18.5 g, 57 mmol), KOH (12.7 g, 226 mmol), and n-butanol (90 mL) were placed in a 300 mL pressure bottle and heated to 120 °C in an oil bath for 3 h. After removing n-butanol under vacuum, the residue is treated with water (300 mL) and then extracted with CHCl (3 × 100 mL). The combined organic phases are washed with brine (2 × 200 mL), dried over anhydrous NaSO, and then evaporated to dryness to give the title compound (11.7 g, 91% yield) as a thick oil, which is used in the next step without further purification.

[0224] Step D: (6bR,10aS)-8-(3-methoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline: Bubble argon into a mixture of (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxaline hydrochloride (266 mg, 1.0 mmol), 1-(2-bromoethyl)-3-methoxybenzene (323 mg, 1.5 mmol), and KCO (415 mg, 3.0 mmol) in dioxane (1.5 mL) for 3 min. The resulting mixture is heated to 80 °C and stirred at this temperature for 24 h. The solvent is removed, and the residue is dissolved in DCM (30 mL) and washed with water (20 mL). The DCM phase is dried over K2CO3, filtered, and concentrated. The resulting residue is purified by silica gel column chromatography using a gradient of 0-55% ethyl acetate:methanol:7N NH3 mixture in methanol (10:1:0.1 v / v / v) in ethyl acetate as the eluent. The title compound is obtained as a pale orange oil (200 mg, 55% yield). 1 HNMR (500 MHz, CDCl3) δ 7.23 - 7.15 (m, 1H), 6.78 (dt, J = 7.3, 1.2 Hz, 1H), 6.74 (dd, J = 6.5, 1.2 Hz, 2H), 6.67 (t, J = 7.6 Hz, 1H), 6.54 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 7.9, 1.0 Hz, 1H), 3.79 (s, 3H), 3.69 - 3.51 (m, 1H), 3.32 (dt, J = 10.0, 2.9 Hz, 1H), 3.29 - 3.22 (m, 2H), 3.22 - 3.15 (m, 1H), 3.11 - 2.93 (m, 1H), 2.87 (s, 3H), 2.86 - 2.73 (m, 4H), 2.60 (q, J = 11.2 Hz, 2H), 2.35 (s, 1H), 2.22 - 2.02 (m, 1H), 1.98 (s, 2H). 13CNMR (126 MHz, CDCl3) δ 159.8, 142.3, 138.1, 135.2, 130.2, 129.5, 121.3, 120.5, 114.6, 112.8, 111.4, 109.1, 64.7, 60.8, 56.4, 55.3, 50.8, 49.2, 44.5, 41.9, 37.7, 33.8, 25.2. HRMS (ESI) m / z C 23 H 29 NO [M+H] + Calculated value: 364.2383; Measured value: 364.2391.

[0225] [Example 75] 2-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]-quinoxalin-8(7H)-yl)ethyl)benzonitrile

[0226] [ka] The synthetic method is similar to Example 71, except that 2-(2-bromoethyl)benzonitrile is added in place of 1-(2-bromoethyl)-3-methoxybenzene in Step D. 52% isolated yield. 1H NMR (500 MHz, CDCl3) δ 7.60 (dd, J = 7.7, 1.4 Hz, 1H), 7.51 (td, J = 7.6, 1.4 Hz, 1H), 7.34 (dd, J = 7.9, 1.2 Hz, 1H), 7.29 (td, J = 7.6, 1.2 Hz, 1H), 6.66 (t, J = 7.7 Hz, 1H), 6.53 (d, J = 7.3 Hz, 1H), 6.41 (dd, J = 8.0, 0.9 Hz, 1H), 3.69 - 3.49 (m, 1H), 3.44 - 3.21 (m, 3H), 3.20 - 3.13 (m, 1H), 3.13 - 3.01 (m, 2H), 3.00 - 2.90 (m, 1H), 2.87 (s, 3H), 2.85 - 2.73 (m, 1H), 2.73 - 2.59 (m, 2H), 2.41 (td, J = 11.3, 3.8 Hz, 1H), 2.13 (t, J = 11.1 Hz, 1H), 2.00 - 1.86 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ144.7, 138.2, 135.1, 132.9, 132.9, 130.1, 130.1, 126.7, 120.4, 118.2, 112.9, 112.8, 109.1, 64.6, 59.5, 56.4, 50.8, 48.8, 44.5, 41.9, 37.7, 32.2, 25.2. HRMS (ESI) m / z C 23 H 26 N4[M+H] + Calculated value: 359.223; Measured value: 359.2226.

[0227] [Example 76] 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)benzonitrile

[0228] [ka] The synthetic method is similar to Example 71, except that 2-(3-bromopropyl)benzonitrile is added in place of 1-(2-bromoethyl)-3-methoxybenzene in Step D. 68% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.60 (dd, J = 7.7, 1.4 Hz, 1H), 7.50 (td, J = 7.7, 1.4 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.31 - 7.26 (m, 1H), 6.64 (t, J = 7.6 Hz, 1H), 6.57 - 6.49 (m, 1H), 6.40 (dd, J = 7.9, 0.9 Hz, 1H), 3.64 - 3.53 (m, 1H), 3.30 (dt, J = 9.9, 2.9 Hz, 1H), 3.26 (dt, J = 11.3, 2.9 Hz, 1H), 3.24 - 3.19 (m, 1H), 3.19 - 3.11 (m, 1H), 2.96 (s, 1H), 2.93 - 2.87 (m, 2H), 2.86 (s, 3H), 2.85 - 2.79 (m, 1H), 2.73 - 2.60 (m, 1H), 2.53 - 2.32 (m, 2H), 2.31 - 2.17 (m, 1H), 2.10 - 1.82 (m, 5H). 13 C NMR (126 MHz, CDCl3) δ 146.5, 138.1, 135.1, 132.9, 132.8, 129.7, 126.5, 120.4, 118.2, 112.8, 112.5, 109.0, 64.7, 57.9, 56.5, 50.8, 49.1, 44.5, 41.9, 37.7, 36.6, 32.5, 28.2, 25.2. HRMS (ESI) m / z C 24 H 28 N4[M+H] + Calculated value: 373.2387; Measured value: 373.2382.

[0229] [Example 77] 1-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)ethyl)pyridin-2(1H)-one

[0230] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)pyridin-2(1H)-one is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 9% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.38 (dd, J = 6.9, 2.0 Hz, 1H), 7.31 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 6.64 (t, J = 7.6 Hz, 1H), 6.53 (dt, J = 9.1, 1.0 Hz, 1H), 6.48 (d, J = 7.3 Hz, 1H), 6.39 (dd, J = 8.0, 0.9 Hz, 1H), 6.14 (td, J = 6.7, 1.4 Hz, 1H), 3.58 (ddd, J = 12.8, 8.3, 2.3 Hz, 1H), 3.31 - 3.24 (m, 2H), 3.23 - 3.15 (m, 4H), 2.92 (td, J = 11.1, 7.7 Hz, 1H), 2.85 (s, 3H), 2.84 - 2.67 (m, 4H), 2.49 (q, J = 9.5 Hz, 1H), 2.20 (t, J = 11.1 Hz, 1H), 1.94 (dt, J = 7.4, 3.2 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 162.7, 139.7, 138.6, 137.9, 135.2, 120.80, 120.6, 112.7, 109.2, 105.8, 64.2, 54.7, 50.6, 49.2, 47.1, 44.4, 42.9, 41.5, 37.6, 24.8. HRMS (ESI) m / z C 21 H 26NO [M+H] + Calculated value: 351.2179; Measured value: 351.2175.

[0231] [Example 78] (6bR,10aS)-8-(4-fluoro-2-methoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0232] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-4-fluoro-2-methoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 65% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.15 - 6.94 (m, 1H), 6.66 (dd, J = 7.9, 7.4 Hz, 1H), 6.62 - 6.49 (m, 3H), 6.41 (dd, J = 7.9, 1.0 Hz, 1H), 3.78 (s, 3H), 3.68 - 3.52 (m, 1H), 3.32 (dt, J = 10.1, 2.9 Hz, 1H), 3.29 - 3.12 (m, 3H), 3.11 - 2.97 (m, 1H), 2.87 (s, 3H), 2.86 - 2.72 (m, 4H), 2.63 - 2.42 (m, 2H), 2.40 - 2.26 (m, 1H), 2.04 (t, J = 11.1 Hz, 1H), 2.01 - 1.89 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 162.3 (d, J = 244.4 Hz), 158.5 (d, J = 8.8 Hz), 138.2, 135.3, 130.7 (d, J = 8.8 Hz), 130.1, 124.0, 120.1, 112.9, 109.0, 106.5 (d, J = 21.4 Hz), 98.8 (d, J = 25.2 Hz), 64.8, 59.1, 56.4, 55.6, 50.8, 49.2, 44.5, 42.0, 37.7, 27.6, 25.2. HRMS (ESI) m / z C 23 H 28 N3OF [M+H] + Calculated value: 382.2289; Measured value: 382.2281.

[0233] [Example 80] (6bR,10aS)-3-Methyl-8-(2-(trifluoromethoxy)phenethyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0234] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-2-(trifluoromethoxy)benzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in Step D. 83% isolated yield. 1H NMR (500 MHz, CDCl3) δ 7.28 (dd, J = 7.6, 2.4 Hz, 1H), 7.24 - 7.11 (m, 3H), 6.67 (t, J = 7.6 Hz, 1H), 6.54 (dd, J = 7.3, 1.0 Hz, 1H), 6.42 (dd, J = 7.9, 0.9 Hz, 1H), 3.66 - 3.56 (m, 1H), 3.33 (dt, J = 10.0, 2.9 Hz, 1H), 3.28 (dt, J = 11.4, 2.9 Hz, 1H), 3.25 - 3.23 (m, 2H), 3.23 - 3.17 (m, 1H), 3.02 - 2.93 (m, 1H), 2.92 - 2.88 (m, 2H), 2.88 (s, 3H), 2.84 (td, J = 10.0, 2.9 Hz, 1H), 2.79 - 2.73 (m, 1H), 2.66 - 2.52 (m, 2H), 2.47 - 2.33 (m, 1H), 2.09 (t, J = 11.1 Hz, 1H), 2.03 - 1.89 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 147.8, 138.2, 135.1, 133.1, 131.3, 130.2, 127.6, 126.9, 120.8 (q, J = 252 Hz), 120.6, 120.5, 112.9, 109.1, 64.7, 59.0, 56.4, 50.8, 49.0, 44.5, 42.0, 37.7, 27.6, 25.2. HRMS (ESI) m / z C 23 H 26 N3OF3[M+H] + Calculated value: 418.2101; Measured value: 418.2097. HRMS (ESI) m / z C 23 H 26 N3OF3[M+H] + Calculated value: 418.2101; Measured value: 418.2097.

