Organic compounds

Abstract

The present invention relates to certain substituted heterocyclic-fused γ-carbolines described herein in free form, solid form, pharmaceutically acceptable salt form and / or substantially pure form, pharmaceutical compositions thereof, and 5-HT 2A The present invention relates to methods for use in treating disorders associated with receptors, serotonin transporter (SERT), pathways associated with the dopamine D1 and D2 receptor signaling systems, and / or μ-opioid receptors.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to and the benefit of U.S. Provisional Application No. 62 / 783,618, filed December 21, 2018, the contents of which are incorporated herein by reference in their entirety.

[0002] Technical Field The present invention relates to certain substituted heterocyclic fused γ-carbolines, pharmaceutical compositions thereof, and 5-HT, in free form, solid form, pharma- ceutical acceptable salt form and / or substantially pure form, as described herein. 2A The present invention relates to methods of use in the treatment of diseases or disorders such as those associated with receptors, serotonin transporter (SERT), pathways associated with the dopamine D1 and / or D2 receptor signaling systems, and / or μ-opioid receptors, e.g., anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, pain-related conditions (including headaches, neuropathic pain, as acute analgesics), fibromyalgia, chronic fatigue, social phobia, gastrointestinal disorders such as gastrointestinal motility dysfunction, and obesity; depression and mood disorders, e.g., those associated with psychosis or Parkinson's disease; psychosis, e.g., schizophrenia associated with depression; bipolar disorder; drug dependence, e.g., opiate dependence and alcohol dependence, drug withdrawal symptoms; obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), and related disorders; and other psychiatric and neurological conditions, as well as combinations with other agents. In some embodiments, the disease or disorder may include symptoms of treatment-resistant depression, cocaine and / or amphetamine dependence, opioid use disorder, and opioid withdrawal. [Background technology]

[0003] Substituted heterocycle-fused γ-carbolines have been shown to mediate the activity of 5-HT2 receptors, particularly 5-HT 2AThese compounds are known to be agonists or antagonists of the 5-HT receptor. These compounds are disclosed in U.S. Patent Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. Patent No. Re. 39680, and U.S. Patent No. Re. 39679. 2A They are disclosed as novel compounds useful for treating disorders related to receptor modulation, such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, headache-related conditions, social phobia, gastrointestinal disorders such as gastrointestinal motility dysfunction, and obesity. U.S. Patent No. 8,309,722 and U.S. Patent No. 7,081,455 also disclose methods for preparing substituted heterocycle-fused γ-carbolines and the use of these γ-carbolines as serotonin agonists and antagonists useful for controlling and preventing central nervous system disorders such as addictive behaviors and sleep disorders.

[0004] Also, U.S. Patent No. 8,598,119 discloses the use of certain substituted heterocycle-fused γ-carbolines for the treatment of coexisting psychotic and depressive disorders, as well as sleep disorders, depressive disorders and / or mood disorders in patients with psychosis or Parkinson's disease. In addition to disorders related to psychosis and / or depression, this patent application discloses the use of certain substituted heterocycle-fused γ-carbolines for the treatment of coexisting psychotic and depressive disorders ... the treatment of coexisting 5-HT 2A These drugs selectively antagonize the dopamine D2 pathway, thereby reducing side effects associated with the highly occupied dopamine D2 pathway or other pathways (e.g., GABA receptors) associated with conventional sedative-hypnotics (e.g., benzodiazepines). A The present application discloses and claims the use of low doses of these compounds useful for treating sleep disorders without side effects from the endothelial cell receptor (including, but not limited to, the onset of drug dependency, hypotonia, weakness, headache, blurred vision, vertigo, nausea, vomiting, epigastric distress, diarrhea, joint pain, and chest pain). U.S. Patent No. 8,648,077 also discloses a method for preparing crystalline toluenesulfonic acid addition salts of these substituted heterocyclic fused γ-carbolines.

[0005] Recent evidence also indicates that the substituted fused heterocyclic γ-carbolines may function in part by NMDA receptor antagonism via mTOR1 signaling, similar to ketamine. Ketamine is a selective NMDA receptor antagonist. Ketamine acts by a system that is not associated with common psychogenic monoamines (serotonin, norepinephrine and dopamine), which is the main reason for its extremely rapid effect. Ketamine directly antagonizes extrasynaptic glutamatergic NMDA receptors, which also indirectly results in the activation of AMPA-type glutamate receptors. Downstream effects involve brain-derived neurotrophic factor (BDNF) and mTORC1 kinase pathways. Similar to ketamine, recent evidence suggests that the compounds disclosed herein and related compounds increase both NMDA- and AMPA-induced currents in rat medial prefrontal cortex pyramidal neurons by activating D1 receptors, and that this is associated with increased mTORC1 signaling. International Application PCT / US2018 / 043100 discloses such effects for certain substituted fused heterocyclic γ-carbolines, and useful therapeutic indications associated therewith.

[0006] US Patent Application Publication No. 2017 / 319580 discloses novel oxo-metabolites of the compounds disclosed in the above publications. These new oxo-metabolites retain many of the unique pharmacological activities of the parent compounds, including serotonin receptor inhibition, SERT inhibition and dopamine receptor modulation. However, these oxo-metabolites were unexpectedly found to also exhibit significant activity at μ-opiate receptors. Analogs of these novel compounds are also disclosed, for example, in International Application Publication No. 2018 / 126140 and International Application Publication No. 2018 / 126143.

[0007] For example, the compound of formula A shown below is a potent serotonin 5-HT 2A It is a receptor antagonist and a μ-opiate receptor partial agonist or biased agonist. The compound also interacts with dopamine receptors, particularly the dopamine D1 receptor. [ka] It is also believed that the compound of formula A can enhance NMDA- and AMPA-mediated signaling through the mTOR pathway through its D1 receptor activity.Thus, the compound of formula A is useful for treating or preventing central nervous system disorders, but the art is in need of additional compounds with this unique biochemical and pharmacological profile, especially those that may have a slightly altered pharmacological or pharmacokinetic profile compared to the compound of formula A.

[0008] Obsessive-compulsive disorder (OCD) and related disorders have become highly prevalent and difficult to treat. OCD is estimated to develop in about 2.3% of people at some point in their lives, and it is estimated that 1.2% of people worldwide suffer from the disorder during any given year. Half of the people who suffer from OCD begin to show symptoms before the age of 20, which can seriously affect their ability to receive a proper and effective education. However, without effective treatment, the disease can last for decades. The mainstay of pharmacological OCD treatment is with selective serotonin reuptake inhibitors (SSRIs). The second line of treatment is with antipsychotic drugs such as clomipramine, risperidone, quetiapine and olanzapine. A significant number of patients do not respond to these drugs or cannot cope with the side effects caused by these drugs. More recently, it has been reported that the opioid analgesic tramadol can be effective in treating OCD. Opiates work by a completely different pathway than traditional OCD medications, and therefore offer the potential for treatment for those who cannot take traditional serotonergic drugs or for whom these drugs are ineffective. However, strong opiate drugs can be addictive, and their use can be contraindicated in some patients. Thus, there remains an urgent need for new treatments for pain, OCD, and other disorders.

[0009] Substance-dependent disorders, such as opiate use disorder (OUD), are another group of disorders that are difficult to treat successfully. Opioid overdoses claim approximately 100 lives each day in the United States, and the opioid epidemic continues to grow in the United States. Methadone, buprenorphine, and naltrexone are most frequently used in the treatment of OUD. Methadone is a μ-opioid receptor (MOP) agonist, buprenorphine is a MOP partial agonist, and naltrexone is a MOP antagonist. Both of these medications have met with limited success, and long-term adherence to treatments prescribed for OUD remains low. These treatments also often exacerbate common comorbidities associated with OUD, such as mood and anxiety disorders, which further increases the risk of remission. Abrupt opioid abuse withdrawal (i.e., going "cold turkey") is also associated with severe side effects, including dysphoria, depression, and anxiety, which common treatments do not address and may exacerbate. Thus, improvements in OUD treatment are urgently needed. Summary of the Invention

[0010] Quick Overview In a first aspect, the disclosure provides a compound of formula I: [ka] [In the formula, R 1 , H, C 1-6 Alkyl, -C(O)-OC(R a )(R b )(R c ), -C(O)-O-CH2-OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 and; R2 and R 3 are independently H, D, and C 1-6 Alkyl (e.g., methyl), C 1-6 is selected from alkoxy (e.g., methoxy), halo (e.g., F), cyano or hydroxy; or R 2 and R 3 and the carbons to which they are attached collectively form a -CH2CH2- group, or R 2 and R 3 and the carbon to which they are attached is absent; L is C 1-6 Alkylene (e.g., ethylene, propylene or butylene), C 1-6 Alkoxy (e.g., propoxy or butoxy), C 2-3 Alkoxy C 1-3 Alkylene (e.g., CH2CH2OCH2), C 1-6 Alkylamino or NC 1-6 Alkyl C 1-6 Alkylamino (e.g., propylamino or N-methylpropylamino), C 1-6 Alkylthio (e.g., -CH2CH2CH2S-), C 1-6 alkylsulfonyl (e.g., -CHCHCHS(O)-), each of which may contain one or more R 4 may be substituted with a moiety; Each R 4 is independently 1-6 Alkyl (e.g., methyl), C 1-6 selected from alkoxy (e.g., methoxy), halo (e.g., F), cyano, or hydroxy; Z is selected from aryl (e.g., phenyl) and heteroaryl (e.g., pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), where the aryl or heteroaryl is selected from one or more R 4 may be substituted with a moiety; R 8 is -C(R a )(R b )(R c), -OC(R a )(R b )(R c ), or -N(R d )(R e ) and; R a , R b and R c are each independently H or C 1-24 alkyl; R d and R e are each independently H and C 1-24 alkyl; R 6 and R 7 are each independently H, C 1-6 Alkyl, carboxy and C 1-6 alkoxycarbonyl; with the proviso that the LZ moiety is not 1-(4-(4-fluorophenyl)-4-oxobutyl), 1-(4-(4-fluorophenyl)-4-hydroxybutyl, or 1-(4-fluoro-1-phenoxy)propyl). The present invention relates to a compound (Compound I) represented by the formula:

[0011] The present disclosure provides further exemplary embodiments of compounds of formula I, in free form or in salt form (e.g., a pharma- ceutically acceptable salt form), e.g., isolated or purified free form or in salt form (e.g., a pharma- ceutically acceptable salt form), including the following:

[0012] 1.1 R 1 is H;

[0013] 1.2 R 1 But, C 1-6 alkyl, e.g., methyl, Compound I;

[0014] 1.3 R 1 -C(O)-OC(R a )(R b )(R c ), Compound I;

[0015] 1.4 R a is H and R b and R c However, each independently, C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 Compound 1.3, selected from alkyl;

[0016] 1.5 R a and R b is H and R c But, C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 Compound 1.3, which is an alkyl;

[0017] 1.6 R a , R b and R c However, each independently, C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 Compound 1.3, selected from alkyl;

[0018] 1.7 R a , R b and R c each is H; compound 1.3;

[0019] 1.8 R a and R b is H and R c But, C 10-14 is alkyl (e.g., R c But CH3(CH2) 10 or CH3(CH2) 14 ), compound 1.3;

[0020] 1.9 R 1 -C(O)-O-CH2-OC(R a )(R b )(R c ), Compound I;

[0021] 1.10 R a is H and R b and R c However, each independently, C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 Compound 1.9, selected from alkyl;

[0022] 1.11 R a and R b is H and R c C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C14 Alkyl, C 15 Alkyl or C 16 Compound 1.9, which is an alkyl;

[0023] 1.12 R a , R b and R c However, each independently, C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 Compound 1.9, selected from alkyl;

[0024] 1.13 R a , R b and R c are each H, compound 1.9;

[0025] 1.14 R 1 -C(R 6 )(R 7 )-OC(O)-R 8 and R 8 -C(R a )(R b )(R c ), Compound I;

[0026] 1.15 R 1 -C(R 6 )(R 7 )-OC(O)-R 8 and R 8 -OC(R a )(R b )(R c ), Compound I;

[0027] 1.16 R a is H and R b and R c However, each independently, C1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl, compound 1.14 or 1.15;

[0028] 1.17 R a and R b is H and R c But, C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl, compound 1.14 or 1.15;

[0029] 1.18 R a , R b and R c However, each independently, C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl, compound 1.14 or 1.15;

[0030] 1.19 R a , R b and Rc Compounds 1.14 or 1.15, each of which is H;

[0031] 1.20 R 6 is H and R 7 C 1-3 is alkyl (e.g., R 7 is methyl or isopropyl), R 8 C 10-14 is alkyl (e.g., R 8 CH3(CH2) 10 or CH3(CH2) 14 ), any of compounds 1.14 to 1.19;

[0032] 1.21 R 1 -C(R 6 )(R 7 )-OC(O)-R 8 and R 8 -N(R d )(R e ), Compound I;

[0033] 1.22 R d is H and R e But independently, C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 Compound 1.21, selected from alkyl;

[0034] 1.23 R d and R e However, each independently, C 1-24 Alkyl, e.g., C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl or C 11 Alkyl, C12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 Compound 1.21, selected from alkyl;

[0035] 1.24 R d and R e each is H, compound 1.21;

[0036] 1.25 R 6 is H and R 7 Any of compounds 1.14-1.24, wherein is H;

[0037] 1.26 R 6 C 1-6 is alkyl, R 7 C 1-6 any of compounds 1.14 to 1.24, wherein the compound is alkyl;

[0038] 1.27 R 6 is H and R 7 C 1-6 any of compounds 1.14 to 1.24, wherein the compound is alkyl;

[0039] 1.28 R 6 is H and R 7 any of compounds 1.14 to 1.24, wherein is carboxy;

[0040] 1.29 R 6 is H and R 7 C 1-6 any of compounds 1.14-1.24 which is an alkoxycarbonyl, e.g., ethoxycarbonyl or methoxycarbonyl;

[0041] 1.30 R 2 and R 3 is H;

[0042] 1.31 R 2 is H and R 3is D;

[0043] 1.32 R 2 and R 3 is D;

[0044] 1.33 L has one or more R 4 optionally substituted with a moiety, C 1-6 Alkylene (e.g., ethylene, propylene or butylene), C 1-6 Alkoxy (e.g., propoxy), C 2-3 Alkoxy C 1-3 Alkylene (e.g., CH2CH2OCH2), C 1-6 alkylamino (e.g., propylamino or N-methylpropylamino), or C 1-6 Compound I, or any of compounds 1.1-1.32, which is alkylthio (e.g., -CH2CH2CH2S-);

[0045] 1.34 L is unsubstituted C 1-6 Compound 1.33, which is an alkylene (e.g., ethylene, propylene, or butylene);

[0046] 1.35 L has one or more R 4 is substituted with a moiety, C 1-6 Compound 1.33, which is an alkylene (e.g., ethylene, propylene, or butylene);

[0047] 1.36 L is unsubstituted C 1-6 Compound 1.33, which is an alkoxy (e.g., propoxy or butoxy);

[0048] 1.37 L has one or more R 4 is substituted with a moiety, C 1-6 Compound 1.33, which is an alkoxy (e.g., propoxy or butoxy);

[0049] 1.38 L is unsubstituted C 2-3 Alkoxy C1-3 Compound 1.33, which is an alkylene (e.g., CH2CH2OCH2);

[0050] 1.39 L has one or more R 4 is substituted with a moiety, C 2-3 Alkoxy C 1-3 Compound 1.33, which is an alkylene (e.g., CH2CH2OCH2);

[0051] 1.40 R 1 , R 2 and R 3 Compound I, or any of compounds 1.1-1.39, wherein each is H;

[0052] 1.41 L of -(CH2) n -X-, where n is an integer selected from 2, 3 and 4, and X is -O-, -S-, -NH-, -N(C 1-6 Compound I, or any of compounds 1.1-1.40, wherein the R is selected from the group consisting of alkyl, aryl ...

[0053] 1.42 L of -(CH2) n Compound 1.41, -X-, where n is an integer selected from 2, 3 and 4, and X is -O-;

[0054] 1.43 L of -(CH2) n -X-, where n is 3 and X is -O-, -S-, -NH-, or -N(C 1-6 alkyl)-(e.g., -N(CH3)-), compound 1.41;

[0055] 1.44 L of -(CH2) n -X-, where n is 3 and X is CH2, compound 1.41;

[0056] 1.45 Z has one or more R 4 Compound I, or any of Compounds 1.1-1.44, which is an aryl (e.g., phenyl) optionally substituted with a moiety;

[0057] 1.46 Z has one or more R 4 Compound 1.45, which is an aryl (e.g., phenyl) substituted with a moiety;

[0058] 1.47 Z is 1, 2, 3 or 4 R 4 Compound 1.46, which is a phenyl substituted with a moiety;

[0059] 1.48 1, 2, 3 or 4 R 4 Compound 1.46, wherein the moieties are independently selected from halo (e.g., fluoro, chloro, bromo, or iodo) and cyano;

[0060] 1.49 Z is one R selected from halo (e.g., fluoro, chloro, bromo or iodo) and cyano. 4 Compound 1.46, which is a phenyl substituted with a moiety (e.g., Z is 4-fluorophenyl, or 4-chlorophenyl, or 4-cyanophenyl);

[0061] 1.50 Z has one or more R 4 Compound I, or any of Compounds 1.1-1.44, which is a heteroaryl, optionally substituted with a moiety (e.g., pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl);

[0062] 1.51 Compound 1.50, wherein the heteroaryl is a monocyclic 5- or 6-membered heteroaryl (e.g., pyridyl, pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, thiophenyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl);

[0063] 1.52 Compound 1.51, wherein said heteroaryl is selected from pyridyl, pyrimidinyl, and pyrazinyl;

[0064] 1.53 Compound 1.50, wherein the heteroaryl is a bicyclic 9- or 10-membered heteroaryl (e.g., indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzodioxolyl, 2-oxo-tetrahydroquinolinyl);

[0065] 1.54 Compound 1.53, wherein said heteroaryl is selected from indazolyl, benzisoxazolyl, quinolinyl, benzodioxolyl, and 2-oxo-tetrahydroquinolinyl;

[0066] 1.55 Compound 1.53, wherein said heteroaryl is selected from indazolyl, benzisoxazolyl, and quinolinyl;

[0067] 1.56 The heteroaryl has 1, 2, 3 or 4 R 4 any of compounds 1.50 to 1.55, substituted with a moiety;

[0068] 1.57 1, 2, 3 or 4 R 4 The moieties are independently halo (e.g., fluoro, chloro, bromo, or iodo), cyano, hydroxy, or C 1-6 Compound 1.56, selected from alkoxy (e.g., methoxy);

