CN120417904A

CN120417904A - Heterocyclic fused γ-carbolines acting on serotonin 5-HT2A receptors

Info

Publication number: CN120417904A
Application number: CN202380089238.3A
Authority: CN
Inventors: 李鹏; R·戴维斯; G·斯奈德; 张蕾; 郑海林; 乔玉普; 张强
Original assignee: Intra Cellular Therapies Inc
Current assignee: Intra Cellular Therapies Inc
Priority date: 2022-12-30
Filing date: 2023-12-29
Publication date: 2025-08-01
Also published as: KR20250123225A; CO2025009460A2; IL321185A; MX2025007656A; WO2024145659A1; AU2023418793A1

Abstract

本发明涉及如本文所述的呈游离、固体、药学上可接受的盐和/或基本上纯形式的特定取代的杂环稠合γ‑咔啉，其药物组合物，以及作为针对血清素(5‑HT_2A)受体的非致幻偏向激动剂或拮抗剂的使用方法，特别是具有偏向β‑抑制蛋白信号传导通路的激动作用。此类化合物可用于治疗情绪障碍、广泛性焦虑症、社交焦虑症、抑郁症、快感缺失和其他神经精神疾病。The present invention relates to specific substituted heterocyclic fused γ-carbolines as described herein in free, solid, pharmaceutically acceptable salt, and/or substantially pure form, pharmaceutical compositions thereof, and methods of use as non-psychedelic biased agonists or antagonists at serotonin (5-HT _2A ) receptors, particularly with biased agonism toward the β-arrestin signaling pathway. Such compounds are useful in treating mood disorders, generalized anxiety disorder, social anxiety disorder, depression, anhedonia, and other neuropsychiatric conditions.

Description

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

Cross Reference to Related Applications

The present application is an international application claiming priority and benefit from U.S. provisional application serial No. 63/478,010 filed at 12, 30, 2022 and U.S. provisional application serial No. 63/603,617 filed at 11, 2023, 28, each of which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to specific substituted heterocyclic fused gamma-carbolines in free, solid, pharmaceutically acceptable salt and/or substantially pure form, pharmaceutical compositions thereof, and methods of use as non-fantasy biased agonists or antagonists against serotonin (5-HT _2A) receptors, particularly having agonism biased towards the beta-arrestin signaling pathway, or as serotonin (5-HT _2A) receptor antagonists, as described herein. Such compounds are useful in the treatment of mood disorders, generalized anxiety disorder, social anxiety disorder, depression, schizophrenia, anorgasmia, and other neuropsychiatric disorders.

Background

Serotonin, also known as 5-hydroxytryptamine (5-HT), is a neurotransmitter that is widely distributed in the brain. Deregulation of serotonergic signaling in the brain has been implicated in the pathogenesis of several neuropsychiatric diseases. Drugs that target 5-HT directly or indirectly, such as 5-HT ₂ receptor agonists and selective serotonin reuptake inhibitors, are widely used in psychiatry for the treatment of a number of mood disorders and for the treatment of psychosis. However, potent 5-HT ₂ agonists tend to lead to hallucinations, which are a dangerous side effect. Serotonergic magic hallucinogens are powerful psychoactive substances that alter both perception and mood, and they may be useful for restoring the function of a dysregulated serotonergic network in the brain. Studies have shown that classical hallucinogen serotonin agonists, such as LSD (D-lysergic acid diacetamide) and galectin (psilocybin) (through its active metabolite, deglutition to galectin (psilocin)), may be very effective in treating many neuropsychiatric disorders, especially depression, but these drugs are not practical due to their hallucinogenic side effects. Fantasy hallucinogens can cause extreme pain (i.e., a "hallucination experience") or persistent or intermittent psychosis, can promote self-injury or injury to others, and are prone to abuse and dependence. Furthermore, serotonergic drugs with 5-HT _2B agonist activity have been reported to cause heart valve disease and/or pulmonary hypertension. Accordingly, efforts have been made to develop novel compounds similar to the hallucinogens with pharmacological profiles for the treatment of mood and other CNS disorders, but without the risk of hallucinations, abuse liabilities, or heart valve diseases.

One well known non-fanciful hallucinogen analog, ergoethylurea, developed in the 70 s of the 20 th century, has been used to treat parkinsonism and migraine attacks. Two non-fanciful hallucinogen analogs have recently been described as having antidepressant-like behavior. Cameron et al produced a novel compound tabernanthalog by modifying the backbone core of the natural hallucinogen ibogaine (ibogaine). Nature,589:474-79 (2021), cell,184:2779-92.e18 (2021). Similarly, the novel analog AAZ-A-154 was derived based on the well-known hallucinogen 5-methoxydimethyiprimary amine, dong et al. However, neither group developed any structure-activity guidance for these compounds, and therefore it was not clear how to rationally design non-fanciful hallucinogen analogs.

There are seven families of serotonin receptors numbered 5-HT ₁ through 5-HT ₇. Except for 5-HT ₃, a ligand-gated ion channel, all serotonin receptors have long been known as G-protein coupled receptors (GPCRs). GPCRs have an intracellular domain that binds to heterotrimeric G proteins. The G protein consists of alpha, beta and gamma subunits in the complex. The G protein heterotrimers are typically in an inactive state and bind to guanosine diphosphate ligands. Binding of agonists to GPCRs results in conformational changes of the intracellular domains of the protein, allowing them to catalyze the exchange of bound GDP with GTP molecules (guanosine triphosphate). This results in the activation of the G protein and its dissociation from the intracellular domain of the GPCR. In particular, the G protein alpha subunit (G-alpha) dissociates and diffuses into the cytosol. There are many types of G-alpha proteins, which differ in their functional roles. Some G-alpha proteins, including G _i、G_o and G _s, modulate the level of cytoplasmic second messenger cAMP (cyclic adenosine monophosphate) by activating or deactivating adenylate cyclase. The G- α -q variant (G _q) acts by activating the phospholipase C enzyme, which cleaves phosphatidylinositol diphosphate (PIP ₂) to form the two second messengers inositol triphosphate (IP ₃) and Diacylglycerol (DAG). IP3 stimulates calcium release from intracellular storage sites, resulting in activation of various calcium-dependent kinases, and DAG stimulates Protein Kinase C (PKC) activation. Since G protein is a rich soluble cytoplasmic protein, agonist-activated GPCRs (which have activated and released their G protein) may bind to additional GDP-binding heterotrimers, thereby activating and releasing the second GTP-binding G-a subunit and so on until the receptor is deactivated.

GPCRs are inactivated in a two-step process. First, they are phosphorylated by a family of enzymes known as G Receptor Kinases (GRKs). This greatly reduces the affinity of the active site of the GPCR for G proteins. In the second step, β -arrestin can competitively bind to the active site of the phosphorylated GPCR, resulting in complete inhibition of G protein binding. The inhibitor protein-GPCR complex then targets the inactive receptor for intracellular recycling or degradation.

Beta-arrestins were originally thought to play a role only in inactivating and targeting the inactivated GPCRs for recycling or degradation. However, it has become increasingly apparent over the past few years that β -arrestins also play a new role in G-protein independent signaling mechanisms. Clearly, the GPCR-arrestin complex produced upon agonist-induced receptor activation and inactivation can act as a scaffold that attracts many other proteins to form a large polyprotein complex. These complexes may then cause 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 in close proximity so that one can phosphorylate the other. The inhibitor protein complex may promote this phosphorylation by binding to both kinase proteins simultaneously. Thus, β -arrestin signaling provides an alternative mechanism for GPCR signaling that is independent of G-protein induced signaling cascades and second messengers.

Signaling bias is the concept that some ligands will bind to GPCRs in such a way as to bias the receptor toward or away from one of the two signaling pathways, G protein-mediated signaling and β -arrestin-mediated information transduction. Several examples of such biased GPCR ligands have been found and create the possibility for functionally selective receptor agonism. For example, mu Opioid Receptor (MOR) is a GPCR coupled to the G _i type alpha subunit, so agonist binding results in inhibition of adenylate cyclase activity and a decrease in cytoplasmic cAMP levels. This G-protein mediated pathway has been found to be responsible for the analgesic activity of morphine and other opioids. However, the recruitment of β -arrestin to the receptor is responsible for the primary opioid side effects, respiratory depression and gastrointestinal motility inhibition. Various MOR ligands have been found that exhibit a bias toward G protein signaling and away from β -arrestin signaling, resulting in improved analgesic efficacy and reduced side effect profiles. This reflects a higher efficacy for agonism via one pathway or another, or even agonism of one pathway and antagonism of another.

Although the 5-HT ₁、5-HT₄、5-HT₅、5-HT₆ and 5-HT ₇ receptors are coupled to G proteins that regulate cAMP, the 5-HT ₂ receptor family is GPCRs coupled to Gq proteins, resulting in a classical signaling cascade mediated by the phosphatidylinositol pathway. It has also been found that the 5-HT ₂ receptor is also capable of activating the beta-inhibitor signaling cascade. It is believed that serotonin agonists must agonize both the G protein signaling pathway and the β -catenin signaling pathway of the 5-HT _2A receptor to cause a hallucination, while agonists that selectively agonize the β -catenin pathway without agonizing the G protein-coupled pathway can provide relief from mood disorders, anxiety disorders, and other CNS disorders without causing unreasonable side effects.

For example, cao et al have recently studied the binding of various compounds to the 5-HT _2A receptor using high resolution X-ray crystallography, including serotonin, dephosphorylated nupharin, LSD, the non-magic hallucinogen analog ergofluorone and Lu Meipai (lumateperone). Science,375:403-11 (2022). They identified a new binding pattern of serotonin and dephosphorylated nupharicin. Traditionally, LSD, ergofluorone, serotonin and dephosphorylated nupharicin are thought to bind in a so-called "orthotopic binding pocket (orthostatic binding pocket, OBP)". In this binding mode, the polycyclic cores of LSD and ergofluorourea bind low in OBP, while the side chains of LSD and ergofluorourea protrude into the so-called "Extended Binding Pocket (EBP)". In contrast, the indole cores of serotonin and dephosphorylated nupharicin were located higher in the OBP, closer to the EBP, but did not protrude significantly into the EBP.

Surprisingly, cao et al found that serotonin and dephosphorylated nuphar had a second binding pattern that was flipped such that the indole core was in EBP with only minimal presence above OBP. The data generated by Cao further suggests that this second binding mode is responsible for increased β -inhibitor protein recruitment by the receptor, thus explaining the presence of biased serotonin receptor agonism. They also provide evidence that G _q -mediated signaling is responsible for the hallucinogenic effects of traditional hallucinogens, and that ligands biased toward β -inhibitor recruitment may provide therapeutic benefits of hallucinogens, such as antidepressant effects, without hallucinogenic side effects.

Substituted heterocyclic fused gamma-carbolines are known to be agonists or antagonists of the 5-HT ₂ receptor, particularly the 5-HT _2A receptor, and are useful in the treatment of central nervous system disorders. These compounds are generally disclosed in U.S. patent nos. 6,548,493, 7,238,690, 6,552,017, 6,713,471, 7,183,282, u.s.re 39.680, and u.s.re 39,679. U.S. patent 8,309,722 and U.S. patent 7,081,455 disclose methods for preparing such substituted heterocyclic fused gamma-carbolines, and the use of these gamma-carbolines as serotonin agonists and antagonists for the control and prevention of central nervous system disorders such as addictive behaviors and sleep disorders.

In addition, U.S. patent 8,598,119 discloses the use of certain substituted heterocyclic fused gamma-carbolines for the treatment of combinations of psychosis and depressive disorders, and sleep, depression, and/or mood disorders in patients suffering from psychosis or parkinson's disease. In addition to disorders associated with psychosis and/or depression, the present patent application also discloses and claims the use of these compounds at low doses to selectively antagonize the 5-HT _2A receptor without affecting the dopamine D ₂ receptor or minimally affecting the dopamine D ₂ receptor, and thus may be used to treat sleep disorders without the side effects associated with the high occupancy of the dopamine D ₂ pathway or with conventional sedative hypnotics (e.g., benzodiazepinesClass) of other pathways (e.g., GABA _A receptor). U.S. patent 8,648,077 discloses a process for preparing crystals of toluene sulfonic acid addition salts of these substituted heterocycle fused gamma-carbolines.

The evidence disclosed in US2021/006009 shows that the above substituted fused heterocyclic gamma-carbolines can act in part by glutamate (NMDA and AMPA receptor) receptor activation, leading to enhanced mTOR1 signalling in a manner similar to ketamine. Ketamine is a selective NMDA receptor antagonist. Ketamine works through a system unrelated to the common psychotropic monoamines (serotonin, norepinephrine, and dopamine), and this may be the main reason for its much faster onset. Ketamine directly antagonizes the extrasynaptic glutamatergic NMDA receptor, which also reduces gabaergic inhibition, resulting in indirect activation of AMPA-type glutamate receptors. Downstream effects of AMPA receptor activation are related to an increase in brain-derived neurotrophic factor (BDNF) levels and activation of the mTORC1 kinase pathway. As with ketamine, recent evidence suggests that compounds related to the present disclosure increase both NMDA and AMPA-induced currents in rat medial prefrontal cortex pyramidal neurons via activation of D1 receptors, and this is associated with an increase in mTORC1 signaling.

US10,245,260 discloses novel oxo metabolites of substituted heterocyclic fused gamma-carbolines as disclosed in the above publications. These novel oxo metabolites retain many of the unique pharmacological activities of the parent compound, including serotonin receptor inhibition, SERT inhibition and dopamine receptor modulation. However, it was unexpectedly found that these oxo metabolites also show significant activity at mu opioid receptors. Analogs of these novel compounds are also disclosed, for example, in publications US10,906,906 and US10,961,245.

One such substituted heterocyclic fused gamma-carboline in the above art is Lu Meipai long shown below,

The chemical name is (4- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-lH-pyrido [3',4':4,5] pyrrolo [ l,2,3-de ] quinoxalin-8 (7H) -yl) -l- (4-fluorophenyl) -l-butanone). It is known to be an extremely potent serotonin receptor (5-HT _2A) antagonist, as well as a modulator of dopamine receptor (D1 and/or D2) signaling and serotonin transporter (SERT) antagonist, and it is useful in the treatment of a variety of central nervous system disorders. It is also known as ITI-007.

Lu Meipai Long Jie antisera to the serotonin-2A (5-HT _2A) receptor, and/or to modulate dopamine receptor signaling at key intracellular phosphoprotein levels. The compounds are primarily known to be useful in the treatment of positive and negative symptoms of schizophrenia, depression (especially acute depression and bipolar depression), anxiety and traumatic disorders (including acute anxiety and post-traumatic stress disorders), and dementia (including Alzheimer's disease and its related symptoms). Lu Meipai as an antidepressant is associated with its antagonism of the 5-HT _2A receptor and its inhibition of the serotonin transporter (SERT), a pharmacological feature common to the SARI class of antidepressants (serotonin antagonists and reuptake inhibitors), which SARI class of antidepressants include trazodone (trazodone), nefazodone (nefazodone), loppiprazole (lorpiprazole) and mepiprazole (mepiprazole).

For the dopamine D2 receptor, lu Meipai has dual properties and acts as both a postsynaptic antagonist and a presynaptic partial agonist of the D2 receptor. It also stimulates phosphorylation of glutamatergic NMDA NR2B (or GluN B) receptors in a mesencephalon limbic specific manner. It is believed that this regioselectivity of the brain region is believed to mediate the therapeutic effects of antipsychotics, along with serotonergic, glutamatergic and dopaminergic interactions, potentially producing antipsychotic effects on positive, negative, affective and cognitive symptoms associated with schizophrenia. The compounds also exhibit inhibition of serotonin reuptake, providing antidepressant activity for the treatment of schizoaffective disorders, co-morbid depression and/or as independent treatment of major depressive disorder. Lu Meipai also has utility in the treatment of bipolar disorders and other psychiatric and neurodegenerative disorders, particularly behavioral disorders associated with dementia, autism and other CNS disorders. These features may be able to improve the quality of life of patients suffering from schizophrenia, enhancing social functions to allow them to more fully integrate into their home and their workplace.

Toluene sulfonic acid Lu Meipai longCurrently available in the united states for the treatment of schizophrenia and bipolar depression. It is currently being clinically tested and developed for additional indications, including Major Depressive Disorder (MDD).

The functional effects of rufipirone on beta-arrestin recruitment and G _q -mediated signaling pathways induced by binding to the 5-HT _2A receptor have not been previously disclosed. The inventors have found that Lu Meipai ron is a potent antagonist of the 5-HT _2A receptor in both beta-arrestin and G _q function assays.

There remains a need for new compounds that have efficacy in the treatment of neuropsychiatric disorders, especially depression, anxiety and schizophrenia. Compounds having a strong biased agonism (e.g., full or partial agonism) for the recruitment of β -arrestin to the 5-HT2A receptor would be particularly beneficial to provide a non-fantasy antidepressant or anxiolytic effect.

Disclosure of Invention

In a first aspect, the present disclosure relates to compounds of formula I (compound I):

Wherein:

X is S, S (O), S (O) ₂、O、CH₂、CHR^b、C(R^b)₂、NH、N(R^a) (e.g., N(CH₃))、N-C(O)-R^a、N-C(O)-O-R^a、N-C(O)-O-CH₂-O-R^a、N-CH₂-O-C(O)-R^a、N⁺(＝O^–)、 spiro-linked C _3-6 cycloalkyl (e.g., cyclopropane) or spiro-linked 3-6 membered heterocycloalkyl (e.g., aziridine or oxetane), wherein the spiro-linked C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more groups selected from C _1-6 alkyl (e.g., methyl), halo C _1-6 alkyl (e.g., trifluoromethyl), C _1-6 alkoxy (e.g., methoxy), C _3-6 cycloalkyl (e.g., cyclopropyl), C _3-6 cycloalkoxy (e.g., cyclopropoxy), and hydroxy;

Y is CH ₂、CHR^c、-C(O)-、C(R^c)₂, a spiro-linked C _3-6 cycloalkyl (e.g., cyclopropane), or a spiro-linked 3-6 membered heterocycloalkyl (e.g., aziridine or oxetane), wherein said spiro-linked C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more groups selected from C _1-6 alkyl (e.g., methyl), halo C _1-6 alkyl (e.g., trifluoromethyl), C _1-6 alkoxy (e.g., methoxy), C _3-6 cycloalkyl (e.g., cyclopropyl), C _3-6 cycloalkoxy (e.g., cyclopropoxy), and hydroxy;

Z is a bond, -S-, 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) -, a spiro-linked C _3-6 cycloalkyl (e.g., cyclopropane), a spiro-linked 3-6 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), wherein the spiro-linked C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more groups selected from C _1-6 alkyl (e.g., methyl), halo C _1-6 alkyl (e.g., trifluoromethyl), C _1-6 alkoxy (e.g., methoxy), C _3-6 cycloalkyl (e.g., cyclopropyl), C _3-6 cycloalkoxy (e.g., cyclopropyloxy), and hydroxy;

A is H, C _3-6 cycloalkyl (e.g., cyclopropyl or cyclohexyl), aryl (e.g., phenyl), or heteroaryl, wherein the cycloalkyl, aryl, or heteroaryl is substituted with 0-5 groups R;

Each R is independently selected from aryl (e.g., phenyl), aryloxy (e.g., phenoxy), heteroaryl (e.g., pyridyl), C _1-6 alkyl (e.g., methyl, ethyl), halogenated C _1-6 alkyl (e.g., trifluoromethyl), C _1-6 alkylsulfonyl (e.g., methylsulfonyl), and, C _1-6 alkoxy (e.g., methoxy, ethoxy), C _1-6 alkylthio (e.g., methylthio), halogen (e.g., F), cyano, C _3-6 cycloalkyl (e.g., cyclopropyl), C _3-6 cycloalkoxy (e.g., cyclopropyloxy), or hydroxy, wherein the aryl group, Each of heteroaryl, alkyl, haloalkyl, alkylsulfonyl, alkoxy, alkylthio, cycloalkyl or cycloalkoxy optionally further substituted with one or more groups selected from aryl (optionally substituted with halogen), halogen, C _1-6 alkyl (e.g., methyl), halo C _1-6 alkyl (e.g., trifluoromethyl), C _1-6 alkylsulfonyl (e.g., methylsulfonyl), 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., cyclopropyloxy), Amino, C _1-6 alkylamino (e.g., methylamino), di (C _1-6 alkyl) amino (e.g., dimethylamino), (C _1-6 alkyl) (C _1-6 alkyl) amino (e.g., methylethylamino), and hydroxy;

R ^a and R ^d are each independently selected from 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 selected from C _1-6 alkyl (e.g., methyl, ethyl, t-butyl), C _1-6 alkoxy, C _3-6 cycloalkyl (e.g., cyclopropyl), C _3-6 cycloalkoxy (e.g., cyclopropyloxy), and C _1-2 alkylaryl (e.g., benzyl or phenethyl);

m is 1 or 2;

n is 1, 2, 3, 4 or 5;

the compound I is in free or salt form (e.g., pharmaceutically acceptable salt form);

With the proviso that when Z is-C (O) -, X is CH ₂ or O, and m is 2, n is not 3, and

With the proviso that when Z is-C (O) -, X is CH ₂, and m is 1, n is not 3, and

Provided that when Z is-C (O) -or-O-, X is NH or N (R ^a), and m is 1, N is not 3;

and with the proviso that when Z is O, X is NCH ₃, Y is-C (O) -, and m is 1, n is not 3.

The present disclosure further provides further embodiments of the first aspect, comprising:

1.1 Compounds I, wherein X is S, S (O), or S (O) ₂;

1.2 Compounds I, wherein X is O;

1.3 Compounds I, wherein X is CH ₂、CHR^b or C (R ^b)₂;

1.4 Compound 1.3 wherein R ^b is independently C _1-6 alkyl (e.g., methyl);

1.5 Compounds I, wherein X is CH ₂;

1.6 Compounds I, wherein X is NH;

1.7 Compounds I, wherein X is N (R ^a);

1.8 Compounds I, wherein X is N-C (O) -R ^a;

1.9 Compounds I, wherein X is N-C (O) -O-R ^a;

1.10 Compounds I, wherein X is N-C (O) -O-CH ₂-O-R^a;

1.11 Compounds I, wherein X is N-CH ₂-O-C(O)-R^a;

1.12 compound I, or any one of 1.7-1.11, wherein R ^a is C _1-2 alkylaryl (e.g., benzyl or phenethyl);

1.13 compound I, or any one of 1.7-1.11, wherein R ^a is C _1-20 alkyl (e.g. methyl or tert-butyl);

1.14 compound I, or any one of 1.7-1.11, wherein R ^a is C _10-20 alkyl (e.g., decyl or dodecyl);

1.15 Compound I, or any one of 1.7-1.11, wherein R ^a is C _1-15 alkyl (e.g., hexyl or octyl);

1.16 compound I, or any one of 1.7-1.11, wherein R ^a is C _7-15 alkyl (e.g., heptyl or nonyl);

1.17 compound I, or any one of 1.7-1.11, wherein R ^a is C _1-6 alkyl (e.g., butyl or hexyl);

1.18 compound I, or any one of 1.7-1.11, wherein R ^a is C _1-4 alkyl (e.g., n-butyl or t-butyl);

1.19 compound I, or any one of 1.7-1.11, wherein R ^a is C _1-3 alkyl (e.g., propyl or isopropyl);

1.20 compound I, or any one of 1.7-1.11, wherein R ^a is C _1-2 alkyl (e.g., methyl or ethyl);

1.21 compound I, or any one of 1.7-1.11, wherein X is N (CH ₃);

Compound I, wherein X is a spiro-linked C _3-6 cycloalkyl (e.g., cyclopropane);

1.23 Compound 1.22 wherein the spiro-linked C _3-6 cycloalkyl is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane and cyclohexane;

1.24 Compound 1.22 wherein the spiro-linked C _3-6 cycloalkyl is cyclopropane;

1.25 Compound I, wherein X is a spiro-linked 3-6 membered heterocycloalkyl (e.g., aziridine or oxetane);

1.26 Compound 1.25 wherein the spiro-linked 3-6 membered heterocycloalkyl is selected from the group consisting of aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine and morpholine;

1.27 Compound 1.25 wherein the spiro-linked 3-6 membered heterocycloalkyl is selected from aziridine;

1.28 compound I, or any one of 1.22-1.27, wherein the spiro-linked C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted;

Compound I, or any one of 1.22-1.27, wherein the spiro-linked C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is substituted with one or more groups selected from:

C _1-6 alkyl (e.g., methyl), halo C _1-6 alkyl (e.g., trifluoromethyl), C _1-6 alkoxy (e.g., methoxy), C _3-6 cycloalkyl (e.g., cyclopropyl), C _3-6 cycloalkoxy (e.g., cyclopropyloxy), and hydroxy;

1.30 compound I, or any one of 1.1-1.29, wherein Y is CH ₂;

1.31 compound I, or any one of 1.1-1.29, wherein Y is-C (O) -;

Compound I, or any one of 1.1-1.29, wherein Y is CHR ^c or C (R ^c)₂;

1.33 Compound 1.32, wherein each R ^c is independently C _1-6 alkyl;

1.34 Compound 1.32, wherein each R ^c is independently selected from methyl, ethyl, and propyl;

1.35 compound I, or any one of 1.1-1.29, wherein Y is a spiro-linked C _3-6 cycloalkyl (e.g., cyclopropane);

1.36 Compound 1.35 wherein the spiro-linked C _3-6 cycloalkyl is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane and cyclohexane;