[0235] [Example 81] (6bR,10aS)-8-(2-ethylphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0236] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-2-ethylbenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 64% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.21 - 7.07 (m, 4H), 6.68 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 7.3 Hz, 1H), 6.43 (dd, J = 8.0, 0.9 Hz, 1H), 3.66 - 3.58 (m, 1H), 3.33 (dt, J = 10.0, 2.9 Hz, 1H), 3.31 - 3.15 (m, 3H), 3.10 - 2.97 (m, 1H), 2.88 (s, 3H), 2.87 - 2.81 (m, 3H), 2.81 - 2.76 (m, 1H), 2.66 (q, J = 7.6 Hz, 2H), 2.61 - 2.46 (m, 2H), 2.43 - 2.28 (m, 1H), 2.07 (t, J = 11.0 Hz, 1H), 2.02 - 1.92 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 142.2, 138.2, 138.0, 135.1, 130.2, 129.8, 128.6, 126.5, 126.0, 120.5, 112.9, 109.1, 64.8, 60.6, 56.5, 50.8, 49.3, 44.6, 42.0, 37.7, 30.4, 25.7, 25.3, 15.7. HRMS (ESI) m / z C 24 H 31 N3[M+H] +Calculated value: 362.2591; Measured value: 362.2588.

[0237] [Example 82] (6bR,10aS)-8-(4-methoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline

[0238] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-4-methoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 36% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.18 - 6.95 (m, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.67 (t, J = 7.6 Hz, 1H), 6.54 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 7.9, 0.9 Hz, 1H), 3.78 (s, 3H), 3.69 - 3.54 (m, 1H), 3.32 (dt, J = 10.0, 3.0 Hz, 1H), 3.30 - 3.17 (m, 3H), 3.12 - 2.95 (m, 1H), 2.88 (s, 3H), 2.86 - 2.71 (m, 4H), 2.71 - 2.48 (m, 2H), 2.44 - 2.26 (m, 1H), 2.06 (t, J = 11.0 Hz, 1H), 2.02 - 1.88 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 158.1, 138.1, 135.2, 132.6, 130.1, 129.7, 120.5, 114.0, 112.8, 109.1, 64.7, 61.1, 56.4, 55.4, 50.8, 49.2, 44.5, 41.9, 37.7, 32.8, 25.1. HRMS (ESI) m / z C 23 H 29NO [M+H] + Calculated value: 364.2383; Measured value: 364.2380.

[0239] [Example 84] 4-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)ethyl)benzonitrile

[0240] [ka] The synthetic method is similar to Example 71, except that 4-(2-bromoethyl)benzonitrile is added in place of 1-(2-bromoethyl)-3-methoxybenzene in Step D. 30% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.39 - 7.27 (m, 2H), 6.66 (t, J = 7.6 Hz, 1H), 6.52 (d, 1H), 6.42 (dd, J = 8.0, 0.9 Hz, 1H), 3.61 (ddd, J = 11.3, 9.8, 2.9 Hz, 1H), 3.32 (dt, J = 9.9, 2.9 Hz, 1H), 3.30 - 3.21 (m, 2H), 3.17 (dt, J = 12.5, 6.3 Hz, 1H), 2.99 - 2.90 (m, 1H), 2.87 (s, 3H), 2.86 - 2.80 (m, 3H), 2.75 - 2.67 (m, 1H), 2.65 - 2.46 (m, 2H), 2.35 (td, J = 11.0, 3.4 Hz, 1H), 2.07 (t, J = 11.1 Hz, 1H), 2.00 - 1.84 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 146.5, 138.1, 135.2, 132.3, 130.0, 129.7, 120.5, 119.2, 112.7, 110.1, 109.1, 64.6, 60.0, 56.4, 50.8, 49.2, 44.5, 41.9, 37.7, 33.9, 25.2. HRMS (ESI) m / z C 23 H 26 N4[M+H] + Calculated value: 359.2230; Measured value: 359.2227.

[0241] [Example 85] (6bR,10aS)-8-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0242] [ka] The synthetic method is similar to Example 71, except that 3-(2-bromoethyl)-6-fluoro-1H-indole is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 9% isolated yield. 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 26.6 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.04 (d, J = 2.3 Hz, 1H), 6.92 (td, J = 9.0, 2.5 Hz, 1H), 6.71 - 6.64 (m, 1H), 6.56 (dd, J = 7.3, 0.9 Hz, 1H), 6.43 (dd, J = 7.9, 0.9 Hz, 1H), 3.62 (ddd, J = 11.4, 9.9, 3.0 Hz, 1H), 3.34 (dt, J = 10.0, 3.0 Hz, 1H), 3.31 - 3.18 (m, 3H), 3.03 (ddd, J = 11.1, 6.1, 1.9 Hz, 1H), 2.98 - 2.90 (m, 3H), 2.88 (s, 3H), 2.85 (td, J = 10.0, 2.9 Hz, 1H), 2.73 - 2.61 (m, 2H), 2.38 (dp, J = 11.1, 7.7 Hz, 1H), 2.10 (dd, J = 11.5, 10.5 Hz, 1H), 2.00 (q, J = 3.4 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 159.0, 157.1, 138.4, 135.4, 133.1, 130.4, 123.7, 120.7, 115.1, 113.1, 112.0 (d, J = 8.8 Hz), 110.7 (d, J = 26.5 Hz), 109.4, 104.1 (d, J = 23.9 Hz), 65.0, 59.8, 56.7, 51.1, 49.6, 44.8, 42.5, 38.0, 25.5, 23.3. HRMS (ESI) m / z C 24 H 27 N4F [M+H] + Calculated value: 391.2293; Measured value: 391.2285.

[0243] [Example 86] 1-(2-Methoxyphenyl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propan-1-one

[0244] [ka] The synthetic method is similar to Example 71, except that 3-bromo-1-(2-methoxyphenyl)propan-1-one is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 36% isolated yield. 1 H NMR (500 MHz, DMSO) δ 7.70 - 7.43 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H), 7.01 (td, J = 7.4, 1.0 Hz, 1H), 6.51 (t, J = 7.6 Hz, 1H), 6.40 (d, J = 7.3 Hz, 1H), 6.36 - 6.27 (m, 1H), 3.87 (s, 3H), 3.57 - 3.38 (m, 1H), 3.36 - 3.21 (m, 3H), 3.16 - 3.03 (m, 3H), 3.03 - 2.94 (m, 1H), 2.78 (s, 3H), 2.73 - 2.59 (m, 4H), 2.27 - 2.11 (m, 1H), 1.94 - 1.82 (m, 2H), 1.79 - 1.64 (m, 1H). 13 C NMR (126 MHz, DMSO) δ 201.3, 157.8, 137.6, 134.8, 133.4, 129.4, 128.2, 120.4, 119.8, 112.3, 108.6, 63.8, 55.7, 53.0, 49.9, 48.5, 43.8, 40.8, 40.6, 37.1, 24.2. HRMS (ESI) m / z C 24 H 29 N3O2[M+H] + Calculated value: 392.2333; Measured value: 392.2326.

[0245] [Example 89] 2-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)ethyl)phenol

[0246] [ka] The synthetic method is similar to Example 71, except that 2-(2-bromoethyl)phenol is added in place of 1-(2-bromoethyl)-3-methoxybenzene in Step D. 10% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.19 - 7.07 (m, 1H), 6.99 (dd, J = 7.5, 1.7 Hz, 1H), 6.90 (dd, J = 8.0, 1.3 Hz, 1H), 6.75 (td, J = 7.4, 1.3 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.52 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 8.0, 0.9 Hz, 1H), 3.71 - 3.51 (m, 1H), 3.43 - 3.20 (m, 4H), 3.19 - 3.05 (m, 1H), 3.01 - 2.92 (m, 1H), 2.88 (s, 3H), 2.87 - 2.77 (m, 3H), 2.76 - 2.58 (m, 2H), 2.49 (td, J = 11.8, 3.6 Hz, 1H), 2.31 - 1.96 (m, 3H). 13 C NMR (126 MHz, CDCl3) δ 157.4, 137.9, 135.3, 131.0, 129.3, 128.4, 127.9, 120.8, 119.0, 117.8, 112.8, 109.2, 64.3, 59.4, 56.3, 50.7, 49.2, 44.6, 41.4, 37.6, 31.7, 24.7. HRMS (ESI) m / z C 22 H 27 NO [M+H] +Calculated value: 350.2227; Measured value: 350.2220.