[0069] 1.58 said heteroaryl has one R selected from halo (e.g., fluoro, chloro, bromo or iodo) and cyano. 4 substituted with a moiety (e.g., the heteroaryl is 6-fluoro-3-indazolyl, 6-chloro-3-indazolyl, 6-fluoro-3-benzisoxazolyl, or 5-chloro-3-benzisoxazolyl), compounds 1.56 or 1.57;

[0070] 1.59 R 2 and R 3and the carbons to which they are attached collectively form a -CHCH- group, e.g., compound I has the formula: [ka] Compound I, or any of compounds 1.1 to 1.58, which is a compound represented by the formula:

[0071] 1.60 R 2 and R 3 and the carbon to which they are attached is absent, e.g., compound I has the formula: [ka] Compound I, or any of compounds 1.1 to 1.58, which is a compound represented by the formula:

[0072] 1.61 The compound is, each independently, in free form or in pharma- ceutically acceptable salt form: [ka] Compound I, or any of compounds 1.1 to 1.60, selected from the group consisting of:

[0073] 1.62 The compound is, each independently, in free form or in pharma- ceutically acceptable salt form: [ka] Compound I, or any of compounds 1.1 to 1.60, selected from the group consisting of:

[0074] 1.63 The compound is, each independently, in free form or in pharma- ceutically acceptable salt form: [ka] Compound I, or any of compounds 1.1 to 1.60, selected from the group consisting of:

[0075] 1.64 The compound is, each independently, in free form or in pharma- ceutically acceptable salt form: [ka] Compound I, or any of compounds 1.1 to 1.60, selected from the group consisting of:

[0076] 1.65 The compound is, each independently, in free form or in pharma- ceutically acceptable salt form: [ka] Compound I, or any of compounds 1.1 to 1.60, selected from the group consisting of:

[0077] 1.66 Compound I, or any of compounds 1.1-1.65, in free form;

[0078] 1.67 Compound I, or any of Compounds 1.1-1.65, in a salt form, e.g., a pharma- ceutically acceptable salt form;

[0079] 1.68 Compound I, or any of compounds 1.1-1.65, wherein the compound is in the form of an acid addition salt, e.g., the hydrochloride salt or the toluenesulfonate salt;

[0080] 1.69 Compound I, or any of compounds 1.1-1.68, in substantially pure diastereomeric form (i.e., substantially free of other diastereomers);

[0081] 1.70 Compound I, or any of compounds 1.1-1.68, having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90%, and most preferably greater than 95%;

[0082] 1.71 Compound I, or any of Compounds 1.1-1.70, in a solid form, e.g., a crystalline form;

[0083] 1.72 Compound I, or any of compounds 1.1-1.71, in isolated or purified form (e.g., at least 90% pure, or at least 95% pure, or at least 98% pure, or at least 99% pure);

[0084] 1.73 When the LZ moiety is 3-(pyridin-4-yloxy)propyl, R 1 Compound I, or any of compounds 1.1 to 1.72, not including any compound in which is H or CH3;

[0085] 1.74 When the LZ moiety is 3-(6-fluorobenzo[d]isoxazol-3-yl)propyl, 3-(6-fluoro-1H-indazol-3-yl)propyl, 3-(isoxazolo[5,4-c]pyridin-3-yl)propyl, or 3-(1H-pyrazolo[3,4-c]pyridin-3-yl)propyl, R 1 Compound I, or any of compounds 1.1 to 1.72, except for compounds in which is H or CH3.

[0086] As noted above, in some embodiments of the present disclosure, particularly in some embodiments of Compound I and in some embodiments of Pharmaceutical Composition I, the embodiments include R 1 is H or CH3; LZ, [ka] Selected from: Contains no compounds. In some embodiments of the disclosure, including particularly the embodiment of Method 1 (described below), the above compounds are included within the scope of the embodiment.

[0087] In a second aspect, the disclosure provides a pharmaceutical composition (Pharmaceutical Composition 1) comprising a compound of Formula I or one of 1.1-1.74, e.g., in admixture with a pharma- ceutically acceptable diluent or carrier. In certain embodiments, the compound of Formula I or any of 1.1-1.74 is in a pharma- ceutically acceptable salt form.

[0088] In further embodiments, the pharmaceutical compositions of the disclosure are for sustained or delayed release formulations (pharmaceutical composition 1-A), e.g., depot formulations. In some embodiments, the compound of Formula I or any of 1.1-1.74, preferably in free form or in a pharma-ceutically acceptable salt form, is provided in an injectable depot dosage form that provides sustained or delayed release of the compound in admixture with a pharma-ceutically acceptable diluent or carrier.

[0089] In certain embodiments, pharmaceutical composition 1-A comprises a compound of any one of Compound I or 1.1-1.74, in free base or pharma- ceutically acceptable salt form, which may be in crystalline form, milled or crystallized into particles or crystals having a microparticulate or nanoparticulate size, e.g., a dose-dependent particle size (e.g., diameter or Dv50) of 0.5-100 microns, e.g., 5-30 microns, 10-20 microns, 20-100 microns, 20-50 microns, or 30-50 microns. Such particles or crystals can be combined with a suitable pharma- ceutically acceptable diluent or carrier, e.g., water, to form an injectable depot formulation. For example, the depot formulation can be formulated for intramuscular or subcutaneous injection with a dose of drug suitable for 4-6 weeks of treatment. In some embodiments, the particles or crystals have a surface area of ​​0.1-5 m 2 / g, e.g., 0.5 to 3.3 m 2 / g, or 0.8 to 1.2 m 2 / g.

[0090] In another embodiment, the present disclosure provides pharmaceutical composition 1-B, which is pharmaceutical composition 1 in which the compound of formula I or later is in a polymer matrix. In one embodiment, the compound of the present disclosure is dispersed or dissolved in the polymer matrix. In a further embodiment, the polymer matrix comprises a standard polymer used in depot formulations, such as a polymer selected from polyesters of hydroxy fatty acids or their derivatives, or polymers of alkyl α-cyanoacrylates, polyalkylene oxalates, polyorthoesters, polycarbonates, polyortho-carbonates, polyamino acids, hyaluronic acid esters, and mixtures thereof. In a further embodiment, the polymer is selected from the group consisting of polylactide, poly d,l-lactide, polyglycolide, PLGA50:50 polymer, PLGA85:15 polymer, and PLGA90:10 polymer. In another embodiment, the polymer is selected from poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers thereof, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers such as albumin, casein, and waxes, such as glycerol mono- and distearate. In a preferred embodiment, the polymer matrix comprises poly(d,l-lactide-co-glycolide).

[0091] Pharmaceutical composition 1-B is particularly useful for sustained or delayed release, where the compound of the present disclosure is released upon degradation of the polymer matrix. These compositions can be formulated (e.g., as a depot composition) for controlled and / or sustained release of the compound of the present disclosure for up to 180 days, for example, about 14 days to about 30 days to about 180 days. For example, the polymer matrix can degrade and release the compound of the present disclosure for about 30 days, about 60 days, or about 90 days. In another example, the polymer matrix can degrade and release the compound of the present disclosure for about 120 days or about 180 days.

[0092] In yet another embodiment, pharmaceutical composition 1 or 1-A or 1-B may be formulated for administration by injection, for example, as a sterile aqueous solution.

[0093] In another embodiment, the present disclosure provides a pharmaceutical composition (Pharmaceutical Composition 1-C) comprising a compound of Formula I or later in an osmotic release controlled oral delivery system (OROS) as described in U.S. Patent Application Publication Nos. 2001 / 0036472 and 2009 / 0202631, the contents of each of which are incorporated herein by reference in their entirety. Thus, in one embodiment, the present disclosure provides a pharmaceutical composition or device (Pharmaceutical Composition P.1) comprising: (a) a gelatin capsule containing any compound of Formula I or later in free form or in pharma- ceutical acceptable salt form, optionally mixed with a pharma- ceutical acceptable diluent or carrier; (b) a multi-layer wall layered on the gelatin capsule, comprising, in order from the capsule outward, (i) a barrier layer, (ii) an expanding layer, and (iii) a semipermeable layer; and (c) and an orifice formed or formable through the wall.

[0094] In another embodiment, the present invention provides a pharmaceutical composition comprising a gelatin capsule containing a compound of formula I or later in liquid, free form or pharma- ceutically acceptable salt form, optionally in admixture with a pharma- ceutically acceptable diluent or carrier, wherein the gelatin capsule is surrounded by a composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, an expanding layer in contact with the barrier layer, a semipermeable layer encompassing the expanding layer, and an exit orifice formed or formable in the wall (pharmaceutical composition P.2).

[0095] In yet another embodiment, the present invention provides a pharmaceutical composition comprising a gelatin capsule containing a compound of formula I or later in liquid, free form or pharma- ceutically acceptable salt form, optionally mixed with a liquid, pharma- ceutically acceptable diluent or carrier, wherein the gelatin capsule is surrounded by a composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, an expanding layer in contact with the barrier layer, a semipermeable layer encompassing the expanding layer, and an exit orifice formed or formable in the wall, wherein the barrier layer forms a seal between the expanding layer and the environment at the exit orifice (pharmaceutical composition P.3).

[0096] In yet another embodiment, the present invention provides a pharmaceutical composition comprising a gelatin capsule containing a compound of formula I or later in liquid, free form or pharma- ceutically acceptable salt form, optionally mixed with a liquid, pharma- ceutically acceptable diluent or carrier, the gelatin capsule being surrounded by a barrier layer in contact with the outer surface of the gelatin capsule, an expanding layer in contact with a portion of the barrier layer, a semipermeable layer encompassing at least the expanding layer, and an exit orifice formed or formable into a dosage form extending from the outer surface of the gelatin capsule to the environment of use (pharmaceutical composition P.4). The expanding layer may be formed into one or more separate sections, for example two sections located on opposite sides or ends of the gelatin capsule.

[0097] In certain embodiments, the compounds of the present disclosure in the osmotic controlled release oral delivery systems (i.e., compositions P.1-P.4) are in a liquid formulation, where the formulation can be a pure liquid active agent or a liquid active agent in a solution, suspension, emulsion or self-emulsifying composition, or the like.

[0098] Further information regarding osmotic release controlled oral delivery system compositions, including the characteristics of the gelatin capsule, barrier layer, expansion layer, semipermeable layer; and orifice, can be found in U.S. Patent Application Publication No. 2001 / 0036472, the contents of which are incorporated herein by reference in their entirety.

[0099] Other osmotic release controlled oral delivery systems for the compounds of Formula I et seq. or pharmaceutical compositions of the present disclosure can be found in U.S. Patent Application Publication No. 2009 / 0202631, the contents of which are incorporated herein by reference in their entirety. Thus, in another embodiment, the present invention provides a composition or device (pharmaceutical composition P.5) comprising: (a) two or more layers, including a first layer and a second layer, the first layer comprising a compound of Formula I et seq. in free form or in a pharma- ceutical acceptable salt form, optionally mixed with a pharma- ceutical acceptable diluent or carrier, and the second layer comprising a polymer; (b) an outer wall surrounding the two or more layers; and (c) an orifice in the outer wall.

[0100] Pharmaceutical composition P.5 preferably utilizes a semipermeable membrane surrounding a trilayer core; in these embodiments, the first layer, referred to as the first drug layer, contains a small amount of drug (e.g., a compound of Formula I or later) and an osmotic modifier such as a salt, the middle layer, referred to as the second drug layer, contains a large amount of drug and excipients and no salt, and the third layer, referred to as the push layer, contains an osmotic modifier and no drug (Pharmaceutical composition P.6). At least one orifice is drilled through the membrane at the first drug layer end of the capsule-shaped tablet.

[0101] Pharmaceutical composition P.5 or P.6 may include a membrane defining a compartment, the membrane surrounding at least a portion of the inner protective subcoat, at least one exit orifice formed or formable therein, and the semipermeable membrane; an expanding layer located in the compartment remote from the exit orifice, the expanding layer being in fluid communication with the semipermeable portion of the membrane; a first drug layer located adjacent to the exit orifice; and a second drug layer located in the compartment between the first drug layer and the expanding layer, the drug layers comprising a compound of the present invention in free form or a pharma-ceutical acceptable salt thereof (pharmaceutical composition P.7). Depending on the relative viscosities of the first and second drug layers, different release profiles are obtained. It is essential to identify the optimal viscosity of each layer. In the present invention, the viscosity is adjusted by the addition of a salt, sodium chloride. The delivery profile from the core depends on the weight, formulation, and thickness of each drug layer.

[0102] In certain embodiments, the present invention provides pharmaceutical composition P.7, wherein the first drug layer comprises a salt and the second drug layer does not comprise a salt. Pharmaceutical compositions P.5-P.7 may optionally include a flux-promoting layer between the membrane and the drug layer.

[0103] Pharmaceutical compositions P.1-P.7 are generally referred to as osmotic release controlled oral delivery system compositions.

[0104] In a third aspect, the present invention provides a method for treating or preventing a central nervous system disorder, comprising administering to a patient in need thereof a compound of Formula I et seq., or any of Pharmaceutical Compositions 1, 1-A, 1-B, 1-C, or P.1 to P.7 (Method 1). In certain embodiments, Method 1 comprises: 1.1 Compound I or any of compounds 1.1 to 1.74 in free form; 1.2 Compound I, or any of 1.1-1.74, in a pharma- ceutically acceptable salt form; 1.3 Compound I or any of 1.1-1.74 in the form of an acid addition salt; 1.4 Pharmaceutical composition 1; 1.5 any of Pharmaceutical Compositions 1-A, 1-B or 1-C; 1.6 Any of pharmaceutical compositions P.1 to P.7; or 1.7 Any of the above osmotic release controlled oral delivery system compositions The method includes administering

[0105] In a further embodiment of the third aspect, the present disclosure provides further embodiments of Method 1, as follows:

[0106] 1.8 Central nervous system disorders include obesity, anxiety (including generalized anxiety, social anxiety, and panic disorder), depression (e.g., treatment-resistant depression and MDD), psychosis (including psychosis associated with dementia, e.g. hallucinations in advanced Parkinson's disease, or paranoid delusions), schizophrenia, sleep disorders (particularly sleep disorders associated with schizophrenia and other psychiatric and neurological disorders), sexual disorders, migraine, pain and pain-related conditions, e.g., headache, idiopathic pain, chronic pain (e.g., moderate to moderately severe chronic pain, e.g., in patients requiring extended 24-hour treatment for other illnesses), neuropathic pain, dental pain, fibromyalgia, chronic fatigue, agoraphobia, social phobia, agitation in dementia (e.g., Alzheimer's disease, Parkinson ... Method 1, or any of Methods 1.1-1.7, wherein the disorder is selected from the group consisting of: agitation in Alzheimer's disease), agitation in autism and related autistic disorders, gastrointestinal disorders, e.g., gastrointestinal motility dysfunction, and dementia, e.g., dementia of Alzheimer's disease or Parkinson's disease; mood disorders; drug dependence, e.g., opiate dependence and / or alcohol dependence, and withdrawal from drug or alcohol dependence (e.g., opiate dependence); opiate overdose; comorbidities associated with drug dependence, e.g., depression, anxiety and psychosis; binge eating disorder; and obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD) and related disorders; or opiate use disorder (OUD);

[0107] 1.9 Central nervous system disorders include serotonin 5-HT agonists, which are also described in U.S. Patent Application Publication No. 2011 / 071080, the contents of which are incorporated herein by reference in their entirety. 2A , method 1, or any of methods 1.1 to 1.8, which is a disorder associated with the dopamine D1 and / or D2 receptor system and / or the serotonin reuptake transporter (SERT) pathway;

[0108] 1.10 Method 1, or any of Methods 1.1-1.9, wherein the central nervous system disorder is a μ-opioid receptor associated disorder;

[0109] 1.11 Method 1, or any of Methods 1.1-1.10, wherein the central nervous system disorder is selected from: (i) psychosis in a patient suffering from depression, e.g., schizophrenia; (2) depression in a patient suffering from psychosis, e.g., schizophrenia; (3) mood disorders associated with psychosis and / or substance dependence, e.g., schizophrenia, or Parkinson's disease; (4) sleep disorders associated with psychosis, e.g., schizophrenia, or Parkinson's disease; and (5) substance addiction, substance use disorder, and / or substance induced disorder, optionally wherein the patient suffers from anxiety or residual symptoms of an anxiety disorder; and optionally wherein the depression is treatment resistant depression;

[0110] 1.12 Method 1 or any of methods 1.1 to 1.11, wherein the central nervous system disorder is a psychosis, e.g. schizophrenia, and the patient is a patient suffering from depression;

[0111] 1.13 Method 1, or any of Methods 1.1-1.12, where the patient cannot tolerate the side effects of conventional antipsychotics, such as chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, brexpiperazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone;

[0112] 1.14 If a patient cannot tolerate the side effects of non-narcotic analgesics and / or opiate and opioid drugs, or the use of opiate drugs is contraindicated in the patient, e.g., due to previous substance abuse or high substance abuse potential, and opiate and opioid drugs are not used, e.g., morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentanyl (alpha-methylfentanyl), Method 1, or any of Methods 1.1-1.13, comprising methylfentanyl, alfentanil, trefantinil, briffentanil, remifentanil, octofentanil, sufentanil, carfentanil, meperidine, prozine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and anileridine, or a combination thereof;

[0113] 1.15 Method 1, or any of Methods 1.1-1.14, where the patient cannot tolerate the side effects of conventional antipsychotics, e.g., haloperidol, brexpiperazole, cariprazine, asenapine, lurasidone, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone;

[0114] 1.16 Method 1 or any of methods 1.1 to 1.15, wherein the disorder is depression and the patient is a patient suffering from a psychosis, e.g. schizophrenia, or Parkinson's disease;

[0115] 1.17 Method 1 or any of methods 1.1 to 1.15, where the disorder is a sleep disorder and the patient suffers from depression;

[0116] 1.18 Method 1 or any of methods 1.1 to 1.15, wherein one or more disorders is a sleep disorder and the patient suffers from a psychosis, e.g. schizophrenia;

[0117] 1.19 Method 1 or any of methods 1.1 to 1.15, where one or more of the disorders is a sleep disorder and the patient has Parkinson's disease;

[0118] 1.20 Method 1 or any of methods 1.1 to 1.15, wherein one or more of the disorders is a sleep disorder and the patient suffers from depression and a psychosis, e.g. schizophrenia, or Parkinson's disease;

[0119] 1.21 Method 1, or any of 1.1 to 1.20, wherein the patient suffers from a substance dependence disorder, optionally in conjunction with the above disorders, for example the patient suffers from opiate dependence, cocaine dependence, amphetamine dependence and / or alcohol dependence, or withdrawal from a drug or alcohol dependence (e.g. opiate dependence, cocaine dependence or amphetamine dependence), and optionally the patient suffers from a co-morbid disorder, such as anxiety, depression or psychosis, or residual symptoms of anxiety or an anxiety disorder and / or mood changes (e.g. depression); further optionally the patient suffers from an opiate overdose;

[0120] 1.22 Any of the above methods, wherein the effective amount is from 1 mg to 1000 mg, e.g., from 2.5 mg to 50 mg, or, for long acting formulations, from 25 mg to 1500 mg, e.g., from 50 mg to 500 mg, or from 250 mg to 1000 mg, or from 250 mg to 750 mg, or from 75 mg to 300 mg;

[0121] 1.23 Any of the above methods, wherein the effective amount is between 1 mg and 100 mg per day, for example between 2.5 mg and 50 mg per day;

[0122] 1.24 Any of the above methods wherein the condition to be treated is dyskinesia, e.g., in a patient receiving a dopamine agonist (e.g., an agent selected from levodopa and levodopa adjuvants (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics, e.g., levodopa);

[0123] 1.25 Any of the above methods, wherein the patient is suffering from Parkinson's disease.