1.37 compound 1.35 wherein the spiro-linked C _3-6 cycloalkyl is cyclopropane;

1.38 compound I, or any one of 1.1-1.29, wherein Y is a spiro-linked 3-6 membered heterocycloalkyl (e.g. aziridine or oxetane);

1.39 Compound 1.38 wherein the spiro-linked 3-6 membered heterocycloalkyl is selected from the group consisting of aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine and morpholine;

1.40 Compound 1.39 wherein the spiro-linked 3-6 membered heterocycloalkyl is aziridine;

1.41 compound I, or any one of 1.35-1.40, wherein the spiro-linked C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted;

Compound I, or any one of 1.35-1.40, wherein the spiro-linked C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is substituted with one or more groups selected from:

1.43 compound I, or any one of 1.1-1.42, wherein Z is a bond;

1.44 compound I, or any one of 1.1-1.42, wherein Z is S, S (O) or S (O) ₂;

1.45 compound I, or any one of 1.1-1.42, wherein Z is O;

1.46 compound I, or any one of 1.1-1.42, wherein Z is NH;

1.47 compound I, or any one of 1.1-1.42, wherein Z is N (R ^a), e.g., N (CH ₃);

1.48 compound I, or any one of 1.1-1.42, wherein Z is-C (O) -;

Compound I, or any one of 1.1-1.42, wherein Z is-C (OH) -, -C (OC _1-6 alkyl), -C (=n-OH) -, -C (=n-OC _1-6 alkyl) -, optionally wherein the C _1-6 alkyl is methyl;

1.50 compound I, or any one of 1.1-1.42, wherein Z is a spiro-linked C _3-6 cycloalkyl (e.g. cyclopropane);

1.51 Compound 1.50 wherein the spiro-linked C _3-6 cycloalkyl is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane and cyclohexane;

1.52 compound 1.50 wherein the spiro-linked C _3-6 cycloalkyl is cyclopropane;

1.53 compound I, or any one of 1.1-1.42, wherein Z is a spiro-linked 3-6 membered heterocycloalkyl (e.g. aziridine or oxetane);

1.54 Compound 1.53 wherein the spiro-linked 3-6 membered heterocycloalkyl is selected from the group consisting of aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, tetrahydropyran, piperazine and morpholine;

1.55 Compound 1.53 wherein the spiro-linked 3-6 membered heterocycloalkyl is aziridine;

Compound I, or any one of 1.49-1.55, wherein said spiro-linked C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is unsubstituted;

Compound I, or any one of 1.49-1.55, wherein the spiro-linked C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is substituted with one or more groups selected from:

1.58 Compounds I, or 1.1 to 1.57, wherein A is a 6-10 membered aryl ring substituted with 0 to 5 groups R, for example selected from phenyl and naphthyl;

1.59 compound I, or any one of 1.1-1.57, wherein a is a 5-10 membered heteroaryl ring substituted with 0-5 groups R;

1.60 Compounds 1.59 wherein A is selected from furan, thiophene (e.g., thiophen-2-yl), pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyridine (e.g., pyridin-4-yl), 2-oxopyridine (e.g., 2-oxopyridin-1 (2H) -yl), pyrimidine, pyridazine, pyrazine, benzofuran (e.g., benzofuran-4-yl, or benzofuran-7-yl, or 2-methylbenzofuran-4-yl), dihydrobenzofuran (e.g., 2, 3-dihydrobenzofuran-7-yl), benzothiophene, indole (e.g., indol-1-yl, indol-3-yl, or indol-5-yl), benzoxazole, benzothiazole, benzimidazole (e.g., benzo)

[D] Imidazol-1-yl), benzisoxazoles (e.g. benzo [ d ] isoxazol-3-yl or benzo

[D] Isoxazol-4-yl), benzisothiazoles (e.g., benzo [ d ] isothiazol-3-yl), benzotriazoles (e.g., benzo [ d ] [1,2, 3-triazol-1-yl), indazoles (e.g., indazol-1-yl, indazol-3-yl, or indazol-7-yl), quinolines (e.g., quinolin-8-yl), isoquinolines (e.g., isoquinolin-7-yl), quinazolines (e.g., quinazolin-7-yl), and quinoxalines (e.g., quinoxalin-5-yl);

1.61 Compound 1.60 wherein A is substituted with 0 groups R;

1.62 Compound 1.60, wherein A is substituted with 1 group R;

1.63 Compound 1.60, wherein A is substituted with 2 groups R;

1.64 Compound 1.58 wherein A is a benzene ring substituted with 0 to 5 groups R;

1.65 Compound 1.64, wherein one group R is present;

1.66 Compound 1.65, wherein the group R is located at the para position of the benzene ring;

1.67 Compound 1.65 wherein the group R is in the meta position of the benzene ring;

1.68 Compound 1.65, wherein the group R is located in the ortho position to the benzene ring;

1.69 compound 1.64, wherein two groups R are present;

1.70 Compound 1.69 wherein the group R is located in the ortho and para positions of the benzene ring;

1.71 Compound 1.69 wherein the group R is located in the meta and para positions of the benzene ring;

1.72 Compound 1.69 wherein the group R is ortho and meta on the same side of the benzene ring;

1.73 Compound 1.69 wherein the groups R are ortho and meta on opposite sides of the benzene ring;

1.74 Compound 1.69 wherein the group R is located in both ortho positions of the benzene ring;

1.75 Compound 1.69 wherein the group R is located in two meta positions of the benzene ring;

1.76 Compound 1.64, wherein three groups R are present;

1.77 Compound 1.76 wherein the group R is located in both ortho and para positions of the benzene ring;

1.78 Compound 1.64, wherein four groups R are present;

1.79 compound 1.64 wherein five groups R are present;

1.80 compound I, or any one 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, cyclopropyloxy, cyclopropylmethoxy, methylamino, 4-fluorophenoxy, and (4-fluorobenzyl) oxy;

1.81 Compounds I, or 1.1 to 1.80, wherein A is selected from the group consisting of phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 2-ethylphenyl,

3-Ethylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 3-fluoro-4-fluorophenyl, 2-cyano-4-fluorophenyl, 3-cyano-4-fluorophenyl, 2-methyl-4-fluorophenyl, 3-methyl-4-fluorophenyl, 2-methoxy-5-fluorophenyl, 2-fluoro-4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 2-hydroxyphenyl, 2, 5-dimethoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 2- (methylsulfonyl) phenyl, 3- (methylthio) phenyl, 4- (methoxyethoxy) phenyl, 4- (4-fluorobenzyloxy) phenyl, 4- (4-fluorophenoxy) phenyl, 3-cyclopropoxyphenyl, 3- (cyclopropylmethoxy) phenyl and 2- (methylamino) phenyl;

1.82 Compound I, or any one of 1.1-1.80, wherein A is selected from pyridin-4-yl, thiophene

-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;

1.83 compound I, or any one of 1.1-1.80, wherein a is selected from 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 compound I, or any one of 1.1-1.83, wherein m is 1;

1.85 compound I, or any one of 1.1-1.83, wherein m is 2;

1.86 compound I, or any one of 1.1-1.85, wherein n is 2;

1.87 compound I, or any one of 1.1-1.85, wherein n is 3;

1.88 compound I, or any one of 1.1-1.85, wherein n is 4;

1.89 compound I, or any one of 1.1-1.85, wherein n is 5;

Compound I, or any one of 1.1-1.89, wherein X is S, O, CH ₂、NH、N(CH₃) or a spiro-linked cyclopropyl, Y is CH ₂, C (O) or a spiro-linked cyclopropyl, and Z is a bond, -O-, -C (O) -, -O (CH ₂)₂ O-, or-C (=noch ₃) -;

1.91 compound I, or any one of 1.1 to 1.89, wherein X is N (CH ₃) or spiro-linked cyclopropyl, Y is CH ₂, C (O) or spiro-linked cyclopropyl, and Z is a bond, -O-, or-C (O) -;

compound I, or any one of 1.1-1.91, of formula 92, wherein the compound of formula I is a compound of formula Ia:

wherein n, Z and a are as defined in any of the preceding embodiments;

Compound I, or any one of 1.1-1.91, of formula I wherein the compound of formula I is a compound of formula Ib:

wherein n, Z and a are as defined in any of the preceding embodiments;

compound I, or any one of 1.1-1.91, of formula I wherein the compound of formula I is a compound of formula Ic:

wherein n, Z and a are as defined in any of the preceding embodiments;

1.95 compound I, or any one of 1.1-1.91, wherein the compound of formula I is a compound of formula Id:

wherein n, Z and a are as defined in any of the preceding embodiments;

1.96 compound I, or any one of 1.1-1.91, wherein the compound of formula I is a compound of formula Ie:

wherein n, Z and a are as defined in any of the preceding embodiments;

1.97 compound I, or any one of 1.1-1.96, wherein n is 4 and Z is a bond;

1.98 compound I, or any one of 1.1-1.96, wherein n is 3 and Z is-O-or-C (O) -;

1.99 compound I, or any one of 1.1-1.96, wherein n is 3 and Z is a bond;

1.100 compound I, or any one of 1.1-1.96, wherein n is 2 and Z is-O-or-C (O) -;

1.101 compound I, or any one of 1.1-1.96, wherein n is 2 and Z is a bond;

1.102 compound I, or any one of 1.1-1.96, wherein n is 1 and Z is-O-or-C (O) -;

1.103 compound I, or any one of 1.1-1.96, wherein n is 1 and Z is a bond;

1.104 compound I, or any one of 1.1-1.103, wherein a is H or C _3-6 cycloalkyl (e.g. cyclopropyl or cyclohexyl), Z is a bond or-C (O) -and n is 1, 2 or 3;

1.105 compound I, or any one of 1.1-1.103, wherein the compound is selected from the group consisting of:

each independently in free or pharmaceutically acceptable salt form;

Compound I, or any one of 1.1-1.105, wherein the compound is a compound of any one of embodiments 1to 180 or is selected from:

Wherein the variables are defined as provided in any one of the following embodiments:

Each independently in free or pharmaceutically acceptable salt form, wherein Cyp refers to a spiro-linked cyclopropyl ring;

Compound I of 1.107, or any one of 1.1-1.105, wherein the compound is selected from the group consisting of:

Compound I, or any one of 1.1-1.107, in free form;

1.109 compound I, or any one of 1.1-1.107, in salt form, e.g. in pharmaceutically acceptable salt form;

Compound I, or any one of 1.1-1.107, wherein the compound is in the form of an acid addition salt, e.g., hydrochloric acid or tosylate salt;

1.111 compound I, or any one of 1.1-1.10, in substantially pure diastereomeric form (i.e., substantially free of other diastereomers);

1.112 compound I or any one of 1.1 to 1.110, having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%;

1.113 compound I or any one of 1.1 to 1.112, in solid form, for example in crystalline form;

Compound I or any one of 1.1-1.113, 1.114, in isolated or purified form (e.g., in at least 90% pure form, or at least 95% or at least 98% or at least 99%).

1.115 Compound I or any one of 1.1-1.114, wherein the compound has at least 60% 5-HT _2A receptor binding affinity at a concentration of 100nM, e.g., at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98% at a concentration of 100 nM;

1.116 compound I or any one of 1.1-1.115, wherein the compound has a 5-HT _2A receptor dissociation constant (K _d) of less than 250nM, or less than 100nM, or less than 70nM, or less than 60nM, or less than 50nM, or less than 40nM, or less than 30nM, or less than 20nM, or less than 10nM;

Compound I or any one of claims 1.1-1.116, 117, wherein the compound is an agonist, e.g., a partial agonist or a full agonist, of β -arrestin signaling via the 5-HT _2A receptor;

1.118 compound 1.116, wherein the compound is a partial agonist of β -arrestin signaling having 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% E _max relative to a full agonist (e.g., α -methyl serotonin);

1.119 Compound 1.117 or 1.118, wherein the EC ₅₀ of a compound has less than 500nM, or less than 200nM, or less than 150nM, or less than 100nM, or less than 70nM, or less than 60nM, or less than 50nM, or less than 40nM, or less than 30nM, or less than 20 nM, of 5-HT _2A receptor beta-inhibitor agonism

NM, or less than 10nM;

1.120 compound 1.117, 1.118, or 1.119, wherein the compound has a β -arrestin signaling relative intrinsic activity (RA _i) of less than 1.0, such as a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8, compared to a reference compound α -methylserotonin;

1.121 compound 1.117, 1.118, or 1.119, wherein the compound has a relative intrinsic activity of β -arrestin signaling greater than 1.0, such as a relative intrinsic activity of 1.0 to 1.2, or 1.0 to 1.4, or 1.0 to 1.6, compared to the reference compound α -methylserotonin;

Compound I or any one of claims 1.1-1.116, wherein the compound is an antagonist of β -inhibitor protein signaling via the 5-HT _2A receptor;

1.123 Compound 1.122, wherein the compound has an IC ₅₀ of less than 300nM, or less than 200nM, or less than 100nM, or less than 70nM, or less than 60nM, or less than 50nM, or less than 40, for antagonism of 5-HT _2A receptor beta-inhibitor

NM, or less than 30nM, or less than 20nM, or less than 10nM;

1.124 Compound I or any one of 1.1-1.116, wherein the compound is not via 5-

Antagonists of beta-inhibitor protein signaling of the HT _2A receptor;

1.125 Compound 1.124, wherein the compound has an IC ₅₀ of greater than 10nM, or greater than 50nM, or greater than 100nM, or greater than 250nM, or greater than 500nM, or greater than 1000nM, or greater than 5000nM, or greater than 10,000nM for antagonism of 5-HT _2A receptor beta-inhibitor;

1.126 Compound I or any one of 1.1-1.125, wherein the compound is not via 5-

Agonists of the G-q signaling of the HT _2A receptor, or weak agonists thereof;

1.127 Compound 1.126, wherein the compound is a partial agonist of G-q signaling, having 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% E _max, preferably less than 50%, or less than 30%, or less than 10% E _max relative to a full agonist (e.g., alpha-methyl serotonin);

1.128 Compounds 1.125 or 1.126, wherein the EC ₅₀ of the Compounds for G-q agonism of the 5-HT _2A receptor is greater than 10nM, or greater than 25nM, or greater than 50nM, or greater than 100nM, or greater than 150nM, or greater than 200nM, or greater than 500

NM, or greater than 1000nM, or greater than 2000nM, or greater than 5000nM, or greater than 10,000nM;

1.129 compound 1.125, 1.126, or 1.127, wherein the compound has a G-q signaling relative intrinsic activity (RA _i) of less than 1.0, such as a relative intrinsic activity of less than 0.8, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3, or less than 0.2, or less than 0.1, or 0.1 to 0.8, or 0.2 to 0.8, or 0.4 to 0.8, or 0.5 to 0.8, or 0.2 to 0.6, or 0.2 to 0.5, or 0.2 to 0.4, or 0.5 to 1.0, or 0.5 to 0.9, or 0.5 to 0.8, or 0.6 to 0.9, or 0.6 to 0.8, compared to a reference compound α -methylserotonin;

Compound I or any one of claims 1.1-1.129, 130, wherein the compound is an antagonist of G-q signaling via the 5-HT _2A receptor;

1.131 Compound 1.130 wherein the compound has an IC ₅₀ of less than 10nM, or less than 25nM, or less than 50nM, or less than 100nM, or less than 150nM, or less than 200nM, or less than 500 nM for antagonism of the 5-HT _2A receptor G-q

nM;

1.132 Compound I or any one of 1.1-1.131, wherein the bias ratio (β -arrestin/G-q) of the compound for 5-HT _2A receptor agonism is at least 2, or at least 5, or at least 10, or at least 25, or at least 50, or at least 100, or at least 150, or at least 200 or at least 500, or at least 1000, or at least 10,000, or undefined (i.e., wherein the compound has any degree of β -arrestin agonism and zero G-q agonism);

1.133 compound I or any one of claims 1.1-1.132, wherein the compound is an antagonist or agonist of D1 and/or D2 dopamine receptors (e.g. having a receptor affinity of at least 70% or an IC50 of less than 100nM at a concentration of 100 nM);

Compound I or any one of claims 1.1-1.132, wherein the compound has no activity at D1 and/or D2 dopamine receptors (e.g. having less than 50% receptor affinity and/or greater than 500nM EC ₅₀ or IC ₅₀ at 100nM concentration);

1.135 compound I or any one of 1.1-1.134, wherein the compound is an antagonist of a serotonin transporter (e.g. has a receptor binding affinity of at least 70% or an IC ₅₀ of less than 100nM at a concentration of 100 nM);

Compound I or any one of 1.1-1.134, wherein the compound has no activity on a serotonin transporter (e.g. has less than 50% receptor binding affinity and/or greater than 500nM EC ₅₀ or IC ₅₀ at a concentration of 100 nM);

1.137 compound I or any one of 1.1-1.136, wherein the compound is an agonist, antagonist or partial agonist of the mu opioid receptor (e.g., EC ₅₀ or IC ₅₀ having at least 70% receptor binding affinity or less than 100nM at a concentration of 100 nM);

1.138 compound I or any one of 1.1-1.136, wherein the compound is inactive against mu opioid receptors (e.g., has less than 50% receptor binding affinity at a concentration of 100nM and/or greater than 500nM EC ₅₀ or IC ₅₀);

Compound I, or any one of 1.1-1.138, wherein the compound is non-fanciful, e.g. at therapeutic doses for the treatment of neuropsychiatric disorders described herein (e.g. depression, anxiety etc.), the compound does not cause visual or auditory hallucinations, visual distortions (e.g. drifting, deformation, relief (or dissipation) of objects and surfaces in the field of view), off-reality, dissociation, delirium, undesired change of state of consciousness;

compound I, or any one of 1.1-1.139, wherein the compound does not stimulate a head twitch response in an animal test model, or is an antagonist of a DOI-induced head twitch response;

1.141 compound I, or any one of 1.1-1.140, wherein the compound is effective in a murine model of depression (tail suspension or forced swim test);

1.142 compound I, or any one of 1.1-1.141, wherein the compound is effective in an animal model of social anxiety disorder or hedonia;

1.143 compound I, or any one of 1.1-1.142, wherein the compound does not have 5-HT _2B agonist activity (e.g., EC50 greater than 100nM, or greater than 500nM, or greater than 1000nM, or greater than 10,000 nM);

1.144 Compound I, or any one of 1.1-1.143, wherein the compound has 5-HT _2B antagonist activity (e.g., IC50 of less than 1000nM, or less than 500nM, or less than 250nM, or less than 100nM, or less than 50nM, or less than 25)

NM, or less than 15 nM);

1.145 Compound I, or any one of 1.1-1.144, wherein the compound has 5-HT _2c agonist activity (e.g., an EC50 of less than 1000nM, or less than 500nM, or less than 250nM, or less than 100nM, or less than 50nM, or less than 25)

NM, or less than 15 nM);

1.146 compound I, or any one of 1.1-1.144, wherein the compound does not have 5-HT _2C antagonist activity (e.g., an IC50 greater than 100nM, or greater than 500nM, or greater than 1000nM, or greater than 10,000 nM);

1.147 Compound I, or any one of 1.1-1.146, wherein the compound binds to an alpha-1A adrenergic receptor (e.g., with an affinity Ki of less than 1000nM, or less than 500nM, or less than 250nM, or less than 200nM, or less than 150

NM, or less than 100nM, or less than 50nM, or less than 25 nM);

1.148 compound I, or any one of 1.1-1.147, wherein the compound does not cause psychosis (e.g., persistent or intermittent psychosis);

Compound I, or any one of 1.1-1.148, wherein the compound does not promote patient self-injury or injury to others;

1.150 compound I, or any one of 1.1-1.149, wherein the compound does not cause heart valve disease or pulmonary hypertension, e.g., wherein the compound is safely administered to a patient suffering from heart co-disease;

1.151 compound I, or any one of 1.1-1.150, wherein the compound does not cause abuse or dependence (e.g. physical or psychological dependence);

Compound I of 152, or any one of 1.1-1.151, wherein the compound is inactive against one or more of adenosine A2A, alpha-1A adrenergic, alpha-2A adrenergic, beta-1 adrenergic, beta-2 adrenergic, GABA-A benzodiazepine Site (BZD, central), CB1 cannabinoid, CB2 cannabinoid, cholecystokinin CCK1, endothelin-up>A (ETA), NMDA, histamine H1, histamine H2, MAO-up>A, muscarinic M1, muscarinic M2, muscarinic M3, nicotinic acetylcholine (neuronal α -4- β -2), deltup>A opioids, kappup>A opioids, mu opioids, serotonin-1 up>A, serotonin-1B, serotonin-3, glucocorticoid (GR), androgens (AR), vasopressin V1 up>A, cardiac calcium channel (dihydropyridine site), hERG potassium channel, voltage-gated potassium channel K _V, sodium channel (site 2), norepinephrine transporter, dopamine transporter and/or serotonin transporter;

1.153 compound 1.152, wherein the compound has less than 60% (e.g., at 100nM test concentration) of radioligand binding inhibition, e.g., less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the in vitro receptor activity (for agonism or antagonism) of any one or more of the receptors or ion channels;

1.154 compound I, or any one of 1.1-1.153, wherein the compound is orally bioavailable (e.g., oral bioavailability of at least 10%, or at least 15%, or at least 20%, or at least 30%, or at least 40%).

As used herein, the term "spiro-linked" is intended to clarify that the C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is present in a spiro ring junction, meaning that one atom of the cyclic group is the 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:

In each of the above examples, the cyclopropane, cyclobutane, aziridine, azetidine, or oxetane may be replaced by any other C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl group, including, but not limited to, cyclopentane, cyclohexane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, or morpholine.

As used hereinafter, "compounds of the invention" refers to compounds of formula I or any one of 1.1-1.154.

In a second aspect, the present disclosure provides a pharmaceutical composition (pharmaceutical composition 1) comprising a compound of the invention, e.g., in admixture with a pharmaceutically acceptable diluent or carrier. In certain embodiments, the compounds of the invention are in the form of pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule, for example, for gastrointestinal absorption (i.e., absorption through the stomach and/or large and small intestines). In some embodiments, the pharmaceutical composition is an oral transmucosal composition, such as 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 intrapulmonary administration (e.g., as an aerosol, spray, 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 a long-acting injectable composition or depot composition, for example, providing sustained or delayed release of the compounds of the invention into the blood stream and body tissues. Or in particular when formulated for intravenous, intrathecal, intraperitoneal or subcutaneous injection, the composition may be an immediate-effect composition, for example, providing immediate release of most or all of the dose into the body fluid.

In a further embodiment, the pharmaceutical composition of the present disclosure is used in a sustained or delayed release formulation (pharmaceutical composition 1-a), such as a depot formulation. In some embodiments, the compounds of the present invention are preferably provided in free or pharmaceutically acceptable salt form, mixed with a pharmaceutically acceptable diluent or carrier, provided in the form of an injectable depot, which provides sustained or delayed release of the compound.

In a particular embodiment, the pharmaceutical composition 1-a comprises a compound of the invention in the form of a free base or a pharmaceutically acceptable salt, optionally in crystalline form, wherein the compound has been milled to a microparticle or nanoparticle size, or the compound has crystallized to a microparticle or nanoparticle size, such as a particle or crystal having a particle size (e.g. diameter or Dv 50) of 0.5 to 100 microns, such as 5-30 microns, 10-20 microns, 20-100 microns, 20-50 microns or 30-50 microns, on a volume basis. 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, depot formulations can be formulated for intramuscular or subcutaneous injection, with a drug dosage suitable for treatment for 4 to 6 weeks. In some embodiments, the surface area of the particles or crystals is from 0.1 to 5m ²/g, for example from 0.5 to 3.3m ²/g or from 0.8 to 1.2m ²/g.

In a further embodiment, the present disclosure provides a pharmaceutical composition 1-B, which is pharmaceutical composition 1, wherein the compound of the present invention is in a polymer matrix. In one embodiment, the compounds of the present disclosure are dispersed or dissolved within a polymer matrix. In a further embodiment, the polymeric matrix comprises a standard polymer for use in depot formulations, such as a polymer selected from polyesters of hydroxy fatty acids and derivatives thereof, or alpha-alkyl cyanoacrylates, polyalkylene oxalates, polyorthoesters, polycarbonates, polyorthoesters, polyamino acids, hyaluronate 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 further embodiments, the polymer is selected from the group consisting of poly (glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly (aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly (orthocarbonates), poly (acetals), poly (lactic acid-caprolactone), polyorthoesters, poly (glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes (e.g., glycerol monostearate and distearate), and the like. In a preferred embodiment, the polymer matrix comprises poly (d, l-lactide-co-glycolide).

Pharmaceutical compositions 1-B are particularly useful for sustained or delayed release, wherein the compounds of the present disclosure are released after degradation of the polymer matrix. These compositions may be formulated for controlled and/or sustained release of the compounds of the present disclosure (e.g., as depot compositions) over a period of up to 180 days (e.g., from about 14 to about 30 to about 180 days). For example, the polymer matrix may degrade and release the compounds of the present disclosure over a period of about 30, about 60, or about 90 days. In further examples, the polymer matrix may degrade and release the compounds of the present disclosure over a period of about 120 or about 180 days.

In yet further embodiments, pharmaceutical composition 1 or 1-A or 1-B may be formulated for administration by injection, for example as a sterile solution.