[0247] [Example 90] (6bR,10aS)-8-(2-Methoxybenzyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0248] [ka] The synthetic method is similar to Example 71, except that 1-(bromomethyl)-2-methoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 35% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.40 (dd, J = 7.4, 1.8 Hz, 1H), 7.25 - 7.17 (m, 1H), 6.95 (td, J = 7.4, 1.1 Hz, 1H), 6.86 (dd, J = 8.2, 1.1 Hz, 1H), 6.75 - 6.57 (m, 1H), 6.50 (dd, J = 7.3, 1.0 Hz, 1H), 6.40 (dd, J = 7.9, 1.0 Hz, 1H), 3.80 (s, 3H), 3.65 - 3.58 (m, 1H), 3.55 (q, 2H), 3.32 (dt, J = 10.0, 3.0 Hz, 1H), 3.29 - 3.16 (m, 3H), 2.99 - 2.89 (m, 1H), 2.87 (s, 3H), 2.82 (td, J = 9.9, 2.9 Hz, 1H), 2.74 - 2.64 (m, 1H), 2.33 (td, J = 11.1, 4.3 Hz, 1H), 2.06 (t, J = 10.9 Hz, 1H), 1.97 - 1.83 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 157.9, 138.2, 135.1, 130.6, 130.4, 128.0, 127.0, 120.5, 120.3, 113.0, 110.6, 108.9, 64.8, 56.6, 56.4, 55.6, 50.8, 49.2, 44.5, 42.0, 37.7, 25.2. HRMS (ESI) m / z C 22 H 27 NO [M+H] + Calculated value: 350.2227; Measured value: 350.2219.

[0249] [Example 91] (6bR,10aS)-8-(2-ethoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0250] [ka] The synthesis method is similar to Example 71, except that 1-(2-chloroethyl)-2-ethoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 78% isolated yield. 1H NMR (500 MHz, CDCl3) δ 7.22 - 7.05 (m, 1H), 6.86 (td, J = 7.4, 1.1 Hz, 1H), 6.81 (dd, J = 8.1, 1.1 Hz, 0H), 6.67 (t, 0H), 6.55 (dd, J = 7.4, 0.9 Hz, 0H), 6.42 (dd, J = 7.9, 1.0 Hz, 0H), 4.02 (q, J = 7.0 Hz, 2H), 3.75 - 3.48 (m, 1H), 3.33 (dt, J = 10.1, 2.9 Hz, 1H), 3.30 - 3.15 (m, 3H), 3.10 - 2.95 (m, 1H), 2.88 (s, 3H), 2.87 - 2.78 (m, 4H), 2.76 - 2.51 (m, 2H), 2.49 - 2.22 (m, 1H), 2.08 (t, J = 11.0 Hz, 1H), 2.03 - 1.90 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 157.0, 138.2, 135.1, 130.4, 130.3, 129.1, 127.3, 120.4, 112.9, 111.3, 109.0, 64.8, 63.5, 59.1, 56.5, 50.8, 49.0, 44.6, 42.0, 37.7, 28.1, 25.3, 15.1. HRMS (ESI) m / z C 24 H 31 NO [M+H] + Calculated value: 378.2540; Measured value: 378.2531.

[0251] [Example 92] (6bR,10aS)-8-(2-(benzofuran-7-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0252] [ka] The synthetic method is similar to Example 71, except that 7-(2-chloroethyl)benzofuran is added in place of 1-(2-bromoethyl)-3-methoxybenzene in Step D. 37% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 2.2 Hz, 1H), 7.44 (dd, J = 7.6, 1.4 Hz, 1H), 7.22 - 7.07 (m, 2H), 6.75 (d, J = 2.2 Hz, 1H), 6.67 (t, J = 7.3 Hz, 1H), 6.56 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 7.9, 0.9 Hz, 1H), 3.62 (ddd, J = 11.4, 10.0, 3.1 Hz, 1H), 3.33 (dt, J = 10.1, 3.0Hz, 1H), 3.31 - 3.19 (m, 3H), 3.21 - 3.09 (m, 2H), 3.10 - 2.99 (m, 1H), 2.88 (s, 3H), 2.87 - 2.81 (m, 2H), 2.78 - 2.68 (m, 2H), 2.50 - 2.32 (m, 1H), 2.12 (t, J = 11.0 Hz, 1H), 2.06 - 1.91 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 153.8, 144.7, 138.2, 135.1, 130.3, 127.3, 124.7, 124.3, 123.0, 120.4, 119.2, 112.9, 109.1, 106.9, 64.7, 58.9, 56.4, 50.8, 49.1, 44.5, 42.0, 37.7, 27.8, 25.2. HRMS (ESI) m / z C 24 H 27 NO [M+H] + Calculated value: 374.2227; Measured value: 374.2236.

[0253] [Example 93] (6bR,10aS)-8-(2-(2-methoxyphenoxy)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0254] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethoxy)-2-methoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 32% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.04 - 6.81 (m, 4H), 6.65 (t, 1H), 6.52 (dd, J = 7.4, 0.9 Hz, 1H), 6.41 (dd, J = 8.1, 0.9 Hz, 1H), 4.18 (t, J = 6.5 Hz, 2H), 3.85 (s, 3H), 3.73 - 3.47 (m, 1H), 3.32 (dt, J = 10.0, 2.9 Hz, 1H), 3.27 (dt, J = 11.3, 2.8 Hz, 1H), 3.24 - 3.17 (m, 2H), 3.07 - 2.92 (m, 1H), 2.87 (s, 3H), 2.86 - 2.75 (m, 4H), 2.56 - 2.32 (m, 1H), 2.15 (t, J = 11.0 Hz, 1H), 2.02 - 1.85 (m, 1H). 13 C NMR (126 MHz, CDCl3) δ 149.7, 148.5, 138.1, 135.1, 130.1, 121.4, 121.0, 120.4, 113.8, 112.9, 112.1, 109.1, 67.1, 64.5, 57.3, 57.0, 56.1, 50.8, 49.6, 44.5, 41.8, 37.7, 25.1. HRMS (ESI) m / z C 23 H 29 N3O2[M+H] + Calculated value: 380.2333; Measured value: 380.2327.

[0255] [Example 94] 3-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)ethyl)benzo[d]isothiazole

[0256] [ka] The synthetic method is similar to Example 71, except that 3-(2-bromoethyl)benzo[d]isothiazole is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 67% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.58 - 7.47 (m, 1H), 7.46 - 7.38 (m, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.55 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 8.0, 0.9 Hz, 1H), 3.67 - 3.54 (m, 3H), 3.39 - 3.31 (m, 5H), 3.30 - 3.16 (m, 3H), 3.08 - 2.98 (m, 1H), 2.98 - 2.90 (m, 2H), 2.88 (s, 3H), 2.86 - 2.77 (m, 2H), 2.44 (td, J = 10.9, 4.9 Hz, 1H), 2.16 (t, J = 11.0 Hz, 1H), 2.03 - 1.90 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 165.1, 152.5, 138.2, 135.1, 134.9, 130.1, 127.7, 124.6, 123.4, 120.5, 120.1, 112.9, 109.1, 64.6, 56.8, 56.4, 50.8, 49.2, 44.5, 41.9, 37.7, 29.5, 25.2. HRMS (ESI) m / z C 23H 26 N4S [M+H] + Calculated value: 391.1951; Measured value: 391.1960.

[0257] [Example 95] (6bR,10aS)-8-(2,5-dimethoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0258] [ka] The synthetic method is similar to Example 71, except that 2-(2-bromoethyl)-1,4-dimethoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 39% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 6.82 - 6.73 (m, 2H), 6.71 - 6.63 (m, 2H), 6.55 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 8.0, 0.9 Hz, 1H), 3.75 (d, J = 2.9 Hz, 6H), 3.71 - 3.50 (m, 1H), 3.33 (dt, J = 10.0, 2.9 Hz, 1H), 3.30 - 3.17 (m, 3H), 3.06 - 2.93 (m, 1H), 2.87 (s, 3H), 2.86 - 2.73 (m, 4H), 2.66 - 2.45 (m, 2H), 2.43 - 2.25 (m, 1H), 2.06 (t, J = 11.1 Hz, 1H), 2.01 - 1.91 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 153.6, 152.0, 138.2, 135.1, 130.3, 130.3, 120.4, 116.8, 112.9, 111.4, 111.3, 109.0, 64.8, 59.1, 56.4, 56.1, 55.8, 50.8, 49.1, 44.5, 42.0, 37.7, 28.3, 25.3. HRMS (ESI) m / z C 24 H 31 N3O2[M+H] + Calculated value: 394.2489; Measured value: 394.2484.

[0259] [Example 96] (6bR,10aS)-8-(4-ethylbenzyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0260] [ka] The synthetic method is similar to Example 71, except that 1-(bromomethyl)-4-ethylbenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 30% isolated yield. 1H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 6.74 - 6.56 (m, 1H), 6.49 (dd, J = 7.4, 0.9 Hz, 1H), 6.41 (dd, J = 7.9, 0.9 Hz, 1H), 3.68 - 3.51 (m, 1H), 3.45 (d, J = 2.4 Hz, 2H), 3.31 (dt, J = 9.9, 3.0 Hz, 1H), 3.29 - 3.21 (m, 2H), 3.20 - 3.13 (m, 1H), 2.87 (s, 3H), 2.86 - 2.79 (m, 2H), 2.65 (q, J = 7.5 Hz, 3H), 2.43 - 2.11 (m, 1H), 1.99 (t, J = 11.2 Hz, 1H), 1.95 - 1.87 (m, 2H), 1.25 (t, J = 7.6 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 143.0, 138.2, 136.0, 135.1, 130.3, 129.3, 127.8, 120.3, 113.0, 109.0, 64.8, 63.2, 56.5, 50.8, 49.1, 44.5, 41.9, 37.7, 28.7, 25.2, 15.7. HRMS (ESI) m / z C 23 H 29 N3[M+H] + Calculated value: 348.2434; Measured value: 348.2428.