[0124] Substance use disorders and substance-induced disorders are two categories of substance-related disorders defined by the 5th edition of the DSM (Diagnostic and Statistical Manual of Mental Disorders, or DSM-5). Substance use disorders are a pattern of symptoms resulting from the use of a substance that an individual continues to take despite experiencing problems as a result. Substance-induced disorders are disorders that are induced by the use of a substance. Substance-induced disorders include addiction, withdrawal, substance-induced psychiatric disorders such as substance-induced psychosis, substance-induced bipolar and related disorders, substance-induced depressive disorders, substance-induced anxiety disorders, substance-induced obsessive-compulsive and related disorders, substance-induced sleep disorders, substance-induced dysfunction, substance-induced delirium, and substance-induced neurocognitive disorders.

[0125] DSM-5 includes criteria for classifying substance use disorder as mild, moderate or severe. In some embodiments of the methods described herein, the substance use disorder is selected from mild substance use disorder, moderate substance use disorder or severe substance use disorder. In some embodiments, the substance use disorder is mild substance use disorder. In some embodiments, the substance use disorder is moderate substance use disorder. In some embodiments, the substance use disorder is severe substance use disorder.

[0126] Anxiety and depression are very common comorbid disorders in patients undergoing treatment for substance use or substance abuse. A common treatment for substance abuse disorders is the combination of buprenorphine, a partial opioid agonist, and naloxone, an opioid antagonist, but both of these drugs have no significant effect on anxiety or depression, and therefore a common result is that a third drug, such as a benzodiazepine anxiolytic or an SSRI antidepressant, must also be prescribed. This makes treatment regimen and patient compliance more difficult. In contrast, the compounds of the present disclosure provide opiate antagonism along with serotonin antagonism and dopamine modulation. This can significantly enhance the treatment of patients with substance use or abuse disorders comorbid with anxiety and / or depression.

[0127] The compounds of the present disclosure may have anxiolytic properties that reduce the need for treatment with anxiolytic drugs in patients suffering from comorbid anxiety.Thus, in some embodiments, the present disclosure provides a method according to any of method 1 or methods 1.1-1.25, wherein the central nervous system disorder is a substance addiction, substance use disorder and / or substance-induced disorder or substance abuse disorder, for example in patients suffering from symptoms of anxiety or diagnosed with anxiety as a comorbid or residual disorder, and the method does not include further administration of an anxiolytic drug, for example, a benzodiazepine.The benzodiazepine is a GABA-modulating compound, including those described with reference to methods 3.1 and 3.2 below.

[0128] In another embodiment of the third aspect, the present disclosure provides a further embodiment of Method 1 as follows:

[0129] 1.26 Method 1, or any of Methods 1.1-1.25, wherein the central nervous system disorder is a disorder selected from obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, hypochondriasis, grooming disorder, kleptomania, pyromania, attention-deficit hyperactivity disorder (ADHD), attention-deficit disorder (ADD), impulse-control disorders, and related disorders, and combinations thereof;

[0130] 1.27 Method 1 or any one of Methods 1.1-1.25, wherein the central nervous system disorder is selected from obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, and impulse control disorder;

[0131] 1.28 Method 1 or any one of methods 1.1 to 1.25, where the central nervous system disorder is obsessive-compulsive disorder (OCD) or obsessive-compulsive personality disorder (OCPD);

[0132] 1.29 Any of the above methods, wherein the patient does not respond to or cannot tolerate the side effects of treatment with selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline;

[0133] 1.30 Any of the above methods, wherein the patient does not respond to or cannot tolerate the side effects of treatment with serotonin-norepinephrine reuptake inhibitors (SNRIs), e.g., venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran and levomilnacipran;

[0134] 1.31 Any of the above methods, wherein the patient does not respond to or cannot tolerate the side effects of treatment with antipsychotics, e.g., clomipramine, risperidone, quetiapine, and olanzapine;

[0135] 1.32 Method 1, or any of Methods 1.1 to 1.25, wherein the central nervous system disorder is a pain disorder, e.g. a pain-related condition, e.g. headache, idiopathic pain, neuropathic pain, chronic pain (e.g. moderate to moderately severe chronic pain, e.g. in patients requiring extended 24-hour treatment for other illnesses), fibromyalgia, dental pain, traumatic pain or chronic fatigue;

[0136] 1.33 If a patient does not respond to or cannot tolerate the side effects of treatment with non-narcotic analgesics and / or opiate and opioid drugs, or the use of opiate drugs is contraindicated in the patient, e.g., due to previous substance abuse or high substance abuse potential, and opiate and opioid drugs are not used, e.g., morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylformamide ... any of the above methods, comprising alpha-methylfentanyl, alfentanil, trefantinil, briffentanil, remifentanil, octofentanil, sufentanil, carfentanil, meperidine, prozine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol and anileridine, or combinations thereof;

[0137] 1.34 Method I, or any of Methods 1.1 to 1.33, wherein the central nervous system disease or disorder is drug dependence (e.g., opiate dependence (i.e., opioid use disorder), cocaine dependence, amphetamine dependence and / or alcohol dependence), or withdrawal from drug or alcohol dependence (e.g., opiate dependence, cocaine dependence or amphetamine dependence) and the patient also suffers from a comorbid disorder, e.g., anxiety, depression or psychosis; optionally the patient also suffers from opiate overdose;

[0138] 1.35 Any of the above methods, wherein the effective amount is from 1 mg to 1000 mg, preferably from 2.5 mg to 50 mg, or for long-acting formulations, from 25 mg to 1500 mg, e.g., from 50 mg to 500 mg, or from 250 mg to 1000 mg, or from 250 mg to 750 mg, or from 75 mg to 300 mg;

[0139] 1.36 Any of the above methods, wherein the effective amount is between 1 mg and 100 mg per day, preferably between 2.5 mg and 50 mg per day.

[0140] In yet another embodiment, the disclosure provides any of the above methods 1 or 1.1-1.36, wherein the disorder is schizophrenia or a sleep disorder. In some embodiments, the schizophrenia is associated with depression.

[0141] In yet another embodiment, the disclosure provides any of Methods 1.1-1.36, wherein the pharmaceutical composition is administered for controlled and / or sustained release of the compound of the invention over a period of about 14 days to about 30 days to about 180 days, preferably about 30 days, about 60 days, or about 90 days. Controlled and / or sustained release is particularly useful for avoiding premature discontinuation of treatment, especially for antipsychotic therapy where non-compliance or non-adherence to dosing regimens is a common occurrence.

[0142] In yet another embodiment, the present invention provides any of the above methods 1 or 1.1-1.36, wherein a depot composition of the disclosure is administered for controlled and / or sustained release of a compound of the present invention over a period of time.

[0143] In another embodiment of the third aspect, the invention provides a method of treating pain according to Method 1, or any of Methods 1.1-1.36, e.g., any, wherein the patient suffers from gastrointestinal and / or pulmonary disorders. Conventional opioid analgesics suffer from two major side effects: gastrointestinal disorders (e.g., nausea, vomiting, and constipation) and respiratory depression. 90-95% of patients taking opioids for pain treatment for extended periods of time develop severe constipation, necessitating the long-term use of laxatives and / or enemas. Stronger opioids, e.g., morphine, oxycodone, and hydromorphone, cause more severe constipation than other opioids. Respiratory depression is the most serious side effect of opioid treatment, especially when patients (intentionally or inadvertently) combine their prescribed opioid analgesic with other legal or illegal respiratory depressants (including alcohol), resulting in a risk of death. Thus, patients who need pain treatment, especially chronic pain treatment, are at particular risk of side effects if they suffer from existing gastrointestinal or pulmonary disorders.Unlike conventional opioid analgesics, the compounds of the present invention provide analgesic relief without significant gastrointestinal side effects and significant respiratory depression.Thus, such compounds provide improved safety and efficacy for patients who need pain treatment and have these existing GI and pulmonary disorders.In a further embodiment, the compounds of the present invention can be combined with conventional opiate drugs to provide improved pain control with dose-sparing effects (and reduced risk of associated side effects) for conventional opiate drugs.

[0144] Thus, in certain embodiments, the present invention further provides:

[0145] 1.37 The patient suffers from pre-existing or concomitant gastrointestinal and / or pulmonary disorders, method 1 or any of 1.1 to 1.36;

[0146] 1.38 Method 1.37, wherein the pre-existing or coexisting disorder is selected from the group consisting of irritable bowel syndrome, pelvic floor disorders, diverticulitis, inflammatory bowel disease, colon or colorectal cancer, celiac disease, non-celiac gluten sensitivity, asthma, chronic obstructive pulmonary disease (COPD), dyspnea, pneumonia, congestive heart failure, interstitial lung disease, pneumothorax, bronchitis, pulmonary embolism and traumatic chest injury (e.g., sternal or rib fractures, intercostal muscle contusion);

[0147] 1.39 Method 1.37 or 1.38, wherein the central nervous system disorder is a pain disorder, e.g., a pain-related condition, such as headache, idiopathic pain, neuropathic pain, chronic pain (e.g., moderate to moderately severe chronic pain, e.g., in patients requiring extended 24-hour treatment for other illnesses), fibromyalgia, dental pain, traumatic pain, or chronic fatigue;

[0148] 1.40 any of Methods 1 or 1.1-1.39, wherein the central nervous system disorder is opiate use disorder, opiate withdrawal, or opiate dependence, and the method provides relief from a withdrawal-induced symptom (e.g., a gastrointestinal symptom, e.g., diarrhea, anxiety, depression, pain, sleep disorders, or a combination thereof);

[0149] 1.41 Any of Methods 1 or 1.1-1.40, wherein the method further comprises co-administration of another opiate or opioid drug, e.g., administered simultaneously, separately or sequentially;

[0150] 1.42 Method 1.41, wherein the additional opiate or opioid drug is selected from the group consisting of morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentantyl, alfentanil, trefantinil, briffentanil, remifentanil, octofentanil, sufentanil, carfentanil, meperidine, prozine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and anileridine, or combinations thereof;

[0151] 1.43 Any of Methods 1 or 1.1-1.42 comprising co-administration of an NMDA receptor antagonist, e.g., administered simultaneously, separately or sequentially;

[0152] 1.44 Method 1.43, wherein the NMDA receptor antagonist is selected from the group consisting of ketamine (e.g., S-ketamine and / or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine and agmatine, or combinations thereof;

[0153] 1.45 Any of Methods 1.37-1.44, wherein the compound is a compound of Formula I where Z is -O-.

[0154] In a fourth aspect, the present invention provides a method for preventing or treating one or more sleep disorders, comprising administering to a patient in need thereof a compound of Formula I et seq., or any of Pharmaceutical Compositions 1, 1-A, 1-B, 1-C, or P.1-P.7 (Method 2). In certain embodiments, Method 2 comprises administering: 2.1. Compound I or any of 1.1 to 1.74 in free form; 2.2. Compound I, or any of 1.1-1.74, in a pharma- ceutically acceptable salt form; 2.3. Compound I, or any of 1.1-1.74, in the form of an acid addition salt; 2.4. Pharmaceutical composition I; 2.5. Any of Pharmaceutical Compositions 1-A, 1-B or 1-C; 2.6. Any of pharmaceutical compositions P.1 to P.7; or 2.7. Any of the above osmotic release controlled oral delivery system compositions.

[0155] In a further embodiment of the fourth aspect, the invention provides methods 2 or 2.1-2.7, wherein the sleep disorder comprises insomnia, frequent awakenings, and unrefreshed awakenings; for example, the following: 2.8 Any of the above methods, wherein the sleep disorder is a sleep maintenance disorder; 2.9 Any of the above methods, wherein the effective amount is 1 mg to 5 mg, preferably 2.5 to 5 mg, per day; 2.10 Any of the above methods, wherein the effective amount is 2.5 mg or 5 mg per day; 2.11 Any of the above methods wherein the sleep disorder is in a patient suffering from or at risk of dyskinesia, e.g., a patient receiving a dopamine agonist selected from levodopa and levodopa adjuvants (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists and anticholinergics, e.g., a patient receiving levodopa; 2.12 Any of the above methods, wherein the patient is suffering from Parkinson's disease.

[0156] In a further embodiment of the fourth aspect, the invention provides any of Methods 2, or 2.1-2.12, wherein the sleep disturbance comprises insomnia, frequent awakenings, and unrefreshed awakenings.

[0157] The compounds of the present disclosure and pharmaceutical compositions of the present disclosure can be used in combination with a second therapeutic agent, particularly at a lower dosage than when each drug is used as a monotherapy, to enhance the therapeutic activity of the combined drug without causing the undesirable side effects that usually occur in conventional monotherapy.Thus, the compounds of the present disclosure can be administered simultaneously, sequentially, or contemporaneously with other antidepressants, antipsychotics, other sleep medications, and / or drugs used to treat Parkinson's disease or mood disorders.In another example, side effects can be reduced or minimized by administering the compounds of the present disclosure in free form or salt form (e.g., pharma-ceutically acceptable salt form) in combination with one or more second therapeutic agents, where (i) the dosage of the second therapeutic agent or (ii) the dosage of both the compounds of the present disclosure and the second therapeutic agent is lower than when the drug / compound is administered as a monotherapy. In certain embodiments, the compounds of the present disclosure are useful for treating dyskinesias in patients receiving dopamine agonists selected from, for example, levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics, e.g., used in the treatment of Parkinson's disease.

[0158] In some further embodiments of the present disclosure, the pharmaceutical compositions of the present disclosure can be used in combination with a second therapeutic agent, where the second therapeutic agent is an opiate antagonist or inverse agonist (e.g., naloxone), to enhance the therapeutic activity of the combined drug without causing undesirable side effects, particularly at lower dosages than when the individual drugs are used as monotherapy. The compounds of the present disclosure can be administered simultaneously, sequentially, or contemporaneously with such opiate antagonist or opiate inverse agonist.

[0159] Thus, in a fifth aspect, the disclosure provides a method further comprising administering to the patient one or more therapeutic agents, the one or more therapeutic agents being a GABA-active (e.g., GABA-potentiating or enhancing activity of GABA transmission) compound, a GABA-B agonist, a 5-HT receptor modulator (e.g., a 5-HT 1A Agonist, 5-HT 2A Antagonist, 5-HT 2Ainverse agonists, melatonin receptor agonists, ion channel modulators (e.g., blockers), serotonin-2 receptor antagonists / reuptake inhibitors (e.g., compounds that have both 5-HT2 antagonism and serotonin reuptake inhibition, i.e., SARIs), orexin receptor antagonists, H3 agonists or antagonists, noradrenergic agonists or antagonists, galanin agonists, CRH antagonists, human growth hormone, growth hormone agonists, estrogen, estrogen agonists, neurokinin-1 agents, antidepressants, and an opiate agonist and / or partial opiate agonist (e.g., a μ-, κ-, or δ-opiate receptor agonist or partial agonist), or an opiate antagonist or inverse agonist (e.g., a μ-, κ-, or δ-opiate receptor antagonist or inverse agonist), a nociceptin agonist, and an antipsychotic, e.g., an atypical antipsychotic (Methods 1-A and 2-A, respectively; collectively "Method 3"). In a further embodiment of the eighth aspect, the disclosure provides Method 1, or any of Methods 1.1-1.45, or Method 2, or any of Methods 2.1-2.12, further comprising administering to the patient one or more therapeutic agents selected from above and further selected from μ-opiates, κ-opiates, δ-opiates, and / or nociceptin / orphanin receptor agonists or partial agonists or antagonists or inverse agonists. In a further embodiment of the tenth aspect, the disclosure also provides Method 1, or any of Methods 1.1-1.45, or Method 2, or any of Methods 2.1-2.12, further comprising administering to the patient one or more therapeutic agents selected from a serotonin HT6 receptor antagonist, and an mGluR-2, -3 or -5 receptor agonist or antagonist (including both positive and negative modulators, and partial agonists).