In a further embodiment, the present disclosure provides a pharmaceutical composition (pharmaceutical composition 1-C) comprising a compound of the present invention as described above in an osmotic controlled release oral delivery system (OROS), described in US2001/0036472 and US 2009/0202631, the contents of each of which are incorporated herein by reference in their entirety. Thus, in one embodiment, the present disclosure provides a pharmaceutical composition or device comprising (a) a gelatin capsule containing a compound of formula I and any of its following in free or pharmaceutically acceptable salt form, optionally admixed with a pharmaceutically acceptable diluent or carrier, (b) a multi-layer wall overlying the gelatin capsule, the multi-layer wall comprising, in order from the capsule outwards, (I) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer, and (c) a hole formed or formable through the wall (pharmaceutical composition p.1).

In a further 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 in admixture with a pharmaceutically acceptable diluent or carrier, surrounded by a composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semipermeable layer surrounding the expandable layer and an outlet aperture formed or formable in the wall (pharmaceutical composition p.2).

In still further embodiments, the present invention provides a composition comprising a gelatin capsule containing a liquid, free or pharmaceutically acceptable salt form of a compound of the present invention, optionally in admixture with a pharmaceutically acceptable diluent or carrier, surrounded by a composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semipermeable layer surrounding the expandable layer, and an outlet orifice formed or formable in the wall, wherein the barrier layer forms a seal (pharmaceutical composition P.3) between the expandable layer and the environment at the outlet orifice.

In still further embodiments, the present invention provides a composition comprising a gelatin capsule comprising a liquid, free or pharmaceutically acceptable salt form of a compound of the present invention, optionally in admixture with a pharmaceutically acceptable diluent or carrier, surrounded by a barrier layer contacting the outer surface of the gelatin capsule, an expandable layer contacting a portion of the barrier layer, a semipermeable layer surrounding at least the expandable layer, and an exit orifice formed or formable in the dosage form that extends from the outer surface of the gelatin capsule to the environment of use (pharmaceutical composition P.4). The expandable layer may be formed in one or more discrete portions, for example, two portions located on opposite sides or ends of the gelatin capsule.

In particular embodiments, the compounds of the present invention in the osmotic controlled release oral delivery system (i.e., in compositions P.1-P.4) are liquid formulations, which may be neat liquid active agents, liquid active agents in solutions, suspensions, emulsions or self-emulsifying compositions, and the like.

Further information regarding osmotic controlled release oral delivery system compositions, including gelatin capsules, barrier layers, expandable layers, semipermeable layers, and pore characteristics, can be found in US 2001/0036472, the contents of which are incorporated herein by reference in their entirety.

Other osmotic controlled release oral delivery systems for the compounds of formula I and subsequent compounds or pharmaceutical compositions of the present disclosure are found in US2009/0202631, the contents of which are incorporated herein by reference in their entirety. Thus, in a further embodiment, the present invention provides a composition or device comprising (a) two or more layers comprising a first layer comprising a compound of the invention in free or pharmaceutically acceptable salt form, optionally mixed with a pharmaceutically acceptable diluent or carrier, and a second layer comprising a polymer, (b) an outer wall surrounding the two or more layers, and (c) a hole in the outer wall (pharmaceutical composition p.5).

Pharmaceutical composition p.5 preferably utilizes a semipermeable layer around a three-layer core, in these embodiments the first layer is referred to as the first drug layer and contains a small amount of drug (e.g. a compound of the invention) and osmotic agent (e.g. salt), the middle layer is referred to as the second drug layer, contains a higher amount of drug, excipients, and is free of salt, and the third layer, referred to as the push layer, contains osmotic agent and is free of drug (pharmaceutical composition P.6). At least one hole is drilled through the film at the end of the first drug layer of the capsule-shaped tablet.

The pharmaceutical composition p.5 or P.6 may comprise a membrane defining a compartment surrounding an inner protective sub-layer in which at least one outlet aperture is formed or formable and at least a portion of which is semipermeable, an expandable layer located within the compartment remote from the outlet aperture and in fluid communication with the semipermeable portion of the membrane, a first pharmaceutical layer located adjacent to the outlet aperture, and a second pharmaceutical layer located within the compartment between the first pharmaceutical layer and the expandable layer, said pharmaceutical layer comprising a compound of the invention (pharmaceutical composition p.7) in free or pharmaceutically acceptable salt form. Depending on the relative viscosities of the first and second drug layers, different release profiles may be obtained. The optimal viscosity for each layer must be determined. In the present invention, the viscosity is adjusted by adding salt and sodium chloride. The delivery profile from the core depends on the weight, formulation and thickness of each drug layer.

In a particular embodiment, the invention provides a pharmaceutical composition p.7, wherein the first pharmaceutical layer comprises a salt and the second pharmaceutical layer does not comprise a salt. The pharmaceutical compositions p.5-p.7 may optionally comprise a flow promoting layer between the membrane and the pharmaceutical layer.

Pharmaceutical compositions p.1-p.7 are commonly referred to as osmotic controlled release oral delivery system compositions.

In a third aspect, the invention provides a method for treating or preventing a central nervous system disorder or more than one central nervous system disorder (method 1), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention (e.g., a compound of formula I), wherein the compound of the invention is a biased agonist of the 5-HT _2A receptor. In a further embodiment of method 1, the present disclosure provides:

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 toluene sulfonic acid addition salt.

1.4 Method 1 or any of 1.1-1.3 wherein the compounds of the invention are administered in the form of a pharmaceutical composition comprising a compound of the invention in admixture with a pharmaceutically acceptable diluent or carrier (e.g., pharmaceutical composition I or 1-A, 1-B,

1-C or any one of p.1 to p.7);

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 method 1 or any one of methods 1.1-1.6, wherein the central nervous system disorder is a disorder susceptible to treatment by agonism of the β -catenin signaling pathway and/or agonism or antagonism of the G-q signaling pathway mediated by the 5-HT _2A receptor;

1.8 method 1 or any one of methods 1.1-1.7, wherein the central nervous system disorder is a disorder involving, mediated by or affected (directly or indirectly) by serotonin 5-HT _2A receptor, dopamine D1 receptor and/or D2 receptor system and/or serotonin reuptake transporter (SERT) pathway and/or mu opioid receptor pathway;

1.9 method 1, or any one of 1.1-1.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected by (directly or indirectly) the serotonin 5-HT _2A receptor, the serotonin reuptake transporter (SERT), but not involving the dopamine D1 receptor or D2 receptor system and not involving the mu opioid receptor pathway, not mediated by or affected by (directly or indirectly);

1.10 method 1, or any one of 1.1-1.7, wherein the central nervous system disorder is a disorder that does not involve, be mediated by, or be affected (directly or indirectly) by one or more of the dopamine D1 receptor, the dopamine D2 receptor, the serotonin reuptake transporter (SERT), or the mu opioid receptor pathway;

1.11 method 1, or any one of 1.1-1.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by the serotonin 5-HT _2A receptor;

1.12 method 1, or any one of 1.1-1.11, wherein the central nervous system disorder is a disorder involving, mediated by or affected (directly or indirectly) by signaling via the β -catenin signaling pathway of the serotonin 5-HT _2A receptor;

1.13 method 1 or any one of methods 1.1-1.12, wherein the central nervous system disorder is a disorder selected from anxiety disorders (including generalized anxiety disorder, social anxiety disorder, and panic disorder) and depression (e.g., refractory depression and major depressive disorder, bipolar depression);

1.14 method 1 or any one of methods 1.1-1.13, wherein the central nervous system disorder is 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-resistant depression, major depressive disorder, and bipolar depression, and

And/or a lack of pleasure;

1.16 method 1, or any one of 1.1-1.15, wherein the patient has any combination of the disorders described in methods 1.7-1.15;

1.17 method 1, or any one of 1.1-1.15, wherein the method is a method for treating or preventing any combination of the disorders described in methods 1.7-1.15;

1.18 method 1 or any of methods 1.1-1.17, wherein the patient is not responsive to or unable to tolerate the side effects of a conventional antidepressant;

1.19 method 1 or any one of methods 1.1-1.18, wherein the patient is unresponsive or intolerant to side effects of treatment with a Selective Serotonin Reuptake Inhibitor (SSRI) such as citalopram (citalopram), escitalopram (escitalopram), fluoxetine (fluxetine), fluvoxamine (fluvoxamine), paroxetine (paroxetine), and sertraline (sertraline);

1.20 method 1 or any one of methods 1.1-1.19, wherein the patient is unresponsive or intolerant to side effects of treatment with a serotonin-norepinephrine reuptake inhibitor (SNRI) such as venlafaxine (venlafaxine), sibutramine (sibutramine), duloxetine (duloxetine), tomoxetine (atomoxetine), desmethylvenlafaxine (desvenlafaxine), milnacipran (milnacipran), and levomilnacipran (levomilnacipran);

1.21 method 1 or any one of methods 1.1-1.20, wherein the patient is unresponsive to treatment with conventional anxiolytic agents such as lorazepam, diazepam, alprazolam, and buspirone or is intolerant of the side effects of the treatment;

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 from 1mg to 1000mg, preferably from 2.5mg to 50mg, or for a long-acting formulation, from 25mg to 1500mg, e.g., from 50mg to 500mg, or from 250mg to 1000mg, or from 250mg to 750mg, or from 75mg to 300mg;

1.23 method 1.22 wherein the therapeutically effective amount is from 1mg to 100mg per day, preferably from 2.5mg to 50mg per day.

1.24 Method 1.22 wherein the therapeutically effective amount of the compound of the invention is from 1mg to 1000mg, e.g., from 2.5mg to 50mg, or for a depot, from 25mg to 1500mg, e.g., from 50mg to 500mg, or from 250mg to 1000mg, or from 250mg to 750mg, or from 75mg to 300mg;

1.25 method 1.22 wherein the therapeutically effective amount of the compound of the invention is from 1mg to 100mg per day, for example from 2.5mg to 50mg per day;

1.26 method 1.22 wherein the therapeutically effective amount of the compound of the invention is 1mg to 5mg, preferably 2.5 to 5mg, per day;

1.27 method 1.22 wherein the therapeutically effective amount of the compound of the invention is 2.5mg or 5mg per day;

1.28 method 1 or any one of 1.1-1.27, wherein the pharmaceutical composition is a sustained release or delayed release formulation, e.g., according to pharmaceutical composition 1-a as described herein;

1.29 method 1 or any one of 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 as described herein;

1.30 method 1 or any one of 1.1-1.29, wherein the pharmaceutical composition is in the form of a tablet or capsule;

1.31 method 1 or any one of 1.1-1.30, wherein the pharmaceutical composition is formulated for oral, sublingual or buccal administration;

1.32 method 1 or any one of 1.1-1.31, wherein the pharmaceutical composition is a fast-dissolving oral tablet (e.g., a fast-dissolving sublingual tablet);

1.33 method 1 or any one of 1.1-1.32, wherein the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (e.g., as an aerosol, spray, or powder for inhalation);

1.34 method 1 or any one of 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 method 1 or any one of 1.1-1.35, wherein the method further comprises concurrently administering one or more additional therapeutic agents, e.g., simultaneously, separately or sequentially;

1.37 method 1.36 wherein the additional therapeutic agent is an antidepressant, optionally wherein the antidepressant is selected from the group consisting of amitriptyline, amoxapine, bupropion, citalopram, chlorimipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarbozine, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protiline, 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 one of 1.1-1.38, wherein the method does not cause psychosis (e.g., persistent or intermittent psychosis);

1.40 method 1, or any one of 1.1-1.39, wherein the method does not promote self-injury or injury to others;

1.41 method 1, or any one of 1.1-1.40, wherein the method does not cause heart valve disease or pulmonary hypertension, e.g., wherein the method is safe for treatment of a patient with heart co-disease;

1.42 method 1, or any one of 1.1-1.41, wherein the method does not cause abuse or dependency (e.g., physical or psychological dependence);

1.43 method 1, or any one of 1.1-1.42, wherein the patient has or has been previously diagnosed with a hallucinogen persistent sensory disorder (HPPD);

1.44 method 1, or any one of 1.1-1.43, wherein the patient has or has been previously diagnosed with a psychotic disorder (e.g., schizophrenia).

In a fourth aspect, the invention provides a method for treating or preventing a central nervous system disorder or more than one central nervous system disorder (method 2), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention (e.g., a compound of formula I), wherein the compound of the invention is an antagonist of the 5-HT _2A receptor. In certain embodiments, method 2 comprises administering:

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 toluene sulfonic acid addition salt.

2.4 Method 2 or any of 2.1-2.3 wherein the compound of the invention is administered in the form of a pharmaceutical composition comprising a compound of the invention in admixture with a pharmaceutically acceptable diluent or carrier (e.g., pharmaceutical composition I or 1-A, 1-B,

1-C or any one of p.1 to p.7);

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 one of pharmaceutical compositions p.1 to p.7;

2.7 method 2 or any one of methods 2.1-2.6, wherein the central nervous system disorder is a disorder susceptible to treatment by antagonism of the 5-HT _2A receptor (e.g., antagonism of the β -arrestin signaling pathway and antagonism of the G-q signaling pathway mediated by the 5-HT _2A receptor);

2.8 method 2 or any one of methods 2.1-2.7, wherein the central nervous system disorder is a disorder involving, mediated by or affected (directly or indirectly) by serotonin 5-HT _2A receptor, dopamine D1 receptor and/or D2 receptor system and/or serotonin reuptake transporter (SERT) pathway and/or mu opioid receptor pathway;

2.9 method 2, or any one of 2.1-2.7, wherein the central nervous system disorder is a disorder involving, mediated by or affected by (directly or indirectly) the serotonin 5-HT _2A receptor or serotonin reuptake transporter (SERT), but not involving the dopamine D1 receptor or D2 receptor system, and not involving, mediated by or affected by the mu opioid receptor pathway;

2.10 method 2, or any one of 2.1-2.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected by (directly or indirectly) the serotonin 5-HT _2A receptor or serotonin reuptake transporter (SERT), but not involving, not mediated by, or affected by (directly or indirectly) the mu opioid receptor pathway;

2.11 method 2, or any one of 2.1-2.7, wherein the central nervous system disorder is a disorder involving, mediated by, or affected (directly or indirectly) by the serotonin 5-HT _2A receptor;

2.12 method 2 or any one of methods 2.1-2.12, wherein the central nervous system disorder is a disorder selected from anxiety, depression, psychosis, schizophrenia, sleep disorders, impulse control disorders, post-traumatic stress disorders, intermittent explosive disorders, and dementia;

2.13 method 2 or any one of methods 2.1-2.13, wherein the central nervous system disorder is anxiety disorder, such as generalized anxiety disorder, social anxiety disorder, and panic disorder;

2.14 method 2 or any one of methods 2.1-2.13, wherein the central nervous system disorder is depression, such as treatment-resistant depression, major depressive disorder, and bipolar depression;

2.15 method 2 or any one of methods 2.1-2.13, wherein the central nervous system disorder is a psychotic disorder, such as schizophrenia;

2.16 method 2.16, wherein the method is effective for treating positive and/or negative symptoms of schizophrenia;

2.17 method 2, or any one of 2.1-2.16, wherein the patient has any combination of the disorders described in methods 2.7-2.16;

2.18 method 2, or any one of 2.1-2.46, wherein the method is a method of treating or preventing any combination of the disorders described in methods 2.7-2.16;

2.19 method 2 or any of methods 2.1-2.18, wherein the patient is unresponsive to or intolerant of the side effects of conventional antipsychotics, e.g., chlorpromazine, haloperidol, fluphenazine, loxapine, mebendazine, molinone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, bripiprazole, calicheazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone;

2.20 method 2 or any of methods 2.1-2.19, wherein the patient is not responsive to or unable to tolerate the side effects of a conventional antidepressant;

2.21 method 2 or any one of methods 2.1-2.20, wherein the patient is nonresponsive or intolerant to 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 one of methods 2.1-2.21, wherein the patient is unresponsive to treatment with a serotonin-norepinephrine reuptake inhibitor (SNRI) such as venlafaxine, sibutramine, duloxetine, tomoxetine, desvenlafaxine, milnacipran, and levomilnacipran or is intolerant of the side effects of such treatment;

2.23 method 2 or any one of methods 2.1-2.22, wherein the patient is unresponsive to treatment with conventional anxiolytic agents such as lorazepam, diazepam, alprazolam, and buspirone or is intolerant of the side effects of the treatment;

2.24 method 2 or any one of methods 2.1-2.23, wherein the patient is unresponsive to or intolerant to side effects of treatment with an antipsychotic agent such as chlorimipramine, 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 from 1mg to 1000mg, preferably from 2.5mg to 50mg, or for a long-acting formulation, from 25mg to 1500mg, e.g., from 50mg to 500mg, or from 250mg to 1000mg, or from 250mg to 750mg, or from 75mg to 300mg;

2.26 method 2.26 wherein the therapeutically effective amount is from 1mg to 100mg per day, preferably from 2.5mg to 50mg per day.

2.27 Method 2.26 wherein the therapeutically effective amount of the compound of the invention is from 1mg to 1000mg, e.g., from 2.5mg to 50mg, or for a depot, from 25mg to 1500mg, e.g., from 50mg to 500mg, or from 250mg to 1000mg, or from 250mg to 750mg, or from 75mg to 300mg;

2.28 method 2.26 wherein the therapeutically effective amount of the compound of the invention is from 1mg to 100mg per day, for example from 2.5mg to 50mg per day;

2.29 method 2.26 wherein the therapeutically effective amount of the compound of the invention is 1mg to 5mg, preferably 2.5 to 5mg, per day;

2.30 methods 2.26 wherein the therapeutically effective amount of the compound of the invention is 2.5mg or 5mg per day;

2.31 method 2 or any of methods 2.1-2.30, wherein the pharmaceutical composition is a sustained release or delayed release formulation, e.g., according to pharmaceutical composition 1-a as 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 polymeric matrix, e.g., according to pharmaceutical composition 1-B as described herein;

2.33 method 2 or any one 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 one 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 intrapulmonary administration (e.g., as an aerosol, spray, 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 one of methods 2.1-2.38, wherein the method further comprises concurrently administering one or more additional therapeutic agents, e.g., concurrently, separately or sequentially, 2.40 method 2.39, wherein the additional therapeutic agents are antipsychotic agents, optionally wherein the antipsychotic agents are selected from the group consisting of chlorpromazine, haloperidol, fluphenazine, loxapine, methodazine, molinone, perphenazine, pimozide, prochlorpyrazine, promazine, thiodazine, thiothixene, trifluoperazine, bripiprazole, caliprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone;

2.41 method 2.39 wherein the additional therapeutic agent is an antidepressant, optionally wherein the antidepressant is selected from the group consisting of amitriptyline, amoxapine, bupropion, citalopram, chlorimipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarbozine, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, ketamine and esketamine;

2.42 method 2.39 wherein the additional therapeutic agent is an atypical antipsychotic agent, optionally wherein the agent is selected from the group consisting of bripiprazole, kallizumab, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone;

2.43 method 2.39 wherein the additional therapeutic agent is an atypical agonist, optionally selected from modafinil, alfufilib, and armodafinil;

2.44 method 2.39 wherein the additional therapeutic agent is an antiparkinsonism agent, optionally selected from L-dopa, co-careldopa, duodopa, darling, amantadine (Symmetrel), benzatropine, biperiden, bromocriptine, entacapone, pergolide, pramipexole, propidine, 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 method 2, or any one of 2.1-2.45, wherein the method does not cause psychosis (e.g., persistent or intermittent psychosis);

2.47 method 2, or any one of 2.1-2.46, wherein the method does not promote self-injury or injury to others;

2.48 method 2, or any one of 2.1-2.47, wherein the method does not cause heart valve disease or pulmonary hypertension, e.g., wherein the method is safe for treatment of a patient with heart co-disease;

2.49 method 2, or any one of 2.1-2.48, wherein the method does not cause abuse or dependency (e.g., physical or psychological dependence).

In some embodiments of the methods described below, pharmaceutical compositions comprising the compounds of the present invention may be administered for controlled and/or sustained release of the compounds of the present invention over a period of about 14 days, about 30 to about 180 days, preferably over a period of about 30, about 60 or about 90 days. Controlled release and/or sustained release are particularly useful for avoiding premature cessation of therapy, particularly for antipsychotic therapy where non-compliance or non-compliance with medication regimens is common.

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

The compounds of the present disclosure (i.e., compounds of the present invention) and the pharmaceutical compositions of the present disclosure may be used in combination with a second therapeutic agent, particularly at lower doses than when used as a single agent for monotherapy, to enhance the therapeutic activity of the combined agents without causing the undesirable side effects common in conventional monotherapy. Thus, the compounds of the present disclosure may be administered simultaneously, sequentially or contemporaneously with other therapeutic agents as described herein above, such as opioids, analgesics, antidepressants, antipsychotics, other hypnotics and/or agents for treating parkinson's disease or mood disorders.

In method 1 and thereafter or method 2 and any of the subsequent embodiments thereof, wherein the compounds of the present disclosure are administered together with one or more second therapeutic agents, the one or more second therapeutic agents may be administered as part of a pharmaceutical composition comprising the compounds of the present disclosure. Or one or more second therapeutic agents may be administered in separate pharmaceutical compositions (e.g., pills, tablets, capsules, and injections) simultaneously, sequentially, or separately with the administration of the compounds of the present disclosure.

In some further embodiments of the present disclosure, the pharmaceutical compositions of the present disclosure may be used in combination with a second therapeutic agent, particularly at lower doses than when used as a single agent for monotherapy, to enhance the therapeutic activity of the combined agents without causing undesirable side effects, wherein the second therapeutic agent is an opioid antagonist or inverse agonist (e.g., naloxone). The compounds of the present disclosure may be administered simultaneously, sequentially or contemporaneously with such opioid antagonists or opioid inverse agonists.

In a fifth aspect, the present disclosure provides the use of a compound of the invention in the manufacture of a medicament for use according to any one of method 1 or method 1.1 to 1.42 or method 2 or any one of method 2.1 to 2.49. In further embodiments, the present disclosure provides compounds of the invention for use in treating a disease or disorder according to any one of methods 1 or methods 1.1-1.42 or method 2 or any one of methods 2.1-2.49.

Detailed Description

The term "biased agonist" as used herein is used to refer to a compound active at the serotonin 5-HT _2A receptor, having partial or full agonism of β -arrestin signaling via the receptor, but antagonism or weak partial agonism of G-q mediated signaling. One useful measure of bias is the "bias ratio" which is calculated as the ratio of the intrinsic relative activity of beta-arrestin signaling (RA _i) to RA _i of G-q signaling. The bias ratio of the non-biased agonist was 1.0. The bias agonist has a non-zero bias ratio. In some embodiments, the compounds of the present disclosure are preferably biased towards β -arrestin signaling, and thus have a bias ratio of greater than 1.0. More preferably, the bias ratio for beta-inhibitor signaling is greater than 10, or greater than 100, or greater than 1000, or 10,000 or more.

As used herein, the term "partial agonist" is understood to mean a compound that has any degree of agonism that is lower than the agonism of a reference standard full agonist. For example, the reference compound for 5-HT _2A receptor agonism is alpha-methyl serotonin. Compounds with maximal efficacy (E _max) less than 100% of the maximal efficacy of alpha-methyl serotonin are partial agonists.

The term "hallucinogen" refers to a compound that causes a hallucination symptom, which is any one or more symptoms selected from the group consisting of visual hallucinations, auditory hallucinations, visual distortions (e.g., drifting, deformation, waving, or dissipation of objects and surfaces in the field of view), off reality, dissociation, delirium, and undesired changes in the state of consciousness. A compound of the present disclosure is considered "non-fanciful" if it does not cause fanciful symptoms at a therapeutically effective dose for treating the neuropsychiatric disorders described herein (e.g., depression, anxiety, etc.).

It should be understood that the terms "opioid" and "opioid" are different in that "opioid" refers to natural products derived from poppy, such as morphine, codeine, and heroin, but "opioid" refers to these natural compounds and semisynthetic and synthetic derivatives thereof, such as fentanyl and analogs thereof.

As used herein, unless otherwise indicated, "alkyl" is a saturated or unsaturated hydrocarbon moiety, e.g., 1 to 21 carbon atoms in length, and any such alkyl group may be straight or branched (e.g., n-butyl or t-butyl), preferably straight, unless otherwise indicated. For example, "C _1-21 alkyl" represents an alkyl group having 1 to 21 carbon atoms. In one embodiment, the alkyl group is optionally substituted with one or more hydroxy groups or C _1-22 alkoxy groups (e.g., ethoxy). In another embodiment, the alkyl group contains from 1 to 21 carbon atoms, preferably straight chain, and is optionally saturated or unsaturated, such as in some embodiments wherein R ₁ is an alkyl chain containing from 1 to 21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, e.g., such that it forms, together with the attached-C (O) -group, a residue of a natural or unnatural saturated or unsaturated fatty acid, such as when cleaved from a compound of formula I.

The term "pharmaceutically acceptable diluent or carrier" is intended to mean diluents and carriers that can be used in pharmaceutical formulations and that are free of substances that are sensitized, pyrogenic or pathogenic and are known to potentially cause or promote a disease. The pharmaceutically acceptable diluents or carriers thus exclude body fluids such as blood, urine, spinal fluid, saliva, etc., as well as their constituent components, e.g., blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in any of several well known monographs about pharmaceutical formulations, such as Anderson, philip o.; knoben, james e.; troutman, william G edit, handbook of Clinical Drug Data, tenth edition, mcGraw-Hill,2002; pratt and Taylor edits, PRINCIPLES OF DRUG ACTION, third edition, churchill Livingston, new York,1990; katzung edits, basic AND CLINICAL Pharmacology, ninth edition, MCGRAW HILL,20037ybg; goodman and Gilman edits, the Pharmacological Basis of Therapeutics, tenth edition, MCGRAW HILL,2001;REMINGTON'S PHARMACEUTICAL SCIENCES, 20 th edition, lippincott Williams & wilkins.; 2000; and Martindale, the Extra Pharmacopoeia, thirty-second edition (The Pharmaceutical Press, london, 1999), all of which are incorporated herein by reference in their entirety.