[0261] [Example 97] (6bR,10aS)-8-(2-(1H-indol-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0262] [ka] The synthetic method is similar to Example 71, except that 3-(2-bromoethyl)-1H-indole is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 31% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.74 - 7.48 (m, 1H), 7.40 - 7.30 (m, 1H), 7.23 - 7.15 (m, 1H), 7.13 - 7.07 (m, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.57 (dd, J = 7.3, 0.9 Hz, 1H), 6.43 (dd, J = 8.0, 0.9 Hz, 1H), 3.73 - 3.52 (m, 1H), 3.34 (dt, J = 10.1, 2.9 Hz, 1H), 3.31 - 3.19 (m, 3H), 3.12 - 3.03 (m, 1H), 3.00 (t, 2H), 2.88 (s, 3H), 2.87 - 2.79 (m, 2H), 2.78 - 2.58 (m, 2H), 2.45 - 2.31 (m, 1H), 2.24 - 2.07 (m, 1H), 2.03 - 1.96 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 138.2, 136.4, 135.1, 130.2, 127.7, 122.1, 121.6, 120.5, 119.3, 119.0, 114.7, 112.9, 111.2, 109.1, 64.7, 59.6, 56.5, 50.8, 49.2, 44.5, 41.9, 37.7, 25.2, 23.0. HRMS (ESI) m / z C 24 H 28 Calculated N4[M+H]+: 373.2387; Found: 373.2378.

[0263] [Example 100] (6bR,10aS)-8-benzyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0264] [ka] The synthetic method is similar to Example 71, except that 1-(bromomethyl)benzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 31% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.39 - 7.30 (m, 4H), 7.30 - 7.23 (m, 1H), 6.75 - 6.58 (m, 1H), 6.48 (dd, J = 7.4, 0.9 Hz, 1H), 6.41 (dd, J = 8.0, 0.9 Hz, 1H), 3.65 - 3.55 (m, 1H), 3.49 (q, J = 3.2 Hz, 2H), 3.32 (dt, J = 9.9, 3.0 Hz, 1H), 3.29 - 3.21 (m, 2H), 3.20 - 3.14 (m, 1H), 2.87 (s, 3H), 2.87 - 2.80 (m, 2H), 2.71 - 2.57 (m, 1H), 2.45 - 2.20 (m, 1H), 2.01 (t, J = 11.1 Hz, 1H), 1.95 - 1.87 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 138.8, 138.2, 135.1, 130.3, 129.3, 128.3, 127.0, 120.3, 112.9, 109.0, 64.8, 63.5, 56.5, 50.8, 49.2, 44.5, 41.9, 37.7, 25.2. HRMS (ESI) m / z C 21 H 25 N3[M+H] + Calculated value: 320.2121; Measured value: 320.2116.

[0265] [Example 101] (6bR,10aS)-8-(3-Methoxybenzyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0266] [ka] The synthetic method is similar to Example 71, except that 1-(bromomethyl)-3-methoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 59% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.23 (t, J = 8.0 Hz, 1H), 7.02 - 6.87 (m, 2H), 6.83 - 6.76 (m, 1H), 6.64 (t, J = 7.6 Hz, 1H), 6.48 (dd, J = 7.4, 0.9 Hz, 1H), 6.41 (dd, J = 7.9, 0.9 Hz, 1H), 3.82 (s, 3H), 3.66 - 3.56 (m, 1H), 3.46 (s, 2H), 3.32 (dt, J = 9.9, 3.0 Hz, 1H), 3.29 - 3.22 (m, 2H), 3.21 - 3.11 (m, 1H), 2.87 (s, 3H), 2.86 - 2.78 (m, 1H), 2.72 - 2.58 (m, 1H), 2.37 - 2.18 (m, 1H), 2.01 (t, J = 11.1 Hz, 1H), 1.96 - 1.88 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 159.8, 140.6, 138.2, 135.1, 130.3, 129.3, 121.6, 120.3, 114.6, 113.0, 112.6, 109.0, 64.8, 63.4, 56.5, 55.3, 50.8, 49.2, 44.5, 41.9, 37.7, 25.2. HRMS (ESI) m / z C 22 H 27 NO [M+H] + Calculated value: 350.2227; Measured value: 350.222.

[0267] [Example 102] (6bR,10aS)-8-(3-ethylbenzyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0268] [ka] The synthetic method is similar to Example 71, except that 1-(bromomethyl)-3-ethylbenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 64% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.24 (t, J = 7.5 Hz, 1H), 7.19 - 7.13 (m, 2H), 7.12 - 7.08 (m, 1H), 6.73 - 6.59 (m, 1H), 6.49 (dd, J = 7.4, 1.0 Hz, 1H), 6.41 (dd, J = 8.0, 0.9 Hz, 1H), 3.77 - 3.56 (m, 1H), 3.46 (s, 2H), 3.32 (dt, J = 9.9, 3.0 Hz, 1H), 3.30 - 3.21 (m, 2H), 3.21 - 3.14 (m, 1H), 2.87 (s, 3H), 2.83 (td, J = 9.9, 2.9 Hz, 1H), 2.66 (q, J = 7.6 Hz, 3H), 2.38 - 2.14 (m, 1H), 2.01 (t, J = 11.1 Hz, 1H), 1.95 - 1.89 (m, 2H), 1.25 (t, J = 7.6 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 144.3, 138.8, 138.2, 135.1, 130.3, 128.9, 128.3, 126.7, 126.6, 120.3, 113.0, 109.0, 64.8, 63.6, 56.5, 50.8, 49.2, 44.5, 41.9, 37.7, 28.9, 25.2, 15.7. HRMS (ESI) m / z C 23 H 29 N3[M+H] +Calculated value: 348.2434; Measured value: 348.2428.

[0269] [Example 103] (6bR,10aS)-8-(4-Methoxybenzyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0270] [ka] The synthetic method is similar to Example 71, except that 1-(bromomethyl)-4-methoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 61% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.23 (d, J = 8.6 Hz, 2H), 6.86 (d, 2H), 6.64 (dd, J = 7.9, 7.3 Hz, 1H), 6.55 - 6.45 (m, 1H), 6.41 (dd, J = 8.0, 0.9 Hz, 1H), 3.81 (s, 3H), 3.61 (ddd, J = 11.3, 9.8, 3.0 Hz, 1H), 3.42 (q, 2H), 3.31 (dt, J = 9.9, 2.9 Hz, 1H), 3.29 - 3.21 (m, 2H), 3.20 - 3.06 (m, 1H), 2.87 (s, 3H), 2.86 - 2.76 (m, 2H), 2.70 - 2.53 (m, 1H), 2.40 - 2.18 (m, 1H), 2.12 - 1.77 (m, 3H). 13 C NMR (126 MHz, CDCl3) δ 158.8, 138.2, 135.1, 130.7, 130.5, 130.3, 120.3, 113.7, 112.9, 109.0, 64.8, 62.8, 56.3, 55.4, 50.8, 49.0, 44.5, 41.9, 37.7, 25.2. HRMS (ESI) m / z C 22 H 27 NO [M+H] +Calculated value: 350.2227; Measured value: 350.2221.

[0271] [Example 104] (6bR,10aS)-8-(2-ethylbenzyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0272] [ka] The synthetic method is similar to Example 71, except that 1-(bromomethyl)-2-ethylbenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 76% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 7.4 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.15 (td, J = 7.1, 2.0 Hz, 1H), 6.64 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 7.3 Hz, 1H), 6.41 (dd, J = 7.9, 0.9 Hz, 1H), 3.74 - 3.58 (m, 1H), 3.45 (q, J = 13.2 Hz, 2H), 3.37 - 3.26 (m, 2H), 3.24 - 3.20 (m, 1H), 3.18 - 3.08 (m, 1H), 2.88 (s, 3H), 2.87 - 2.80 (m, 2H), 2.74 (q, J = 7.6 Hz, 2H), 2.66 - 2.61 (m, 1H), 2.29 (td, J = 10.8, 4.6 Hz, 1H), 2.02 (t, J = 11.1 Hz, 1H), 1.97 - 1.82 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ143.6, 138.2, 136.5, 135.1, 130.4, 130.2, 128.6, 127.2, 125.5, 120.3, 113.0, 109.0, 64.9, 60.7, 56.7, 50.8, 49.3, 44.5, 42.1, 37.7, 25.6, 25.4, 15.5. HRMS (ESI) m / z C 23 H 29 N3[M+H] + Calculated value: 348.2434; Measured value: 348.2428.

[0273] [Example 106] (6bR,10aS)-3-Methyl-8-(2-(methylsulfonyl)phenethyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0274] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-2-(methylsulfonyl)benzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in Step D. 38% isolated yield. 1H NMR (500 MHz, CDCl3) δ 8.17 - 7.91 (m, 1H), 7.68 - 7.51 (m, 1H), 7.46 - 7.34 (m, 2H), 6.66 (dd, J = 7.9, 7.3 Hz, 1H), 6.53 (dd, J = 7.4, 0.9 Hz, 1H), 6.41 (dd, J = 7.9, 0.9 Hz, 1H), 3.60 (ddd, J = 11.3, 9.9, 3.0 Hz, 1H), 3.32 (dt, J = 10.0, 3.0 Hz, 1H), 3.29 - 3.17 (m, 5H), 3.10 (s, 3H), 3.01 - 2.94 (m, 1H), 2.87 (s, 3H), 2.86 - 2.77 (m, 2H), 2.76 - 2.61 (m, 2H), 2.56 - 2.35 (m, 1H), 2.16 (t, J = 11.0 Hz, 1H), 2.07 - 1.86 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 140.6, 139.0, 138.1, 135.1, 133.8, 132.5, 130.0, 129.7, 127.1, 120.4, 112.9, 109.1, 64.6, 60.6, 56.4, 50.8, 48.9, 45.0, 44.5, 41.9, 37.7, 30.6, 25.1. HRMS (ESI) m / z C 23 H 29 N3O2S [M+H] + Calculated value: 412.2053; Measured value: 412.2043.