[0160] In a further embodiment of the fifth aspect, the invention provides Method 3 (i.e., Method 1-A or 2-A), further comprising administering to the patient one or more therapeutic agents, in free form or in pharma- ceutically acceptable salt form, as follows:

[0161] 3.1 Method 1-A or 2-A, wherein the therapeutic agent is a compound that modulates GABA activity (e.g., enhances activity and facilitates GABA transmission);

[0162] 3.2 Method 1-A or 2-A or 3.1, wherein the GABA compound is selected from the group consisting of one or more of doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zeleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT201 (Evotec Pharmaceuticals), and estazolam;

[0163] 3.3 Method 1-A or 2-A, wherein the therapeutic agent is an additional 5HT2a receptor antagonist;

[0164] 3.4 Method 1-A or 2-A or 3.3, wherein the additional 5HT2a receptor antagonist is selected from one or more of pimavanserin, ketanserin, risperidone, eplivanserin, vorinanserin (Sanofi-Aventis, France), pulvanserin, MDL100907 (Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San Diego, CA) and AVE8488 (Sanofi-Aventis, France);

[0165] 3.5 Method 1-A or 2-A, wherein the therapeutic agent is a melatonin receptor agonist;

[0166] 3.6 Method 1-A or 2-A or 3.5, wherein the melatonin receptor agonist is selected from one or more of melatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II Discovery), and agomelatine;

[0167] 3.7 Method 1-A or 2-A, wherein the therapeutic agent is an ion channel blocker;

[0168] 3.8 Method IA or 2-A or 3.7, wherein the ion channel blocker is one or more of lamotrigine, gabapentin, and pregabalin;

[0169] 3.9 Method 1-A or 2-A, wherein the therapeutic agent is an orexin receptor antagonist;

[0170] 3.10 Method 1-A or 2-A or 3.9, wherein the orexin receptor antagonist is selected from the group consisting of orexin, 1,3-biaryl urea, SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline) and benzamide derivatives;

[0171] 3.11 Method 1-A or 2-A, wherein the therapeutic agent is a serotonin-2 receptor antagonist / reuptake inhibitor (SARI);

[0172] 3.12 Method 1-A or 2-A or 3.11, wherein the serotonin-2 receptor antagonist / reuptake inhibitor (SARI) is selected from the group consisting of one or more of Org50081 (Organon-Netherlands), ritanserin, nefazodone, sarzone, and trazodone;

[0173] 3.13 Method 1-A or 2-A, wherein the therapeutic agent is a 5HTIa agonist;

[0174] 3.14 Method 1-A or 2-A or 3.13, wherein the 5HTIa agonist is selected from the group consisting of one or more of repinotan, sarizotan, eptapyrone, buspirone and MN-305 (MediciNova, San Diego, CA);

[0175] 3.15 Method 1-A or 2-A, wherein the therapeutic agent is a neurokinin-1 agent;

[0176] 3.16 Method 1-A or 2-A or 3.15, where the neurokinin-1 agent is casopitant (GlaxoSmithKline);

[0177] 3.17 The therapeutic agent is an antipsychotic, Method 1-A or 2-A;

[0178] 3.18 Method 1-A or 2-A or 3.17, wherein the antipsychotic is selected from the group consisting of chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, brexpiperazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone;

[0179] 3.19 The therapeutic agent is an antidepressant, Method 1-A or 2-A;

[0180] 3.20 Method 1-A or 2-A or 3.19, wherein the antidepressant is selected from amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine;

[0181] 3.21 The antipsychotic is an atypical antipsychotic, Method 1-A or 2-A, 3.17 or 3.18;

[0182] 3.22 Methods 1-A or 2-A, or any of 3.17 through 3.21, wherein the atypical antipsychotic is selected from the group consisting of brexpiperazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone;

[0183] 3.23 The therapeutic agent is selected from any of methods 3.1-3.22, e.g., modafinil, armodafinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zeleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT201 (Evotec Pharmaceuticals), estazolam, pimavanserin, ketanserin, risperidone, eplivanserin, vorinancerin (Sanofi-Aventis, France), pulvanserin, MDL100907 (Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San Diego, CA), AVE8488 (Sanofi-Aventis, France), repinotan, sarizotan, eptapyrone, buspirone, MN-305 (MediciNova, San Diego, CA), melatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II Discovery), agomelatine, lamotrigine, gabapentin, pregabalin, orexin, 1,3-biarylurea, SB-334867-a (GlaxoSmithKline,UK), GW649868 (GlaxoSmithKline), benzamide derivatives, Org50081 (Organon-Netherlands), ritanserin, nefazodone, sarzone, trazodone, casopitant (GlaxoSmithKline), amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, pheneridine sulfate Method 1-A or 2-A, wherein the compound is selected from the group consisting of aztreonine, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, brexpiperazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone;

[0184] 3.24 Method 1-A or 2-A, wherein the therapeutic agent is an H3 agonist;

[0185] 3.25 Method 1-A or 2-A, wherein the therapeutic agent is an H3 antagonist;

[0186] 3.26 Method 1-A or 2-A, wherein the therapeutic agent is a noradrenergic agonist or antagonist;

[0187] 3.27 Method 1-A or 2-A, wherein the therapeutic agent is a galanin agonist;

[0188] 3.28 Method 1-A or 2-A, wherein the therapeutic agent is a CRH antagonist;

[0189] 3.29 Method 1-A or 2-A, where the therapeutic agent is human growth hormone;

[0190] 3.30 Method 1-A or 2-A, wherein the therapeutic agent is a growth hormone agonist;

[0191] 3.31 Method 1-A or 2-A, where the therapeutic agent is an estrogen;

[0192] 3.32 Method 1-A or 2-A, wherein the therapeutic agent is an estrogen agonist;

[0193] 3.33 Method 1-A or 2-A, wherein the therapeutic agent is a neurokinin-1 agent;

[0194] 3.34 Method 1-A or 2-A, wherein a therapeutic agent is combined with a compound of Formula I or later, and the therapeutic agent is an anti-Parkinson's agent, e.g., L-dopa, cocalerdopa, duodopa, stalevo, symmetrel, benztropine, biperiden, bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline, and tolcapone;

[0195] 3.35 Method 1-A or 2-A, wherein the therapeutic agent is an opiate agonist or partial opiate agonist, e.g., a μ agonist or partial agonist, or a κ agonist or partial agonist, e.g., a mixed agonist / antagonist (e.g., a drug with partial μ agonist activity and κ antagonist activity);

[0196] 3.36 Method 3.35, wherein the therapeutic agent is buprenorphine, and optionally the method does not include concomitant treatment with an anti-anxiety agent, e.g., a GABA compound or a benzodiazepine;

[0197] 3.37 Method 1-A or 2-A, wherein a compound of formula (I) can be used to treat sleep disorders, depression, psychosis, or a combination thereof in a patient suffering from a recited disease and / or Parkinson's disease;

[0198] 3.38 Method 1-A or 2-A, wherein the disorder is selected from at least one or more of a psychiatric illness, e.g., schizophrenia, depression, a mood disorder, a sleep disorder (e.g., sleep maintenance and / or sleep onset), or a combination of those disorders;

[0199] 3.39 Method 1-A or 2-A, wherein the therapeutic agent is an opiate receptor antagonist or inverse agonist, e.g., a full opiate antagonist, e.g., selected from naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodein, cyprodim, or nor-binaltorphimine;

[0200] 3.40 Any of the above methods, wherein the disorder is a sleep disorder;

[0201] 3.41 Any of the above methods, wherein the disorder is a sleep disorder associated with a psychosis, e.g., schizophrenia, or Parkinson's disease.

[0202] In a sixth aspect of the invention, the combination of a compound of the present disclosure and one or more second therapeutic agents described in any of Methods 1-A, 2-A, or Methods 3 or 3.1-3.41 can be administered to a patient as a single pharmaceutical composition, such as a depot composition as described above. The combination composition can include a mixture of the combined drugs, as well as two or more separate compositions of the drugs, where the individual compositions can be, for example, co-administered together to a patient.

[0203] In certain embodiments, Methods 1-A, 2-A, 3 or 3.1-3.41 comprise administering to a patient in need thereof a compound of the invention in free form or in a pharma- ceutically acceptable salt form in combination with an atypical antipsychotic, e.g., a compound selected from brexpiperazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone or paliperidone, e.g., to reduce the dosage of the atypical antipsychotic and / or to reduce side effects.

[0204] In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprise administering to a patient in need thereof a compound of the invention in combination with an antidepressant, such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine or venlafaxine, in free form or in pharma- ceutically acceptable salt form. Alternatively, the antidepressant can be used as an adjunct in addition to the compound of the invention.

[0205] In yet another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprise administering to a patient in need thereof a compound of the invention in free or pharma- ceutically acceptable salt form in combination with a compound that modulates GABA activity, such as doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zeleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT201 (Evotec Pharmaceuticals), estazolam, or combinations thereof. In other embodiments, the methods described herein do not further comprise administration of a GABA compound, a benzodiazepine, or other anti-anxiety drug.

[0206] In another preferred embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprise administering to a patient in need thereof a compound of the present invention in combination with doxepin in free form or in pharma- ceutically acceptable salt form. The dosage of doxepin can vary within a range known to those skilled in the art. In one example, a 10 mg dose of doxepin can be combined with any dose of the compound of the present invention.

[0207] In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprise administering to a patient in need thereof a compound of the invention (e.g., as part of a daily regimen) in combination with an atypical stimulant, such as modafinil, adrafinil or armodafinil. Regimen incorporating compounds of the invention with such drugs may be useful in treating, for example, bipolar depression, dementia associated with schizophrenia, and excessive sleepiness and fatigue in conditions such as Parkinson's disease and cancer, promoting more regular sleep and avoiding side effects such as psychosis or mania associated with high levels of such drugs.

[0208] In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41 comprise administering to a patient in need thereof a compound of the invention (e.g., as part of a daily dosing regimen) in combination with an opiate receptor antagonist or inverse agonist, e.g., a full opiate antagonist, e.g., selected from naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodein, cyprodim, or nor-binaltorphimine.

[0209] In a sixth aspect, the present invention provides the use of a compound or composition as described below for the treatment or prevention of one or more of the disorders above (in the manufacture of a medicament), e.g. in Method 1 or any of 1.1 to 1.45, in Method 2 and any of 2.1 to 2.12, in Method 1-A, 2-A, and Method 3 or 3.3 to 3.41, or any other method described herein: 6.1. Compound I or any of 1.1-1.74 in free form; 6.2. Compound I, or any of 1.1-1.74, in a pharma- ceutically acceptable salt form; 6.3. Compound I, or any of 1.1-1.74, in the form of an acid addition salt; 6.4. Pharmaceutical composition 1; 6.5. Any of Pharmaceutical Compositions 1-A, 1-B or 1-C; 6.6. Any of pharmaceutical compositions P.1 to P.7; or 6.7. Any of the above osmotic release controlled oral delivery system compositions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0210] Detailed Description The compounds of formula A, and related compounds, have been shown to have a variety of useful pharmaceutical properties, each of which is expected to be shared by the compounds of the present disclosure. For example, compounds of formula A exhibit potent 5-HT agonist activity along with moderate D1, D2 and SERT antagonism. 2A, D1 and μ opiate antagonistic activity. Moreover, it has been unexpectedly found that such compounds can function as "biased" μ opiate ligands. This means that when the compounds bind to the μ opiate receptor, they can function as partial μ agonists through G protein-coupled signaling, but as μ antagonists through β-arrestin signaling. This is in contrast to conventional opiate agonists morphine and fentanyl, which tend to potently activate both G protein signaling and β-arrestin signaling. Activation of β-arrestin signaling by such drugs is believed to mediate the gastrointestinal dysfunction and respiratory depression typically mediated by opiate drugs. Thus, it is believed that the compounds according to the present invention, particularly those represented by formula I, provide pain relief with less severe gastrointestinal and respiratory side effects than existing opiate analgesics. This effect has been shown in preclinical studies of the biased μ agonist oliceridine, as well as in phase II and III clinical trials. Oliceridine has been shown to produce bias μ agonism through G protein-coupled signaling with reduced β-arrestin signaling compared to morphine, which is related to its ability to produce analgesia with reduced respiratory side effects compared to morphine. Furthermore, these compounds are believed to be useful in the treatment of opiate overdose, since they antagonize the β-arrestin pathway, inhibiting the most severe opiate side effects while still providing pain relief. Furthermore, these compounds also have a sleep-promoting effect due to their serotonergic activity. Many people suffering from chronic pain have difficulty sleeping due to pain, so these compounds may help such patients sleep through the night through the synergistic effect of serotonergic activity and opiate receptor activity.

[0211] Thus, in certain embodiments, the compounds of the present disclosure may be used alone or in combination with opiate antagonists or inverse agonists (e.g., naloxone or naltrexone) in methods for treating opiate use disorder (OUD), opiate overdose, or opiate withdrawal. It is expected that the compounds of the present disclosure will show a strong ability to reduce the dysphoria and psychiatric comorbidities associated with drug withdrawal (e.g., mood and anxiety disorders, sleep disorders), and also provide strong analgesia, but without the side effects (e.g., GI effects and pulmonary depression) and abuse potential seen with other opioid treatments (e.g., oxycodone, methadone, or buprenorphine). The unique pharmacological profile of these compounds also mitigates the risk of adverse drug-drug interactions (e.g., alcohol). Thus, these compounds are particularly suitable for treating symptoms associated with opiate use disorder and opiate withdrawal. In addition to the direct effects of the compounds on μ receptor activity, the effects of the compounds on serotonergic pathways result in antidepressant, sleep-promoting, and anxiolytic effects. Because depression and anxiety are important factors that lead patients to be susceptible to opioid use in the first place, the compounds disclosed herein reduce the symptoms of opiate withdrawal while simultaneously reducing the psychiatric comorbidities that drive opioid use (a two-pronged strategy that reduces the risk of remission). The sleep maintenance provided by these compounds further improves the quality of life for patients undergoing OUD treatment.

[0212] In some embodiments of the present disclosure, compounds of formula I have one or more biologically labile functional groups located within the compound, such that natural metabolic activity results in removal of the labile functional group, resulting in another compound of formula I. For example, a group R 1 C(O)-OC(R a )(R b )(R c ), -C(O)-O-CH2-OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8If, under biological conditions, this substitution undergoes hydrolysis to give R 1 H, and thus the original compound is converted to R 1 Some of these prodrug compounds have little or only moderate biological activity, but 1 When the compound is hydrolyzed to a compound where R is H, the compound becomes highly biologically active. Thus, depending on the compound selected, administration of the compounds of the present disclosure to a patient in need thereof may result in immediate biological and therapeutic effects, or immediate and delayed biological and therapeutic effects, or only delayed biological and therapeutic effects. Thus, such prodrug compounds may be used in combination with a prodrug having R 1 In this manner, some compounds of the present disclosure are particularly suitable for formulation as long-acting injectable (LAI) or "depot" pharmaceutical compositions. Without being bound by theory, an injected "depot" containing a compound of the present disclosure slowly releases the compound into body tissues where it is slowly metabolized to form R 1 is H. Such depot formulations can be further tailored by the selection of appropriate components to control the rate of elution and release of the compounds of the present disclosure. Such prodrug forms of compounds related to the compounds of formula I have been previously disclosed, for example, in International Application PCT / US2018 / 043102 (WO2019 / 023063).

[0213] As used herein, unless otherwise specified, "alkyl" is a saturated or unsaturated hydrocarbon moiety, e.g., from 1 to 21 carbon atoms in length; such alkyl may be straight or branched chain (e.g., n-butyl or tert-butyl), and is preferably straight chain, unless otherwise specified. For example, "C 1-21 "Alkyl" means an alkyl having 1 to 21 carbon atoms. In one embodiment, the alkyl is selected from the group consisting of one or more hydroxyl or C 1-22It may be substituted with an alkoxy (e.g., ethoxy) group. In another embodiment, the alkyl contains 1-21 carbon atoms, is preferably straight chained, and is optionally saturated or unsaturated, e.g., in some embodiments, where R1 is an alkyl chain containing 1-21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, e.g., together with the -C(O)- to which it is attached, e.g., when cleaved from a compound of formula I, forms the residue of a natural or unnatural saturated or unsaturated fatty acid.

[0214] The term "pharmaceutical acceptable diluents or carriers" is intended to mean diluents and carriers that are useful in pharmaceutical formulations and do not contain substances that are allergenic, pyrogenic or pathogenic, and substances known to potentially cause or promote disease. Thus, pharmaceutical acceptable diluents or carriers do not include bodily fluids, such as blood, urine, cerebrospinal fluid, saliva, and the like, and their components, such as blood cells and circulating proteins. Suitable pharma- ceutically acceptable diluents and carriers can be found in any of several well-known treatises on pharmaceutical formulations, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002;Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990;Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg;Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000;and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999, all of which are incorporated herein by reference in their entireties.

[0215] 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 it has been isolated from a synthetic process (e.g., from a reaction mixture) or from a natural source or a combination thereof. Thus, the terms "purified," "in purified form," or "in isolated and purified form" with respect to a compound refer to the physical state of the compound after it has been obtained from a purification process described herein or known to one of skill in the art (e.g., chromatography, recrystallization, LC-MS and LC-MS / MS techniques, etc.) with sufficient purity to be characterized by standard analytical techniques described herein or known to one of skill in the art.

[0216] Unless otherwise specified, the compounds of the present disclosure, such as compounds I or 1.1-1.74 (collectively, compounds of formula I and thereafter), can be present in free base form or in salt form, such as pharma- ceutically acceptable salt form, such as an acid addition salt. Acid addition salts of compounds of the present invention that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid or toluenesulfonic acid. Additionally, salts of compounds of the present 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 a compound of the present invention is a toluenesulfonic acid addition salt.

[0217] The compounds of the present disclosure are intended for use as pharmaceuticals, and therefore pharma- ceutically acceptable salts are preferred. Salts that are not suitable for pharmaceutical use may be useful, for example, for the isolation or purification of the free compounds of the present invention, and therefore are also included within the scope of the compounds of the present disclosure.

[0218] The compounds of the present disclosure may contain one or more chiral carbon atoms. Thus, the compounds may exist in individual isomeric forms, such as enantiomeric or diastereomeric forms, or as mixtures of individual forms, such as racemic / diastereomeric mixtures. Any isomers in which the asymmetric center is in the (R)-, (S)-, or (R,S)-configuration may exist. It should be understood that the present invention encompasses both optically active isomers individually and their mixtures (e.g., racemic / diastereomeric mixtures). Thus, the compounds of the present invention may be racemic mixtures, or may be predominantly, for example, in pure or substantially pure isomeric form, for example, with an enantiomeric / diastereomeric excess ("ee") of greater than 70%, preferably greater than 80%, more preferably greater than 90%, and most preferably greater than 95%. 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, and the like).

[0219] Geometric isomers, by the nature of substituents on double bonds or rings, may be cis (Z) or trans (E) forms and both isomers are encompassed within the scope of the present invention.

[0220] The compounds of the present disclosure are also intended to include stable or unstable isotopes. Stable isotopes are non-radioactive isotopes that contain one additional neutron compared to the same abundant nuclide (i.e., element). The activity of compounds containing such isotopes is retained, and such compounds are also believed to have utility for measuring the pharmacokinetics of non-isotopic analogs. For example, hydrogen atoms at certain positions of the compounds of the present disclosure can be replaced with deuterium (a non-radioactive stable isotope). Examples of known stable isotopes include deuterium ( 2 H or D), 13 C. 15 N, 18 Alternatively, unstable isotopes, which are radioactive isotopes that contain a number of additional neutrons compared to the homogeneous abundant nuclide (i.e., element), e.g., 123 I,131 I, 125 I, 14 C. 18 F may be replaced by the corresponding abundant species of I, C, and F. Another example of a useful isotope of the compounds of the invention is: 14 C isotopes. These radioisotopes are useful for radioimaging and / or pharmacokinetic studies of the compounds of the invention. Substitution of atoms with natural isotopic distribution by heavier isotopes may also result in desirable changes in pharmacokinetic rates, provided that these substitutions are made at sites involved in metabolism. For example, deuterium ( 2 Incorporation of H) can slow metabolic degradation if the hydrogen position is a site of enzymatic or metabolic activity.