The terms "purified", "in purified form" or "in isolated and purified form" with respect to a compound refer to the physical state of the compound after separation from the synthetic process (e.g., from the reaction mixture) or from natural sources or combinations thereof. Thus, the terms "purified", "in purified form" or "in isolated and purified form" with respect to a compound refer to the compound as it is in a physical state after being obtained from one or more purification methods described herein or well known to those of skill in the art (e.g., chromatography, recrystallization, LC-MS and LC-MS/MS techniques, etc.), in a purity sufficient to be characterizable by standard analytical techniques described herein or well known to those of skill in the art.

Unless otherwise indicated, the compounds of the present invention may exist in free base form or in salt form, e.g., in pharmaceutically acceptable salt form, e.g., as acid addition salts. The acid addition salts of the compounds of the present invention are sufficiently basic, for example, with an inorganic or organic acid, for example hydrochloric acid or toluene sulphonic acid. In addition, salts of the compounds of the invention that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, or salts with organic bases that provide a physiologically acceptable cation. In a particular embodiment, the salt of the compound of the invention is a toluene sulfonic acid addition salt or a hydrochloric acid addition salt.

The compounds of the present invention are intended for use as medicaments, and therefore pharmaceutically acceptable salts are preferred. Salts unsuitable for pharmaceutical use may be used, for example, to isolate or purify the free compounds of the present invention and are therefore also included within the scope of the compounds of the present disclosure.

The compounds of the present invention may contain one or more chiral carbon atoms. Thus, these compounds exist as individual isomers, e.g. enantiomers or diastereomers, or as mixtures of individual forms, e.g. racemic/diastereomeric mixtures. Any isomer in which the asymmetric center is in the (R) -, (S) -or (R, S) -configuration may be present. The present invention is understood to include both the individual optically active isomers and mixtures thereof (e.g., racemic/diastereomeric mixtures). Thus, the compounds of the invention may be in racemic mixtures or may be predominantly in the form of, for example, pure or substantially pure isomers, for example, greater than 70% enantiomeric/diastereomeric excess ("ee"), 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.).

Geometrical isomers essentially concerning substituents on the double bond or ring may exist in cis (Z) or trans (E) form and both isomeric forms are included within the scope of the present invention.

The compounds of the present disclosure are also intended to include stable and unstable isotopes thereof. Stable isotopes are nonradioactive isotopes that contain an additional neutron compared to the enriched nuclides of the same species (i.e., element). It is expected that the activity of compounds containing such isotopes will remain, and that such compounds may also be useful for measuring the pharmacokinetics of non-isotopic analogs. For example, a hydrogen atom at a position on a compound of the present disclosure may be replaced with deuterium (a non-radioactive stable isotope). Examples of known stable isotopes include, but are not limited to, deuterium (² H or D), ¹³C、¹⁵N、¹⁸ O. Or an unstable isotope is a radioisotope containing additional neutrons, such as ¹²³I、¹³¹I、¹²⁵I、¹⁴C、¹⁸ F, compared to the enriched nuclides of the same species (i.e., element), which can replace the corresponding enriched species I, C and F. Another example of a useful isotope of a compound of the present invention is the ¹⁴ C isotope. These radioisotopes may be used in radioimaging and/or pharmacokinetic studies of the compounds of the present invention. Furthermore, when such substitutions are made at metabolically susceptible sites, substitution of atoms having a natural isotopic distribution with heavier isotopes may result in desirable changes in pharmacokinetic rates. For example, when the position of the hydrogen is an enzyme or a metabolically active site, incorporation of deuterium (² H) in place of hydrogen can slow down metabolic degradation.

The compounds of the invention may be included as depot formulations, for example, by dispersing, dissolving or encapsulating the compounds of the invention in a polymer matrix as described above, such that the compounds are released continuously as the polymer degrades over time. The release of the compounds of the present invention from the polymer matrix provides for controlled and/or delayed and/or sustained release of the compounds, for example, from a drug depot composition into a subject (e.g., a warm-blooded animal, such as a human) to which the drug depot is administered. Thus, the drug depot delivers the compounds of the invention to the subject at a concentration effective to treat a particular disease or medical condition over a sustained period of time (e.g., 14-180 days, preferably about 30, about 60, or about 90 days).

Polymers of the polymer matrix that may be used in the compositions of the present invention (e.g., the depot compositions of the present invention) may include polyesters of hydroxy fatty acids and derivatives thereof or other agents such as polylactic acid, polyglycolic acid, polycyitric acid, polymaleic acid, poly-beta-hydroxybutyric acid, epsilon-caprolactone ring-opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer or polyglycolic acid-polyethylene glycol copolymer), polymers of alpha-alkyl cyanoacrylates (e.g., poly (2-butyl cyanoacrylate)), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene-propylene carbonate), polyorthocarbonates, polyaminoacids (e.g., poly gamma-L-alanine, poly gamma-benzyl-L-glutamic acid or poly gamma-methyl-L-glutamic acid), hyaluronic acid esters, and the like, and one or more of these polymers may be used.

If the polymers are copolymers, they may be any of random, block and/or graft copolymers. When the above-mentioned α -hydroxycarboxylic acid, hydroxydicarboxylic acid, and hydroxytricarboxylic acid have optical activity in the molecule thereof, any of the D-isomer, L-isomer, and/or DL-isomer may be used. In particular, an α -hydroxycarboxylic acid polymer (preferably a lactic acid-glycolic acid polymer), an ester thereof, a poly α -cyanoacrylate, or the like, and a lactic acid-glycolic acid copolymer (also referred to as poly (lactide- α -glycolide) or poly (lactic acid-co-glycolic acid), hereinafter referred to as PLGA) may be used. Thus, in one aspect, the polymer useful in the polymer matrix is PLGA. As used herein, the term PLGA includes polymers of lactic acid (also known as polylactides, polylactic acid or PLA). Most preferably, the polymer is a biodegradable poly (d, l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymer material. The term "biocompatible" is defined as a polymeric material that is non-toxic, non-carcinogenic, and does not significantly induce inflammation of body tissue. The matrix material should be biodegradable, wherein the polymeric material should degrade through the body process into products that are easily handled by the body and should not accumulate in the body. The products of biodegradation should also be biocompatible with the body, as the polymer matrix is biocompatible with the body. Specific 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), copolymerized oxalates, polycaprolactone, polydioxanone, poly (orthocarbonates), poly (acetals), poly (lactic acid-caprolactone), polyorthoesters, poly (glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes (e.g., glycerol monostearate and distearate), and the like. A preferred polymer for use in the practice of the invention is dl (polylactide-co-glycolide). Preferably, the molar ratio of lactide to glycolide in such copolymers is in the range of about 75:25 to 50:50.

Useful PLGA polymers can have a weight average molecular weight of about 5,000 to 500,000 daltons, preferably about 150,000 daltons. Depending on the degradation rate to be achieved, polymers of different molecular weights may be used. For the diffusion mechanism of drug release, the polymer should remain intact until all of the drug is released from the polymer matrix and then degraded. 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 by ring-opening polymerization from cyclic lactide, glycolide, and the like using a suitable catalyst. (see EP-0058481B2;Effects of polymerization variables on PLGA properties:molecular weight,composition and chain structure).

It is believed that the degradation of PLGA by means of the whole solid polymer composition is biodegradable due to the decomposition of hydrolytically and enzymatically cleavable ester bonds to form lactic acid and glycolic acid under biological conditions, e.g. in the presence of water and biological enzymes found in the tissues of warm-blooded animals such as humans. Lactic acid and glycolic acid are both water-soluble, non-toxic products of normal metabolism that can be further biodegraded to form carbon dioxide and water. In other words, PLGA is believed to be degraded by means of hydrolysis of its ester groups in the presence of water, for example in the body of a warm-blooded animal (e.g. a human), to produce lactic acid and glycolic acid, and to produce an acidic microclimate. Lactic acid and glycolic acid are by-products of various metabolic pathways in the body under normal physiological conditions in warm-blooded animals (e.g., humans) and are therefore well tolerated and produce minimal systemic toxicity.

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

Star polymers can be prepared using polyhydroxy compounds (e.g., polyols such as glucose or mannitol) as initiators. The polyol contains at least 3 hydroxyl groups and has a molecular weight of up to about 20,000 daltons, wherein at least 1, preferably at least 2, e.g., on average 3, of the hydroxyl groups of the polyol are in the form of ester groups containing polylactide or copolylactide chains. Branched polyesters, such as poly (d, l-lactide-co-glycolide), have a central glucose moiety with rays of linear polylactide chains.

The depot compositions of the invention as described above (long acting injectable compositions having a compound of the invention in a polymeric matrix) may comprise a polymer in the form of microparticles or nanoparticles, or a polymer in liquid form in which the compound of the invention is dispersed or encapsulated. "microparticles" refers to solid particles containing a compound of the present invention in solution or solid form, wherein such compound is dispersed or dissolved in a polymer as the matrix of the particles. By appropriate choice of polymeric materials, microparticle formulations can be prepared wherein the resulting microparticles exhibit diffusion release and biodegradation release characteristics.

When the polymer is in particulate form, the particles may be prepared using any suitable method, for example by solvent evaporation or solvent extraction. For example, in solvent evaporation methods, the compounds and polymers of the invention may be dissolved in a volatile organic solvent (e.g., a ketone such as acetone, a halogenated hydrocarbon such as chloroform or methylene chloride, a halogenated aromatic hydrocarbon, a cyclic ether such as dioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile, or an alcohol such as ethanol) and dispersed in an aqueous phase containing a suitable emulsion stabilizer (e.g., polyvinyl alcohol PVA). The organic solvent is then evaporated to provide microparticles having the compound of the present invention encapsulated therein. In solvent extraction, the compounds and polymers of the present invention may be dissolved in a polar solvent (e.g., acetonitrile, methylene chloride, methanol, ethyl acetate, or methyl formate) and then dispersed in an aqueous phase (e.g., water/PVA solution). An emulsion is produced to provide microparticles having the compound of the present invention encapsulated therein. Spray drying is an alternative manufacturing technique for preparing microparticles.

Additional methods of preparing the microparticles of the present invention are also described in both U.S. Pat. No. 4,389,330 and U.S. Pat. No. 4,530,840.

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

Solvents that may be employed in the practice of the present invention for preparing such compositions comprising the compounds of the present invention and a polymeric matrix material include organic solvents such as acetone, halogenated hydrocarbons such as chloroform, methylene chloride, and the like, aromatic hydrocarbon compounds, halogenated aromatic hydrocarbon compounds, cyclic ethers, alcohols such as benzyl alcohol, ethyl acetate, and the like. In one embodiment, the solvent used in the practice of the present invention may be a mixture of benzyl alcohol and ethyl acetate. Further information on the preparation of microparticles useful in the present invention can be found in U.S. patent publication No. 2008/0069885, the contents of which are incorporated herein by reference in their entirety.

The amount of the compounds of the present disclosure incorporated into the microparticles is generally in the range of from about 1 wt% to about 90 wt%, preferably from 30 to 50 wt%, more preferably from 35 to 40 wt%. Wt% refers to the parts of a compound of the present disclosure per total weight of the microparticles.

The pharmaceutical depot composition can comprise a pharmaceutically acceptable diluent or carrier, such as a water miscible diluent or carrier.

Details of osmotic controlled release oral delivery system compositions can be found in EP 1 539115 (U.S. publication No. 2009/0202631) and WO 2000/35419 (US 2001/0036472), the respective contents of which are incorporated herein by reference in their entirety.

By "therapeutically effective amount" is meant any amount of a compound of the invention (e.g., as contained in a drug depot) that, when administered to a subject having a disease or disorder, is effective to cause a reduction, alleviation or regression of the disease or disorder over a period of time intended for treatment.

The dosage employed in practicing the present invention will of course vary depending upon, for example, the particular disease or condition to be treated, the particular compound of the present invention employed, the mode of administration, and the desired treatment. Unless otherwise indicated, the amount of a compound of the invention (whether administered as a free base or salt form) used for administration refers to or is based on the amount of the compound of the invention in the free base form (i.e., the amount is calculated based on the amount of free base).

The compounds of the present invention may be administered by any satisfactory route, including oral, parenteral (intravenous, intramuscular, intranasal, pulmonary or subcutaneous) or transdermal. In certain embodiments, the compounds of the invention (e.g., in depot formulations) are preferably administered parenterally, e.g., by injection, e.g., intramuscular or subcutaneous injection.

Generally, as explained above, for the therapeutic methods disclosed herein or the use of the compounds of the invention as described above, oral administration at a dose on the order of about 1mg to 100mg once daily, indicates that satisfactory results are obtained, preferably once daily, 2.5mg to 50mg, for example 2.5mg, 5mg, 10mg, 20mg, 30mg, 40mg or 50mg, preferably via oral administration.

For some disease treatments, lower doses are satisfactory, in particular for sleep disorder treatment, for example about 2.5mg to 5mg, for example 2.5mg, 3mg, 4mg or 5mg of a compound of the invention in free or pharmaceutically acceptable salt form, once daily, preferably via oral administration.

For treatment methods involving co-administration of a second therapeutic agent, satisfactory results may be obtained at dosages of less than 100mg, preferably less than 50mg, for example less than 40mg, less than 30mg, less than 20mg, less than 10mg, less than 5mg, less than 2.5mg, once daily.

For the treatment of disorders disclosed herein, wherein a depot composition is used to achieve a longer duration of action, the dosage will be higher, e.g., higher than 1-100mg, e.g., 25mg, 50mg, 100mg, 500mg, 1000mg or greater than 1000mg, relative to a shorter acting composition. The duration of action of the compounds of the present disclosure can be controlled by manipulating the polymer composition (i.e., polymer: drug ratio and particle size). When the composition of the present invention is a depot composition, it is preferably administered by injection.

Pharmaceutically acceptable salts of the compounds of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts may be prepared by reacting the free base form of these compounds with a stoichiometric amount of the appropriate acid in water or an organic solvent or a mixture of both, with non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile being generally preferred. Further details of the preparation of these salts, such as tosylate in amorphous or crystalline form, can be found in U.S. 8,309,722, 8.648,077, 9,199,995 and 9,586,960.

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

The term "concurrently" when referring to therapeutic use means that two or more active ingredients are administered to a patient as part of a disease or disorder treatment regimen, whether the two or more active ingredients are administered at the same or different times or by the same or different routes of administration. The concurrent administration of two or more active ingredients may be at different times of the same day, or on different dates, or at different frequencies.

The term "simultaneously" when referring to therapeutic use means that two or more active ingredients are administered simultaneously or about simultaneously by the same route of administration.

The term "alone" when referring to therapeutic use refers to the simultaneous or about simultaneous administration of two or more active ingredients by different routes of administration.

A process for preparing the compounds of the invention:

Compounds of formula A and methods for their synthesis, including the synthesis of intermediates used in the synthesis schemes described below, have been disclosed, for example, in U.S.10,245,260 and U.S. 2022/0041600 and U.S. 2022/0064166, the contents of which are incorporated herein by reference in their entirety.

The synthesis of similar fused gamma-carbolines has been disclosed in, for example, U.S.8,309,722, U.S.8,993,572, US2017/0183350, 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 may be prepared using similar procedures.

Other compounds of the present disclosure may be prepared by similar procedures known to those skilled in the art.

Separation or purification of diastereomers of the compounds of the invention may be accomplished 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.

Salts of the compounds of the present disclosure may be prepared similarly as described in U.S. Pat. nos. 6,548,493, 7,238,690, 6,552,017, 6,713,471, 7,183,282, 8,648,077, 9,199,995, 9,586,860, u.s.re39680 and u.s.re39679, the contents of each of which are incorporated by reference in their entirety.

Diastereomers of the compounds prepared can be used, for example, at room temperatureAY-H,5 μ,30x250mm and separation by HPLC eluting with 10% ethanol/90% hexane/0.1% dimethylethylamine. Peaks can be detected at 230nm, yielding an ee of 98-99.9% of diastereoisomers.

Examples

Methods for synthesizing the disclosed compounds are known in the art. In particular, methods for synthesizing tetracyclic core structures, and methods for making various modifications and variations to the pendant side chains on the piperidine ring have been disclosed. See, for example, li et al ,Journal of Medicinal Chemistry 57:2670-2682(2014)、U.S.6,713,471、U.S.6,552,017、U.S.7,071,186、U.S.8,309,722、U.S.9,708,322、U.S.10,245,260、U.S.10,688,097、U.S.10,961,245、U.S.10,906,906、U.S.11,427,587、U.S.11,453,670 and US2022/0048910, the contents of each of which are incorporated herein by reference in their entirety.

The compounds of the present disclosure may be prepared according to the following general scheme:

scheme 1

Typical reagents and conditions are (a) ethyl magnesium bromide, titanium isopropoxide, THF, 25 ℃, (b) 90% etoh solution of saturated KOH, 100 ℃, (C) RX, KI, DIPEA, DMF, 75 ℃.

Scheme 2

Typical reagents and conditions (a) 4-bromo-1-butene, DIPEA, KI, dioxane, 110 ℃, (b) DBU, pd (OAc) ₂, tricyclohexylphosphine, DMF, 140 ℃, (C) ZnEt ₂、CH₂I₂、CH₂Cl₂, 0 ℃, (d) 90% etoh solution of saturated KOH, 100 ℃, (e) RX, KI, DIPEA, DMF, 75 ℃.

Scheme 3

Typical reagents and conditions are (a) RX, DIPEA, KI, 18-crown-6, dioxane, 95 ℃, or RX, K ₂CO₃, dioxane, 60 ℃. The tetracyclic starting materials may be prepared according to known methods, for example according to scheme 3-a below:

Typical reagents and conditions (a) N-methyl chloroacetamide, DIPEA, KI, dioxane, reflux for 48h, (b) CuI, K ₂CO₃, DMEDA, dioxane, reflux for 24h, (C) BH ₃ -THF, 60 ℃ for 20h, (d) KOH, N-BuOH, 120 ℃ for 3h.

Scheme 4

Typical reagents and conditions (a) ROH, triton B, KOH, 18-crown-6, 150 ℃.

According to the general scheme above, the following compounds of examples 1 to 180 have been or will be synthesized and characterized:

representative synthetic examples are as follows.

Example 2.1- (4-fluorophenyl) -5- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) pentan-1-one

The synthesis was performed in analogy to example 71, wherein 5-chloro-1- (4-fluorophenyl) -1-pentanone was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 17% isolated yield .¹H NMR(500MHz,DMSO)δ8.10–8.01(m,2H),7.40–7.28(m,2H),6.53–6.46(m,1H),6.43–6.38(m,1H),6.32(dd,J＝7.9,1.0Hz,1H),3.43(ddd,J＝11.5,9.7,3.0Hz,1H),3.26(dt,J＝11.4,2.9Hz,3H),3.10(ddd,J＝6.8,4.3,2.4Hz,1H),3.02(dd,J＝7.8,6.7Hz,2H),2.78(s,3H),2.74(ddd,J＝11.3,6.2,1.7Hz,1H),2.68(td,J＝9.9,2.8Hz,1H),2.54(t,J＝11.5Hz,1H),2.35–2.15(m,2H),2.07(td,J＝11.5,2.9Hz,1H),1.92–1.82(m,1H),1.80–1.69(m,2H),1.62(p,J＝7.3Hz,2H),1.54–1.41(m,2H).HRMS(ESI)m/z calculated for C ₂₅H₃₀FN₃O[M+H]⁺: 408.2446, found: 408.2446.

Example 3.1- (4-fluorophenyl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,7,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (9H) -yl) propan-1-one.

To a degassed solution of 2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) ethan-1-ol hydrogen chloride (3.0 g,11.3 mmol) in anhydrous dioxane (20 mL) was added N, N-diisopropylethylamine (3.0 g,22.6 mmol), 3-chloro-1- (4-fluorophenyl) propan-1-one (2.3 g,12.4 mmol), potassium iodide (2.3 g,13.6 mmol) and a catalytic amount of 18-crown-6 under argon. The resulting mixture was heated to 95 ℃ and stirred for 6.5 hours. After cooling to room temperature, the solvent was removed and the residue was suspended in ethyl acetate (50 mL) and water (50 mL). The aqueous phase was separated and extracted twice with ethyl acetate (30 mL). The combined organic phases were dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography using a gradient of 0-20% mixed solvent in ethyl acetate [ 7N NH ₃ in ethyl acetate/methanol (10:1:0.1 v/v) ] to give the title product as a brown solid (0.8 g, yield 16％).MS(ESI)m/z 380.2[M+1]⁺.¹H NMR(500MHz,DMSO)δ9.15(s,1H),8.19–8.07(m,2H),7.42(t,J＝8.8Hz,2H),6.62(t,J＝7.7Hz,1H),6.50(d,J＝7.3Hz,1H),6.44(d,J＝7.9Hz,1H),3.68–3.57(m,3H),3.53–3.41(m,5H),3.35(q,J＝2.6Hz,1H),3.23(d,J＝5.8Hz,1H),3.14(q,J＝13.1Hz,1H),2.82(s,4H),2.76–2.61(m,2H),2.29(d,J＝15.5Hz,1H),2.07(t,J＝14.8Hz,1H).

Example 4.1- (4-fluorophenyl) -4- ((6 b 'R,10a' S) -3 '-methyl-6 b',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.

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 4-chloro-1- (4-fluorophenyl) butan-1-one was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. Yield of 13% separation .MS(ESI)m/z 420.3[M+1]⁺.¹H NMR(500MHz,DMSO)δ8.09–7.99(m,2H),7.40–7.28(m,2H),6.56–6.51(m,2H),6.48(dd,J＝6.6,2.5Hz,1H),3.11(ddd,J＝6.8,4.3,2.6Hz,1H),3.00(t,J＝6.9Hz,2H),2.91(dt,J＝10.3,6.3Hz,1H),2.74(dd,J＝11.4,6.3Hz,1H),2.69(dd,J＝10.0,2.0Hz,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＝10.9Hz,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＝9.8,6.3,4.1Hz,1H).

Example 5.1- (4-fluorophenyl) -6- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) hexan-1-one

The synthesis was performed in analogy to example 71, wherein 6-chloro-1- (4-fluorophenyl) -1-hexanone was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 11% isolated yield .¹H NMR(500MHz,CDCl₃)δ8.46(s,1H),6.87–6.77(m,2H),6.75–6.71(m,1H),6.70–6.66(m,2H),6.64(dd,J＝7.9,1.2Hz,1H),3.99(t,J＝5.8Hz,2H),3.57(dt,J＝12.1,6.3Hz,1H),3.45(ddd,J＝11.9,6.4,2.0Hz,1H),3.39–3.26(m,2H),3.18–2.99(m,2H),2.92(dd,J＝9.9,2.2Hz,1H),2.90–2.79(m,1H),2.71(s,3H),2.54(t,J＝11.7Hz,1H),2.48–2.39(m,1H),2.37(d,J＝10.0Hz,1H),2.32–2.23(m,2H),2.18(d,J＝3.4Hz,2H),2.04(dq,J＝15.5,2.7Hz,1H).¹³C NMR(126MHz,CDCl₃)δ167.43,157.18(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 calculated for C ₂₆H₃₂FN₃O[M+H]⁺: 422.2602, found: 422.2602.

Example 6.1- (4- (2-methoxyethoxy) phenyl) -4- ((6 bR,10 aS) -3-methyl-2, 3,6b,7,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (9H) -yl) butan-1-one.

A mixture of 2-methoxyethyl-1-ol (1.5 mL), 1- (4-fluorophenyl) -4- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-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-phenylmethylammonium hydroxide (0.3 g,1.7 mmol) and 85% KOH (0.1 g,1.5 mmol) was heated by microwaves under argon at 150℃for 3 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness. The residue was adjusted to pH 9 by adding aqueous NH ₄ Cl with stirring, and the resulting suspension was extracted three times with dichloromethane (3X 10 mL). The combined organic phases were dried over MgSO ₄ and concentrated. The residue was purified by column chromatography on silica gel using a gradient of 0-40% mixed solvent in dichloromethane [ dichloromethane/methanol in 7N NH ₃ (10:1:0.1 v/v) ]. The title product was obtained as a brown solid (0.4 g, yield 35％).MS(ESI)m/z450.3[M+1]⁺.¹H NMR(500MHz,MeOD)δ8.05–7.95(m,2H),7.09–6.99(m,2H),6.61(t,J＝7.7Hz,1H),6.50(d,J＝7.3Hz,1H),6.43(dd,J＝8.0,0.9Hz,1H),4.27–4.17(m,2H),3.81–3.75(m,2H),3.52(ddd,J＝11.8,10.1,3.2Hz,1H),3.44(s,3H),3.38(t,J＝3.0Hz,1H),3.31(d,J＝3.0Hz,2H),3.29(t,J＝2.9Hz,1H),3.15(ddd,J＝6.5,4.2,2.2Hz,1H),3.08(dt,J＝10.8,6.3Hz,1H),2.85(s,4H),2.77(td,J＝10.0,2.8Hz,2H),2.51–2.37(m,2H),2.32(td,J＝11.9,3.0Hz,1H),2.04–1.86(m,5H).