[0275] [Example 108] (6bR,10aS)-8-(Cyclohexylmethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0276] [ka] The synthetic method is similar to Example 71, except that (iodomethyl)cyclohexane is added in place of 1-(2-bromoethyl)-3-methoxybenzene in Step D. 27% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 6.78 - 6.61 (m, 1H), 6.52 (dd, J = 7.4, 0.9 Hz, 1H), 6.40 (dd, J = 7.9, 0.9 Hz, 1H), 3.60 (ddd, J = 11.3, 9.8, 3.0 Hz, 1H), 3.31 (dt, J = 10.0, 3.0 Hz, 1H), 3.26 (dt, J = 11.3, 2.9 Hz, 1H), 3.21 (dt, J = 6.5, 3.2 Hz, 1H), 3.19 - 3.12 (m, 1H), 2.87 (s, 3H), 2.85 - 2.78 (m, 2H), 2.67 - 2.56 (m, 1H), 2.27 - 2.12 (m, 1H), 2.13 - 1.99 (m, 2H), 2.02 - 1.86 (m, 3H), 1.83 - 1.63 (m, 5H), 1.59 - 1.43 (m, 1H), 1.37 - 1.05 (m, 3H), 0.99 - 0.77 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 138.21 135.1, 130.5, 120.3, 112.9, 109.0, 66.1, 64.8, 57.2, 50.8, 49.7, 44.5, 41.9, 37.7, 35.5, 32.3, 32.3, 29.9, 27.0, 26.4, 25.2. HRMS (ESI) m / z C 21 H 31 N3[M+H] + Calculated value: 326.2591; Measured value: 326.2583.

[0277] [Example 109] (6bR,10aS)-8-(5-fluoro-2-methoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0278] [ka] The synthetic method is similar to that of Example 71, except that 2-(2-bromoethyl)-4-fluoro-1-methoxybenzene is added in Step D instead of 1-(2-bromoethyl)-3-methoxybenzene. 1 H NMR (500 MHz, CDCl3) δ 7.01 - 6.81 (m, 2H), 6.74 (dd, J = 8.8, 4.5 Hz, 1H), 6.70 - 6.63 (m, 1H), 6.54 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 7.9, 0.9 Hz, 1H), 3.77 (s, 3H), 3.61 (ddd, J = 11.3, 9.9, 3.0 Hz, 1H), 3.42 - 3.17 (m, 4H), 3.02 (t, J = 8.4 Hz, 1H), 2.87 (s, 3H), 2.86 - 2.78 (m, 4H), 2.60 (p, J = 6.5 Hz, 2H), 2.42 (s, 1H), 2.29 - 1.86 (m, 3H). 13 C NMR (126 MHz, CDCl3) δ 157.0 (d, J = 238.14 Hz), 153.8, 138.2, 135.1, 130.8, 130.3, 120.4, 117.0 (d, J = 22.68 Hz), 112.9, 112.9 (d, HRMS (ESI) m / z C 23 H 28 N3OF [M+H] + Calculated value: 382.2289; Measured value: 382.2280.

[0279] [Example 110] (6bR,10aS)-8-(3-ethylphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0280] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-3-ethylbenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 51% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.20 (td, J = 7.4, 0.8 Hz, 1H), 7.10 - 6.96 (m, 3H), 6.67 (t, J = 7.6 Hz, 1H), 6.55 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 8.0, 0.9 Hz, 1H), 3.62 (ddd, J = 11.3, 9.9, 3.0 Hz, 1H), 3.33 (dt, J = 10.0, 2.9 Hz, 1H), 3.30 - 3.19 (m, 3H), 3.11 - 2.99 (m, 1H), 2.88 (s, 3H), 2.87 - 2.77 (m, 4H), 2.76 - 2.49 (m, 4H), 2.48 - 2.28 (m, 1H), 2.23 - 1.87 (m, 3H), 1.23 (t, J = 7.6 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ144.5, 140.3, 138.1, 135.2, 130.0, 128.5, 128.5, 126.1, 125.7, 120.5, 112.8, 109.1, 64.6, 60.9, 56.3, 50.8, 49.1, 44.5, 41.7, 37.7, 33.6, 28.9, 25.0, 15.7. HRMS (ESI) m / z C 24 H 31 N3[M+H] + Calculated value: 362.2591; Measured value: 362.2583.

[0281] [Example 111] (6bR,10aS)-8-(3-ethoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0282] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-3-ethoxybenzene is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 27% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.18 (td, J = 7.4, 1.3 Hz, 1H), 6.89 - 6.71 (m, 3H), 6.67 (t, J = 7.6 Hz, 1H), 6.54 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 7.9, 0.9 Hz, 1H), 4.01 (q, J = 7.0 Hz, 2H), 3.61 (ddd, J = 11.3, 9.9, 3.0 Hz, 1H), 3.43 - 3.21 (m, 4H), 3.14 - 2.98 (m, 1H), 2.87 (s, 3H), 2.87 - 2.76 (m, 4H), 2.73 - 2.53 (m, 2H), 2.42 (t, J = 12.0 Hz, 1H), 2.22 - 1.86 (m, 3H), 1.40 (t, J = 7.0 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ159.2, 141.7, 138.0, 135.2, 129.9, 129.5, 121.1, 120.6, 115.2, 112.8, 112.1, 109.2, 64.5, 63.4, 60.6, 56.1, 50.8, 49.1, 44.5, 41.6, 37.7, 33.5, 24.9, 15.0. HRMS (ESI) m / z C 24 H 31 NO [M+H] +Calculated value: 378.2540; Measured value: 378.2531.

[0283] [Example 113] (6bR,10aS)-8-(2-(1H-benzo[d]imidazol-1-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0284] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-1H-benzo[d]imidazole is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 43% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 7.86 - 7.74 (m, 1H), 7.61 - 7.41 (m, 1H), 7.41 - 7.27 (m, 2H), 6.69 (t, J = 7.7 Hz, 1H), 6.51 (d, J = 7.4 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.68 (ddd, J = 14.3, 8.0, 6.2 Hz, 1H), 4.59 (ddd, J = 14.3, 8.0, 6.0 Hz, 1H), 3.67 - 3.52 (m, 1H), 3.42 (dt, J = 11.9, 6.3 Hz, 1H), 3.34 - 3.23 (m, 3H), 3.20 (ddd, J = 11.6, 6.4, 2.0 Hz, 1H), 3.10 (ddd, J = 13.0, 7.9, 6.2 Hz, 1H), 3.06 - 2.95 (m, 2H), 2.87 (s, 3H), 2.85 - 2.79 (m, 1H), 2.79 - 2.66 (m, 1H), 2.37 (t, J = 11.5 Hz, 1H), 2.33 - 2.18 (m, 1H), 2.08 - 1.97 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 165.18, 143.23, 142.51, 137.80, 135.67, 133.51, 128.47, 124.24, 123.51, 121.57, 120.40, 113.03, HRMS (ESI) m / z C 23 H 27 N5[M+H] + Calculated value: 374.2339; Measured value: 374.2330.

[0285] [Example 114] (6bR,10aS)-8-(2-(1H-benzo[d][1,2,3]triazol-1-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0286] [ka] The synthesis method is similar to Example 71, except that 1-(2-bromoethyl)-1H-benzo[d][1,2,3]triazole is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 18% isolated yield. 1H NMR (500 MHz, CDCl3) δ 8.06 (dt, J = 8.4, 1.0 Hz, 1H), 7.66 (dt, J = 8.4, 1.0 Hz, 1H), 7.51 (ddd, J = 8.3, 7.0, 1.0 Hz, 1H), 7.38 (ddd, J = 8.2, 6.9, 1.0 Hz, 1H), 6.67 (t, J = 7.7 Hz, 1H), 6.49 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 8.0, 0.9 Hz, 1H), 5.03 - 4.85 (m, 2H), 3.59 (ddd, J = 11.1, 10.0, 3.2 Hz, 1H), 3.31 - 3.20 (m, 4H), 3.20 - 3.07 (m, 3H), 2.98 - 2.89 (m, 1H), 2.87 (s, 3H), 2.85 (s, 1H), 2.62 (td, J = 11.9, 3.4 Hz, 1H), 2.30 (t, J = 11.1 Hz, 1H), 2.05 (ddt, J = 14.8, 12.4, 4.4 Hz, 1H), 1.97 (dt, J = 14.8, 2.8 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 165.18, 143.23, 142.51, 137.80, 135.67, 133.51, 128.47, 124.24, 123.51, 121.57, 120.40, 113.03, 110.19,109.89,77.67,77.42,77.16,63.80,56.59,55.68,50.86,49.25,44.76,41.67,40.52,37.87,23.73. C22H26N6 [M+H] + Calculated value: 375.2292; Measured value: 375.2283.

[0287] [Example 115] (6bR,10aS)-8-(2-(1H-indazol-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0288] [ka] The synthetic method is similar to Example 71, except that 3-(2-chloroethyl)-1H-indazole is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 16% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.72 (dt, J = 8.1, 1.0 Hz, 1H), 7.42 (dt, J = 8.4, 0.9 Hz, 1H), 7.36 (ddd, J = 8.3, 6.8, 1.1 Hz, 1H), 7.14 (ddd, J = 7.9, 6.8, 1.0 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.54 (dd, J = 7.4, 0.9 Hz, 1H), 6.42 (dd, J = 8.0, 0.9 Hz, 1H), 3.62 (ddd, J = 11.3, 10.0, 3.0Hz, 1H), 3.33 (dt, J = 10.0, 3.0 Hz, 1H), 3.31 - 3.18 (m, 5H), 3.13 - 2.99 (m, 1H), 2.87 (s, 3H), 2.87 - 2.79 (m, 3H), 2.45 (s, 1H), 2.23 - 2.10 (m, 1H), 2.09 - 1.94 (m, 3H). 13 C NMR (126 MHz, CDCl3) δ 145.26, 141.13, 137.87, 134.92, 129.79, 126.65, 122.12, 120.29, 120.25, 120.09, 112.65, 109.72, 108.87, 64.36, 57.48, 56.09, 50.54, 48.81, 44.29, 41.52, 37.44, 24.81, 24.63. HRMS (ESI) m / z C23 H 27 N5[M+H] + Calculated value: 374.2339; Measured value: 374.2330.