[0221] The compounds of the present disclosure may be included as depot formulations, for example by dispersing, dissolving or encapsulating the compounds of the present invention in a polymer matrix as described above, and the compounds are released continuously as the polymer degrades over time. 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 the pharmaceutical depot composition, to a subject to which the pharmaceutical depot is administered, for example a warm-blooded animal, such as a human. Thus, the pharmaceutical depot delivers the compounds of the present invention to the subject at concentrations effective to treat a particular disease or condition over an extended period of time, for example 14 to 180 days, preferably about 30, 60 or 90 days.

[0222] Polymers useful for the polymer matrix in the compositions of the invention (e.g., depot compositions of the invention) include polyesters of hydroxy fatty acids and their derivatives, or other agents, such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, ε-caprolactone ring-opening polymers, lactic acid-glycolic acid copolymers, 2-hydroxybutyric acid-glycolic acid copolymers, polylactic acid-polyethylene glycol copolymers, or polyglycolic acid-polyethylene glycol copolymers), alkyl α-cyanoacrylates (e.g., poly(butyl 2-cyanoacrylates) and the like). The polymers may include polymers such as poly(aminobutyric acid)s, poly(alkylene oxalates) (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene propylene carbonate), polyortho-carbonates, polyamino acids (e.g., poly-gamma-L-alanine, poly-gamma-benzyl-L-glutamic acid or poly-y-methyl-L-glutamic acid), hyaluronic acid esters, and the like, one or more of which may be used.

[0223] When the polymer is a copolymer, it can be either random, block and / or graft copolymer. When the above-mentioned α-hydroxycarboxylic acid, hydroxydicarboxylic acid and hydroxytricarboxylic acid have optical activity in the molecule, any one of D-isomer, L-isomer and / or DL-isomer can be used. In particular, α-hydroxycarboxylic acid polymer (preferably lactic acid-glycolic acid polymer), its ester, poly-α-cyanoacrylic acid ester, etc. can be used, and lactic acid-glycolic acid copolymer (also called poly(lactide-α-glycolide) or poly(lactic acid-co-glycolic acid), hereinafter called PLGA) is preferred. Thus, in one embodiment, the polymer useful for the polymer matrix is ​​PLGA. As used herein, the term PLGA includes polymers of lactic acid (also called polylactide, poly(lactic acid) or PLA). Most preferably, the polymer is a biodegradable poly(d,l-lactide-co-glycolide) polymer.

[0224] In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymeric material. The term "biocompatible" is defined as a polymeric material that is non-toxic, non-carcinogenic, and does not induce significant inflammation in body tissues. The matrix material should be biodegradable, where the polymeric material should be broken down by internal processes into products that can be easily excreted by the body and should not accumulate in the body. The products of biodegradation should also be biocompatible with the body in that the polymeric matrix is ​​biocompatible with the body. Specific useful examples of polymer matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the above, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers such as albumin, casein, and waxes such as glycerol mono- and distearate. A preferred polymer for use in the practice of the invention is dl(polylactide-co-glycolide). The molar ratio of lactide to glycolide in such copolymers is preferably in the range of about 75:25 to 50:50.

[0225] The weight average molecular weight of useful PLGA polymers can be about 5,000 to 500,000 Daltons, preferably about 150,000 Daltons. Depending on the degradation rate to be achieved, polymers of various molecular weights can be used. For a diffusion mechanism of drug release, the polymer should remain intact until all the drug is released from the polymer matrix, and then degrade. Drugs can also be released from the polymer matrix if the polymer excipient bioerodes.

[0226] PLGA may be prepared by any conventional method or may be commercially available. For example, PLGA may be prepared from cyclic lactide, glycolide, etc. by ring-opening polymerization with a suitable catalyst (see EP 0058481 B2; Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

[0227] PLGA is believed to be biodegradable by the degradation of the entire solid polymer composition through the decomposition of hydrolyzable and enzymatically cleavable ester bonds under biological conditions (e.g., in the presence of water and biological enzymes that can be found in the tissues of warm-blooded animals such as humans) to form lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism that can be further decomposed to form carbon dioxide and water. In other words, PLGA is believed to be decomposed in the body of a warm-blooded animal, such as a human, in the presence of water by hydrolysis of its ester groups to produce lactic acid and glycolic acid, creating an acidic microenvironment. Lactic acid and glycolic acid are by-products of various metabolic pathways in the body of a warm-blooded animal, such as a human, under normal physiological conditions, and therefore are well tolerated and have minimal systemic toxicity.

[0228] In another embodiment, the polymer matrix useful in the present invention may comprise a star polymer, in which the structure of the polyester is star-shaped. These polyesters have a single polyol residue as the central moiety surrounded by chains of acid residues. The polyol moiety may be, for example, glucose or, for example, mannitol. These esters are known and are described in GB 2,145,422 and U.S. Pat. No. 5,538,739, the contents of each of which are incorporated herein by reference.

[0229] Star polymers can be produced using polyhydroxy compounds, such as polyols, such as glucose or mannitol, as initiators. The polyols contain at least three hydroxy groups and have a molecular weight of up to about 20,000 Daltons, and at least one, preferably at least two, for example an average of three, of the hydroxy groups of the polyol are in the form of ester groups, which contain polylactide or co-polylactide chains. Branched polyesters, such as poly(d,l-lactide-co-glycolide), have a central glucose moiety with multiple linear polylactide chains.

[0230] The above depot compositions of the invention (e.g. compositions 6 and 6.1-6.10 in a polymer matrix) may comprise a polymer in the form of microparticles or nanoparticles or in liquid form in which the compound of the invention is dispersed or encapsulated. By "microparticle" it is meant a solid particle containing the compound of the invention either in solution or in solid form in which the compound of the invention is dispersed or dissolved within a polymer that acts as the matrix of the particle. By appropriate selection of the polymeric material, microparticle formulations can be made in which the resulting microparticles exhibit both diffusional and biodegradable release properties.

[0231] When the polymer is in microparticle form, the microparticle can be produced by suitable methods, for example, by solvent evaporation or solvent extraction. For example, in the solvent evaporation method, the compound of the present invention and the polymer can be dissolved in a volatile organic solvent (e.g., ketone such as acetone, halogenated hydrocarbon such as chloroform or methylene chloride, halogenated aromatic hydrocarbon, cyclic ether such as dioxane, ester such as ethyl acetate, nitrile such as acetonitrile, or 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 obtain microparticles in which the compound of the present invention is encapsulated. In the solvent extraction method, the compound of the present invention and the polymer can be dissolved in a polar solvent (e.g., acetonitrile, dichloromethane, methanol, ethyl acetate or methyl formate) and then dispersed in an aqueous phase (e.g., water / PVA solution). An emulsion is prepared to provide the microparticles in which the compound of the present invention is encapsulated. Spray drying is another manufacturing technique for producing microparticles.

[0232] Alternative methods for producing the microparticles of the present invention are also described in both US Pat. No. 4,389,330 and US Pat. No. 4,530,840.

[0233] The microparticles of the present invention can be manufactured by any method that can produce microparticles in a size range that is acceptable for use in injectable compositions. One preferred manufacturing method is described in U.S. Pat. No. 4,389,330. In this method, the active agent is dissolved or dispersed in a suitable solvent. To the active agent-containing medium, a polymer matrix material is added in an amount relative to the active ingredient that provides a product with the desired active agent loading. If desired, all components of the microparticle product can be blended together in the solvent medium.

[0234] Solvents for the compounds of the present invention and polymer matrix materials that can be used in the practice of the present invention include organic solvents such as acetone; halogenated hydrocarbons such as chloroform, methylene chloride, etc.; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols such as benzyl alcohol; ethyl acetate, etc. In one embodiment, the solvent for use in the practice of the present invention can be a mixture of benzyl alcohol and ethyl acetate. Further information regarding the preparation of microparticles useful in the present invention can be found in U.S. Patent Application Publication No. 2008 / 0069885, the contents of which are incorporated herein by reference in their entirety.

[0235] The amount of the compound of the present disclosure incorporated into the microparticles is typically in the range of about 1% to about 90% by weight, preferably 30-50% by weight, and more preferably 35-40% by weight, where weight % refers to the portion of the compound of the present disclosure per total weight of the microparticle.

[0236] The pharmaceutical depot composition may comprise a pharma- ceutically acceptable diluent or carrier, such as a water-miscible diluent or carrier.

[0237] Details of osmotic controlled release oral delivery system compositions can be found in European Patent Application Publication No. 1539115 (U.S. Patent Application Publication No. 2009 / 0202631) and International Patent Application Publication No. WO 2000 / 35419 (U.S. Patent Application Publication No. 2001 / 0036472), the contents of each of which are incorporated herein by reference in their entirety.

[0238] A "therapeutically effective amount" is an amount of a compound of the invention (e.g., as contained in a pharmaceutical depot) that, when administered to a subject suffering from a disease or disorder, is effective to cause relief, remission or regression of the disease or disorder over the period of time contemplated for treatment.

[0239] Dosages used in the practice of the present invention will, of course, vary depending, for example, on the particular disease or condition being treated, the particular compound of the present invention being used, the mode of administration, and the desired therapy. Unless otherwise specified, amounts of the compounds of the present invention for administration (administered as a free base or salt form) refer to or are based on the amount of the compound of the present invention in free base form (i.e., calculations of the amount are based on the amount of free base).

[0240] The compounds of the invention may be administered by any suitable route, including orally, parenterally (intravenously, intramuscularly or subcutaneously) or transdermally. In certain embodiments, for example in a depot formulation, the compounds of the invention are preferably administered parenterally, for example by injection, for example intramuscularly or intravenously.

[0241] In general, methods 1 and 1.1 to 1.45, methods 2 and 2.1 to 2.12, methods 1-A and 2-A, and methods 3 and 3.1 to 3.41, or a combination of diseases such as, for example, at least a combination of depression, psychosis, such as the above (1) psychosis in a patient suffering from depression, e.g., schizophrenia; (2) depression in a patient suffering from a psychosis, e.g., schizophrenia; (3) psychosis, e.g., schizophrenia, or mood disorder associated with Parkinson's disease; (4) psychosis Satisfactory results for the use of the disclosed compounds for the treatment of (5) sleep disorders associated with disorders such as schizophrenia, or Parkinson's disease; and (6) substance addiction, substance use disorder, and / or substance-induced disorder have been demonstrated to be obtained by oral administration, preferably at a dose of about 1 mg to 100 mg once daily, preferably 2.5 mg to 50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg once daily.

[0242] Satisfactory results for the use of the compounds of the present disclosure as described above for the treatment of Methods 2 or 2.1-2.12, or for treating, for example, sleep disorders alone, have been shown to be obtained by administering orally, preferably once daily, a dose of about 2.5 mg to about 5 mg, e.g., 2.5 mg, 3 mg, 4 mg or 5 mg, of a compound of the present invention in free form or in a pharma- ceutically acceptable salt form.

[0243] Satisfactory results for either Method IA or Method II-A, or 3.1 to 3.41, have been shown to be obtained with less than 100 mg, preferably less than 50 mg, e.g., less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg, less than 2.5 mg, once daily. Satisfactory results for either Method 2-A, or 3.1 to 3.41, have been shown to be obtained with less than 5 mg, preferably less than 2.5 mg, once daily.

[0244] For the treatment of disorders described herein, where depot compositions are used to achieve a longer duration of action, the dosage is higher than short acting compositions, e.g., higher than 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or more than 1000 mg. The duration of action of the compounds of the present disclosure can be controlled by manipulating the polymer composition, i.e., the polymer:drug ratio, and the microparticle size. When the composition of the present invention is a depot composition, administration by injection is preferred.

[0245] The pharmaceutically acceptable salts of the compounds of the present disclosure can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods.Generally, such salts can be prepared by reacting the free base form of these compounds with stoichiometric amount of suitable acid in water or organic solvent or the mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.More details on the preparation of these salts, such as toluenesulfonic acid salts in amorphous or crystalline form, can be found in International Patent Application No. PCT / US08 / 03340 and / or US Provisional Application No. 61 / 036,069 (corresponding to US Patent Application Publication No. 2011 / 112105).

[0246] Pharmaceutical compositions containing the compounds of the present disclosure can be prepared using conventional diluents or excipients (such as, but not limited to, sesame oil) and techniques known in the galenic art.Accordingly, oral dosage forms can include tablets, capsules, liquids, suspensions, etc.

[0247] The term "concurrently" when referring to therapeutic use means administration of two or more active ingredients to a patient as part of a treatment regimen for a disease or disorder, whether the two or more active agents are given at the same or different times, or by the same or different routes of administration. Concurrent administration of two or more active ingredients can be at different times on the same day, or on different days, or with different frequencies.

[0248] The term "simultaneously" when referring to therapeutic use means the administration of two or more active ingredients at the same time, or near the same time, by the same route of administration.

[0249] The term "separately" when referring to therapeutic uses means the administration of two or more active ingredients at the same time, or near the same time, by different routes of administration.

[0250] Method for preparing the compounds of the present invention: Compounds of formula A and methods of synthesis thereof, including the synthesis of intermediates used in the synthetic scheme below, are disclosed, for example, in U.S. Pat. No. 8,309,722 and Published Patent Application No. 2017 / 319580. Synthesis of analogous fused γ-carbolines is disclosed, for example, in U.S. Pat. No. 8,309,722, U.S. Pat. No. 8,993,572, U.S. Pat. Appl. Publication No. 2017 / 0183350, WO 2018 / 126140 and WO 2018 / 126143, the contents of each of which are incorporated herein by reference in their entirety. Compounds of the present disclosure can be prepared using similar methods.

[0251] R 1 C(O)-OC(R a )(R b )(R c ), -C(O)-O-CH2-OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 Compounds of the formula: can be prepared using procedures similar to those described in International Application PCT / US2018 / 043102 (International Application No. 2019 / 023063).

[0252] Other compounds of the present disclosure can be prepared by analogous procedures known to those skilled in the art.

[0253] The diastereomers of the compounds of the present invention can be isolated or purified by conventional methods known in the art, such as column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving bed technology, and the like.

[0254] Salts of the compounds of the present disclosure can be prepared similarly as disclosed in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; 8,648,077; 9,199,995; 9,586,860; U.S. Reissue Patent No. 39680; and U.S. Reissue Patent No. 39679, the contents of each of which are incorporated herein by reference in their entirety.

[0255] The diastereomers of the compounds produced can be separated by HPLC, for example, using a CHIRALPAK® AY-H, 5μ, 30×250 mm column at room temperature and eluting with 10% ethanol / 90% hexane / 0.1% dimethylethylamine. Peaks can be detected at 230 nm to produce diastereomers with 98-99.9% ee. EXAMPLES

[0256] Example 1: Synthesis of (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0257] A mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (100 mg, 0.436 mmol), 1-(3-chloroproxy)-4-fluorobenzene (100 μL, 0.65 mmol) and potassium iodide (KI) (144 mg, 0.87 mmol) in dimethylformamide (DMF) (2 mL) is degassed with argon for 3 minutes and N,N-diisopropylethylamine (DIPEA) (150 μL, 0.87 mmol) is added. The resulting mixture is heated to 78° C. and stirred at this temperature for 2 hours. The mixture is cooled to room temperature and then filtered. The filter cake is purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate in methanol / 7N NH3 in methanol (1:0.1 v / v) mixture as eluent to give the partially purified product, which is further purified on a semi-preparative HPLC system using a gradient of 0-60% acetonitrile in water containing 0.1% formic acid over 16 min to give the title product as a solid (50 mg, 30% yield). MS (ESI) m / z 406.2 [M+1] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.3 (s, 1H), 7.2 - 7.1 (m, 2H), 7.0 - 6.9 (m, 2H), 6.8 (dd, J = 1.03, 7.25 Hz, 1H), 6.6 (t, J = 7.55 Hz, 1H), 6.6 (dd, J = 1.07, 7.79 Hz, 1H), 4.0 (t, J = 6.35 Hz, 2H), 3.8 (d, J = 14.74 Hz, 1H), 3.3 - 3.2 (m, 3H), 2.9 (dd, J = 6.35, 11.13 Hz, 1H), 2.7 - 2.6 (m, 1H), 2.5 - 2.3 (m, 2H), 2.1 (t, J = 11.66 Hz, 1H), 2.0 (d, J = 14.50 Hz, 1H), 1.9 - 1.8 (m, 3H), 1.7 (t, J = 11.04 Hz, 1H).

[0258] Example 2: Synthesis of (6bR,10aS)-8-(3-(6-fluoro-1H-indazol-3-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0259] Step 1: To a stirred solution of BCl3·MeS (10.8 g, 60 mmol) in toluene at 0-5 °C, 3-fluoroaniline (5.6 mL, 58 mmol) is added, followed by 4-chlorobutyronitrile (7.12 g, 68.73 mmol) and aluminum chloride (AlCl3) (8.0 g, 60.01 mmol). The mixture is stirred at 130 °C overnight and cooled to 50 °C. Hydrochloric acid (3N, 30 mL) is carefully added and the resulting solution is stirred at 90 °C overnight. The resulting brown solution is cooled to room temperature and evaporated to dryness. The residue is dissolved in dichloromethane (DCM) (20 mL) and basified with saturated Na2CO3 to pH = 7-8. The organic phase is separated, dried over Na2CO3 and then concentrated. The residue is purified by silica gel column chromatography using a gradient of 0-20% ethyl acetate in hexane as eluent to give 2'-amino-4-chloro-4'-fluorobutyrophenone as a yellow solid (3.5 g, 28% yield). MS (ESI) m / z 216.1 [M+1] + .

[0260] Step 2: To a suspension of 2'-amino-4-chloro-4'-fluorobutyrophenone (680 mg, 3.2 mmol) in concentrated HCl (14 mL) at 0-5 °C is added NaNO2 (248 mg, 3.5 mmol) in water (3 mL). The resulting brown solution is stirred at 0-5 °C for 1 h, then SnCl2·2H2O (1.74 g, 7.7 mmol) in concentrated HCl (3 mL) is added. The mixture is stirred at 0-5 °C for an additional 1 h, then dichloromethane (30 mL) is added. The reaction mixture is filtered, the filtrate is dried over K2CO3 and evaporated to dryness. The residue is purified by silica gel column chromatography using a 0-35% ethyl acetate in hexane gradient as eluent to give 3-(3-chloropropyl)-6-fluoro-1H-indazole (400 mg, 60% yield) as a white solid. MS (ESI) m / z 213.1 [M+1] + .