Example 7.1- (4-fluorophenyl) -4- ((7 a ' S,11a ' R) -5',6',8',9',11',11a ' -hexahydrospiro [ cyclopropane-1, 4' -pyrido [3',4':4,5] pyrrolo [3,2,1-ij ] quinolin ] -10' (7 a ' H) -yl) butan-1-one.

The synthesis was analogous to the synthesis of the compound of example 8 according to scheme 2, wherein 4-chloro-1- (4-fluorophenyl) butan-1-one was added in place of 1- (3-chloropropoxy) -4-fluorobenzene in step E. 21% isolated yield. MS (ESI) m/z 405.31[ M+H ] ⁺.

Example 8. (7 a'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 ].

Step A (4 aS,9 bR) -6-bromo-5- (but-3-en-1-yl) -3, 4a, 5-tetrahydro-1H-pyrido [4,3-b ] indole-2 (9 bH) -carboxylic acid ethyl ester A mixture of (4 aS,9 bR) -6-bromo-1, 3, 4a,5,9 b-hexahydro-2H-pyrido [4,3-b ] indole-2-carboxylic acid ethyl ester (6.514 g,20.0 mmol), 4-bromo-1-butene (4.05 g,30.0 mmol), DIPEA (5.17 g, 40.98 g,30.0 mmol) and KI (4.98 g,30.0 mmol) in anhydrous dioxane (17 mL) was heated at 110℃for 48 hours under an argon atmosphere. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was suspended in DCM (200 mL) and washed with water (100 mL). The DCM phase was separated, dried over K ₂CO₃ and concentrated to a brown oil. The oil product was purified by silica gel column chromatography using a gradient of 0-70% ethyl acetate in hexane as eluent. The title compound (3.6 g,48% yield) was obtained as a brown oil, MS (ESI) m/z 379.16[ M+H ] ⁺.

Step B (6 bR,10 aS) -2-oxo-2, 3,6B,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline-8 (7H) -carboxylic acid ethyl ester Pd (OAc) ₂ (24 mg,0.11 mmol) was added to a degassed solution of (4 aS,9 bR) -6-bromo-5- (but-3-en-1-yl) -3, 4a, 5-tetrahydro-1H-pyrido [4,3-B ] indole-2 (9 bH) -carboxylic acid ethyl ester (850 mg,2.24 mmol), K ₂CO₃ (1.1 mg,7.92 mmol) and tricyclohexylphosphine (59 mg,0.21 mmol) in DMF (6 mL) under an argon atmosphere. The resulting mixture was stirred at 140 ℃ for 3 hours. After evaporation of the reaction solvent, the residue was purified by flash column chromatography on silica gel using a gradient of 0-30% ethyl acetate in hexane as eluent. The title compound was obtained as a beige solid (200 mg,30% yield). MS (ESI) m/z 299.13[ M+H ] ⁺.

Step C (7 a ' 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' (7 a ' H) -carboxylic acid ethyl ester CH ₂I₂ (600 mg,2.23 mmol) was added dropwise to a stirred solution of ZnEt ₂ (1.5M, 0.7mL,1.1mmol in toluene) in dichloromethane (0.5 mL) under an argon atmosphere and the mixture was stirred at 0℃for 50 min. A solution of (6 bR,10 aS) -2-oxo-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline-8 (7H) -carboxylic acid ethyl ester (165 mg,0.553 mmol) in dichloromethane (0.5 mL) was added and the resulting mixture was stirred at 0℃for 4 hours. The reaction was then quenched with saturated NH ₄ Cl (0.5 mL) and neutralized with saturated NaHCO ₃ (10 mL). The resulting solution was extracted with dichloromethane (20 mL) and the organic layer was evaporated to dryness. The residue was purified by column chromatography on silica gel using a gradient of 0-100% of a mixture in ethyl acetate, ethyl acetate: methanol: 7N NH ₃ in methanol (10:1:0.1 v/v/v) as eluent. The title compound was obtained as a beige solid (75 mg,43% yield). MS (ESI) m/z 313.14[ M+H ] ⁺.

Step D (7 a ' 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 ]. Ethyl (70 g,0.224 mmol) was suspended in a 90% EtOH solution of saturated KOH at room temperature and heated by microwaves at 100℃for 4 hours under stirring. The reaction was cooled to room temperature, and ethyl acetate (20 mL) was added. The mixture was washed with water (10 mL) and then brine (10 mL). The ethyl acetate phase was separated, dried over K ₂CO₃ and concentrated. The residue was further dried under high vacuum to give the title compound as a beige solid (70 mg, yield > 100%). The crude product was used directly in the next step without any further purification. MS (ESI) m/z 241.17[ M+H ] ⁺.

Step E (7 a ' 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 (7 a ' 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 bubbled with argon for 3min, followed by the addition of DIPEA (0.35 mL,0.2 mmol). The mixture was stirred at 75 ℃ for 2 hours 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 K ₂CO₃, and the filtrate was filtered and concentrated. The residue was purified by HPLC to give the final compound as a pale orange oil (8 mg,25% yield). MS (ESI) M/z393.29[ M+H ] ⁺.

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

The procedure is analogous to that of example 3 according to scheme 3, wherein 1- (2- (2-chloroethoxy) ethoxy ] -4-fluorobenzene is added instead of 3-chloro-1- (4-fluorophenyl) propan-1-one. 19% isolated yield. MS (ESI) m/z 412.2[ M+1] ⁺.

Example 13.1- (4- ((4-fluorobenzyl) oxy) phenyl) -4- ((6 bR,10 aS) -3-methyl-2, 3,6b,7,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (9H) -yl) butan-1-one.

The synthesis was analogous to the synthesis of the compound of example 6 according to scheme 4, with (4-fluorophenyl) methanol being added instead of 2-methoxyethan-1-ol. Yield of 68% isolation .MS(ESI)m/z 500.3[M+1]⁺.¹H NMR(500MHz,CDCl₃)δ8.03–7.95(m,2H),7.47–7.39(m,2H),7.15–7.07(m,2H),7.04–6.98(m,2H),6.67(t,J＝7.6Hz,1H),6.53(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝7.9,0.9Hz,1H),3.62(ddd,J＝11.3,9.8,2.8Hz,1H),3.31(ddt,J＝18.9,11.3,2.9Hz,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＝9.8,2.7Hz,2H),2.69(s,1H),2.42(s,2H),2.27(s,1H),1.95(d,J＝25.3Hz,6H),1.28(s,1H),0.93–0.83(m,1H).

Example 14.1- (4-fluorophenyl) -3- ((6 b 'R,10a' S) -3 '-methyl-6 b',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.

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 3-chloro-1- (4-fluorophenyl) propan-1-one was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. Yield of 63% isolation .¹H NMR(500MHz,CDCl₃)δ7.99(dd,J＝8.9,5.4Hz,2H),7.13(dd,J＝8.6,8.6Hz,2H),6.67(d,J＝5.9Hz,2H),6.61(dd,J＝5.8,3.2Hz,1H),3.35–3.26(m,1H),3.17(s,3H),2.90(t,J＝5.7Hz,2H),2.87–2.81(m,2H),2.70(s,3H),2.69–2.63(m,1H),2.42(d,J＝9.9Hz,2H),2.21(t,J＝11.1Hz,1H),1.96–1.85(m,2H),1.26(t,J＝7.1Hz,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).

Example 15 (6 b ' 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 ].

Step A (6 b 'R,10a' S) -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) -carboxylic acid ethyl ester ethyl bromide (3.0M in Et ₂ O, 13.6mL,10 mmol) was added dropwise to a vigorously stirred solution of (6 bR,10 aS) -3-methyl-2-oxo-2, 3,6b,7,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline-8 (9H) -carboxylic acid ethyl ester (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 hours and then quenched with saturated NH ₄ Cl (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 was separated, dried over K ₂CO₃ and concentrated to give a brown oil. The crude oil was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate in hexane as eluent. The title compound was obtained as a pale brown solid (3.12 g,70% yield). MS (ESI) m/z 328.16[ M+H ] ⁺.

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 ]. Ethyl (6B 'R,10a' S) -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) was suspended in a 90% EtOH solution of saturated KOH (17 mL) at room temperature and the reaction was heated under stirring for 4 hours at 100 ℃. The reaction was cooled to room temperature, and then ethyl acetate (200 mL) was added. The mixture was washed with water (100 mL) and then brine (100 mL). The ethyl acetate phase was separated, dried over K ₂CO₃ and concentrated. The residue was further dried under high vacuum to give the title compound as a beige solid (1.0 g,72% yield). The crude product was used directly in the next step without any further purification. MS (ESI) m/z 256.17[ M+H ] ⁺.

Step C (6 b ' 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 (6 b ' 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 bubbled with argon for 3 minutes, followed by the addition of DIPEA (0.41 mL,2.35 mmol). The mixture was stirred at 75 ℃ for 2h 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 was dried over K ₂CO₃, and the filtrate was filtered and concentrated. The resulting product was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate in hexane as eluent. The final compound was obtained as a pale brown oil (338 mg,73% yield) ).MS(ESI)m/z 394.25[M+H]⁺.¹H NMR(500MHz,CDCl₃)δ6.96(dd,J＝9.2,8.2Hz,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＝9.9Hz,2H),2.25(t,J＝10.3Hz,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).

Example 16.1- (4-fluoro-2-methylphenyl) -3- ((6 b 'R,10a' S) -3 '-methyl-6 b',9',10',10a '-tetrahydro-1' H,3 'H-spiro [ cyclopropa-1, 2' -pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin ] -8 '(7'H) -yl) propan-1-one.

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 3-chloro-1- (o-tolyl) propan-1-one was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. 30% isolated yield. MS (ESI) m/z 394.28[ M+H ] ⁺.

Example 17 (6 b ' R,10a ' S) -8' - (2- (4-fluoro-2-methylphenoxy) ethyl) -3' -methyl-6 b ',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 ].

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 1- (2-chloroethoxy) -2-methylbenzene was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. 33% isolated yield. MS (ESI) m/z 408.33[ M+H ] ⁺.

Example 19 (6 b ' R,10a ' S) -8' - (3- (3-chlorophenyl) propyl) -3' -methyl-6 b ',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 ].

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 1- (3-bromopropyl) -3-chlorobenzene was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. 70% isolated yield. MS (ESI) m/z 408.29[ M+H ] ⁺.

EXAMPLE 20 (6 b ' R,10a ' S) -8' - (3- (3-methoxyphenyl) propyl) -3' -methyl-6 b ',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 ].

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 1- (3-bromopropyl) -3-methoxybenzene was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. 70% isolated yield. MS (ESI) m/z 404.35[ M+H ] ⁺.

EXAMPLE 21 (6 b ' 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 ].

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 1- (3-bromopropyl) -3- (trifluoromethyl) benzene was added in step C instead of 1- (2-bromoethoxy) -4-fluorobenzene. 58% isolated yield. MS (ESI) m/z 442.28[ M+H ] ⁺.

Example 22- (6 b ' R,10a ' S) -8' - (3- (2-chlorophenyl) propyl) -3' -methyl-6 b ',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 ].

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 1- (3-bromopropyl) -2-chlorobenzene was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. 80% isolated yield. MS (ESI) m/z 408.29[ M+H ] ⁺.

Example 23- (6 b ' 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 ].

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 1- (3-bromopropyl) -2-methylbenzene was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. 79% isolated yield. MS (ESI) m/z 388.35[ M+H ] ⁺.

Example 24 (6 b ' R,10a ' S) -8' - (2-chlorophenyl) -3' -methyl-6 b ',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 ].

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 1- (2-bromoethyl) -2-chlorobenzene was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. 39% isolated yield. MS (ESI) m/z 394.27[ M+H ] ⁺.

Example 25. (6 b ' R,10a ' S) -8' - (2-methoxyphenylethyl) -3' -methyl-6 b ',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 ].

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 1- (2-bromoethyl) -2-methoxybenzene was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. 66% isolated yield. MS (ESI) m/z 390.32[ M+H ] ⁺.

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

The procedure is analogous to example 71, wherein 1- (2-bromoethoxy) -4-fluorobenzene is added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 75% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.03–6.92(m,2H),6.89–6.79(m,2H),6.66(t,J＝7.6Hz,1H),6.52(d,J＝7.3Hz,1H),6.41(d,J＝7.8Hz,1H),4.07(td,J＝6.0,1.2Hz,2H),3.61(ddd,J＝11.2,9.9,3.0Hz,1H),3.32(dt,J＝9.9,2.9Hz,1H),3.27(dt,J＝11.3,2.9Hz,1H),3.25–3.16(m,2H),2.95(ddd,J＝11.3,6.0,1.9Hz,1H),2.87(s,3H),2.85–2.81(m,1H),2.81–2.69(m,3H),2.41(dt,J＝11.2,7.9Hz,1H),2.12(t,J＝11.0Hz,1H),1.96(dt,J＝7.3,4.0Hz,2H).¹³C NMR(126MHz,CDCl₃)δ157.4(d,J＝239.4Hz),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 calculated for C ₂₂H₂₆N₃OF[M+H]⁺: 368.2133, found: 368.2138.

EXAMPLE 27 (6 bR,10 aS) -8- (2- (4-fluoro-2-methylphenoxy) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline

The synthesis was performed in analogy to example 71, wherein 1- (2-chloroethoxy) -4-fluoro-2-toluene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 50% isolated yield .¹HNMR(500MHz,CDCl₃)δ6.92–6.82(m,1H),6.73(dd,J＝8.9,4.6Hz,1H),6.66(t,J＝7.6Hz,1H),6.52(dd,J＝7.4,0.9Hz,1H),6.41(dd,J＝7.9,0.9Hz,1H),4.08(td,J＝5.9,1.2Hz,2H),3.62(ddd,J＝11.3,10.0,3.0Hz,1H),3.32(dt,J＝10.0,2.9Hz,1H),3.27(dt,J＝11.3,2.9Hz,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＝11.1Hz,1H),2.01–1.85(m,2H).¹³C NMR(126MHz,CDCl₃)δ157.1(d,J＝239.4Hz),153.3,138.1,135.1,130.1,128.9(d,J＝2.5Hz),120.5,117.4(d,J＝25.2Hz),112.8,112.4(d,J＝25.2Hz),112.2(d,J＝12.6Hz),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 calculated for C ₂₃H₂₈N₃OF[M+H]⁺: 382.2289, found: 382.2292.

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

The synthesis was performed in analogy to example 71, wherein 1- (3-chloropropyl) -2-methoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 69% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.21–7.07(m,2H),6.94–6.78(m,2H),6.65(t,J＝7.6Hz,1H),6.52(dd,J＝7.5,0.9Hz,1H),6.40(dd,J＝8.1,0.9Hz,1H),3.81(s,3H),3.60(ddd,J＝11.2,9.9,3.0Hz,1H),3.31(dt,J＝10.0,2.9Hz,1H),3.26(dt,J＝11.3,2.9Hz,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＝9.9,2.9Hz,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(126MHz,CDCl₃)δ157.6,138.2,135.1,130.8,130.3,129.9,127.1,120.4,120.4,112.8,110.3,109.0,64.8,58.7,56.5,55.3,50.8,49.2,44.5,41.9,37.7,28.4,27.2,25.2.HRMS(ESI)m/z calculated for C ₂₄H₃₁N₃O[M+H]⁺: 378.2540, found: 378.2533.

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

The synthesis was performed in analogy to example 71, wherein 1- (3-bromopropyl) -3-methoxybenzene was added in place of1- (2-bromoethyl) -3-methoxybenzene in step D. The 73% isolation yield .¹H NMR(500MHz,CDCl₃)δ7.19(td,J＝7.7,0.7Hz,1H),6.78(d,J＝1.2Hz,1H),6.76–6.70(m,2H),6.65(t,J＝7.6Hz,1H),6.52(d,J＝1.0Hz,1H),6.40(dd,J＝7.9,0.9Hz,1H),3.80(s,3H),3.69–3.48(m,1H),3.31(dt,J＝9.9,2.9Hz,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＝9.9,2.8Hz,1H),2.73–2.64(m,1H),2.61(t,J＝6.8Hz,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).¹³CNMR(126MHz,CDCl₃)δ159.7,144.1,138.1,135.1,130.3,129.4,121.0,120.4,114.3,112.8,111.2,109.0,64.7,58.4,56.5,55.3,50.8,49.2,44.5,41.9,37.7,34.0,28.7,25.2.HRMS(ESI)m/z was calculated for C ₂₄H₃₁N₃ O [ M+H ] + 378.2540, found 378.2529.

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

The synthesis was performed in analogy to example 71, wherein 1- (3-bromopropyl) -3-chlorobenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. Yield .¹H NMR(500MHz,CDCl₃)δ7.24–7.17(m,2H),7.17–7.12(m,1H),7.10–7.01(m,1H),6.65(t,J＝7.6Hz,1H),6.52(dd,J＝7.4,0.9Hz,1H),6.41(dd,J＝7.9,0.9Hz,1H),3.68–3.53(m,1H),3.31(dt,J＝9.9,2.9Hz,1H),3.27(dt,J＝11.3,2.9Hz,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).¹³C NMR(126MHz,CDCl₃)δ144.5,138.1,135.1,134.2,130.2,129.7,128.7,126.7,126.0,120.4,112.8,109.0,64.7,58.1,56.5,50.8,49.2,44.5,41.9,37.7,33.6,28.6,25.2.HRMS(ESI)m/z isolated 72% calculated for C ₂₃H₂₈ClN₃[M+H]⁺: 382.2045, found: 382.2037.

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

The synthesis was performed in analogy to example 71, wherein 1- (3-bromopropyl) -2-chlorobenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 75% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.33(dd,J＝7.8,1.4Hz,1H),7.22(dd,J＝7.5,1.9Hz,1H),7.17(td,J＝7.4,1.4Hz,1H),7.12(td,J＝7.6,1.9Hz,1H),6.65(t,J＝7.6Hz,1H),6.52(dd,J＝7.4,0.9Hz,1H),6.40(dd,J＝7.9,1.0Hz,1H),3.66–3.54(m,1H),3.31(dt,J＝9.9,2.9Hz,1H),3.27(dt,J＝11.3,2.9Hz,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＝9.9,2.9Hz,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(126MHz,CDCl₃)δ140.0,138.1,135.1,134.1,130.5,130.3,129.6,127.4,126.8,120.4,112.8,109.0,64.8,58.3,56.5,50.8,49.2,44.5,41.9,37.7,31.7,27.2,25.2.HRMS(ESI)m/z calculated for C ₂₃H₂₈ClN₃[M+H]⁺: 382.2045, found: 382.2038.

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

The synthesis was performed in analogy to example 71, in which 1- (3-bromopropyl) -3- (trifluoromethyl) benzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 88% isolated yield .¹HNMR(500MHz,CDCl₃)δ7.52–7.41(m,2H),7.41–7.30(m,2H),6.65(t,J＝7.6Hz,1H),6.52(dd,J＝7.3,0.9Hz,1H),6.41(dd,J＝8.0,0.9Hz,1H),3.67–3.54(m,1H),3.31(dt,J＝9.9,3.0Hz,1H),3.27(dt,J＝11.3,2.9Hz,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＝6.8Hz,2H),2.67–2.61(m,1H),2.44–2.30(m,2H),2.24(td,J＝10.9,4.5Hz,1H),2.11–1.90(m,3H),1.85(p,J＝7.6Hz,2H).¹³C NMR(126MHz,CDCl₃)δ143.3,138.1,135.1,132.0,130.7(q,J＝32.8),130.2,128.8,125.3(q,J＝3.8Hz),124.4(q,J＝277.2Hz),122.8(q,J＝3.8Hz),120.4,112.8,109.0,64.7,57.9,56.5,50.8,49.2,44.5,41.9,37.7,33.7,28.6,25.2.HRMS(ESI)m/z calculated for C ₂₄H₂₈F₃N₃[M+H]⁺: 416.2308, found: 416.2298.

EXAMPLE 33 (6 bR,10 aS) -8- (2-chlorophenyl-ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline

The synthesis was performed in analogy to example 71, wherein 1- (2-bromoethyl) -2-chlorobenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 46% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.32(dd,J＝7.7,1.5Hz,1H),7.23(dd,J＝7.5,1.9Hz,1H),7.18(td,J＝7.4,1.5Hz,1H),7.13(td,J＝7.5,1.9Hz,1H),6.67(t,J＝7.6Hz,1H),6.55(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝8.0,0.9Hz,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＝10.0,2.9Hz,1H),2.80–2.73(m,1H),2.69–2.49(m,2H),2.44–2.30(m,1H),2.10(t,J＝11.1Hz,1H),2.04–1.92(m,2H).¹³C NMR(126MHz,CDCl₃)δ138.2,138.2,135.1,134.2,131.0,130.2,129.6,127.6,127.0,120.4,112.9,109.1,64.7,58.7,56.4,50.8,49.1,44.5,42.0,37.7,31.4,25.2.HRMS(ESI)m/z calculated for C ₂₂H₂₆ClN₃[M+H]⁺: 368.1888, found: 368.1879.

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

The synthesis was performed in analogy to example 71, in which 1- (2-bromoethyl) -2-methoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 88% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.18(td,J＝7.8,1.7Hz,1H),7.14(dd,J＝7.4,1.8Hz,1H),6.87(td,J＝7.4,1.1Hz,1H),6.83(dd,J＝8.2,1.1Hz,1H),6.67(t,J＝7.6Hz,1H),6.56(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝8.0,0.9Hz,1H),3.80(s,3H),3.71–3.53(m,1H),3.33(dt,J＝10.0,2.9Hz,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＝10.7Hz,1H),2.02–1.92(m,2H).¹³C NMR(126MHz,CDCl₃)δ157.7,138.2,135.1,130.4,130.4,129.0,127.4,120.5,120.4,112.9,110.4,109.0,64.8,59.1,56.4,55.4,50.8,49.1,44.5,42.0,37.7,28.1,25.3.HRMS(ESI)m/z calculated for C ₂₃H₂₉N₃O[M+H]⁺: 364.2383, found: 364.2375.

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

The synthesis was performed in analogy to example 71, wherein 1- (3-bromopropyl) -2-methylbenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 81% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.18–7.01(m,4H),6.65(t,J＝7.6Hz,1H),6.52(dd,J＝7.3,0.9Hz,1H),6.41(dd,J＝7.9,0.9Hz,1H),3.68–3.51(m,1H),3.32(dt,J＝9.9,2.9Hz,1H),3.27(dt,J＝11.3,2.9Hz,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＝9.9,2.8Hz,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(126MHz,CDCl₃)δ140.6,138.1,136.0,135.1,130.3,128.9,126.0,126.0,120.4,112.8,109.0,64.7,58.7,56.6,50.8,49.2,44.5,41.9,37.7,31.2,27.7,25.2,19.4.HRMS(ESI)m/z calculated for C ₂₄H₃₁N₃[M+H]⁺: 362.2591, found: 362.2582.

Example 36.1- (4-fluorophenyl) -3- ((8 aS,12 aR) -4,5,6,7,9,10,12 a-octahydroazepineAnd [3,2,1-hi ] pyrido [4,3-b ] indol-11 (8 aH) -yl) propan-1-one

The synthesis is carried out in analogy to example 71, wherein 3-chloro-1- (4-fluorophenyl) propan-1-one and (8 aS,12 aR) -4,5,6,7,8a,9,10,11,12 a-decahydroazepine are used in step DAnd [3,2,1-hi ] pyrido [4,3-b ] indoles. 46% isolated yield .¹H NMR(500MHz,CDCl₃)δ8.18–7.86(m,1H),7.19–7.05(m,1H),6.92(ddd,J＝12.4,7.4,1.3Hz,1H),6.68(t,J＝7.4Hz,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＝12.1,2.0Hz,1H),2.37(td,J＝11.8,2.9Hz,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(126MHz,CDCl3)δ197.8,165.9(d,J＝252Hz),152.9,133.6(d,J＝2.5Hz),133.4,130.9(d,J＝12.6Hz),129.7,127.4,121.1,119.4,115.8(d,J＝25.2Hz),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 calculated for C ₂₄H₂₇FN₂O[M+H]⁺: 379.2180, found: 379.2170.

EXAMPLE 37 (8 aS,12 aR) -11- (2- (4-fluorophenoxy) ethyl) -4,5,6,7,8a,9,10,11,12 a-decahydroazaAnd [3,2,1-hi ] pyrido [4,3-b ] indoles

A synthetic procedure analogous to example 71, wherein 1- (2-bromoethoxy) -4-fluorobenzene and (8 aS,12 aR) -4,5,6,7,8a,9,10,11,12 a-decahydroazepine are used in step DAnd [3,2,1-hi ] pyrido [4,3-b ] indoles. Yield .¹H NMR(500MHz,CDCl₃)δ7.08–6.88(m,4H),6.88–6.77(m,2H),6.69(t,J＝7.3Hz,1H),4.06(t,J＝6.0Hz,2H),3.34–3.23(m,2H),3.22–3.15(m,1H),2.99–2.83(m,2H),2.76(dq,J＝11.8,5.7Hz,3H),2.65(ddd,J＝14.8,11.6,2.3Hz,1H),2.57–2.46(m,1H),2.41(td,J＝11.7,3.2Hz,1H),2.14–1.85(m,5H),1.82–1.69(m,1H),1.64–1.48(m,1H).¹³C NMR(126MHz,CDCl₃)δ157.5(d,J＝239.4Hz),155.1,153.0,133.4,129.7,127.4,121.1,119.4,115.9(d,J＝37.8Hz),115.8,66.8,64.0,58.0,57.6,52.0,49.9,41.0,35.4,30.2,27.3,25.9.HRMS(ESI)m/z isolated 72% calculated for C ₂₃H₂₇FN₂O[M+H]⁺: 379.2180, found: 379.2171.