[0289] [Example 126] (6bR,10aS)-8-(2-(1H-indazol-1-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0290] [ka] The synthetic method is similar to Example 71, except that 1-(2-bromoethyl)-1H-indazole is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 25% isolated yield. 1H NMR (500 MHz, CDCl3) δ 8.04 - 7.97 (m, 1H), 7.72 (dt, J = 8.1, 1.0 Hz, 1H), 7.45 (dq, J = 8.5, 0.9 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.14 (ddd, J = 8.0, 6.8, 0.9 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.50 (dd, J = 7.4, 0.9 Hz, 1H), 6.41 (dd, J = 8.0, 0.9 Hz, 1H), 4.54 (t, J = 7.3 Hz, 2H), 3.64 - 3.54 (m, 1H), 3.28 (ddt, J = 18.6, 11.3, 2.9 Hz, 2H), 3.20 (ddd, J = 6.6, 3.9, 2.5 Hz, 1H), 3.17 - 3.08 (m, 1H), 2.92 - 2.87 (m, 3H), 2.86 (s, 3H), 2.85 - 2.78 (m, 2H), 2.68 (ddt, J = 11.0, 4.7, 2.1 Hz, 1H), 2.40 (td, J = 11.2, 3.9 Hz, 1H), 2.14 (t, J = 11.1 Hz, 1H), 1.91 (q, J = 4.1 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 139.48, 137.85, 134.88, 132.91, 129.67, 126.01, 123.87, 120.95, 120.33, 120.21, 112.55, 108.98, 108.82, 64.21, 57.33, 56.52, 50.50, 49.14, 46.86, 44.21, 41.57, 37.42, 24.87. HRMS (ESI) m / z C 23 H 27 N5[M+H] + Calculated value: 374.2339; Measured value: 374.2330.

[0291] [Example 131] 3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-phenylpropan-1-one

[0292] [ka] The synthetic method is similar to Example 71, with 1-phenylpropan-1-one being added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 68% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 7.99 - 7.92 (m, 2H), 7.61 - 7.52 (m, 1H), 7.50 - 7.41 (m, 2H), 6.70 - 6.60 (m, 1H), 6.52 (dd, J = 7.5, 1.0 Hz, 1H), 6.41 (dd, J = 8.0, 0.9 Hz, 1H), 3.61 (ddd, J = 11.3, 9.9, 3.0 Hz, 1H), 3.29 (ddt, J = 23.4, 11.4, 2.9 Hz, 2H), 3.24 - 3.13 (m, 4H), 2.94 - 2.88 (m, 2H), 2.87 (s, 3H), 2.86 - 2.78 (m, 2H), 2.74 - 2.66 (m, 1H), 2.38 (td, J = 11.3, 4.0 Hz, 1H), 2.13 - 2.02 (m, 1H), 2.00 - 1.87 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 199.19, 137.86, 136.88, 134.88, 132.92, 129.79, 128.48, 127.94, 120.20, 112.56, 108.81, 64.32, 60.26, 56.19, 53.26, 50.52, 48.95, 44.24, 41.64, 37.42, 36.14, 24.94, 14.08. HRMS (ESI) m / z 23 H 27 NO [M+H] +Calculated value: 362.2227; Measured value: 362.2223.

[0293] [Example 175] (6bR,10aS)-3,8-Dimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0294] [ka] The synthetic method is similar to Example 71, except that iodomethane is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 31% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 6.70 - 6.59 (m, 1H), 6.52 (dd, J = 7.4, 0.9 Hz, 1H), 6.41 (dd, J = 8.0, 0.9 Hz, 1H), 3.60 (ddd, J = 11.3, 9.9, 3.0 Hz, 1H), 3.31 (dt, J = 9.9, 3.0 Hz, 1H), 3.27 (dt, J = 11.3, 2.9 Hz, 1H), 3.23 - 3.08 (m, 2H), 2.87 (s, 3H), 2.85 - 2.71 (m, 2H), 2.60 (dtd, J = 11.2, 3.5, 1.9 Hz, 1H), 2.26 (s, 3H), 2.24 - 2.15 (m, 1H), 2.05 - 1.83 (m, 3H). 13 C NMR (126 MHz, CDCl3) δ 138.1, 135.1, 130.2, 120.4, 112.8, 109.0, 64.1, 58.6, 51.1, 50.8, 46.7, 44.5, 42.0, 37.7, 25.2. HRMS (ESI) m / z C 15 H 21 N3[M+H] + Calculated value: 244.1808; Measured value: 244.1804.

[0295] [Example 176] (6bR,10aS)-8-Ethyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0296] [ka] The synthetic method is similar to Example 71, except that iodoethane is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 65% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 6.68 (t, J = 7.7 Hz, 1H), 6.53 (d, J = 7.4 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 3.77 - 3.56 (m, 1H), 3.55 - 3.44 (m, 1H), 3.40 - 3.20 (m, 4H), 3.17 - 3.06 (m, 1H), 2.87 (s, 3H), 2.85 - 2.72 (m, 3H), 2.68 (td, J = 12.5, 3.0 Hz, 1H), 2.52 - 2.33 (m, 1H), 2.27 (t, J = 11.7 Hz, 1H), 2.12 - 1.96 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 137.5, 135.4, 128.4, 121.2, 112.8, 109.5, 63.7, 53.9, 52.1, 50.6, 47.6, 44.5, 39.9, 37.6, 23.1, 10.2. HRMS (ESI) m / z C 16 H 23 N3[M+H] + Calculated value: 258.1965; Measured value: 258.1960.

[0297] [Example 177] (6bR,10aS)-3-Methyl-8-propyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0298] [ka] The synthetic method is similar to Example 71, except that 1-iodopropane is added in place of 1-(2-bromoethyl)-3-methoxybenzene in step D. 45% isolated yield. 1 H NMR (500 MHz, CDCl3) δ 6.74 - 6.61 (m, 1H), 6.52 (dd, J = 7.3, 0.9 Hz, 1H), 6.40 (dd, J = 8.0, 0.9 Hz, 1H), 3.61 (ddd, J = 11.3, 9.9, 3.0 Hz, 1H), 3.31 (dt, J = 10.0, 2.9 Hz, 1H), 3.26 (dt, J = 11.3, 2.9 Hz, 1H), 3.24 - 3.21 (m, 1H), 3.17 (dt, J = 10.9, 6.4 Hz, 1H), 2.94 - 2.87 (m, 1H), 2.82 (td, J = 10.0, 2.9 Hz, 1H), 2.70 - 2.55 (m, 1H), 2.44 - 2.06 (m, 3H), 2.00 - 1.78 (m, 3H), 1.53 (h, J = 7.5 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 138.2, 135.1, 130.3, 120.4, 112.9, 109.0, 64.8, 61.1, 56.6, 50.8, 49.2, 44.5, 41.9, 37.7, 25.2, 20.3, 12.2. HRMS (ESI) m / z C 17 H 25 N3[M+H] + Calculated value: 272.2121; Measured value: 272.2116.

[0299] The remaining compounds up to Example 180 may be prepared following similar procedures.

[0300] [Example 181] Receptor binding profile Standard receptor binding for serotonin, dopamine, and mu-opioid receptors, and the serotonin transporter, is determined according to literature procedures. For example, the following literature procedures may be used, each of which is incorporated herein by reference in its entirety: 5-HT 2A D2: Bryant, HU et al. (1996), Life Sci., 15:1259-1268; D2: Hall, DA and Strange, PG (1997), Brit. J. Pharmacol., 121:731-736; D1: Zhou, QY et al. (1990), Nature, 347:76-80; SERT: Park, YM et al. (1999), Anal. Biochem., 269:94-104; mu opioid receptor: Wang, JB et al. (1994), FEBS Lett., 338:217-222. For example, human 5-HT 2A , 5-HT 2B , and / or 5-HT 2C Using human recombinant HEK-293 cells expressing the receptor, receptor binding assays were performed using agonist radioligands. 125 A competitive assay against I-(+ / -)-DOI can be performed to determine the Ki due to displacement.

[0301] Generally, results are expressed as a percent of control specific binding obtained in the presence of test compound:

[0302]

number

[0303]

number

[0304] I C 50 The Λ value (concentration causing half-maximal inhibition of control specific binding) and Hill coefficient (nH) are determined by nonlinear regression analysis of competition curves generated with mean replicate values ​​using curve fitting of the Hill equation.

[0305]

number

[0306]

number

[0307] The compound of formula A (ITI-007, lumateperone) is used as a comparator in the assay.

[0308] The following receptor affinity results are obtained (using the compound of formula A for comparison):

[0309] [Table 4-1]

[0310] [Table 4-2]

[0311] [Table 4-3]

[0312] [Table 4-4]

[0313] As shown, many of the compounds of the present disclosure exhibit significantly greater receptor selectivity than the reference compound of Formula A. For example, the compounds of Examples 14, 15, and 16 exhibit little D1, D2, or Mu receptor affinity, but retain strong affinity at the serotonin 2A receptor.

[0314] The selected compounds were 5-HT 2B and / or 5-HT 2C It was also tested in a receptor binding assay against the receptor. Some results are shown in the table below:

[0315] [Table 5]

[0316] The selected compounds were agonists (EC 50 ) or antagonist (IC 50 ) as 5-HT 2B and 5-HT 2C The receptors were also tested in functional assays. Some results are shown in the table below:

[0317] [Table 6]

[0318] Some compounds are further tested in receptor profiling panel consisting of agonist and / or antagonist radioligand binding assay.The test compound is carried out at 100nM concentration.The binding of compound is calculated as the inhibition percentage of the binding of specific radioligand to the receptor (or ion channel) being tested, which may be agonist or antagonist.The following receptors and ion channels are included in the panel:

[0319] [Table 7-1]

[0320] [Table 7-2] The compounds of the present disclosure are unexpectedly found to have high selectivity with few off-target interactions. For example, the compounds interact significantly (>45% inhibition) only with the following receptors: alpha-1A (e.g., 40-80% inhibition), serotonin-2A (e.g., 50-100% inhibition), and serotonin-2B (50-100% inhibition), while having little activity (<40% inhibition) at other receptors commonly associated with side effects, such as serotonin-1A, serotonin-1B, serotonin-3, muscarinic, other adrenergic, and histamine receptors.