[0261] Step 3: (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (100 mg, 0.436 mmol), 3-(3-chloropropyl)-6-fluoro-1H-indazole (124 mg, 0.65 mmol) and KI (144 mg, 0.87 mmol) are degassed with argon for 3 minutes and DIPEA (150 μL, 0.87 mmol) is added. The resulting mixture is stirred at 78 ° C for 2 hours and then cooled to room temperature. The resulting precipitate is filtered. The filter cake is purified on a semi-preparative HPLC system using a gradient of 0-60% acetonitrile in water containing 0.1% formic acid over 16 min to give (6bR,10aS)-8-(3-(6-fluoro-1H-indazol-3-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one as an off-white solid (50 mg, 28% yield). MS (ESI) m / z 406.2 [M+1] + . 1H NMR (500 MHz, DMSO-d6) δ 12.7 (s, 1H), 10.3 (s, 1H), 7.8 (dd, J = 5.24, 8.76 Hz, 1H), 7.2 (dd, J = 2.19, 9.75 Hz, 1H), 6.9 (ddd, J = 2.22, 8.69, 9.41 Hz, 1H), 6.8 - 6.7 (m, 1H), 6.6 (t, J = 7.53 Hz, 1H), 6.6 (dd, J = 1.07, 7.83 Hz, 1H), 3.8 (d, J = 14.51 Hz, 1H), 3.3 - 3.2 (m, 1H), 3.2 (s, 2H), 2.9 (dt, J = 6.35, 14.79 Hz, 3H), 2.7 - 2.6 (m, 1H), 2.4 - 2.2 (m, 2H), 2.1 (t, J = 11.42 Hz, 1H), 2.0 - 1.8 (m, 3H), 1.8 - 1.7 (m, 1H), 1.7 (t, J = 10.89 Hz, 1H).

[0262] Example 3: Synthesis of (6bR,10aS)-8-(3-(6-fluorobenzo[d]isoxazol-3-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0263] A mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (148 mg, 0.65 mmol), 3-(3-chloropropyl)-6-fluorobenzo[d]isoxazole (276 mg, 1.3 mmol) and KI (210 mg, 1.3 mmol) is degassed with argon, then DIPEA (220 μL, 1.3 mmol) is added. The resulting mixture is stirred at 78° C. for 2 hours, then cooled to room temperature. The mixture is concentrated in vacuum. The residue is suspended in dichloromethane (50 mL) and then washed with water (20 mL). The organic phase is dried over K2CO3, filtered and then concentrated in vacuum. The crude product is purified by silica gel column chromatography using a gradient of 0-10% methanol in ethyl acetate containing 1% 7N NH3 to give the title product as a solid (80 mg, 30% yield). MS (ESI) m / z 407.2 [M+1] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.3 (s, 1H), 8.0 - 7.9 (m, 1H), 7.7 (dd, J = 2.15, 9.19 Hz, 1H), 7.3 (td, J = 2.20, 9.09 Hz, 1H), 6.8 (d, J = 7.22 Hz, 1H), 6.6 (t, J = 7.54 Hz, 1H), 6.6 (d, J = 7.75 Hz, 1H), 3.8 (d, J = 14.53 Hz, 1H), 3.3 (s, 1H), 3.2 (s, 1H), 3.2 - 3.1 (m, 1H), 3.0 (t, J = 7.45 Hz, 2H), 2.9 - 2.8 (m, 1H), 2.7 - 2.5 (m, 1H), 2.4 - 2.2 (m, 2H), 2.2 - 2.0 (m, 1H), 2.0 - 1.8 (m, 3H), 1.8 - 1.6 (m, 2H).

[0264] Example 4: Synthesis of 4-(3-((6bR,10aS)-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)propoxy)benzonitrile [ka]

[0265] Step 1: A degassed suspension of ethyl (4aS,9bR)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (21.5 g, 66.2 mmol), chloroacetamide (9.3 g, 100 mmol) and KI (17.7 g, 107 mmol) in dioxane (60 mL) is stirred at 104° C. for 48 hours. The solvent is removed and the residue is suspended in dichloromethane (200 mL) and extracted with water (100 mL). The separated dichloromethane phase is dried over potassium carbonate (K2CO3) for 1 hour and then filtered. The filtrate is evaporated to give the crude product as a brown oil. Ethyl acetate (100 mL) is added to the brown oil and the mixture is sonicated for 2 minutes. A yellow solid gradually precipitates from the mixture and returns to a gel after standing at room temperature for another 2 hours. Additional ethyl acetate (10 mL) is added and the resulting solid is filtered. The filter cake is rinsed with ethyl acetate (2 mL) and further dried under high vacuum to give ethyl (4aS,9bR)-5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate as an off-white solid (19 g, 75% yield). This product is used directly in the next step without further purification. MS (ESI) m / z 382.0 [M+H] + .

[0266] Step 2: A mixture of (4aS,9bR)-5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-ethyl carboxylate (12.9 g, 33.7 mmol), KI (10.6 g, 63.8 mmol), CuI (1.34 g, 6.74 mmol) in dioxane (50 mL) is purged with argon for 5 min. To this mixture is added N,N,N,N'-tetramethylethylenediamine (3 mL) and the resulting suspension is stirred at 100 °C for 48 h. The reaction mixture is cooled to room temperature and poured onto a silica gel pad and filtered. The filter cake is rinsed with ethyl acetate (1 L x 2). The combined filtrate is concentrated to dryness to give the product (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester as a white solid (8 g, 79% yield). MS (ESI) m / z 302.1 [M+H]+.

[0267] Step 3: (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester (6.4 g, 21.2 mmol) is suspended in HBr / acetic acid solution (64 mL, 33% w / w) at room temperature. The mixture is heated at 50° C. for 16 hours. After cooling and treatment with ethyl acetate (300 mL), the mixture is filtered. The filter cake is washed with ethyl acetate (300 mL) and then dried under vacuum. The resulting HBr salt is then suspended in methanol (200 mL) and cooled with dry ice in isopropanol. Under vigorous stirring, ammonia solution (10 mL, 7N in methanol) is slowly added to the suspension to adjust the pH of the mixture to 10. The resulting mixture was dried in vacuum without further purification to give crude (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (8.0 g) which was used directly in the next step. MS (ESI) m / z 230.2 [M+H] + .

[0268] Step 4: A mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (100 mg, 0.436 mmol), 4-(3-bromopropoxy)benzonitrile (99 mg, 0.40 mmol) and KI (97 mg, 0.44 mmol) in DMF (2 mL) is purged with argon for 3 min and diisopropylethylamine (DIPEA) (80 μL, 0.44 mmol) is added. The resulting mixture is heated to 76 ° C and stirred at this temperature for 2 h. The solvent is removed and the residue is purified by silica gel column chromatography using a gradient of 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate to give the title product as a white foam (35 mg, 45% yield). MS (ESI) m / z 389.1 [M+1] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.3 (s, 1H), 7.8 (d, J = 8.80 Hz, 2H), 7.1 (d, J = 8.79 Hz, 2H), 6.8 (d, J = 7.39 Hz, 1H), 6.6 (t, J = 7.55 Hz, 1H), 6.6 (d, J = 6.78 Hz, 1H), 4.1 (t, J = 6.36 Hz, 2H), 3.8 (d, J = 14.53 Hz, 1H), 3.3 - 3.2 (m, 3H), 3.0 - 2.8 (m, 1H), 2.7 - 2.6 (m, 1H), 2.5 - 2.3 (m, 2H), 2.2 - 2.0 (m, 1H), 2.0 - 1.8 (m, 3H), 1.8 - 1.7 (m, 1H), 1.7 (t, J = 11.00 Hz, 1H).

[0269] Example 5: Synthesis of (6bR,10aS)-8-(3-(4-chlorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0270] To a degassed mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxalin-2(3H)-one (110 mg, 0.48 mmol), 1-(3-bromopropoxy)-4-chlorobenzene (122 mg, 0.49 mmol) and KI (120 mg, 0.72 mmol) in DMF (2.5 mL) is added DIPEA (100 μL, 0.57 mmol). The resulting mixture is heated to 76 °C and stirred at this temperature for 2 h. The solvent is removed and the residue is purified by silica gel column chromatography using a gradient of 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate. Obtain the title product as a white solid (41 mg, 43% yield). (ESI) m / z 398.1 [M+1] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.3 (s, 1H), 7.4 - 7.2 (m, 2H), 6.9 (d, J = 8.90 Hz, 2H), 6.8 - 6.7 (m, 1H), 6.6 (t, J = 7.53 Hz, 1H), 6.6 (dd, J = 1.04, 7.80 Hz, 1H), 4.0 (t, J = 6.37 Hz, 2H), 3.8 (d, J = 14.53 Hz, 1H), 3.3 - 3.2 (m, 3H), 2.9 - 2.8 (m, 1H), 2.7 - 2.6 (m, 1H), 2.4 (ddt, J = 6.30, 12.61, 19.24 Hz, 2H), 2.1 - 2.0 (m, 1H), 2.0 - 1.9 (m, 1H), 1.9 - 1.7 (m, 3H), 1.7 (t, J = 10.98 Hz, 1H).

[0271] Example 6: Synthesis of (6bR,10aS)-8-(3-(quinolin-8-yloxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0272] A mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (120 mg, 0.52 mmol), 8-(3-chloropropoxy)quinoline (110 mg, 0.50 mmol) and KI (120 mg, 0.72 mmol) in DMF (2.5 mL) is purged with argon for 3 min and DIPEA (100 μL, 0.57 mmol) is added. The resulting mixture is heated to 76 °C and stirred at this temperature for 2 h. The solvent is removed and the residue is suspended in dichloromethane (30 mL) and washed with water (10 mL). The dichloromethane phase is dried over K2CO3. The separated organic phase is evaporated to dryness. The residue is purified by silica gel column chromatography using a gradient of 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate to give the title product as a light brown solid (56 mg, 55% yield). (ESI) m / z 415.2 [M+1] + . 1H NMR (500 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.9 (dd, J = 1.68, 4.25 Hz, 1H), 8.3 (dd, J = 1.71, 8.33 Hz, 1H), 7.7 - 7.5 (m, 3H), 7.3 (dd, J = 1.50, 7.44 Hz, 1H), 7.0 - 6.8 (m, 1H), 6.8 - 6.5 (m, 2H), 4.4 (t, J = 5.85 Hz, 2H), 3.9 (d, J = 14.55 Hz, 1H), 3.8 - 3.6 (m, 2H), 3.5 (s, 1H), 3.4 (d, J = 14.47 Hz, 1H), 2.9 (b, 1H), 2.3 (d, J = 23.61 Hz, 5H), 1.3 (d, J = 7.00 Hz, 3H).

[0273] Example 7: Receptor Binding Profile Receptor binding was determined for the compound of Example 1 (compound of formula A) and the compounds of Examples 2-6 using the procedures of the following publications, each of which is incorporated herein by reference in its entirety: 5-HT 2A :Bryant, HU et al. (1996), Life Sci., 15:1259-1268;D2:Hall, DA and Strange, PG (1997), Brit. J. Pharmacol., 121:731-736;D1:Zhou, QY et al. (1990), Nature, 347:76-80;SERT:ParkPark, YM et al. (1999), Anal. Biochem., 269:94-104; μ opiate receptor: Wang, JB et al. (1994), FEBS Lett., 338:217-222.

[0274] Generally, results are expressed as a percentage of control specific binding obtained in the presence of test compound:

number

number

[0275] I C 50 Values ​​(concentration producing half-maximal inhibition of control specific binding) and Hill coefficients (nH) were calculated using Hill equation curve fitting:

number

number

[0276] The following receptor affinity results are obtained: [Table 1] Additional compounds of formula I are prepared by procedures similar to those described in Examples 1-6. The receptor affinity results for these compounds are shown in the table below: [Table 2]

[0277] Example 8: DOI-induced head spasm model in mice R-(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) is an agonist of the serotonin 5-HT2 receptor family. When administered to mice, it produces a behavioral profile associated with high frequency of head twitches. The frequency of these head twitches during a given period can be taken as an estimate of 5-HT2 receptor agonism in the brain. Conversely, this behavioral assay can be used to determine 5-HT2 receptor antagonism in the brain by administering DOI with or without an antagonist and recording the reduction in DOI-induced head twitches following administration of the antagonist.

[0278] The method of Darmani et al., Pharmacol Biochem Behav. (1990) 36:901-906, the contents of which are incorporated herein by reference in their entirety, is used with minor modifications. (±)-DOI HCl is injected subcutaneously and the mice are immediately housed in conventional plastic cages. The number of head twitches is counted for 6 min starting 1 min after DOI administration. Test compounds are administered orally 0.5 h prior to DOI injection. The results are expressed as EC 50 The results are shown in the table below: [Table 3] The results show that the compound of Example 1 potently blocks DOI head twitches and inhibits the in vitro 5-HT 2A It shows that the results are consistent.

[0279] Example 9: Mouse tail flick assay The mouse tail flick assay is a measurement of analgesia as indicated by the pain reflex threshold of restrained mice. Male CD-1 mice are placed with their tails under the focused beam of a high intensity infrared heat source, which heats the tail. The animal can withdraw its tail from the heat source at any time if it becomes uncomfortable. The amount of time between turning on the heating device and flicking the mouse's tail out of the path of the heat source (latency) is recorded. Administration of morphine produces analgesia, which causes a delay in the mouse's response to heat (increased latency). Preadministration of a morphine (MOR) antagonist, i.e., naloxone (NAL), reverses this effect, resulting in normal latencies. This test is used as a functional assay to measure antagonism of the μ-opiate receptor.

[0280] Example 9a: Antagonism of morphine-induced analgesia by the compound of Example 1 Ten male CD-1 mice (approximately 8 weeks old) are assigned to each of five treatment groups. Groups are treated as follows: Group (1) [negative control]: 0.25% methylcellulose vehicle is orally administered 60 min prior to the tail flick test and saline vehicle is orally administered 30 min prior to the tail flick test; Group (2) [positive control]: 0.25% methylcellulose vehicle is orally administered 60 min prior to the test and 5 mg / kg morphine in saline is orally administered 30 min prior to the test; Group (3) [positive control]: 3 mg / kg naloxone in saline is orally administered 50 min prior to the test and 5 mg / kg morphine in saline is orally administered 30 min prior to the test; Groups (4)-(6): 0.1 mg / kg, 0.3 mg / kg or 1 mg / kg of the test compound in 0.25% methylcellulose vehicle is orally administered 60 min prior to the test and 5 mg / kg morphine is orally administered 30 min prior to the test. The results are presented in the table below as mean latencies measured in seconds: [Table 4]

[0281] The results demonstrate that the compound of Example 1 exerts a dose-dependent blockade of morphine-induced μ opiate receptor activity.

[0282] Example 9b: Analgesic effect of the compound of Example 1 inhibited by naloxone In a second study using the mouse tail flick assay described above, the compound of Example 1 is further compared at doses of 1.0 mg / kg, 3.0 mg / kg and 10 mg / kg to morphine at 5 mg / kg, with and without pretreatment with naloxone at 3 mg / kg (ip). In the pretreated groups, naloxone is administered 20 minutes prior to the tail flick test. In the non-pretreated controls, saline is administered 20 minutes prior to the tail flick test. In each group, vehicle, morphine or the compound of Example 1 is administered 30 minutes prior to the tail flick test. The results are presented in the table below as mean latency (seconds): [Table 5]

[0283] It can be seen that administration of the compound of Example 1 at all doses significantly increases the latency to tail flick, and this effect is attenuated by pretreatment with naloxone.The results show that the compound of Example 1 produces a dose-dependent analgesic effect, and further suggest that this effect is mediated by μ-opioid receptor agonism.

[0284] Example 9c: Time course of analgesic activity, compound of Example 1 The tail flick assay described above is repeated to determine the time course of analgesia resulting from administration of the compound of Example 1. Mice are administered (1) vehicle 30 min prior to the assay, (2) 5 mg / kg morphine 30 min prior to the assay, or (3)-(7) 1 mg / kg of the compound of Example 3 subcutaneously 30 min, 2 hr, 4 hr, 8 hr, or 24 hr prior to the assay. The results are presented in the table below as mean latency (seconds): [Table 6]

[0285] The results show that compound of Example 1 produces effective analgesia when administered 30 minutes or 2 hours before tail flick assay (ANOVA, P<0.001 vs. vehicle). When administered 4 hours, 8 hours or 24 hours before tail flick assay, 1 mg / kg compound of Example 1 does not produce analgesic effects that are significantly different from vehicle control. Thus, compound of Example 1 does not produce long-term analgesia, which means that compound of Example 1 has low abuse potential and low risk of drug-drug interactions compared to other opiate analgesics.

[0286] Example 9d: Analgesic effect of chronic administration of the compound of Example 1 The above tail flick assay is repeated using a test model in which animals receive a chronic treatment regimen for 14 days and then an acute treatment 30 minutes prior to the tail flick assay. Mice are divided into three major groups with six subgroups with 10 mice each. The three groups receive either (A) vehicle, (B) 0.3 mg / kg of the compound of Example 1, or (C) 3.0 mg / kg of the compound of Example 2 as chronic treatments. Additionally, each subgroup receives either (1) vehicle, or (2)-(6) 0.01, 0.03, 0.1, 0.3 or 1.0 mg / kg of the compound of Example 1 as acute treatments. All treatments are administered subcutaneously. The results are shown in the table below as mean latency (seconds) to tail flick: [Table 7]

[0287] It can be seen that acute treatment with the compound of Example 1 at 0.1, 0.3 and 1.0 mg / kg produces a statistically significant dose-dependent analgesic effect compared to intragroup acute treatment with vehicle. This is true for each of the chronic groups (A), (B) and (C). Compared to pretreatment with vehicle, pretreatment with the compound of Example 1 at 0.3 mg / kg or 3.0 mg / kg generally shows a statistically significant decrease in tail flick latency when comparing the same acute treatment subgroups. These results indicate that after 14 days of chronic treatment, some tolerance occurs to the analgesic effect of the compound of Example 1, but the analgesic effect obtained remains effective despite chronic pretreatment.

[0288] Example 10: CNS Phosphoprotein Profile A comprehensive molecular phosphorylation study is also carried out to test the central nervous system (CNS) profile of the compound of Example 1. The degree of protein phosphorylation of selected important central nervous system proteins is measured in the nucleus accumbens of mice. The proteins tested include ERK1, ERK2, Glu1, NR2B and TH (tyrosine hydroxylase), and the compound of Example 1 is compared with the antipsychotic drugs risperidone and haloperidol.

[0289] Mice were treated with 3 mg / kg of the compound of Example 1 or 2 mg / kg of haloperidol. Mice were sacrificed 30 minutes to 2 hours after injection by focused whole brain microwave irradiation, and brain phosphoproteins were stored as they were present at the time of death. The nucleus accumbens was then dissected from each mouse brain, sliced, and frozen in liquid nitrogen. Samples were further prepared for phosphoprotein analysis by SDS-PAGE electrophoresis followed by phosphoprotein-specific immunoblotting as described in Zhu H, et al., Brain Res. 2010 Jun 25; 1342:11-23. Phosphorylation at each site was quantified, normalized to the total level of the protein (non-phosphorylated), and expressed as a percentage of the level of phosphate in vehicle-treated control mice.