EXAMPLE 38 (8 aS,12 aR) -11- (2-methoxyphenylethyl) -4,5,6,7,8a,9,10,11,12 a-decahydroazaAnd [3,2,1-hi ] pyridine [4,3-b ] indole

A synthetic method analogous to example 71, wherein 1- (2-bromoethyl) -2-methoxybenzene and (8 aS,12 aR) -4,5,6,7,8a,9,10,11,12 a-decahydroazepine are used in step DAnd [3,2,1-hi ] pyrido [4,3-b ] indoles. 83% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.18(td,J＝7.7,1.8Hz,1H),7.13(dd,J＝7.4,1.8Hz,1H),6.97(dd,J＝7.3,1.3Hz,1H),6.92(dd,J＝7.5,1.2Hz,1H),6.87(td,J＝7.4,1.1Hz,1H),6.83(dd,J＝8.2,1.1Hz,1H),6.70(t,J＝7.4Hz,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＝11.7,3.2Hz,1H),2.17–1.93(m,4H),1.85(t,J＝11.2Hz,1H),1.82–1.71(m,1H),1.65–1.48(m,1H).¹³C NMR(126MHz,CDCl₃)δ157.7,153.0,133.7,130.4,129.6,129.0,127.4,127.3,121.2,120.5,119.4,110.4,64.3,59.1,57.4,55.4,52.0,49.4,41.2,35.4,30.2,28.2,27.3,26.0.HRMS(ESI)m/z calculated for C ₂₄H₃₀N₂O[M+H]⁺: 363.2431, found: 363.2421.

Example 39. (6 b ' R,10a ' S) -8' - (3- (2-methoxyphenyl) propyl) -3' -methyl-6 b ',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 ].

The synthesis was analogous to the synthesis of the compound of example 15 according to scheme 1, wherein 1- (3-chloropropyl) -2-methoxybenzene was added in place of 1- (2-bromoethoxy) -4-fluorobenzene in step C. 76% isolated yield. MS (ESI) m/z 404.36[ M+H ] ⁺.

EXAMPLE 41.1- (4-fluoro-2-methylphenyl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) propan-1-one

The synthesis was performed in analogy to example 71, in which 3-chloro-1- (4-fluoro-2-methylphenyl) propan-1-one was added in place of1- (2-bromoethyl) -3-methoxybenzene in step D. 27% isolated yield .¹HNMR(500MHz,CDCl₃)δ7.78–7.60(m,1H),7.05–6.82(m,2H),6.76–6.58(m,1H),6.50(dd,J＝7.4,0.9Hz,1H),6.40(dd,J＝8.0,0.9Hz,1H),3.60(ddd,J＝11.3,9.9,2.9Hz,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＝11.6,3.4Hz,1H),2.04(t,J＝11.1Hz,1H),1.99–1.80(m,2H).¹³C NMR(126MHz,CDCl₃)δ202.2,164.0(d,J＝253.3Hz),142.2(d,J＝8.8Hz),138.1,135.1,134.3(d,J＝3.8Hz),131.0(d,J＝8.8Hz),130.0,120.5,118.8(d,J＝21.4Hz),112.8,112.6(d,J＝21.4Hz),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 calculated for C ₂₄H₂₈FN₃O[M+H]⁺: 394.2289, found: 394.2284.

EXAMPLE 42 (8 aS,12 aR) -11- (2- (4-fluorophenoxy) ethyl) -6,7,8a,9,10,11,12 a-octahydro-5H- [1,4] oxazapineAnd [2,3,4-hi ] pyrido [4,3-b ] indoles

A synthetic method analogous to example 71, wherein 1- (2-bromoethoxy) -4-fluorobenzene and (8 aS,12 aR) -6,7,8a,9,10,11,12 a-octahydro-5H- [1,4] oxazapine are used in step DAnd [2,3,4-hi ] pyrido [4,3-b ] indoles. 45% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.01–6.92(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＝5.9Hz,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＝11.6,3.3Hz,1H),2.24–1.78(m,5H).¹³C NMR(126MHz,CDCl₃)δ157.5(d,J＝239.4Hz),155.1,146.7,142.9,135.5,120.6,119.6,117.7,115.9(d,J＝37.8Hz),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 calculated for C ₂₂H₂₅N₂O₂F[M+H]⁺: 369.1973, found: 369.1965.

Example 43.1- (4-fluorophenyl) -3- ((8 aS,12 aR) -6,7,9,10,12 a-hexahydro-5H- [1,4] oxazapineAnd [2,3,4-hi ] pyrido [4,3-b ] indol-11 (8 aH) -yl) propan-1-one

A synthetic method analogous to example 71, wherein 3-chloro-1- (4-fluorophenyl) propan-1-one and (8 aS,12 aR) -6,7,8a,9,10,11,12 a-octahydro-5H- [1,4] oxazapine are used in step DAnd [2,3,4-hi ] pyrido [4,3-b ] indoles. Yield .¹H NMR(500MHz,CDCl₃)δ8.09–7.90(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).¹³C NMR(126MHz,CDCl₃)δ197.7,165.9(d,J＝252Hz),146.8,142.9,135.5,133.6(d,J＝3.8Hz),130.9(d,J＝12.6Hz),120.6,119.6,117.7,115.9(d,J＝12.6Hz),72.0,64.2,57.1,53.4,50.3,49.2,41.6,36.3,31.1,25.6.HRMS(ESI)m/z isolated 44% calculated for C ₂₃H₂₅N₂O₂F[M+H]⁺: 381.1973, found: 381.1967.

Example 44.1- (4-fluorophenyl) -3- ((8 aS,12 aR) -6,7,9,10,12 a-hexahydro-5H-pyrido [4,3-b ] [1,4] thiazepineAnd [2,3,4-hi ] indol-11 (8 aH) -yl) propan-1-one

A synthetic method is analogous to example 71, wherein 3-chloro-1- (4-fluorophenyl) propan-1-one and (8 aS,12 aR) -6,7,8a,9,10,11,12 a-octahydro-5H-pyrido [4,3-b ] [1,4] thiazepine are used in step DAnd [2,3,4-hi ] indole. 25% isolated yield .¹H NMR(500MHz,CDCl₃)δ8.08–7.91(m,2H),7.18–7.04(m,2H),6.95(dd,J＝7.8,1.2Hz,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＝11.4,3.3Hz,1H),2.23–2.07(m,1H),2.06–1.96(m,2H),1.94–1.79(m,2H).¹³C NMR(126MHz,CDCl₃)δ197.7,165.9(d,J＝252Hz),152.3,133.7,133.6(d,J＝2.5Hz),130.9(d,J＝12.6Hz),129.0,121.3,119.9,119.8,115.9(d,J＝12.6Hz),63.9,56.7,53.5,49.3,47.3,41.0,36.4,32.1,30.6,25.8.HRMS(ESI)m/z calculated for C ₂₃H₂₅N₂OFS[M+H]⁺: 397.1744, found: 397.1738.

Example 45.1- (4-fluorophenyl) -3- ((7 aS,11 aR) -5,6,8,9,11 a-hexahydro-4H-pyrido [3',4':4,5] pyrrolo [3,2,1-ij ] quinolin-10 (7 aH) -yl) propan-1-one

The procedure is analogous to example 71, wherein 3-chloro-1- (4-fluorophenyl) propan-1-one and (7 aS,11 aR) -5,6,7a,8,9,10,11 a-octahydro-4H-pyrido [3',4':4,5] pyrrolo [3,2,1-ij ] quinoline are used in step D. 30% isolated yield .¹H NMR(500MHz,CDCl₃)δ8.12–7.84(m,2H),7.19–7.05(m,2H),7.01–6.80(m,2H),6.63(t,J＝7.4Hz,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＝10.2,3.6Hz,1H),2.38(td,J＝11.7,3.2Hz,1H),2.24–2.04(m,3H),2.03–1.96(m,1H),1.95–1.85(m,1H).¹³C NMR(126MHz,CDCl₃)δ197.8,165.9(d,J＝252Hz),149.8,133.6(d,J＝25.2Hz),131.0,130.9(d,J＝12.6Hz),126.9,121.0,120.6,118.7,115.8(d,J＝25.2Hz),64.0,56.3,53.5,49.1,44.7,41.1,36.4,25.1,24.3,23.2.HRMS(ESI)m/z calculated for C ₂₃H₂₅N₂OF[M+H]⁺: 365.2024, found: 365.2019.

Example 46.1- (4-fluorophenyl) -3- ((6 bR,10 aS) -1,2,6b,9,10 a-hexahydropyrido [4,3-b ] [1,4] thiazino [2,3,4-hi ] indol-8 (7H) -yl) propan-1-one

The procedure is analogous to example 71, wherein 3-chloro-1- (4-fluorophenyl) propan-1-one and (6 bR,10 aS) -1,2,6b,7,8,9,10 a-octahydropyrido [4,3-b ] [1,4] thiazino [2,3,4-hi ] indole are used in step D. 29% isolated yield .¹H NMR(500MHz,CDCl₃)δ8.06–7.93(m,2H),7.19–7.06(m,2H),6.96–6.75(m,2H),6.64(t,J＝7.5Hz,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＝11.4,3.3Hz,1H),2.06(t,J＝11.0Hz,1H),2.01–1.88(m,2H).¹³C NMR(126MHz,CDCl₃)δ197.7,165.9(d,J＝252Hz),145.1,133.6(d,J＝12.6Hz),131.7,130.9(d,J＝12.6Hz),124.4(d,J＝12.6Hz),119.9,119.7,116.3,115.9(d,J＝12.6Hz),63.6,56.1,53.4,49.0,43.8,40.4,36.3,27.4,25.0.HRMS(ESI)m/z calculated for C ₂₂H₂₃N₂OFS[M+H]⁺: 383.1588, found: 383.1582.

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

Step A (6 bR,10 aS) -3-methyl-2-oxo-2, 3,6b,7,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline-8 (9H) -carboxylic acid ethyl ester A suspension of (4 aS,9 bR) -6-bromo-1, 3, 4a,5,9 b-hexahydro-2H-pyrido [4,3-b ] indole-2-carboxylic acid ethyl ester (25 g,76.9 mmol), N-methylchloroacetamide (12.4 g,115.3mmol,1.5 eq.), potassium iodide (19.2 g,116 mmol) and diisopropylethylamine (26.6 mL,153.1mmol,2.0 eq.) in dioxane (63 mL) was refluxed for 48 hours. The reaction mixture was then cooled to about 80 ℃ and copper iodide (2.92 g,15.4mmol,0.2 eq.) potassium carbonate (23.3 g,168.2mmol,2.2 eq.) dimethyl ethylenediamine (4.96 mL,46.1mmol,0.6 eq.) and additional dioxane (38 mL) were added at this temperature. The resulting mixture was heated to reflux for a further 24 hours and then cooled to 40 ℃. The cooled mixture was poured into a quick-grade silica gel plug (63 g) and eluted with 6.25L ethyl acetate under vacuum. The eluate was concentrated to a solid residue (320 g) and then redissolved in hot ethanol (80 ml). The mixture was cooled to ambient temperature and stirred overnight, then cooled to 0-5 ℃, aged for 1h and filtered. The filter cake was washed with cold ethanol (15 ml) and allowed to air dry 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＝1.2,7.8Hz,1H),6.82(t,J＝7.8Hz,1H),6.90(dd,J＝1.2,7.2Hz,1H).MS(ESI)m/z 316.2[M+H]⁺.

Step B (6 bR,10 aS) -3-methyl-2, 3,6B,7,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo- [1,2,3-de ] quinoxaline-8 (9H) -carboxylic acid ethyl ester A solution of 1M ₃ -THF complex in THF (196 ml,196.2mmol,2.8 eq.) was slowly added via an addition funnel to a suspension of (6 bR,10 aS) -3-methyl-2-oxo-2, 3,6B,7,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline-8 (9H) -carboxylic acid ethyl ester (21.8 g,69.13 mmol) in 50ml THF at room temperature. The resulting clear solution was stirred at 60 ℃ for 20 hours and then cooled in an ice bath to about 10 ℃. MeOH (33 mL) was slowly added to the cooled mixture via the addition funnel while maintaining the internal temperature below 25 ℃. The resulting mixture was stirred in an ice bath for about 30 minutes and then concentrated in vacuo to give a yellow paste. The crude paste was then partitioned between EtOAc (218 mL) and water (218 mL). The separated organic layer was dried (Na ₂SO₄), filtered, and concentrated under reduced pressure to give the title compound (20.76 g,99% yield) as a yellow liquid ).¹HNMR(CDCI₃,300MHz)δ1.28(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);¹³CNMR(CDCl₃,75MHz)δ14.9,24.7,37.7,39.9,41.4,44.4,45.8,50.7,61.4,65.0,109.3,113.3,120.6,128.8,135.1,138.2,155.6.

Step C (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo- [1,2,3-de ] quinoxaline Ethyl (18.5 g,57 mmol), KOH (12.7 g,226 mmol) and n-butanol (90 mL) were placed in a 300mL pressure bottle and heated in an oil bath at 120℃for 3 hours. After removal of n-butanol in vacuo, the residue was treated with water (300 mL) and then extracted with CH ₂Cl₂ (3X 100 mL). The combined organic phases were washed with brine (2×200 mL), dried over anhydrous Na ₂SO₄, and evaporated to dryness to give the title compound as a dense oil (11.7 g,91% yield) which was used in the next step without further purification.

Step D (6 bR,10 aS) -8- (3-methoxyphenylethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido- [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline A mixture of (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-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 K ₂CO₃ (418 mg,3.0 mmol) in dioxane (1.5 mL) is bubbled with argon for 3 minutes. The resulting mixture was heated to 80 ℃ and stirred at this temperature for 24 hours. The solvent was removed and the residue was dissolved in DCM (30 mL) and washed with water (20 mL). The DCM phase was dried over K ₂CO₃, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel using a gradient of 0-55% of a mixture in ethyl acetate, ethyl acetate: methanol: 7N NH ₃ in methanol (10:1:0.1 v/v/v) as eluent. The title compound was obtained as a pale orange oil (200 mg,55% yield ).¹HNMR(500MHz,CDCl₃)δ7.23–7.15(m,1H),6.78(dt,J＝7.3,1.2Hz,1H),6.74(dd,J＝6.5,1.2Hz,2H),6.67(t,J＝7.6Hz,1H),6.54(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝7.9,1.0Hz,1H),3.79(s,3H),3.69–3.51(m,1H),3.32(dt,J＝10.0,2.9Hz,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＝11.2Hz,2H),2.35(s,1H),2.22–2.02(m,1H),1.98(s,2H).¹³CNMR(126MHz,CDCl₃)δ159.8,142.3,138.1,135.2,130.2,129.5,121.3,120.5,114.6,112.8,111.4,109.1,64.7,60.8,56.4,55.3,50.8,49.2,44.5,41.9,37.7,33.8,25.2.HRMS(ESI)m/z calculated for C ₂₃H₂₉N₃O[M+H]⁺: 364.2383; found: 364.2391.

Example 75.2- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] -quinoxalin-8 (7H) -yl) ethyl) benzonitrile

The synthesis was performed in analogy to example 71, wherein 2- (2-bromoethyl) benzonitrile was added in step D instead of 1- (2-bromoethyl) -3-methoxybenzene. 52% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.60(dd,J＝7.7,1.4Hz,1H),7.51(td,J＝7.6,1.4Hz,1H),7.34(dd,J＝7.9,1.2Hz,1H),7.29(td,J＝7.6,1.2Hz,1H),6.66(t,J＝7.7Hz,1H),6.53(d,J＝7.3Hz,1H),6.41(dd,J＝8.0,0.9Hz,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＝11.3,3.8Hz,1H),2.13(t,J＝11.1Hz,1H),2.00–1.86(m,2H).¹³C NMR(126MHz,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 calculated for C ₂₃H₂₆N₄[M+H]⁺: 359.223, found: 359.2226.

Example 76.2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) propyl) benzonitrile

The synthesis was performed in analogy to example 71, wherein 2- (3-bromopropyl) benzonitrile was added in step D instead of 1- (2-bromoethyl) -3-methoxybenzene. 68% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.60(dd,J＝7.7,1.4Hz,1H),7.50(td,J＝7.7,1.4Hz,1H),7.33(d,J＝7.7Hz,1H),7.31–7.26(m,1H),6.64(t,J＝7.6Hz,1H),6.57–6.49(m,1H),6.40(dd,J＝7.9,0.9Hz,1H),3.64–3.53(m,1H),3.30(dt,J＝9.9,2.9Hz,1H),3.26(dt,J＝11.3,2.9Hz,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).¹³C NMR(126MHz,CDCl₃)δ146.5,138.1,135.1,132.9,132.8,129.7,126.5,120.4,118.2,112.8,112.5,109.0,64.7,57.9,56.5,50.8,49.1,44.5,41.9,37.7,36.6,32.5,28.2,25.2.HRMS(ESI)m/z calculated for C ₂₄H₂₈N₄[M+H]⁺: 373.2387, found: 373.2382.

Example 77.1- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) ethyl) pyridin-2 (1H) -one

The procedure is analogous to example 71, wherein 1- (2-bromoethyl) pyridin-2 (1H) -one is added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. Yield .¹H NMR(500MHz,CDCl₃)δ7.38(dd,J＝6.9,2.0Hz,1H),7.31(ddd,J＝8.9,6.6,2.1Hz,1H),6.64(t,J＝7.6Hz,1H),6.53(dt,J＝9.1,1.0Hz,1H),6.48(d,J＝7.3Hz,1H),6.39(dd,J＝8.0,0.9Hz,1H),6.14(td,J＝6.7,1.4Hz,1H),3.58(ddd,J＝12.8,8.3,2.3Hz,1H),3.31–3.24(m,2H),3.23–3.15(m,4H),2.92(td,J＝11.1,7.7Hz,1H),2.85(s,3H),2.84–2.67(m,4H),2.49(q,J＝9.5Hz,1H),2.20(t,J＝11.1Hz,1H),1.94(dt,J＝7.4,3.2Hz,2H).¹³C NMR(126MHz,CDCl₃)δ162.7,139.7,138.6,137.9,135.2,120.80,120.6,112.7,109.2,105.8,64.2,54.7,50.6,49.2,47.1,44.4,42.9,41.5,37.6,24.8.HRMS(ESI)m/z isolated 9% calculated for C ₂₁H₂₆N₄O[M+H]⁺: 351.2179, found: 351.2175.

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

The synthesis was performed in analogy to example 71, wherein 1- (2-bromoethyl) -4-fluoro-2-methoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 65% isolated yield .¹HNMR(500MHz,CDCl₃)δ7.15–6.94(m,1H),6.66(dd,J＝7.9,7.4Hz,1H),6.62–6.49(m,3H),6.41(dd,J＝7.9,1.0Hz,1H),3.78(s,3H),3.68–3.52(m,1H),3.32(dt,J＝10.1,2.9Hz,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＝11.1Hz,1H),2.01–1.89(m,2H).¹³C NMR(126MHz,CDCl₃)δ162.3(d,J＝244.4Hz),158.5(d,J＝8.8Hz),138.2,135.3,130.7(d,J＝8.8Hz),130.1,124.0,120.1,112.9,109.0,106.5(d,J＝21.4Hz),98.8(d,J＝25.2Hz),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 calculated for C ₂₃H₂₈N₃OF[M+H]⁺: 382.2289, found: 382.2281.

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

The synthesis was performed in analogy to example 71, in which 1- (2-bromoethyl) -2- (trifluoromethoxy) benzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 83% isolated yield .¹HNMR(500MHz,CDCl₃)δ7.28(dd,J＝7.6,2.4Hz,1H),7.24–7.11(m,3H),6.67(t,J＝7.6Hz,1H),6.54(dd,J＝7.3,1.0Hz,1H),6.42(dd,J＝7.9,0.9Hz,1H),3.66–3.56(m,1H),3.33(dt,J＝10.0,2.9Hz,1H),3.28(dt,J＝11.4,2.9Hz,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＝10.0,2.9Hz,1H),2.79–2.73(m,1H),2.66–2.52(m,2H),2.47–2.33(m,1H),2.09(t,J＝11.1Hz,1H),2.03–1.89(m,2H).¹³C NMR(126MHz,CDCl₃)δ147.8,138.2,135.1,133.1,131.3,130.2,127.6,126.9,120.8(q,J＝252Hz),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 calculated for C ₂₃H₂₆N₃OF₃[M+H]⁺: 418.2101, found: 418.2097.HRMS (ESI) m/z calculated for C ₂₃H₂₆N₃OF₃[M+H]⁺: 418.2101; found: 418.2097.

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

The synthesis was performed in analogy to example 71, in which 1- (2-bromoethyl) -2-ethylbenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 64% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.21–7.07(m,4H),6.68(t,J＝7.6Hz,1H),6.56(d,J＝7.3Hz,1H),6.43(dd,J＝8.0,0.9Hz,1H),3.66–3.58(m,1H),3.33(dt,J＝10.0,2.9Hz,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＝7.6Hz,2H),2.61–2.46(m,2H),2.43–2.28(m,1H),2.07(t,J＝11.0Hz,1H),2.02–1.92(m,2H),1.22(t,J＝7.6Hz,3H).¹³C NMR(126MHz,CDCl₃)δ142.2,138.2,138.0,135.1,130.2,129.8,128.6,126.5,126.0,120.5,112.9,109.1,64.8,60.6,56.5,50.8,49.3,44.6,42.0,37.7,30.4,25.7,25.3,15.7.HRMS(ESI)m/z calculated for C ₂₄H₃₁N₃[M+H]⁺: 362.2591, found: 362.2588.

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

The synthesis was performed in analogy to example 71, in which 1- (2-bromoethyl) -4-methoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 36% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.18–6.95(m,2H),6.83(d,J＝8.7Hz,2H),6.67(t,J＝7.6Hz,1H),6.54(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝7.9,0.9Hz,1H),3.78(s,3H),3.69–3.54(m,1H),3.32(dt,J＝10.0,3.0Hz,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＝11.0Hz,1H),2.02–1.88(m,2H).¹³C NMR(126MHz,CDCl₃)δ158.1,138.1,135.2,132.6,130.1,129.7,120.5,114.0,112.8,109.1,64.7,61.1,56.4,55.4,50.8,49.2,44.5,41.9,37.7,32.8,25.1.HRMS(ESI)m/z calculated for C ₂₃H₂₉N₃O[M+H]⁺: 364.2383, found: 364.2380.

Example 84.4- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) ethyl) benzonitrile

The synthesis was performed in analogy to example 71, wherein 4- (2-bromoethyl) benzonitrile was added in step D instead of 1- (2-bromoethyl) -3-methoxybenzene. 30% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.56(d,J＝8.4Hz,2H),7.39–7.27(m,2H),6.66(t,J＝7.6Hz,1H),6.52(d,1H),6.42(dd,J＝8.0,0.9Hz,1H),3.61(ddd,J＝11.3,9.8,2.9Hz,1H),3.32(dt,J＝9.9,2.9Hz,1H),3.30–3.21(m,2H),3.17(dt,J＝12.5,6.3Hz,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＝11.0,3.4Hz,1H),2.07(t,J＝11.1Hz,1H),2.00–1.84(m,2H).¹³C NMR(126MHz,CDCl₃)δ146.5,138.1,135.2,132.3,130.0,129.7,120.5,119.2,112.7,110.1,109.1,64.6,60.0,56.4,50.8,49.2,44.5,41.9,37.7,33.9,25.2.HRMS(ESI)m/z calculated for C ₂₃H₂₆N₄[M+H]⁺: 359.2230, found: 359.2227.

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

The procedure is analogous to example 71, wherein 3- (2-bromoethyl) -6-fluoro-1H-indole is added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. Yield .¹H NMR(500MHz,CDCl3)δ8.05(d,J＝26.6Hz,1H),7.27–7.19(m,2H),7.04(d,J＝2.3Hz,1H),6.92(td,J＝9.0,2.5Hz,1H),6.71–6.64(m,1H),6.56(dd,J＝7.3,0.9Hz,1H),6.43(dd,J＝7.9,0.9Hz,1H),3.62(ddd,J＝11.4,9.9,3.0Hz,1H),3.34(dt,J＝10.0,3.0Hz,1H),3.31–3.18(m,3H),3.03(ddd,J＝11.1,6.1,1.9Hz,1H),2.98–2.90(m,3H),2.88(s,3H),2.85(td,J＝10.0,2.9Hz,1H),2.73–2.61(m,2H),2.38(dp,J＝11.1,7.7Hz,1H),2.10(dd,J＝11.5,10.5Hz,1H),2.00(q,J＝3.4Hz,2H).¹³C NMR(126MHz,CDCl₃)δ159.0,157.1,138.4,135.4,133.1,130.4,123.7,120.7,115.1,113.1,112.0(d,J＝8.8Hz),110.7(d,J＝26.5Hz),109.4,104.1(d,J＝23.9Hz),65.0,59.8,56.7,51.1,49.6,44.8,42.5,38.0,25.5,23.3.HRMS(ESI)m/z isolated 9% calculated for C ₂₄H₂₇N₄F[M+H]⁺: 391.2293, found: 391.2285.