[0321] These results are particularly surprising because compounds having a tetracyclic core corresponding to or related to that of the compounds of the present disclosure but lacking a side chain (i.e., compounds of Formula I where n is 0 and ZA is H) have been found to have significant activity in receptor assays for serotonin-1A (>70% inhibition), serotonin-1B (>50% inhibition), serotonin-2A (>70% inhibition), and serotonin-2B (>80% inhibition).

[0322] [Example 182] Biased agonism / antagonism 5-HT 2AGq signaling agonism / antagonism at receptors. Selected compounds were compared with 5-HT on Gq mobilization. 2A Agonist and antagonist assays are performed: alpha-methylserotonin is used as a reference control for agonist assays, and altanserin is used as a control for antagonist assays.

[0323] Agonist assay: human 5-HT 2A CHO-K1 cells (ES-313-AF) expressing β-glucanase β were obtained from PerkinElmer and used according to the supplier's recommendations. Frozen cells were thawed in a 37°C water bath and then resuspended in 10 mL of Ham's F-12 medium containing 10% FBS. Cells were harvested by centrifugation at 150 g for 5 minutes and then resuspended in 3 x 10 β-glucanase ... 5 Resuspend the cells at 1 x 10 cells / L. Under sterile conditions, add coelenterazine H to the cell suspension to a final concentration of 5 μM. Wrap the Falcon tube in aluminum foil and place it on a rotating wheel (approximately 45° angle and 7 rpm / min speed) for 4 hours at room temperature. The cells are then diluted to 1 x 10 cells / L in assay buffer. 5 The cells were diluted to 1000 cells / mL and transferred to an aluminum foil-wrapped beaker on a magnetic stirrer. After 1 hour of incubation, 50 μL of cells (5,000 cells / well) were injected into 50 μL of increasing concentrations of test compound in wells of a 96-well white plate. Luminescence was immediately recorded for 20 seconds using a FLUOstar Omega luminescence detector (BMG LABTECH). Digitonin at a final concentration of 50 μM in assay buffer was used as a positive control to measure receptor-independent cellular calcium responses. Curve fitting was performed using GraphPad Prism, and the EC was calculated using a 4-parameter logistic fit. 50 Determine the maximal response (E) by subtracting the lowest value from the highest value of the dose-response curve. max ) value.

[0324] Antagonist assay: 50 μL of cells (5,000 cells / well) are mixed with 50 μL of increasing concentrations of test compound in the wells of a 96-well white plate, and the plate is then incubated at room temperature for 15 minutes. Afterwards, 50 μL of alpha-methylserotonin (its measured EC 80 A final assay concentration corresponding to 1000 µL of ... 50 For antagonists, use the modified Cheng Prusoff formula: K B =IC 50 / (1+(A / EC 50A )) (where A is the concentration of the reference agonist alpha-methylserotonin and EC 50A is the EC value for the reference agonist alpha-methylserotonin 50 value) to calculate the apparent dissociation constant (K B ) is calculated.

[0325] 5-HT 2A Beta-arrestin signaling agonism / antagonism at receptors. Selected compounds were compared to 5-HT receptors for beta-arrestin recruitment. 2A Agonist and antagonist assays are performed: alpha-methylserotonin is used as a reference control for agonist assays, and altanserin is used as a control for antagonist assays.

[0326] Agonist assay: human 5-HT 2AReceptor-expressing U2OS cells (93-0401E3CP19L) were obtained from Eurofins DiscoverX and used according to the supplier's recommendations. Frozen cells were thawed in a 37°C water bath and then mixed with 0.5 mL of pre-warmed cell plating reagent. The cells were gently pipetted up and down several times to ensure uniform distribution before being transferred to 11.5 mL of pre-warmed cell plating reagent and poured into a disposable reagent reservoir. 100 μL of cells were plated into each well of a 96-well tissue culture plate, and the plate was incubated at 37°C (5% CO2) for 24 hours. 10 μL of test compound at increasing concentrations was added to the cells in the 96-well plate, and the plate was then incubated at room temperature for 3 hours. After the addition of 55 μL of prepared detection reagent and an additional 1 hour of incubation, samples were read on an Envision luminescence plate reader. All assay points were determined in duplicate, and data are presented as average values. Curve fitting was performed using Prism software (Graphpad), and EC was calculated using a 4-parameter logistic fit. 50 Determine the maximal response (E) by subtracting the lowest value from the highest value of the dose-response curve. max ) value.

[0327] Antagonist assay: 5 μL of test compound at increasing concentrations is added intracellularly in a 96-well plate, and the plate is incubated at 37°C (5% CO) for 30 min. Then, 5 μL of α-methylserotonin (final assay concentration), followed by 50 μL of alpha-methylserotonin (its measured EC 80 ) is added and the plate is incubated for 3 hours at room temperature. After the addition of 55 μL of prepared detection reagent and a further 1 hour of incubation, samples are read on an Envision luminescence plate reader. All assay points are determined in duplicate and data are presented as mean values. Curve fitting was performed using Prism software (Graphpad) and EC values ​​were calculated using a 4-parameter logistic fit. 50For antagonists, use the modified Cheng Prusoff formula: K B =IC 50 / (1+(A / EC 50A )) (where A is the concentration of the reference agonist alpha-methylserotonin and EC 50A is the EC value for the reference agonist alpha-methylserotonin 50 value) to calculate the apparent dissociation constant (K B ) is calculated.

[0328] For both the Gq signaling agonism assay and the beta-arrestin signaling agonism assay, EC 50 (concentration effective for 50% activation) and E max (maximum activation) is determined.

[0329] The maximum efficacy of the compound (E max ) is calculated as the percentage of the maximal signaling activity induced by the compound compared to the maximal signaling activity induced by the full agonist alpha-methylserotonin. This is an indicator of the intrinsic activity of the compound. Any degree of maximal activity lower than the maximal activity of the full agonist reference indicates that the test compound is a partial agonist.

[0330] Intrinsic activity (E max ), the relative intrinsic activity (RA i ) is another method for quantifying partial versus full agonism of receptor activity, but it also takes into account compound potency. It is calculated using the following formula:

[0331]

number

[0332] Bias score. The bias score (or bias ratio) is the relative intrinsic activity (RA) of Gq signaling to agonism. i Relative intrinsic activity (RA) for agonism of beta-arrestin signaling compared toi ) is calculated as the ratio of

[0333] The results are shown in the table below (RA i = relative intrinsic activity compared to the positive controls methylserotonin or altanserin).

[0334] [Table 8-1]

[0335] [Table 8-2]

[0336] [Table 8-3]

[0337] [Table 8-4]

[0338] [Table 8-5]

[0339] The compounds of Examples 2, 4, and 5 are each strong (full) antagonists of the Gq signaling pathway, with the compound of Example 4 having antagonist activity comparable to the unbiased reference compound of Formula A. Preferably, for non-hallucinogenic activity, the compound should have either antagonist activity in the Gq signaling pathway or partial agonist activity with low intrinsic efficacy. Full agonist activity (i.e., high intrinsic activity) in the Gq signaling pathway is thought to cause hallucinogenic side effects.

[0340] For maximum efficacy, the compounds of the present disclosure are preferably agonists of beta-arrestin-mediated signaling, either as partial agonists or full agonists. Therefore, in combination with the lack of agonist activity in the Gq pathway, they should be strongly biased toward beta-arrestin signaling. However, the compounds of Examples 2, 4, and 5 are antagonists of beta-arrestin signaling. For example, the compound of Example 4, like the compound of Formula A, has equally strong antagonist activity in both the Gq and beta-arrestin signaling pathways. Therefore, it may be a potent antidepressant and antipsychotic drug like lumateperone (ITI-007), but does not exhibit the hallmarks of the hallucinogenic antidepressant family.

[0341] In contrast, compounds of Examples 14, 15, and 16, in particular, exhibit partial agonist activity in the beta-arrestin assay and a significant bias toward beta-arrestin-mediated agonism, with compound of Example 15, in particular, having zero Gq-mediated agonist activity. Compounds of Examples 24, 25, and 40 also exhibit zero Gq-mediated agonist activity, but compound of Example 24 is a beta-arrestin antagonist and compounds of Examples 25 and 40 are beta-arrestin partial agonists.

[0342] The results collectively demonstrate a wide variety of functional activity profiles for compounds according to the present disclosure, each of which offers a variety of potential uses and secondary effect or side effect profiles.

[0343] The data further show a tendency that compounds with 2- or 3-atom side chain linkers preferentially activate the beta-arrestin signaling pathway with various levels of intrinsic activity. For example, compounds where n is 2 or 3 and Z is a bond, or compounds where n is 1 or 2 and Z is a group that leaves one atom between them (e.g., -C(O)-, -O-, or a group equivalent to carbonyl). For some embodiments, the side chain linker is preferably 3 atoms long, thus n is 3 and Z is a bond, or n is 2 and Z is a group that leaves one atom between them.

[0344] For example, a comparison of the results for the congener compounds of Examples 2, 3, 4, and 129, each with Z=—C(O)— with n ranging from 1 to 5, and Reference Compound A, suggests that having shorter or longer linkers can reduce or eliminate beta-arrestin agonist activity (n=1, 3, 4, 5) compared to the optimal length linker (n=2). Indeed, in this series, all compounds exhibited 5-HT antagonist activity. 2A Although they bind strongly to the receptor (Ki = 0.5-53 nM), only the compound in Example 3 exhibits not only beta-arrestin agonist activity but also Gq antagonist activity. In contrast, Compound A, where n = 3, is not an agonist but rather a potent beta-arrestin signaling antagonist and a Gq signaling antagonist.