[0290] The results show that, in contrast to haloperidol, which produces a greater than 400% increase in TH phosphorylation, and risperidone, which produces a greater than 500% increase, the compound of Example 1 has no significant effect on tyrosine hydroxylase phosphorylation at Ser40 at 30 and 60 minutes, indicating that the compounds of the present invention do not interfere with dopamine metabolism.

[0291] The results further show that the compound of Example 1 has no significant effect on NR2B phosphorylation at Tyr1472 at 30-60 minutes. The compound produces a slight increase in GluR1 phosphorylation at Ser845 and a slight decrease in ERK2 phosphorylation at Thr183 and Tyr185. Protein phosphorylation at various sites of specific proteins is known to be associated with various activities of cells, such as protein trafficking, ion channel activity, strength of synaptic signaling and changes in gene expression. Phosphorylation of Tyr1472 in NMDA glutamate receptors has been shown to be essential for the maintenance of neuropathic pain. Phosphorylation of Ser845 in GluR1 AMPA-type glutamate receptors is associated with several aspects of enhanced synaptic transmission and enhanced synaptic localization of the receptor, supporting long-term potentiation associated with cognitive performance. It has also been reported that phosphorylation of this residue increases the probability of channel opening. Phosphorylation of ERK2 kinase, a member of the MAP kinase cascade, at residues T183 and Y185 is required for full activation of this kinase, which is involved in many aspects of cell physiology, including regulation of cell proliferation, survival, and transcription. This kinase has been reported to be important in synapse formation and cognitive function.

[0292] Example 11: Marble-burying study in mice (OCD model) The marble-burying test is used to measure repetitive and anxiety-related behaviors in rodents. It is based on the observation that rats and mice will bury harmful or innocuous objects in their bedding and has been used as an animal model to measure the effects of pharmacological interventions in the treatment of repetitive behavior disorders such as OCD.

[0293] First, mice are divided into four treatment groups: (1) vehicle negative control, (2) 0.3 mg / kg of the compound of Example 1, (3) 1.5 mg / kg of the compound of Example 1, and (4) 20 mg / kg of MPEP (2-methyl-6-(phenylethynyl)pyridine) positive control. MPEP is a selective mGluR5 glutamate receptor antagonist. Mice in groups (2) and (3) are orally administered the compound of Example 1 at the indicated doses in 0.5% methylcellulose aqueous vehicle 30 minutes prior to testing. Mice in group (1) are orally administered vehicle, and mice in group (4) are given an intraperitoneal injection of MPEP immediately prior to the start of testing.

[0294] Testing is performed in rectangular cages with 4-5 cm of wood chip bedding in a room with the window shades lowered and the door closed to minimize distractions. Fifteen clean marbles are evenly distributed on the bedding in three rows of five marbles each. House one mouse in each cage. Leave the mice in their cages for 30 minutes. At the end of the test, remove the mice and count the number of marbles buried at least 2 / 3 deep. The results are shown in the table below: [Table 8]

[0295] The results show a statistically significant decrease in marble burying in mice treated with 0.3 mg / kg (p<0.01) and 1.5 mg / kg (p<0.001) of compound Example 1 compared to controls. Furthermore, a clear dose-response relationship is evident. This result supports the utility of Example 1 in OCD treatment applications.

[0296] Example 12: μ Opiate Receptor Activity Assay The compound of Example 1 is tested in CHO-K1 cells expressing hOP3 (human μ-opiate receptor μ1 subtype) using a HTRF-based cAMP assay kit (cAMP Dynamic2 Assay Kit from Cisbio, #62AM4PEB). Frozen cells are thawed in a 37°C water bath and resuspended in 10mL of Ham's F-12 medium containing 10% FBS. Cells are harvested by centrifugation and resuspended in assay buffer (5nM KCl, 1.25mM MgSO4, 124mM NaCl, 25mM HEPES, 13.3mM glucose, 1.25mM KH2PO4, 1.45mM CaCl2, 0.5g / L protease-free BSA, 1mM IBMX). Buprenorphine, a μ-opiate receptor partial agonist, and naloxone, a μ-opiate receptor antagonist, and DAMGO, a synthetic opioid peptide full agonist, are used as controls.

[0297] For agonist assays, 12 μL of cell suspension (2500 cells / well) is mixed with 6 μL of forskolin (final assay concentration 10 μM) in wells of a 384-well white plate, combined with 6 μL of increasing concentrations of test compound, and the plate is incubated at room temperature for 30 min. Lysis buffer is added and incubated for an additional hour before measuring cAMP concentrations according to the kit instructions. All assay points are measured in triplicate. Curve fitting is performed using XLfit software (IDBS) and EC values ​​are calculated using a 4-parameter logistic fit. 50 The agonist assay measures the ability of a test compound to inhibit forskolin-stimulated cAMP accumulation.

[0298] For antagonist assays, 12 μL of cell suspension (2500 cells / well) is mixed with 6 μL of increasing concentrations of test compound, combined in wells of a 384-well white plate, and the plate is incubated at room temperature for 10 minutes. 2 -N-MePhe4 Six microliters of a mixture of 10-Gly-ol-enkepherin (final assay concentration 10 nM) and forskolin (final assay concentration 10 μM) is added and the plate is incubated for 30 minutes at room temperature. Lysis buffer is added and after a further hour of incubation, cAMP concentrations are measured according to the kit instructions. All assay points are measured in triplicate. Curve fitting is performed using XLfit software (IDBS) and ICs are calculated using a four-parameter logistic fit. 50 The apparent dissociation constant (K B The antagonist assay measures the ability of a test compound to reverse the inhibition of forskolin-induced cAMP accumulation caused by DAMGO.

[0299] The results are shown in the table below. The results show that the compound of Example 1 has a significantly higher IC 50 It has been shown to be a weak antagonist of the μ receptor, exhibiting moderately high affinity, but only about 22% agonist activity compared to DAMGO (compared to buprenorphine's activity of about 79% compared to DAMGO), and a partial agonist. The compound of Example 1 has also been shown to have moderately strong partial agonist activity. [Table 9]

[0300] Buprenorphine is a drug used for chronic pain treatment and opiate withdrawal, but has the problem that users can become addicted due to its high partial agonist activity. To counter this, a commercial combination of buprenorphine and naloxone is used (sold as Suboxone). Without being bound by theory, it is believed that the compounds of the present invention, which are weaker partial μ agonists than buprenorphine and have some moderate antagonist activity, can more effectively treat patients with pain and / or opiate withdrawal, with a lower risk of addiction.

[0301] Additional related studies using recombinant human MOP-β-arrestin signaling pathways demonstrated that the compound of Example 1 does not stimulate β-arrestin signaling through the MOP receptor at concentrations up to 10 μM, but does not stimulate β-arrestin signaling through the MOP receptor at IC 50 It has been found to be an antagonist with an EC of 0.189 μM. In contrast, the full opioid agonist Met-enkephalin has an EC of 0.08 μM. 50 stimulates β-arrestin signaling.

[0302] Example 13: Rat Tolerance / Dependence Studies The compound of Example 1 is evaluated during repeated (28 days) daily subcutaneous administration to male Sprague-Dawley rats to monitor drug effects on dosing and to determine whether pharmacological tolerance occurs. Additionally, behavioral, physical and physiological signs of the rats are monitored after abrupt cessation of repeated administration to determine whether the compound induces physical dependence to withdrawal. Pharmacological studies are also performed in parallel with the tolerance and dependence studies to determine plasma drug exposure levels of the compound at the specific doses used in the tolerance and dependence studies. Morphine is used as a positive control to ensure the validity of the model and as a reference control drug from a similar pharmacological class.

[0303] The compound of Example 1 is evaluated at two doses, 0.3 and 3 mg / kg, administered subcutaneously four times daily. Repeated dosing is found to produce peak plasma concentrations of 15-38 ng / mL (mean, n=3) at 0.3 mg / kg and 70-90 ng / mL (mean, n=3) at 3 mg / kg. Peak concentrations are reached 30 minutes to 1.5 hours after dosing, with comparable results obtained on days 1, 14, and 28 of dosing.

[0304] It is found that at both doses of Example 1, there is no significant effect on the body weight, food and water intake, or body temperature of the animals during either the administration or withdrawal phase. It is found that the main behavioral and physical effects caused by repeated administration at 0.3 mg / kg are hunched posture, Straub tail, and piloerection during the administration phase. At higher doses, the main behavioral and physical signs observed are hunched posture, subdued behavior, Straub tail, tail rattle, and piloerection.

[0305] A similar profile of behavioral and physical signs is observed after abrupt cessation of the compound on day 28 of the study. No rearing and increased body tone are observed during the dosing period at 0.3 mg / kg, but are found to increase significantly during the withdrawal phase. At the higher doses, mild rearing is observed during the dosing period, but more pronounced rearing and increased body tone are observed during the withdrawal phase.

[0306] As a positive control, morphine is administered orally at 30 mg / kg twice daily. This dosing regimen is observed to be associated with changes in body weight, food and water intake, rectal temperature, and clinical signs consistent with the development of tolerance and withdrawal-induced dependence, as expected. Body weight was significantly increased compared to the vehicle-treated control group on days 2 and 3, but was significantly decreased on day 5. Morphine significantly reduced food intake on days 1-9. Thereafter, food intake is generally observed to be less than the control group, but was not significantly different from controls on days 9, 13, 14, 16, 18, 21, 22, and 25. These effects on body weight and food intake indicate tolerance to the effects of morphine.

[0307] Water intake in the morphine-treated group is also found to be significantly lower than the control group on 25 of the 28 days during the treatment period. Body temperature is also generally significantly lower than the control group during the treatment period, most notably on days 20, 21 and 27. The main behavioral effects induced by morphine during the treatment period are observed to be Straub's tail, jumping, digging, increased body tone, increased locomotor activity, explosive movement and exopthalmus.

[0308] Furthermore, withdrawal of morphine on day 28 results in an initial further decrease in food intake, followed by rebound hyperphagia, with food intake observed to be significantly increased on day 33 compared to the control group. Food intake returns to control levels by day 35. Similarly, rats previously administered morphine also show an initial decrease in water intake on day 29, followed by rebound hyperdipsia (water consumption returns to control levels by day 31). Furthermore, a statistically significant decrease in rectal body temperature is observed during administration, but body temperature returns to control levels during the withdrawal phase.

[0309] Furthermore, new behavioral and physical signs were observed during the withdrawal phase from morphine, indicating the presence of dependence. These signs included piloerection, ataxia / rolling gait, wet dog shakes, and pinched abdomen. Other abnormal behaviors observed during the administration phase gradually disappeared during the withdrawal phase. By day 35, rearing was the only behavioral or physical sign observed with high incidence in rats previously administered morphine.

[0310] Thus, repeated administration of morphine is shown to produce clear signs of tolerance and dependence in this study, with changes in body weight, food and water intake, rectal temperature, and clinical signs consistent with the development of tolerance and withdrawal-induced dependence, demonstrating the relevance of the study method in detecting physiological changes during and after administration.

[0311] In contrast, four repeated doses of the compound of Example 1, both at 0.3 and 3 mg / kg, do not induce tolerance during 28 days of subcutaneous administration. Furthermore, at higher doses, a similar but reduced profile of behavioral and physical signs is observed upon withdrawal, which is not considered to be of clinical significance. Overall, therefore, the compound of Example 1 has been found not to induce a physical dependence syndrome upon cessation of administration.

[0312] Example 14: Oxycodone Dependence Withdrawal Study in Mice Oxycodone is administered to male C57BL / 6J mice in an escalating dose regimen of 9, 17.8, 23.7, and 33 mg / kg bid (7 hours between injections) on days 1-2, 3-4, 5-6, and 7-8, respectively, for 8 days. On the morning of day 9, mice are administered either 0.3, 1, or 3 mg / kg of the compound of Example 1 subcutaneously. Thirty minutes later, an injection of vehicle or an injection of 3 mg / kg of naloxone is administered. Another cohort of mice serves as negative controls, and these mice are administered saline on days 1-8 instead of oxycodone. On day 9, these mice are administered either vehicle (as above, followed by naloxone) or 3 mg / kg (sc) of the compound of Example 1 (as above, followed by naloxone).

[0313] On the 9th day, immediately after injection of naloxone (or vehicle), mice are individually housed in transparent plastic cages and observed continuously for 30 min. Mice are monitored for typical physical signs of opiate withdrawal, including jumping, violent shaking, paw tremors, backing, ptosis and diarrhea. All such behaviors are recorded as new occurrences if they are separated by at least 1 s or are interrupted by normal behavior. Animal weights are also recorded immediately before and 30 min after naloxone (or vehicle) injection. Data are analyzed by ANOVA, where appropriate, followed by Tukey's test for multiple comparisons. Significance levels are established at p<0.05.

[0314] The results are shown in the table below: [Table 10]

[0315] The total number of symptoms includes leg tremors, jumping, and violent tremors. It can be seen that naloxone induces significant total number of symptoms, leg tremors, jumping, and body weight change (p≦0.0001 for each) in oxycodone-treated mice. The compound of Example 1 causes a significant reduction in total number of symptoms and leg tremors at all doses tested. In addition, the compound also causes a significant reduction in jumping and attenuated body weight loss at 3.0 mg / kg.

[0316] These results demonstrate that the compound of Example 1 dose-dependently reduces the signs and symptoms of opiate withdrawal following abrupt cessation of opiate administration in opiate-dependent rats.

[0317] Example 15: Formalin Paw Test (Inflammatory Pain Model) Subplantar administration of a chemical stimuli such as formalin causes immediate pain and discomfort in mice, followed by inflammation. Subcutaneous injection of a 2.5% formalin solution (37 wt% aqueous formaldehyde solution, diluted with saline) into the hind paw produces a biphasic response: an acute pain response and a delayed inflammatory response. Thus, this animal model provides information on both acute and subacute / tonic pain in the same animal.

[0318] C57 mice are habituated in the observation chamber. Thirty minutes before formalin administration, mice are administered vehicle by subcutaneous injection, 5 mg / kg morphine (in saline) by subcutaneous injection, or 0.3, 1.0 or 3.0 mg / kg of the compound of Example 1 (in 45% w / v aqueous cyclodextrin solution) by subcutaneous injection. In addition, another set of mice is treated with control vehicle or 3.0 mg / kg of the compound of Example 1 by oral administration instead of subcutaneous injection.

[0319] Mice are then injected subcutaneously with 20 μL of 2.5% formalin solution into the plantar surface of the left hind paw. Over the next 40 min, the total time spent licking or biting the treated hind paw is recorded. The first 10 min represents the acute nociceptive response, while the latter 30 min represents the delayed inflammatory response. At 1 min intervals, the behavior of each animal is assessed using a "Mean Behavioral Rating" scored on a scale of 0 to 4: 0: No reaction, animal asleep 1: The animal walks nimbly on the treated leg, e.g. on its toes 2: The animal is holding up the treated paw 3: The animal is shaking the treated paw 4: Animal licking or biting the treated paw Data are analyzed by ANOVA, where appropriate, followed by post-hoc comparisons using Fisher's test. Significance is established at p<0.05.

[0320] The results are shown in the table below. [Table 11]

[0321] The results show significant treatment effects during both the early (0-10 min) and late (11-40 min) phases of the response. Post-hoc comparisons show that subcutaneous injection of morphine or compound of Example 1 (3 mg / kg) significantly attenuates the pain behavior ratings evoked by formalin injection and significantly reduces licking time compared to vehicle treatment. Post-hoc comparisons also show that subcutaneous injection of morphine or compound of Example 1 (3 mg / kg) and oral administration of compound of Example 1 (3 mg / kg) significantly reduces the time spent licking. The mean pain behavior ratings were also reduced with the subcutaneous use of 1.0 mg / kg compound and with the oral use of 3.0 mg / kg compound, although these effects were not statistically significant in this study. The subcutaneous use of compound of Example 1 at 1.0 mg / kg reduced licking time as well, but the results were not statistically significant in this study. It was found that no mice in the study groups underwent significant changes in body weight.

[0322] Example 16: Self-administration in heroin-maintained rats Studies were conducted to determine whether heroin-addicted rats would self-administer the compound of Example 1 and found that they did not, further highlighting the non-addictive nature of the compounds of the present disclosure.

[0323] The study is conducted in three phases. In the first phase, rats are first trained to press a lever for food, then an intravenous jugular catheter is placed and they are trained to self-administer heroin. In response to a cue (illumination of a light in the cage), the animal presses the lever three times, resulting in one injection of heroin through the catheter. Heroin is provided at an initial dose of 0.05 mg / kg / injection, which is then increased to 0.015 mg / kg / injection. This trained response is then extinguished by replacing the heroin supply with saline. In the second phase, the saline solution is replaced by a solution of the compound of Example 1 at one of four doses: 0.0003 mg / kg / injection, 0.001 mg / kg / injection, 0.003 mg / kg / injection and 0.010 mg / kg / injection. Individual mice are administered one or two doses of the compound in an ascending fashion. This response is then abolished with an injection of saline, followed by a third phase in which heroin use is repeated at 0.015 mg / kg / injection. The purpose of the third phase is to demonstrate that at the end of the study the rats still exhibit addictive behavior to heroin. The results of the study are shown in the table below: [Table 12]

[0324] The results show that rats showed a statistically significant increase in lever pressing when administered heroin, but no significant difference when administered saline or the compound of Example 1. Thus, the results suggest that rats do not become addicted to the compound of Example 1.

[0325] Example 17: Animal Pharmacokinetic Data The pharmacokinetic profile of the compound of Example 1 is studied in several animals using standard procedures.

[0326] Example 17a: Rat PK studies In the first study, rats are dosed with the compound of Example 1 either intravenously (IV) at 1 mg / kg in a 45% Trapposol vehicle or orally (PO) at 10 mg / kg in a 0.5% CMC vehicle (N=3 per group). In the second study, rats are dosed with the compound of Example 1 either PO at 10 mg / kg or subcutaneously (SC) at 3 mg / kg in a 45% Trapposol vehicle (N=6 per group). Plasma concentrations of the drug are measured at 0-48 hours after dosing. Representative results are shown in the table below (* indicates plasma concentrations below measurable quantification levels): [Table 13]

[0327] Example 17b: Mouse PK studies A similar study is performed in mice using a 10 mg / kg PO dose of the compound of Example 1, with the following results: Tmax=0.25 hours; Cmax=279 ng / mL; AUC(0-4h)=759 ng·hr / mL; blood-plasma ratios (0.25-4h) ranging from 3.7 to 6.6. The study is also performed at a dose of 0.1 mg / kg SC. Representative results are shown in the table below: [Table 14]

[0328] Taken together, these results indicate that the compound of Example 1 is well absorbed, distributed to the brain and tissues, and retained with a reasonably long half-life to allow for once-daily administration of therapeutic doses.