EXAMPLE 86.1- (2-methoxyphenyl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) propan-1-one

The synthesis was performed in analogy to example 71, wherein 3-bromo-1- (2-methoxyphenyl) propan-1-one was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 36% isolated yield .¹HNMR(500MHz,DMSO)δ7.70–7.43(m,2H),7.15(d,J＝8.3Hz,1H),7.01(td,J＝7.4,1.0Hz,1H),6.51(t,J＝7.6Hz,1H),6.40(d,J＝7.3Hz,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).¹³C NMR(126MHz,DMSO)δ201.3,157.8,137.6,134.8,133.4,129.4,128.2,120.4,119.8,112.3,108.6,63.8,55.7,53.0,49.9,48.5,43.8,40.8,40.6,37.1,24.2.HRMS(ESI)m/z calculated for C ₂₄H₂₉N₃O₂[M+H]⁺: 392.2333, found: 392.2326.

Example 89.2- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) ethyl) phenol

The synthesis was performed in analogy to example 71, wherein 2- (2-bromoethyl) phenol was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 10% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.19–7.07(m,1H),6.99(dd,J＝7.5,1.7Hz,1H),6.90(dd,J＝8.0,1.3Hz,1H),6.75(td,J＝7.4,1.3Hz,1H),6.67(t,J＝7.6Hz,1H),6.52(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝8.0,0.9Hz,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＝11.8,3.6Hz,1H),2.31–1.96(m,3H).¹³C NMR(126MHz,CDCl₃)δ157.4,137.9,135.3,131.0,129.3,128.4,127.9,120.8,119.0,117.8,112.8,109.2,64.3,59.4,56.3,50.7,49.2,44.6,41.4,37.6,31.7,24.7.HRMS(ESI)m/z calculated for C ₂₂H₂₇N₃O[M+H]⁺: 350.2227, found: 350.2220.

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

The synthesis was performed in analogy to example 71, wherein 1- (bromomethyl) -2-methoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 35% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.40(dd,J＝7.4,1.8Hz,1H),7.25–7.17(m,1H),6.95(td,J＝7.4,1.1Hz,1H),6.86(dd,J＝8.2,1.1Hz,1H),6.75–6.57(m,1H),6.50(dd,J＝7.3,1.0Hz,1H),6.40(dd,J＝7.9,1.0Hz,1H),3.80(s,3H),3.65–3.58(m,1H),3.55(q,2H),3.32(dt,J＝10.0,3.0Hz,1H),3.29–3.16(m,3H),2.99–2.89(m,1H),2.87(s,3H),2.82(td,J＝9.9,2.9Hz,1H),2.74–2.64(m,1H),2.33(td,J＝11.1,4.3Hz,1H),2.06(t,J＝10.9Hz,1H),1.97–1.83(m,2H).¹³C NMR(126MHz,CDCl₃)δ157.9,138.2,135.1,130.6,130.4,128.0,127.0,120.5,120.3,113.0,110.6,108.9,64.8,56.6,56.4,55.6,50.8,49.2,44.5,42.0,37.7,25.2.HRMS(ESI)m/z calculated for C ₂₂H₂₇N₃O[M+H]⁺: 350.2227, found: 350.2219.

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

The synthesis was performed in analogy to example 71, in which 1- (2-chloroethyl) -2-ethoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 78% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.22–7.05(m,1H),6.86(td,J＝7.4,1.1Hz,1H),6.81(dd,J＝8.1,1.1Hz,0H),6.67(t,0H),6.55(dd,J＝7.4,0.9Hz,0H),6.42(dd,J＝7.9,1.0Hz,0H),4.02(q,J＝7.0Hz,2H),3.75–3.48(m,1H),3.33(dt,J＝10.1,2.9Hz,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＝11.0Hz,1H),2.03–1.90(m,2H),1.40(t,J＝7.0Hz,3H).¹³C NMR(126MHz,CDCl₃)δ157.0,138.2,135.1,130.4,130.3,129.1,127.3,120.4,112.9,111.3,109.0,64.8,63.5,59.1,56.5,50.8,49.0,44.6,42.0,37.7,28.1,25.3,15.1.HRMS(ESI)m/z calculated for C ₂₄H₃₁N₃O[M+H]⁺: 378.2540, found: 378.2531.

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

The synthesis was performed in analogy to example 71, in which 7- (2-chloroethyl) benzofuran was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 37% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.60(d,J＝2.2Hz,1H),7.44(dd,J＝7.6,1.4Hz,1H),7.22–7.07(m,2H),6.75(d,J＝2.2Hz,1H),6.67(t,J＝7.3Hz,1H),6.56(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝7.9,0.9Hz,1H),3.62(ddd,J＝11.4,10.0,3.1Hz,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＝11.0Hz,1H),2.06–1.91(m,2H).¹³C NMR(126MHz,CDCl₃)δ153.8,144.7,138.2,135.1,130.3,127.3,124.7,124.3,123.0,120.4,119.2,112.9,109.1,106.9,64.7,58.9,56.4,50.8,49.1,44.5,42.0,37.7,27.8,25.2.HRMS(ESI)m/ calculated for C ₂₄H₂₇N₃O[M+H]⁺: 374.2227, found: 374.2236.

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

The synthesis was performed in analogy to example 71, in which 1- (2-bromoethoxy) -2-methoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 32% isolated yield .¹HNMR(500MHz,CDCl₃)δ7.04–6.81(m,4H),6.65(t,1H),6.52(dd,J＝7.4,0.9Hz,1H),6.41(dd,J＝8.1,0.9Hz,1H),4.18(t,J＝6.5Hz,2H),3.85(s,3H),3.73–3.47(m,1H),3.32(dt,J＝10.0,2.9Hz,1H),3.27(dt,J＝11.3,2.8Hz,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＝11.0Hz,1H),2.02–1.85(m,1H).¹³C NMR(126MHz,CDCl₃)δ149.7,148.5,138.1,135.1,130.1,121.4,121.0,120.4,113.8,112.9,112.1,109.1,67.1,64.5,57.3,57.0,56.1,50.8,49.6,44.5,41.8,37.7,25.1.HRMS(ESI)m/z calculated for C ₂₃H₂₉N₃O₂[M+H]⁺: 380.2333, found: 380.2327.

Example 94.3- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) ethyl) benzo [ d ] isothiazole

The synthesis was performed in analogy to example 71, in which 3- (2-bromoethyl) benzo [ D ] isothiazole was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 67% isolated yield .¹HNMR(500MHz,CDCl₃)δ7.98(d,J＝8.0Hz,1H),7.92(d,J＝8.2Hz,1H),7.58–7.47(m,1H),7.46–7.38(m,1H),6.67(t,J＝7.6Hz,1H),6.55(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝8.0,0.9Hz,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＝10.9,4.9Hz,1H),2.16(t,J＝11.0Hz,1H),2.03–1.90(m,2H).¹³C NMR(126MHz,CDCl₃)δ165.1,152.5,138.2,135.1,134.9,130.1,127.7,124.6,123.4,120.5,120.1,112.9,109.1,64.6,56.8,56.4,50.8,49.2,44.5,41.9,37.7,29.5,25.2.HRMS(ESI)m/z calculated for C ₂₃H₂₆N₄S[M+H]⁺: 391.1951, found: 391.1960.

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

The synthesis was performed in analogy to example 71, wherein 2- (2-bromoethyl) -1, 4-dimethoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 39% isolated yield .¹HNMR(500MHz,CDCl₃)δ6.82–6.73(m,2H),6.71–6.63(m,2H),6.55(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝8.0,0.9Hz,1H),3.75(d,J＝2.9Hz,6H),3.71–3.50(m,1H),3.33(dt,J＝10.0,2.9Hz,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＝11.1Hz,1H),2.01–1.91(m,2H).¹³C NMR(126MHz,CDCl₃)δ153.6,152.0,138.2,135.1,130.3,130.3,120.4,116.8,112.9,111.4,111.3,109.0,64.8,59.1,56.4,56.1,55.8,50.8,49.1,44.5,42.0,37.7,28.3,25.3.HRMS(ESI)m/z calculated for C ₂₄H₃₁N₃O₂[M+H]⁺: 394.2489, found: 394.2484.

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

The synthesis was performed in analogy to example 71, in which 1- (bromomethyl) -4-ethylbenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 30% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.24(d,J＝8.2Hz,2H),7.15(d,J＝8.2Hz,2H),6.74–6.56(m,1H),6.49(dd,J＝7.4,0.9Hz,1H),6.41(dd,J＝7.9,0.9Hz,1H),3.68–3.51(m,1H),3.45(d,J＝2.4Hz,2H),3.31(dt,J＝9.9,3.0Hz,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＝7.5Hz,3H),2.43–2.11(m,1H),1.99(t,J＝11.2Hz,1H),1.95–1.87(m,2H),1.25(t,J＝7.6Hz,3H).¹³C NMR(126MHz,CDCl₃)δ143.0,138.2,136.0,135.1,130.3,129.3,127.8,120.3,113.0,109.0,64.8,63.2,56.5,50.8,49.1,44.5,41.9,37.7,28.7,25.2,15.7.HRMS(ESI)m/z calculated for C ₂₃H₂₉N₃[M+H]⁺: 348.2434, found: 348.2428.

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

The procedure is analogous to example 71, wherein 3- (2-bromoethyl) -1H-indole is added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 31% isolation yield .¹H NMR(500MHz,CDCl₃)δ8.00(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＝2.4Hz,1H),6.68(t,J＝7.6Hz,1H),6.57(dd,J＝7.3,0.9Hz,1H),6.43(dd,J＝8.0,0.9Hz,1H),3.73–3.52(m,1H),3.34(dt,J＝10.1,2.9Hz,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).¹³C NMR(126MHz,CDCl₃)δ138.2,136.4,135.1,130.2,127.7,122.1,121.6,120.5,119.3,119.0,114.7,112.9,111.2,109.1,64.7,59.6,56.5,50.8,49.2,44.5,41.9,37.7,25.2,23.0.HRMS(ESI)m/z calculated for C ₂₄H₂₈N₄ [ M+H ] + 373.2387; found 373.2378.

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

The synthesis was performed in analogy to example 71, in which 1- (bromomethyl) benzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 31% isolated yield .¹H NMR(500MHz,CDCl3)δ7.39–7.30(m,4H),7.30–7.23(m,1H),6.75–6.58(m,1H),6.48(dd,J＝7.4,0.9Hz,1H),6.41(dd,J＝8.0,0.9Hz,1H),3.65–3.55(m,1H),3.49(q,J＝3.2Hz,2H),3.32(dt,J＝9.9,3.0Hz,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＝11.1Hz,1H),1.95–1.87(m,2H).¹³C NMR(126MHz,CDCl₃)δ138.8,138.2,135.1,130.3,129.3,128.3,127.0,120.3,112.9,109.0,64.8,63.5,56.5,50.8,49.2,44.5,41.9,37.7,25.2.HRMS(ESI)m/z calculated for C ₂₁H₂₅N₃[M+H]⁺: 320.2121, found: 320.2116.

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

The synthesis was performed in analogy to example 71, wherein 1- (bromomethyl) -3-methoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. Yield .¹H NMR(500MHz,CDCl₃)δ7.23(t,J＝8.0Hz,1H),7.02–6.87(m,2H),6.83–6.76(m,1H),6.64(t,J＝7.6Hz,1H),6.48(dd,J＝7.4,0.9Hz,1H),6.41(dd,J＝7.9,0.9Hz,1H),3.82(s,3H),3.66–3.56(m,1H),3.46(s,2H),3.32(dt,J＝9.9,3.0Hz,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＝11.1Hz,1H),1.96–1.88(m,2H).¹³C NMR(126MHz,CDCl₃)δ159.8,140.6,138.2,135.1,130.3,129.3,121.6,120.3,114.6,113.0,112.6,109.0,64.8,63.4,56.5,55.3,50.8,49.2,44.5,41.9,37.7,25.2.HRMS(ESI)m/z isolated 59% calculated for C ₂₂H₂₇N₃O[M+H]⁺: 350.2227, found: 350.222.

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

The synthesis was performed in analogy to example 71, wherein 1- (bromomethyl) -3-ethylbenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 64% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.24(t,J＝7.5Hz,1H),7.19–7.13(m,2H),7.12–7.08(m,1H),6.73–6.59(m,1H),6.49(dd,J＝7.4,1.0Hz,1H),6.41(dd,J＝8.0,0.9Hz,1H),3.77–3.56(m,1H),3.46(s,2H),3.32(dt,J＝9.9,3.0Hz,1H),3.30–3.21(m,2H),3.21–3.14(m,1H),2.87(s,3H),2.83(td,J＝9.9,2.9Hz,1H),2.66(q,J＝7.6Hz,3H),2.38–2.14(m,1H),2.01(t,J＝11.1Hz,1H),1.95–1.89(m,2H),1.25(t,J＝7.6Hz,3H).¹³C NMR(126MHz,CDCl₃)δ144.3,138.8,138.2,135.1,130.3,128.9,128.3,126.7,126.6,120.3,113.0,109.0,64.8,63.6,56.5,50.8,49.2,44.5,41.9,37.7,28.9,25.2,15.7.HRMS(ESI)m/z calculated for C ₂₃H₂₉N₃[M+H]⁺: 348.2434, found: 348.2428.

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

The synthesis was performed in analogy to example 71, wherein 1- (bromomethyl) -4-methoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 61% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.23(d,J＝8.6Hz,2H),6.86(d,2H),6.64(dd,J＝7.9,7.3Hz,1H),6.55–6.45(m,1H),6.41(dd,J＝8.0,0.9Hz,1H),3.81(s,3H),3.61(ddd,J＝11.3,9.8,3.0Hz,1H),3.42(q,2H),3.31(dt,J＝9.9,2.9Hz,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).¹³C NMR(126MHz,CDCl₃)δ158.8,138.2,135.1,130.7,130.5,130.3,120.3,113.7,112.9,109.0,64.8,62.8,56.3,55.4,50.8,49.0,44.5,41.9,37.7,25.2.HRMS(ESI)m/z calculated for C ₂₂H₂₇N₃O[M+H]⁺: 350.2227, found: 350.2221.

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

The synthesis was performed in analogy to example 71, wherein 1- (bromomethyl) -2-ethylbenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. Yield .¹H NMR(500MHz,CDCl₃)δ7.32(d,J＝7.4Hz,1H),7.25–7.18(m,2H),7.15(td,J＝7.1,2.0Hz,1H),6.64(t,J＝7.6Hz,1H),6.48(d,J＝7.3Hz,1H),6.41(dd,J＝7.9,0.9Hz,1H),3.74–3.58(m,1H),3.45(q,J＝13.2Hz,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＝7.6Hz,2H),2.66–2.61(m,1H),2.29(td,J＝10.8,4.6Hz,1H),2.02(t,J＝11.1Hz,1H),1.97–1.82(m,2H),1.22(t,J＝7.6Hz,3H).¹³C NMR(126MHz,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 isolated at 76% calculated for C ₂₃H₂₉N₃[M+H]⁺: 348.2434, found: 348.2428.

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

The synthesis was performed in analogy to example 71, in which 1- (2-bromoethyl) -2- (methylsulfonyl) benzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 38% isolated yield .¹HNMR(500MHz,CDCl₃)δ8.17–7.91(m,1H),7.68–7.51(m,1H),7.46–7.34(m,2H),6.66(dd,J＝7.9,7.3Hz,1H),6.53(dd,J＝7.4,0.9Hz,1H),6.41(dd,J＝7.9,0.9Hz,1H),3.60(ddd,J＝11.3,9.9,3.0Hz,1H),3.32(dt,J＝10.0,3.0Hz,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＝11.0Hz,1H),2.07–1.86(m,2H).¹³C NMR(126MHz,CDCl₃)δ140.6,139.0,138.1,135.1,133.8,132.5,130.0,129.7,127.1,120.4,112.9,109.1,64.6,60.6,56.4,50.8,48.9,45.0,44.5,41.9,37.7,30.6,25.1.HRMS(ESI)m/z calculated for C ₂₃H₂₉N₃O₂S[M+H]⁺: 412.2053, found: 412.2043.

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

The synthesis was performed in analogy to example 71, in which (iodomethyl) cyclohexane was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 27% isolated yield .¹H NMR(500MHz,CDCl₃)δ6.78–6.61(m,1H),6.52(dd,J＝7.4,0.9Hz,1H),6.40(dd,J＝7.9,0.9Hz,1H),3.60(ddd,J＝11.3,9.8,3.0Hz,1H),3.31(dt,J＝10.0,3.0Hz,1H),3.26(dt,J＝11.3,2.9Hz,1H),3.21(dt,J＝6.5,3.2Hz,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).¹³C NMR(126MHz,CDCl₃)δ138.21 135.1,130.5,120.3,112.9,109.0,66.1,64.8,57.2,50.8,49.7,44.5,41.9,37.7,35.5,32.3,32.3,29.9,27.0,26.4,25.2.HRMS(ESI)m/z calculated for C ₂₁H₃₁N₃[M+H]⁺: 326.2591, found: 326.2583.

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

The synthesis was performed in analogy to example 71, wherein 2- (2-bromoethyl) -4-fluoro-1-methoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 41% isolated yield .¹HNMR(500MHz,CDCl₃)δ7.01–6.81(m,2H),6.74(dd,J＝8.8,4.5Hz,1H),6.70–6.63(m,1H),6.54(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝7.9,0.9Hz,1H),3.77(s,3H),3.61(ddd,J＝11.3,9.9,3.0Hz,1H),3.42–3.17(m,4H),3.02(t,J＝8.4Hz,1H),2.87(s,3H),2.86–2.78(m,4H),2.60(p,J＝6.5Hz,2H),2.42(s,1H),2.29–1.86(m,3H).¹³C NMR(126MHz,CDCl₃)δ157.0(d,J＝238.14Hz),153.8,138.2,135.1,130.8,130.3,120.4,117.0(d,J＝22.68Hz),112.9,112.9(d,J＝22.68Hz),111.1(d,J＝7.56Hz),109.1,64.7,58.7,56.4,56.0,50.8,49.1,44.6,41.9,37.7,28.0,25.2.HRMS(ESI)m/z calculated for C ₂₃H₂₈N₃OF[M+H]⁺: 382.2289, found: 382.2280.

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

The synthesis was performed in analogy to example 71, in which 1- (2-bromoethyl) -3-ethylbenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 51% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.20(td,J＝7.4,0.8Hz,1H),7.10–6.96(m,3H),6.67(t,J＝7.6Hz,1H),6.55(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝8.0,0.9Hz,1H),3.62(ddd,J＝11.3,9.9,3.0Hz,1H),3.33(dt,J＝10.0,2.9Hz,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＝7.6Hz,3H).¹³C NMR(126MHz,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 calculated for C ₂₄H₃₁N₃[M+H]⁺: 362.2591, found: 362.2583.

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

The synthesis was performed in analogy to example 71, in which 1- (2-bromoethyl) -3-ethoxybenzene was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 27% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.18(td,J＝7.4,1.3Hz,1H),6.89–6.71(m,3H),6.67(t,J＝7.6Hz,1H),6.54(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝7.9,0.9Hz,1H),4.01(q,J＝7.0Hz,2H),3.61(ddd,J＝11.3,9.9,3.0Hz,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＝12.0Hz,1H),2.22–1.86(m,3H),1.40(t,J＝7.0Hz,3H).¹³C NMR(126MHz,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 calculated for C ₂₄H₃₁N₃O[M+H]⁺: 378.2540, found: 378.2531.

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

The procedure is analogous to example 71, wherein 1- (2-bromoethyl) -1H-benzo [ D ] imidazole is added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 43% isolated yield .¹HNMR(500MHz,CDCl₃)δ8.21(s,1H),7.86–7.74(m,1H),7.61–7.41(m,1H),7.41–7.27(m,2H),6.69(t,J＝7.7Hz,1H),6.51(d,J＝7.4Hz,1H),6.43(d,J＝8.0Hz,1H),4.68(ddd,J＝14.3,8.0,6.2Hz,1H),4.59(ddd,J＝14.3,8.0,6.0Hz,1H),3.67–3.52(m,1H),3.42(dt,J＝11.9,6.3Hz,1H),3.34–3.23(m,3H),3.20(ddd,J＝11.6,6.4,2.0Hz,1H),3.10(ddd,J＝13.0,7.9,6.2Hz,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＝11.5Hz,1H),2.33–2.18(m,1H),2.08–1.97(m,1H).¹³C NMR(126MHz,CDCl₃)δ165.18,143.23,142.51,137.80,135.67,133.51,128.47,124.24,123.51,121.57,120.40,113.03,110.19,109.89,77.67,77.42,77.16,63.80,56.59,55.68,50.86,49.25,44.76,41.67,40.52,37.87,23.73.HRMS(ESI)m/z calculated for C ₂₃H₂₇N₅[M+H]⁺: 374.2339, found: 374.2330.

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

The procedure is analogous to example 71, wherein 1- (2-bromoethyl) -1H-benzo [ D ] [1,2,3] triazole is added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 18% isolation yield .¹H NMR(500MHz,CDCl₃)δ8.06(dt,J＝8.4,1.0Hz,1H),7.66(dt,J＝8.4,1.0Hz,1H),7.51(ddd,J＝8.3,7.0,1.0Hz,1H),7.38(ddd,J＝8.2,6.9,1.0Hz,1H),6.67(t,J＝7.7Hz,1H),6.49(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝8.0,0.9Hz,1H),5.03–4.85(m,2H),3.59(ddd,J＝11.1,10.0,3.2Hz,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＝11.9,3.4Hz,1H),2.30(t,J＝11.1Hz,1H),2.05(ddt,J＝14.8,12.4,4.4Hz,1H),1.97(dt,J＝14.8,2.8Hz,1H).¹³C NMR(126MHz,CDCl₃)δ165.18,143.23,142.51,137.80,135.67,133.51,128.47,124.24,123.51,121.57,120.40,113.03,110.19,109.89,77.67,77.42,77.16,63.80,56.59,55.68,50.86,49.25,44.76,41.67,40.52,37.87,23.73.HRMS(ESI)m/z calculated for C22H26N6[ M+H ] ⁺: 375.2292; found: 375.2283.

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

The procedure is analogous to example 71, wherein 3- (2-chloroethyl) -1H-indazole is added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 16% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.72(dt,J＝8.1,1.0Hz,1H),7.42(dt,J＝8.4,0.9Hz,1H),7.36(ddd,J＝8.3,6.8,1.1Hz,1H),7.14(ddd,J＝7.9,6.8,1.0Hz,1H),6.67(t,J＝7.6Hz,1H),6.54(dd,J＝7.4,0.9Hz,1H),6.42(dd,J＝8.0,0.9Hz,1H),3.62(ddd,J＝11.3,10.0,3.0Hz,1H),3.33(dt,J＝10.0,3.0Hz,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).¹³CNMR(126MHz,CDCl₃)δ145.26,141.13,137.87,134.92,129.79,126.65,122.12,120.29,120.25,120.09,112.65,109.72,108.87,64.36,57.48,56.09,50.54,48.81,44.29,41.52,37.44,24.81,24.63.HRMS(ESI)m/z calculated for C ₂₃H₂₇N₅[M+H]⁺: 374.2339, found: 374.2330.

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

The procedure is analogous to example 71, wherein 1- (2-bromoethyl) -1H-indazole is added in step D instead of 1- (2-bromoethyl) -3-methoxybenzene. 25% isolated yield .¹H NMR(500MHz,CDCl₃)δ8.04–7.97(m,1H),7.72(dt,J＝8.1,1.0Hz,1H),7.45(dq,J＝8.5,0.9Hz,1H),7.40–7.34(m,1H),7.14(ddd,J＝8.0,6.8,0.9Hz,1H),6.65(t,J＝7.6Hz,1H),6.50(dd,J＝7.4,0.9Hz,1H),6.41(dd,J＝8.0,0.9Hz,1H),4.54(t,J＝7.3Hz,2H),3.64–3.54(m,1H),3.28(ddt,J＝18.6,11.3,2.9Hz,2H),3.20(ddd,J＝6.6,3.9,2.5Hz,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＝11.0,4.7,2.1Hz,1H),2.40(td,J＝11.2,3.9Hz,1H),2.14(t,J＝11.1Hz,1H),1.91(q,J＝4.1Hz,1H).¹³C NMR(126MHz,CDCl₃)δ139.48,137.85,134.88,132.91,129.67,126.01,123.87,120.95,120.33,120.21,112.55,108.98,108.82,64.21,57.33,56.52,50.50,49.14,46.86,44.21,41.57,37.42,24.87.HRMS(ESI)m/z calculated for C ₂₃H₂₇N₅[M+H]⁺: 374.2339, found: 374.2330.

EXAMPLE 131.3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) -1-phenylpropan-1-one

The synthesis was performed in analogy to example 71, wherein 1-phenylpropan-1-one was added in step D instead of 1- (2-bromoethyl) -3-methoxybenzene. 68% isolated yield .¹H NMR(500MHz,CDCl₃)δ7.99–7.92(m,2H),7.61–7.52(m,1H),7.50–7.41(m,2H),6.70–6.60(m,1H),6.52(dd,J＝7.5,1.0Hz,1H),6.41(dd,J＝8.0,0.9Hz,1H),3.61(ddd,J＝11.3,9.9,3.0Hz,1H),3.29(ddt,J＝23.4,11.4,2.9Hz,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＝11.3,4.0Hz,1H),2.13–2.02(m,1H),2.00–1.87(m,2H).¹³C NMR(126MHz,CDCl₃)δ199.19,137.86,136.88,134.88,132.92,129.79,128.48,127.94,120.20,112.56,108.81,64.32,60.26,56.19,53.26,50.52,48.95,44.24,41.64,37.42,36.14,24.94,14.08.HRMS(ESI)m/z calculated for C ₂₃H₂₇N₃O[M+H]⁺: 362.2227, found: 362.2223.