[0345] The data suggest that the substituent pattern around the A ring is 5-HT, allowing for the linking group Z. 2AThe data also suggest that the binding mode of the compound to the receptor can be influenced. For some series of compounds, agonist versus antagonist binding can depend on the choice of group Z or the presence or absence of electron-donating or electron-withdrawing groups on ring A. This allows the desired activity of the molecule to be tuned by optimizing these various groups to achieve either strong agonism and / or strong antagonism in the signaling pathway, including mixed agonist / antagonist activity against beta-arrestin signaling (e.g., the compound of Example 34). The data suggest that small electron-donating groups on ring A can promote the beta-arrestin activity of agonists, while larger groups or electron-withdrawing groups on ring A can quench the beta-arrestin activity of agonists.

[0346] While the compounds of the present disclosure offer a variety of relevant receptor binding activities, it should be noted that the desirable antidepressant, anxiolytic, and other CNS therapeutic properties of hallucinogens are currently believed to be related to beta-arrestin signaling at 5-HT2A receptors, and it remains to be determined whether some degree of Gq signaling is also desirable. While strong Gq signaling leads to hallucinogenic effects, it is still possible that some degree of Gq signaling may be present, which may be beneficial for the therapeutic use of the compounds, without causing undue risk of hallucinogenic behavior. Indeed, patients without a history of psychosis or hallucinogen-induced persistent perception disorder (HPPD) may tolerate higher levels of Gq signaling, while patients with such a history may be best served by compounds that more completely lack Gq signaling.

[0347] [Example 183] In vivo characterization Selected compounds (test compounds) are subjected to rodent functional model assays to determine in vivo efficacy.

[0348] Head-to-head assay. 5-HT 2AAgonist-induced stereotyped head-shaking responses are used as a behavioral surrogate for hallucinations. See Halberstadt, et al., Neuropharmacology, 167, 107933 (2020). Head-shaking responses are an indicator of a compound's hallucinogenic potency in humans and occur almost immediately after administration of classic hallucinogens in rodents. By definition, head-shaking is a rapid movement of the head from one side to the other. Head-shaking is used to assess the potential hallucinogenic potential of compounds (up to 10 mg / kg) compared with a positive control DOI (2.5 mg / kg). Male C57bl / 6 mice (9 weeks old) are administered test compounds and vehicle via subcutaneous (SC) injection. Mice receiving the positive control DOI are administered intraperitoneal (IP) injections. Thirty minutes after treatment, a blinded observer records the number of head-shaking responses for 5 minutes.

[0349] Open-field test of anxiety-like behavior. Adult mice are allowed to habituate to the test room for 1 hour, then receive an 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. The session is filmed using Anymaze software (Stoelting Co., IL) using a ceiling-mounted camera. Locomotor activity is measured by the software within a given arena. Additional central arenas, all measuring 100 cm x 100 cm, are predefined for each zone.

[0350] Rat Social Interaction Test. Test compounds (0.3, 1.0, 3, and 3.0 mg / kg, or alternatively 1, 3, and 10 mg / kg) or vehicle (0.5% aqueous CMC) are injected SC 30 minutes before behavioral testing. During the test phase, pairs of identically treated Sprague-Dawley male rats are placed in a white Plexiglas open-field arena and allowed to interact for 6 minutes. Social interactions include sniffing the other rat, grooming the other rat, climbing on, under, or around the other rat, chasing the other rat, and exploring the other rat's anogenital region. The time the rats spent 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.

[0351] mTOR signaling in the prefrontal cortex (PFC). Male adult mice were SC injected with either test compound (1 mg / kg) or vehicle. 24 hours after injection, brain samples from the PFC region were collected, and synaptoneurosome-enriched fractions were collected and prepared for Western blotting. Quantitative analysis of phospho-protein immunoblots was performed to determine the total levels of each protein. Changes in the amounts of phosphorylated ERK, Akt, mTOR, and P70S6K proteins in the PFC were determined compared to vehicle-treated mice, as previously described (Dutheil, et al., J. Neuroscience, 43(5):863-77, 2023).

[0352] Compounds according to the present disclosure (e.g., Examples 3, 14, 15, 25, 40, 69, 70, 71, 72, 92, 98, 99, 107, 112, 117, 118) are found to induce non-hallucinogenic activity in test animals, increase social interaction, and / or reduce anxiety measures. For example, unlike serotonergic hallucinogens, even high doses of the test compounds up to 10 mg / kg do not induce hallucinogenic behavior, as indicated by head-shake rates comparable to those of controls (e.g., <10 head-shakes per 5 minutes, or less than 5 head-shakes or less than 1 head-shake per 5 minutes (mean results)) and substantially less than those induced by DOI (p<0.0001). The test compounds also show a dose-dependent increase in social interaction between rats, and data show that even the lowest tested dose of 0.3 mg / kg is effective. In the open field test, test compound is found to dose-dependently reduce anxiety-like behavior, including the time spent in the central arena and the number of times of entering the central arena, without changing the level of locomotor activity or immobility.The lowest dose tested, 1 mg / kg, is found to be effective.These results demonstrate functional anxiolytic activity.

[0353] The test compounds were also found to stimulate mTOR signaling in the medial PFC of mice, as demonstrated by increases in p-ERK, p-mTOR, and p-P70s6k in the brain regions tested. The mTOR signaling pathway has been shown to contribute to enhanced neuroplasticity and cognitive function, which is altered in brain regions associated with major depressive disorder. Rapid-acting antidepressants have been reported to stimulate this pathway in the prefrontal cortex.

[0354] [Example 184] Pharmacokinetic evaluation Compounds according to the present disclosure are subjected to a standard oral pharmacokinetics study protocol in Sprague-Dawley rats (male, 200-400 g). Test compounds are administered to rats either IV at 1 mg / kg or PO at 10 mg / kg using 0.05 M citrate phosphate buffer as the vehicle. Other potential vehicles include PEG-400 and aqueous 10% Trapposol / 1% Tween 80, depending on the compound's solubility. In some studies, a third group may utilize subcutaneous administration (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-dose. After treatment, plasma samples are analyzed for the presence of the test compound and, in some cases, for the presence of major predicted metabolites (e.g., N-des-methyl metabolites). The time to maximum concentration (Tmax), maximum plasma concentration (Cmax), and area under the curve (AUC) are calculated from the data. A comparison of the AUC values ​​for oral versus IV administration provides an indication of the oral bioavailability of the test compound.

[0355] Compounds tested include Examples 40, 99, 107, 112, 117, and 118. The compounds are found to have acceptable oral bioavailability.

[0356] The foregoing examples are merely illustrative and are not intended to limit the scope of the present disclosure in any way.

Claims

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

2. X is NH or N(R ａ ) (e.g., N(CH ３ 2. The compound of claim 1, wherein

3. X is S, S(O), S(O) ２ or O.

4. X is spiro bond C ３～６ 10. The compound of claim 1 which is a cycloalkyl (e.g., cyclopropane).

5. Y is CH ２ or —C(O)—.

6. Y is spiro bond C ３～６ 5. A compound according to any one of claims 1 to 4 which is cycloalkyl (e.g. cyclopropane).

7. Z is a bond, CH ２ 7. The compound according to claim 1, wherein the aryl group is —C(O)—, —C(O)—, or —O—.

8. A compound according to any preceding claim, wherein A is a 6-10 membered aryl ring, for example selected from phenyl and naphthyl, substituted by 0-5 groups R.

9. 8. The compound of any one of claims 1 to 7, wherein A is a 5-10 membered heteroaryl ring substituted by 0-5 groups R.

10. A is furan, thiophene (e.g., thiophen-2-yl), pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyridine (e.g., pyrid-4-yl), 2-oxopyridine (e.g., 2-oxopyridin-1(2H)-yl), pyrimidine, pyridazine, pyrazine, benzofuran (e.g., benzofuran-4-yl, or benzofuran-7-yl, or 2-methylbenzofuran-4-yl), dihydrobenzofuran (e.g., 2,3-dihydrobenzofuran-7-yl), benzothiophene, indole (e.g., indol-1-yl, indol-3-yl, or indol-5-yl), benzoxazole, benzothiazole, each substituted by 0 to 5 groups R.

8. A compound according to any one of claims 1 to 7, wherein the compound is selected from: 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).

11. 8. The compound of any of claims 1 to 7, wherein A is phenyl substituted with 0 to 5 groups R, each group R being independently selected from methyl, trifluoromethyl, methoxy, F, Cl, cyano, hydroxy, 2-methoxyethoxy, and (4-fluorobenzyl)oxy.

12. 12. The compound of any one of claims 1 to 11, selected from any one of the compounds of Examples 1 to 180.

13. 13. A compound according to any one of claims 1 to 12 in the form of a pharmaceutically acceptable salt.

14. 5-HT ２Ａ 14. The compound of any one of claims 1 to 13, which is an agonist of beta-arrestin receptor-mediated signaling.

15. 5-HT ２Ａ 14. The compound of any one of claims 1 to 13, which is an antagonist of beta-arrestin receptor-mediated signaling.

16. 5-HT ２Ａ 16. A compound according to any one of claims 1 to 15, which is neither an agonist nor an antagonist of receptor-mediated Gq signalling, or is a weak agonist or antagonist thereof.

17. 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 5-HT ２Ａ 17. The compound of any one of claims 1 to 16, having a bias ratio (beta-arrestin / Gq) for receptor agonism or antagonism.

18. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 in free or pharmaceutically acceptable salt form (e.g., a pharmaceutically acceptable salt form) in admixture with a pharmaceutically acceptable diluent or carrier.

19. A method for the treatment or prevention of central nervous system disorders, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 17, in free or pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 18.

20. 19. Use of a compound according to any one of claims 1 to 17, in free or pharmaceutically acceptable salt form, or a pharmaceutical composition according to claim 18, in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for the treatment or prevention of a central nervous system disorder.

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