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

The synthesis was performed in analogy to example 71, in which methyl iodide was added in step D instead of 1- (2-bromoethyl) -3-methoxybenzene. 31% isolated yield .¹H NMR(500MHz,CDCl₃)δ6.70–6.59(m,1H),6.52(dd,J＝7.4,0.9Hz,1H),6.41(dd,J＝8.0,0.9Hz,1H),3.60(ddd,J＝11.3,9.9,3.0Hz,1H),3.31(dt,J＝9.9,3.0Hz,1H),3.27(dt,J＝11.3,2.9Hz,1H),3.23–3.08(m,2H),2.87(s,3H),2.85–2.71(m,2H),2.60(dtd,J＝11.2,3.5,1.9Hz,1H),2.26(s,3H),2.24–2.15(m,1H),2.05–1.83(m,3H).¹³C NMR(126MHz,CDCl₃)δ138.1,135.1,130.2,120.4,112.8,109.0,64.1,58.6,51.1,50.8,46.7,44.5,42.0,37.7,25.2.HRMS(ESI)m/z calculated for C ₁₅H₂₁N₃[M+H]⁺: 244.1808, found: 244.1804.

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

The synthesis was performed in analogy to example 71, in which iodoethane was added in place of 1- (2-bromoethyl) -3-methoxybenzene in step D. 65% isolated yield .¹H NMR(500MHz,CDCl₃)δ6.68(t,J＝7.7Hz,1H),6.53(d,J＝7.4Hz,1H),6.42(d,J＝7.9Hz,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＝12.5,3.0Hz,1H),2.52–2.33(m,1H),2.27(t,J＝11.7Hz,1H),2.12–1.96(m,1H),1.29(t,J＝7.2Hz,3H).¹³C NMR(126MHz,CDCl₃)δ137.5,135.4,128.4,121.2,112.8,109.5,63.7,53.9,52.1,50.6,47.6,44.5,39.9,37.6,23.1,10.2.HRMS(ESI)m/z calculated for C ₁₆H₂₃N₃[M+H]⁺: 258.1965, found: 258.1960.

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

The synthesis was performed in analogy to example 71, in which 1-iodopropane was added in step D instead of 1- (2-bromoethyl) -3-methoxybenzene. 45% isolated yield .¹H NMR(500MHz,CDCl₃)δ6.74–6.61(m,1H),6.52(dd,J＝7.3,0.9Hz,1H),6.40(dd,J＝8.0,0.9Hz,1H),3.61(ddd,J＝11.3,9.9,3.0Hz,1H),3.31(dt,J＝10.0,2.9Hz,1H),3.26(dt,J＝11.3,2.9Hz,1H),3.24–3.21(m,1H),3.17(dt,J＝10.9,6.4Hz,1H),2.94–2.87(m,1H),2.82(td,J＝10.0,2.9Hz,1H),2.70–2.55(m,1H),2.44–2.06(m,3H),2.00–1.78(m,3H),1.53(h,J＝7.5Hz,2H),0.89(t,J＝7.4Hz,3H).¹³C NMR(126MHz,CDCl₃)δ138.2,135.1,130.3,120.4,112.9,109.0,64.8,61.1,56.6,50.8,49.2,44.5,41.9,37.7,25.2,20.3,12.2.HRMS(ESI)m/z calculated for C ₁₇H₂₅N₃[M+H]⁺: 272.2121, found: 272.2116.

The remaining compounds up to example 180 can be prepared according to similar procedures.

Example 181 receptor binding Profile

Standard receptor binding to serotonin, dopamine and mu opioid receptors and to serotonin transporter was determined according to literature procedures. For example, the following literature procedures can be used, each of which is incorporated herein by reference in its entirety: 5-HT _2A: bryant, H.U. et al (1996), life Sci.,15:1259-1268; D2: hall, D.A. and Strange, P.G. (1997), brit.J. Pharmacol.,121:731-736; D1: zhou, Q.Y. et al (1990), nature,347:76-80; SERT: park, Y.M. et al (1999), anal.biochem.,269:94-104;Mu opioid receptor:Wang,J.B et al (1994), FEBS Lett., 338:217-222). For example, receptor binding assays can be performed via a competitive assay for the agonist radioligand ¹²⁵ I- (+/-) -DOI, using human recombinant HEK-293 cells expressing human 5-HT _2A、5-HT_2B and/or 5-HT _2C receptors, by substitution to determine Ki.

In general, the results are expressed as the percentage of control specific binding obtained in the presence of the test compound:

Percent inhibition of control specific binding:

IC ₅₀ values (concentration that causes half-maximal inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of competition curves generated from average replicates using Hill equation curve fitting:

Where y=specific binding, a=left asymptote of the curve, d=right asymptote of the curve, c=compound concentration, C ₅₀＝IC₅₀, nh=slope factor. The analysis is performed using internal software and by means of a software interface with commercial software for(1997 From SPSS inc.) generated data were compared for verification. The inhibition constant (Ki) was calculated using the Cheng-Prusoff equation:

Where L = concentration of radioligand in the assay and K _D = affinity of radioligand for receptor. Scatchard plot was used to determine K _D.

The compound of formula A (ITI-007, lu Meipai long) was used as a comparison in the assay.

The following receptor affinity results were obtained (wherein the compound of formula a is used for comparison):

as shown, many compounds of the present disclosure exhibit significantly higher receptor selectivity than the reference compound of formula a. For example, the compounds of examples 14, 15 and 16 show little D1, D2 or μ receptor affinity, but maintain a strong affinity for serotonin 2A receptors.

Selected compounds were also tested in receptor binding assays for 5-HT _2B and/or 5-HT _2C receptors. The following table shows some of the results:

Selected compounds were also tested as agonists (EC ₅₀) or antagonists (IC ₅₀) in receptor function assays for the 5-HT _2B and 5-HT _2C receptors. The following table shows some of the results:

Some compounds were subjected to additional tests in the receptor profiling group (receptor profiling panel) consisting of agonist and/or antagonist radioligand binding assays. Assays were performed using test compounds at a concentration of 100 nM. Compound binding is calculated as the percent inhibition of binding of a particular radioligand to the receptor (or ion channel) being tested, which may be an agonist or an antagonist. Included in the group are the following receptors and ion channels:

Unexpectedly, it was found that the compounds of the present disclosure have high selectivity with little off-target interactions. For example, compounds only interact significantly (> 45% inhibition) with alpha-1A (e.g., 40-80% inhibition), serotonin-2A (e.g., 50-100% inhibition) and serotonin-2B (50-100% inhibition), while activity is not significant (< 40% inhibition) for other receptors typically associated with side effects, such as serotonin-1A, serotonin-1B, serotonin-3, muscarinic, other adrenergic and histamine receptors.

These results are particularly surprising because compounds having a tetracyclic core corresponding to or associated with the compounds of the present disclosure (i.e., compounds of formula I wherein n is 0 and z-a is H) were found to have significant activity in the receptor assays for serotonin-1A (> 70% inhibition), serotonin-1B (> 50% inhibition), serotonin-2A (> 70% inhibition) and serotonin-2B (> 80% inhibition).

EXAMPLE 182 bias agonism/antagonism

Agonism/antagonism of G-q signaling at the 5-HT _2A receptor. 5-HT _2A agonist and antagonist assays were performed on selected compounds for G-q recruitment. Alpha-methyl serotonin was used as a reference control for agonist assays, while ataserin was used as a control for antagonist assays.

Agonist assay CHO-K1 cells expressing human 5-HT _2A (ES-313-AF) were obtained from Perkinelmer and used according to the supplier's recommendations. Frozen cells were thawed in a 37℃water bath and then resuspended in 10mL ham's F-12 medium containing 10% FBS. Cells were recovered by centrifugation at 150g for 5min and then resuspended at 3X10 ⁵ cells/L in pre-warmed assay buffer (DMEM/HAM's F-12, HEPES) in Falcon tubes. Coelenterazine H was added to the cell suspension under sterile conditions to a final concentration of 5 μm. Falcon tubes were wrapped in aluminum foil and placed on a rotating wheel (approximately 45 ° angle and 7rpm/min speed) for 4 hours at room temperature. The cells were then diluted to 1x10 ⁵ cells/mL in assay buffer and transferred to a beaker wrapped with aluminum foil on a magnetic stirrer. After 1 hour incubation, 50 μl of cells (5,000 cells/well) were injected into the 96-well white plate wells at progressively increasing concentrations of 50 μl of test compound. Immediately, the light emission was recorded for 20 seconds using a FLUOstar Omega luminescence detector (BMG LABTECH). Digitalis saponin (digitonin) at a final concentration of 50. Mu.M in assay buffer was used as a positive control to measure receptor independent cellular calcium response. Curve fitting was performed using GRAPHPAD PRISM and EC ₅₀ values were determined using a 4-parameter logistic fit and the maximum response (E _max) value was calculated by subtracting the bottom value from the top value of the dose response curve.

Antagonist assay 50 μl of cells (5,000 cells/well) were mixed with increasing concentrations of 50 μl of test compound in wells of a 96-well white plate, and the plate was then incubated for 15 minutes at room temperature. Thereafter, 50. Mu.L of alpha-methyl serotonin (the final measured concentration corresponds to EC ₈₀ measured thereof) was injected, and immediately the light emission was recorded with a FLUOstar Omega luminescence detector (BMG LABTECH) for 20 seconds. Curve fitting was performed using Prism and IC ₅₀ values were determined using a4 parameter logistic fit. For antagonists, the apparent dissociation constant (K _B) was calculated using the modified Cheng-Prusoff equation-K _B＝IC₅₀/(1+(A/EC_50A) -where A is the concentration of the reference agonist alpha-methylserotonin and EC _50A is the EC ₅₀ value of the reference agonist alpha-methylserotonin.

Agonism/antagonism of β -arrestin signaling at the 5-HT2A receptor. 5-HT _2A agonist and antagonist assays were performed on selected compounds for beta-inhibitor recruitment. Alpha-methyl serotonin was used as a reference control for agonist assays, while ataserin was used as a control for antagonist assays.

Agonist assay U2OS cells expressing the human 5-HT _2A receptor (93-0401E 3CP 19L) were obtained from Eurofins DiscoverX and used according to the supplier's recommendations. Frozen cells were thawed in a 37 ℃ water bath and then mixed with 0.5mL of pre-heated cell plating reagent (CELL PLATING REAGENT). Cells were gently removed up and down several times to ensure uniform distribution before transferring to 11.5mL of pre-warmed cell plating reagent and pouring into disposable reagent reservoirs. mu.L of cells were plated into each well of a 96-well tissue culture plate and the plates were incubated at 37℃for 24 hours (5% CO ₂). The test compound was added to cells in 96-well plates at increasing concentrations of 10 μl and the plates were then incubated for 3 hours at room temperature. After adding 55. Mu.L of the prepared detection reagent and incubating for another 1 hour, the samples were read on an Envision luminescence reader. All assay points were measured in duplicate and the data is presented as an average. Curve fitting was performed using Prism software (Graphpad), EC ₅₀ values were determined using a 4-parameter logistic fit, and the maximum response (E _max) value was calculated by subtracting the bottom value from the top value of the dose response curve.

Antagonist assay 5 μl of test compound was added to cells in 96-well plates at increasing concentrations and the plates were incubated at 37 ℃ for 30min (5% co ₂). Thereafter, 5. Mu.L of alpha-methyl serotonin (final measured concentration). Thereafter, 50 μl of α -methyl serotonin (the final assay concentration corresponds to its measured EC ₈₀) was added and the plate incubated for 3 hours at room temperature. After adding 55. Mu.L of the prepared detection reagent and incubating for another 1 hour, the samples were read on an Envision luminescence reader. All assay points were measured in duplicate and the data is presented as an average. Curve fitting was performed using Prism software (Graphpad) and EC ₅₀ values were determined using a 4-parameter logistic fit. For antagonists, the apparent dissociation constant (K _B) was calculated using the modified Cheng-Prusoff equation-K _B＝IC₅₀/(1+(A/EC_50A) -where A is the concentration of the reference agonist alpha-methylserotonin and EC _50A is the EC ₅₀ value of the reference agonist alpha-methylserotonin.

EC ₅₀ (effective concentration for 50% activation) and E _max (maximum activation) were determined for both the G-q signaling agonism assay and the β -arrestin signaling agonism assay.

The maximum efficacy of a compound (E _max) is calculated as the percentage of the maximum signaling activity induced by the compound to the maximum signaling activity induced by the full agonist alpha-methyl serotonin. This is an indication of the intrinsic activity of the compound. Any maximal degree of activity below the full agonist reference indicates that the test compound is a partial agonist.

Like intrinsic activity (E _max), intrinsic relative activity (RA _i) is another method of quantifying partial and full agonism of receptor activity, but it also considers the efficacy of the compounds. It is calculated using the following formula:

Bias score. The bias score (or bias ratio) is calculated as the ratio of the intrinsic relative activity of beta-inhibitor signaling agonism (RA _i) to the intrinsic relative activity of G-q signaling agonism (RA _i).

The results are shown in the following table (RA _i = intrinsic relative activity compared to positive control methylserotonin or ataserin):

The compounds of examples 2,4 and 5 are each strong (complete) antagonists of the G-q signaling pathway, wherein the compound of example 4 has antagonistic activity comparable to the non-biased reference compound of formula a. Preferably, for non-magic activity, the compound should have antagonistic activity against the G-q signaling pathway, or partial agonist activity (with low intrinsic efficacy). Full agonist activity (i.e., high intrinsic activity) on the G-q signaling pathway is thought to cause illusive side effects.

For maximum efficacy, the compounds of the present disclosure are preferably agonists of β -inhibitor-mediated signaling, either as partial agonists or as full agonists. Thus, binding lacks agonist activity on the G-q pathway, which should be strongly biased towards β -arrestin signaling. However, the compounds of examples 2, 4 and 5 are antagonists of β -arrestin signaling. For example, the compound of example 4 (very similar to the compound of formula a) has a rather strong antagonistic activity against both G-q and β -inhibitor signaling pathways. Thus, while it may be a potent antidepressant, antipsychotic agent, such as Lu Meipai long (ITI-007), it does not exhibit the unique features of the fantasy antidepressant family.

In contrast, the compounds of examples 14, 15 and 16 showed in particular partial agonist activity in the β -arrestin assay and biased significantly towards β -arrestin mediated agonism, especially the compound of example 15, which had zero G-q mediated agonist activity. The compounds of examples 24, 25 and 40 also showed zero G-q mediated agonist activity, but the compound of example 24 was a β -arrestin antagonist and the compounds of examples 25 and 40 were β -arrestin partial agonists.

The results collectively show various functional activity profiles of the compounds according to the present disclosure, which will provide each of them with the potential for different uses and secondary or side effect profiles.

The data further show a trend that compounds with 2 or 3 atom side chain linkers preferentially activate β -arrestin signaling pathways with different levels of intrinsic activity. For example, compounds in which n is 2 or 3 and Z is a bond, or compounds in which n is 1 or 2 and Z is a group bridged by an atom (group one-atomacross) (e.g., -C (O) -, -O-or carbonyl equivalent). For some embodiments, the side chain linker is preferably 3 atoms in length, thus where n is 3 and Z is a bond, or n is 2 and Z is a bridging group of one atom.

For example, comparison of the results of the homologs of examples 2, 3,4 and 129 with reference compound a (each having z= -C (O) -, where n is 1-5) shows that having a shorter or longer linker may reduce or eliminate β -arrestin agonist activity (n=1, 3,4, 5) compared to the linker of optimal length (n=2). In fact, in this series, only the compound of example 3 showed β -arrestin agonist activity, but Gq antagonist activity, although all compounds bound strongly as antagonists to the 5-HT _2A receptor (ki=0.5-53 nM). In contrast, compound a, where n=3, is a potent antagonist of β -arrestin signaling, rather than an agonist, and Gq signaling antagonist.

The data also indicate that the pattern of substituents around the A ring may affect the pattern of binding of the compound to the 5-HT _2A receptor, as may the linking group Z. For some series of compounds, agonist and antagonist binding may depend on the choice of group Z, or on the presence or absence of electron donating or electron withdrawing groups on ring A. This allows for the modulation of the desired activity of the molecule by optimizing these different groups, achieving strong agonism and/or strong antagonism in the signaling pathway, including mixed agonist/antagonist activity of beta-inhibitor signaling (e.g., the compound of example 34). The data indicate that small electron donating groups on ring a may promote agonistic β -arrestin activity, while larger groups or electron withdrawing groups on ring a may eliminate agonistic β -arrestin activity.

While the compounds of the present disclosure provide a range of related receptor binding activities, it should be noted that the desirable antidepressant, anxiolytic and other CNS therapeutic properties of the hallucinogen are currently believed to be associated with β -arrestin signaling at the 5-HT _2A receptor, but it has not been established that some degree of Gq signaling is also desirable. Although strong Gq signaling may lead to hallucination, there may still be some degree of Gq information conduction that may be beneficial for the therapeutic use of the disclosed compounds without undue risk of hallucination. In fact, higher levels of Gq signaling may be allowed in patients without a history of psychosis or hallucinogen sustained perception disorder (HPPD), while compounds that are more completely free of Gq signaling may be optimal in patients with such a history.

EXAMPLE 183 in vivo characterization

Rodent functional model assays were performed on selected compounds (test compounds) to determine in vivo efficacy.

Head tics determination. Patterned head twitch response induced by 5-HT _2A agonists is used as a behavioral agent for hallucinations. See Halberttadt et al, neuropharmacology,167,107933 (2020). Head twitch response is an indicator of the hallucinogenic efficacy of a compound in humans and occurs almost immediately after administration of classical hallucinogens in rodents. By definition, head twitch refers to the rapid movement of the head from one side to the other. Head twitches were used to evaluate the potential propensity of the compounds (at most 10 mg/kg) to illusion relative to the positive control DOI (2.5 mg/kg). Male C57bl/6 mice (9 weeks old) were administered test compounds and vehicle via Subcutaneous (SC) injection. Mice receiving positive control DOI received Intraperitoneal (IP) injections. 30 minutes after treatment, the number of head twitch reactions was recorded by blind observers for 5 minutes.

Open field test of anxiety-like behavior. Adult mice were acclimatized in the test chamber for one hour, and then injected with test compound (1, 3 or 10 mg/kg) or methylcellulose vehicle at the posterior flank SC. For testing, the animals were placed in one of four areas in a square device measuring 500cmx 500cm for 15 minutes. The experimental procedure was photographed using a ceiling mounted camera using Anymaze software (stoning Co, IL). Athletic activity is measured by software within a predefined area. Each area predefines an additional central area, with an area of 100cm x 100cm.

And (5) testing social interaction of rats. Test compounds (0.3, 1.0, 3 and 3.0mg/kg, or 1,3 and 10 mg/kg) or vehicle (0.5% cmc in water) were SC injected 30 minutes prior to behavioral testing. During the test phase, a pair of rats receiving the same treatment (Sprague Dawley males) were placed in a white plexiglas (Plexiglass) open field area and allowed to interact for 6 minutes. Social interactions include sniffing the additional rat, grooming the additional rat, crawling under or around the additional rat, following the additional rat, and exploring the anogenital area of the additional rat. During the 6 minute test, the time it takes for the rats to interact with each other was recorded by a trained observer. Chlorodinitrogen(IP, 5 mg/kg) was used as a positive control.

MTOR signaling in the prefrontal cortex (PFC). Male adult mice SC were injected with test compound (1 mg/kg) or vehicle. At 24 hours post injection, samples from the PFC region of the brain were collected and synaptic neurosphere enriched fractions were collected and prepared for western blotting. Quantitative analysis of phosphorylation (p) western blot was determined relative to the total level of each protein. Changes in the amounts of phosphorylated ERK, akt, mTOR and P70S6K protein in PFC relative to vehicle treated mice were determined as described previously (Dutheil et al, J. Neuroscience,43 (5): 863-77, 2023).

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) were found to elicit non-fanciful activity in the test animals, increase social interactions, and/or reduce anxiety metrics. For example, unlike serotonergic maze DOI, even high doses of up to 10mg/kg of the test compound do not cause a hallucinogenic behavior, as shown by a head twitch rate comparable to the control group (e.g., < 10 head twitches every 5 minutes, or less than 5 head twitches or less than 1 head twitches (average result)) and significantly lower than the head twitch rate induced by DOI (p < 0.0001). The test compounds also showed a dose-dependent increase in social interactions between rats, and the data showed that even the lowest test dose of 0.3mg/kg was effective. In open field tests, test compounds were found to reduce anxiety-like behavior, including time in and number of entries into the central area, dose-dependently without altering the level of motor activity or quiescence. The lowest dose tested of 1mg/kg was found to be effective. These results demonstrate functional anxiolytic activity.

The test compounds were also found to stimulate mTOR signaling in the murine medial PFC as shown by testing the brain regions for increases in P-ERK, P-mTOR and P-P70s6 k. mTOR signaling pathways have been shown to contribute to neuroplasticity and enhance cognitive function, and are altered in areas of the brain associated with major depressive disorder. Quick-acting antidepressants have been reported to stimulate this pathway in the prefrontal cortex.

EXAMPLE 184 pharmacokinetic evaluation

Compounds according to the present disclosure were subjected to standard test protocols for oral pharmacokinetics in Sprague-Dawley rats (male, 200-400 g). Test compounds were administered to rats at 1mg/kg IV or 10mg/kg PO using 0.05M citrate phosphate buffer as vehicle. Other potential vehicles include PEG-400 and 10% trapnosol/1% tween 80 in water, depending on the solubility of the compound. In some studies, the third group may utilize subcutaneous administration (e.g., at 1mg/kg SC). Plasma samples were collected at 2, 5, 15 and 30 minutes and 1, 2, 4, 8 and 24 hours post-dose. After treatment, the plasma samples are analyzed for the presence of the test compound and, in some cases, the presence of the primary intended metabolite (e.g., N-desmethylmetabolite). The time to maximum concentration (T _max), maximum plasma concentration (C _max) and area under the curve (AUC) were calculated from the data. Comparison between AUC values for oral and IV administration provides oral bioavailability of the test compounds.

The compounds tested included examples 40, 99, 107, 112, 117 and 118. These compounds were found to have acceptable oral bioavailability.

The foregoing embodiments are merely exemplary and are not meant to limit the scope of the present disclosure in any way.

Claims

1. Compounds of formula I

Wherein:

m is 1 or 2;

n is 1, 2, 3, 4 or 5;

The compounds of formula I are in free or salt form (e.g., pharmaceutically acceptable salt form);

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

3. The compound of claim 1, wherein X is S, S (O), S (O) ₂, or O.

4. The compound of claim 1, wherein X is a spiro-linked C _3-6 cycloalkyl (e.g., cyclopropane).

5. The compound of any one of claims 1-4, wherein Y is CH ₂ or-C (O) -.

6. The compound of any one of claims 1-4, wherein Y is a spiro-linked C _3-6 cycloalkyl (e.g., cyclopropane).

7. The compound of any one of claims 1-6, wherein Z is a bond, CH ₂, -C (O) -or-O-.

8. A compound according to any one of claims 1-7, wherein a is a 6-10 membered aryl ring substituted with 0-5 groups R, such as selected from phenyl and naphthyl.

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

10. The compound of any one of claims 1-7, wherein a is selected from furan, thiophene (e.g., thiophen-2-yl), pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyridine (e.g., pyridin-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-methylbenzan-4-yl), dihydrobenzofuran (e.g., 2, 3-dihydrobenzofuran-7-yl), benzothiophene, indole (e.g., indol-1-yl, indol-3-yl, or indol-5-yl), benzoxazole, benzothiazole, benzimidazole (e.g., benzo [ d ] imidazol-1-yl), benzisoxazole (e.g., benzo [ d ] isoxazol-3-yl), benzooxazol (e.g., benzo [ d ] isothiazol-4-yl), benzisothiazole (e.g., benzo [ d ] isothiazol-3-yl), benzotriazol (e.g., indol-3-yl), benzoquinolin (e.g., benzoquinolin-1, 7-yl), benzoquinolin-3-yl, or indol-5-yl) Quinazolines (e.g., quinazolin-7-yl) and quinoxalines (e.g., quinoxalin-5-yl), each substituted with 0-5 groups R.

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

12. The compound of any one of claims 1-11, wherein the compound is selected from any one of examples 1-180.

13. The compound of any one of claims 1-12, in the form of a pharmaceutically acceptable salt.

14. The compound of any one of claims 1-13, wherein the compound is an agonist of β -arrestin signaling via the 5-HT _2A receptor.

15. The compound of any one of claims 1-13, wherein the compound is an antagonist of β -arrestin signaling via the 5-HT _2A receptor.

16. The compound of any one of claims 1-15, wherein the compound is not an agonist or antagonist of G-q signaling via the 5-HT _2A receptor, or is a weak agonist or antagonist thereof.

17. The compound of any one of claims 1-16, wherein the compound has a bias ratio (β -arrestin/G-q) 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 for agonism or antagonism of the 5-HT _2A receptor.

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

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

20. Use of a compound according to any one of claims 1-17 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.