[0329] Example 18: Gastrointestinal Function The effect of the compound of Example 1 on gastrointestinal motility in rats is examined by monitoring the rate of intestinal passage of a bolus of activated charcoal. Rats are treated with either (1) aqueous carboxymethylcellulose vehicle, (2) morphine (5 mg / kg, SC), or (3) the compound of Example 1 (0.3, 1.0, or 3.0 mg / kg, SC) 30 minutes prior to an oral bolus of 15% aqueous activated charcoal. The result is the motility rate, calculated as the distance traveled by the charcoal as a percentage of the total length of the animal's intestine. The results are shown in the table below: [Table 15]

[0330] These results show that the compound of Example 1 has no significant effect on gastrointestinal motility at doses up to 3 mg / kg. In contrast, as expected, morphine reduces gastric motility by approximately 50%.

[0331] In further experiments, rats were pretreated SC with either vehicle, morphine (5 mg / kg) or compound of Example 1 (3 mg / kg) 60 minutes prior to charcoal bolus administration, and then treated with either morphine (5 mg / kg), morphine plus compound of Example 1 (0.3 mg / kg or 3 mg / kg), or compound of Example 1 (3 mg / kg) alone. The results are shown in the table below. Groups 2 and 3 were injected with morphine first, followed immediately by compound of Example 1: [Table 16]

[0332] The results show that the compound of Example 1 reverses the inhibition of gastrointestinal motility caused by morphine when administered either concomitantly with morphine or sequentially before morphine, and the blockade of the effects of morphine is enhanced when pretreatment is used.

[0333] Without being bound by theory, it is believed that these differences arise because the compounds of Example 1 act as MOP-biasing ligands and that they do not activate the downstream beta-arrestin signaling pathway, a pathway that has been shown to mediate opiate-related side effects, including constipation and respiratory depression.

[0334] Example 19: Pulmonary Function The effect of the compound of Example 1 on the lung function of rats is examined by monitoring the respiratory rate, tidal volume and minute ventilation of rats after subcutaneous administration of 0.3, 1.0 and 3.0 mg / kg of the compound of Example 1 compared to vehicle control. Measurements are taken at 0, 15, 60, 120 and 240 minutes after administration of the compound. No significant differences are found between the vehicle and any of the test groups at any time point. The 60 minute results, which are representative of the results obtained, are shown in the table below: [Table 17]

[0335] Example 20: (6bR,10aS)-8-(3-(3-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0336] Step 1: A mixture of 3-fluorophenol (1 mL, 11 mmol), 1,3-dibromopropane (1.35 mg, 13.3 mmol) and K2CO3 (1.83 g, 13.3 mmol) in CH3CN (4 mL) is bubbled with argon for 3 min. The resulting mixture is heated to 80 °C and stirred at this temperature overnight. The reaction mixture is filtered and the filter cake is washed three times with ethyl acetate (10 mL). The combined filtrate is evaporated and the residue is dried under high vacuum. The product 1-(3-bromopropoxy)-3-fluorobenzene is obtained as a colorless liquid (2.3 g, 89% yield). This product is used directly in the next reaction without further purification.

[0337] Step 2: A suspension of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxalin-2(3H)-one·HBr salt (500 mg, 1.28 mmol), 1-(3-bromopropoxy)-3-fluorobenzene (0.358 g, 1.53 mmol) and KI (0.424 mg, 2.56 mmol) in DMF (4 mL) is purged with argon for 3 min and DIPEA (0.89 mL, 5.12 mmol) is added. The resulting mixture is heated to 80 °C and stirred at this temperature for 6 h. The solvent is removed and the residue is purified by silica gel column chromatography eluting with 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate. The title product is obtained as a white solid (185 mg, 38% yield). MS (ESI) m / z 382.1 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.48 - 7.07 (m, 3H), 7.07 - 6.91 (m, 1H), 6.92 - 6.80 (m, 1H), 6.74 (dd, J = 7.7 Hz, 1H), 6.69 - 6.59 (m, 1H), 4.23 - 4.09 (m, 2H), 3.95 (d, J = 14.5 Hz, 1H), 3.81 - 3.62 (m, 1H), 3.60 - 3.45 (m, 3H), 3.46 - 3.36 (m, 2H), 3.28 - 3.19 (m, 0H), 3.19 - 3.03 (m, 1H), 2.70 - 2.54 (m, 1H), 2.43 - 2.30 (m, 1H), 2.28 - 2.13 (m, 2H), 2.13 - 2.01 (m, 1H).

[0338] Example 21: (6bR,10aS)-8-(3-(2-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0339] Step 1: A mixture of 2-fluorophenol (1 mL, 11.2 mmol), 1,3-dibromopropane (1.37 mg, 13.4 mmol) and K2CO3 (2.32 g, 16.8 mmol) in CH3CN (8 mL) is purged with argon for 3 min. The resulting mixture is heated to 80 °C and stirred at this temperature overnight. The reaction mixture is filtered and the filter cake is washed three times with ethyl acetate (10 mL). The combined filtrate is evaporated and the residue is dried under high vacuum. The product 1-(3-bromopropoxy)-2-fluorobenzene is obtained as a yellow liquid (2.38 g, 91% yield). The product is used directly in the next reaction without further purification.

[0340] Step 2: A suspension of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxalin-2(3H)-one·HBr salt (500 mg, 1.28 mmol), 1-(3-bromopropoxy)-2-fluorobenzene (0.358 g, 1.53 mmol) and KI (0.424 mg, 2.56 mmol) in DMF (4 mL) is purged with argon for 3 min and DIPEA (0.89 mL, 5.12 mmol) is added. The resulting mixture is heated to 80 °C and stirred at this temperature for 6 h. The solvent is removed and the residue is purified by silica gel column chromatography eluting with 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate. The title product is obtained as a white solid (57 mg, 12% yield). MS (ESI) m / z 382.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.48 - 7.07 (m, 3H), 7.07 - 6.91 (m, 1H), 6.92 - 6.80 (m, 1H), 6.74 (dd, J = 7.7 Hz, 1H), 6.69 - 6.59 (m, 1H), 4.23 - 4.09 (m, 2H), 3.95 (d, J = 14.5 Hz, 1H), 3.81 - 3.62 (m, 1H), 3.60 - 3.45 (m, 3H), 3.46 - 3.36 (m, 2H), 3.28 - 3.19 (m, 0H), 3.19 - 3.03 (m, 1H), 2.70 - 2.54 (m, 1H), 2.43 - 2.30 (m, 1H), 2.28 - 2.13 (m, 2H), 2.13 - 2.01 (m, 1H).

[0341] Example 22: (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-3-isopropyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0342] To a mixture of triphenylphosphine (213 mg, 0.813 mmol), (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (155 mg, 0.406 mmol) and isopropanol (62 μL, 0.813 mmol) in THF (1 mL) is added diethyl azodicarboxylate (128 μL, 0.813 mmol). The mixture is stirred at room temperature overnight and the solvent is removed. The residue is purified by silica gel column chromatography eluting with 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate. The title product is obtained as a white solid (62 mg, 36% yield). MS (ESI) m / z 424.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.14 - 7.07 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.86 (d, J = 7.3 Hz, 1H), 6.78 - 6.70 (m, 1H), 4.81 - 4.65 (m, 1H), 3.98 (t, J = 6.4 Hz, 2H), 3.87 (d, J = 14.4 Hz, 1H), 3.25 - 3.16 (m, 2H), 2.92 - 2.81 (m, 1H), 2.70 - 2.60 (m, 1H), 2.45 - 2.32 (m, 2H), 2.10 (t, J = 12.1 Hz, 1H), 1.98 - 1.91 (m, 1H), 1.90 - 1.76 (m, 3H), 1.72 - 1.64 (m, 1H), 1.46 (d, J = 6.9 Hz, 3H), 1.39 (d, J = 6.9Hz, 3H).

[0343] Example 23: (6bR,10aS)-8-(3-(4-iodophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0344] Dry DMF (4 mL) is added to a mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxalin-2(3H)-one·HBr (0.50 g, 1.28 mmol), 1-(3-bromopropoxy)-4-iodobenzene (0.523 g, 1.53 mmol), N,N-diisopropylethylamine (0.89 mL, 5.11 mmol) and potassium iodide (0.424 g, 2.56 mmol) at room temperature under argon atmosphere. The mixture is heated to 80° C. and stirred for 4 h. The solvent is evaporated and the residue is purified by flash silica gel column chromatography eluting with a gradient of 0-50% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v / v)] in ethyl acetate. The title compound is obtained as a white solid (0.232 g, 37% yield). MS (ESI) m / z 490.1 [M+H] + .

[0345] Example 24: (6bR,10aS)-8-(3-(4-bromophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0346] Dry DMF (4 mL) is added to a mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxalin-2(3H)-one·HBr (0.50 g, 1.28 mmol), 1-bromo-4-(3-bromopropoxy)benzene (0.451 g, 1.53 mmol), N,N-diisopropylethylamine (0.89 mL, 5.11 mmol) and potassium iodide (0.424 g, 2.56 mmol) at room temperature under argon atmosphere. The mixture is heated to 80° C. and stirred overnight. The solvent is evaporated and the residue is purified by flash silica gel column chromatography eluting with a gradient of 0-50% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v / v)] in ethyl acetate. The title compound is obtained as a white solid (0.17 g, 30% yield). MS (ESI) m / z 443.0 [M+H] + .

[0347] Example 25: (6bR,10aS)-8-(3-(p-tolyloxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0348] Step 1: To a degassed suspension of 4-methylphenol (770 μL, 4.3 mmol) and K2CO3 (710 mg, 5.2 mmol) in acetonitrile (8 mL) is added 1,3-dibromopropane (530 μL, 5.2 mmol) under stirring. The resulting mixture is heated to 80 °C and stirred at this temperature overnight. After cooling to room temperature, the reaction mixture is concentrated, the residue is suspended in water (20 mL) and extracted with dichloromethane (2 × 30 mL). The combined dichloromethane phases are dried over Na2CO3 and filtered. The filtrate is evaporated to give the crude product 1-(3-bromopropoxy)-4-methylbenzene as a colorless oil (0.53 g). This product is used directly in the next step without further purification.

[0349] Step 2: A mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (450 mg, 1.9 mmol), 1-(3-bromopropoxy)-4-methylbenzene (530 mg, 2.8 mmol) and KI (480 mg, 2.8 mmol) in DMF (10 mL) is purged with argon for 10 min and DIPEA (1.0 mL, 5.9 mmol) is added. The resulting mixture is heated to 76° C. and stirred at this temperature for 2 h. After cooling to room temperature, the reaction mixture is evaporated to dryness. The residue is purified by silica gel column chromatography eluting with a gradient of 0-50% ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v) in ethyl acetate to give the title compound as a brown solid (51.5 mg, 7.2% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.21 - 6.91 (m, 2H), 6.84 - 6.74 (m, 3H), 6.64 (t, J = 7.5 Hz, 1H), 6.58 (dd, J = 7.8, 1.0 Hz, 1H), 3.95 (t, J = 6.4 Hz, 2H), 3.80 (d, J = 14.5 Hz, 1H), 3.30 - 3.24 (m, 2H), 3.22 (dd, J = 10.6, 6.4 Hz, 1H), 2.88 - 2.81 (m, 1H), 2.64 (d, J = 11.6 Hz, 1H), 2.38 (dt, J = 14.8, 7.1 Hz, 2H), 2.22 (s, 3H), 2.14 - 2.03 (m, 1H), 1.94 (dd, J = 14.4, 2.6 Hz, 1H), 1.90 - 1.73 (m, 3H), 1.67 (t, J = 11.0 Hz, 1H). MS (ESI) m / z 378.2 [M+1] + .

[0350] Example 26: (5bR,9aS)-7-(3-(4-fluorophenoxy)propyl)-5b,6,7,8,9,9a-hexahydroimidazo-[4,5,1-hi]pyrido[4,3-b]indol-1(2H)-one [ka]

[0351] Step 1: A degassed suspension of (4aR,9bS)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (19.24 g, 76.01 mmol), potassium carbonate (21.01 g, 152 mmol), 1-(3-chloropropoxy)-4-fluorobenzene (21.54 mL, 136.82 mmol) and N-ethyl-N-isopropylpropan-2-amine (26.5 mL, 152 mmol) in anhydrous DMF (47 mL) is stirred at 80° C. for 2 h. The solvent is removed, the residue is suspended in water (250 mL) and extracted with dichloromethane (3×300 mL). The combined dichloromethane phases are evaporated to dryness and further dried under high vacuum. The product is obtained as a brown solid. This product is used directly in the next step without further purification.

[0352] Step 2: A mixture of the product from step 1 (6.85 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (0.60 mL, 2.89 mmol), copper(I) iodide (185 mg, 0.969 mmol) and cesium carbonate (6.25 g, 19317 mmol) in DMA (6.7 mL) is purged with argon for 5 min and ammonia (15 N, 7.0 mL, 105 mmol) is added. The resulting mixture is heated in a microwave at 95° C. for 4.5 h. The reaction mixture is cooled to room temperature and then poured onto a pad of basic aluminum oxide and filtered. The filter pad is washed with ethyl acetate (8×50 mL). The combined filtrates are evaporated to dryness under reduced pressure. The resulting residue is purified by silica gel column chromatography eluting with 0-100% mixed solvent [ethyl acetate:methanol:7N NH3 (10:1:0.1 v / v)] in ethyl acetate to obtain the product (4aS,9bR)-2-(3-(4-fluorophenoxy)propyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-6-amine as a grey solid.

[0353] Step 3: To a stirred solution of the product from step 2 (0.696 mmol) in pyridine (2.5 mL) at room temperature, add ethyl chloroformate (200 mg, 1.81 mmol) in pyridine (0.5 mL) dropwise under argon. The resulting solution is stirred at room temperature for 0.5 h and at 100° C. for 20 h. The solvent is removed and the residue is purified by silica gel column chromatography using a gradient of 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate as eluent. The product is obtained as an off-white solid.

[0354] Step 4: To a stirred solution of the product from step 3 (0.178 mmol) in toluene (1.5 mL) is added lithium bis(trimethylsilyl)amide (1 M in THF, 712 μL, 0.712 mmol). The mixture is stirred at room temperature for 1 h and heated to 75° C. for 1 h. The solvent is removed and the residue is dissolved in methanol and filtered. The filtrate is purified by semi-preparative reverse phase HPLC using a gradient of 0-20% acetonitrile in water containing 0.1% formic acid as eluent to give the title product as an off-white solid. MS (ESI) m / z 368.0746 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.32 (s, 1H), 7.29 - 7.23 (m, 2H), 7.11 - 7.04 (m, 2H), 6.99 (d, J = 5.7 Hz, 2H), 6.89 (dd, J = 5.6, 2.5 Hz, 1H), 4.09 (t, J = 6.4 Hz, 2H), 3.11 - 2.99 (m, 1H), 2.79 - 2.72 (m, 1H), 2.70 - 2.66 (m, 2H), 2.61 (t, J = 6.9 Hz, 3H), 2.58 - 2.50 (m, 1H), 2.34 - 2.23 (m, 1H), 2.11 - 1.96 (m, 3H).

[0355] Example 27: (8aS,12aR)-11-(3-(4-fluorophenoxy)propyl)-6,7,8a,9,10,11,12,12a-octahydro-[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indol-5(4H)-one [ka]

[0356] Step 1: To a degassed solution of ethyl (4aS,9bR)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (5.15 g, 15.8 mmol) in DMF (50 mL) is added KOH (0.93 g, 15.8 mmol). The mixture is stirred at room temperature for 5 min and acrylamide (1.69 g, 23.7 mmol) is added. After stirring at room temperature overnight, the reaction mixture is evaporated to dryness. The residue is suspended in dichloromethane (100 mL) and extracted with water (30 mL). The organic solution is dried over MgSO4 and filtered. The filtrate is evaporated to dryness and the residue is purified by silica gel column chromatography eluting with a gradient of 0-10% methanol in ethyl acetate. The product, ethyl (4aS,9bR)-5-(3-amino-3-oxopropyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate, is obtained as a yellow oil (3.0 g, 48% yield). MS (ESI) m / z 395.9 [M+1] + .

[0357] Step 2: To a degassed mixture of (4aS,9bR)-ethyl 5-(3-amino-3-oxopropyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (1.90 g, 4.8 mmol), K2CO3 (1.45 g, 10.5 mmol), CuI (182 mg, 0.96 mmol) in dioxane (20 mL) is added N,N,N',N'-tetramethylethylenediamine (0.43 mL, 2.9 mmol) at room temperature. The reaction mixture is heated to 99 °C and stirred at this temperature over the weekend. After cooling to room temperature, the reaction mixture is evaporated to dryness. The residue is suspended in dichloromethane (100 mL) and extracted with water (50 mL). The organic solution is dried over MgSO4 and filtered. The filtrate is evaporated to dryness and the residue is purified by column chromatography eluting with 100% ethyl acetate. The product (8aS,12aR)-ethyl 5-oxo-4,5,6,7,9,10,12,12a-octahydro-[1,4]diazepino-[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate is obtained as a brown solid (210 mg, 14% yield). MS (ESI) m / z 316.1 [M+1] + .

[0358] Step 3: Compound (8aS,12aR)-5-oxo-4,5,6,7,9,10,12,12a-octahydro-[1,4]diazepino-[3,2,1-hi]pyrido-[4,3-b]indole-11(8aH)-carboxylate ethyl (90 mg, 0.28 mmol) is suspended in HBr solution (33% in acetic acid, 1.0 mL) at room temperature. The suspension is stirred at 70° C. for 2 hours, then cooled to 0° C. in an ice bath. Ethyl acetate (5.0 mL) is added, the resulting mixture is filtered, and the filter cake is dried in vacuum. The resulting product is suspended in methanol (10 mL) and cooled with dry ice and 2-propanol. Ammonia (7N in methanol, 3 mL) is slowly added until the pH of the solution is ≧14. The solvent is evaporated to give the product (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-[1,4]diazepino[3,2,1-hi]pyrido[4,3-b]indol-5(4H)-one as a brown solid (132 mg). The crude product is used directly in the next step without further purification. MS (ESI) m / z 244.1 [M+1] + .

[0359] Step 4: A mixture of (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-[1,4]diazepino[3,2,1-hi]-pyrido[4,3-b]indol-5(4H)-one (110 mg, 0.45 mmol), 1-(3-chloroproxy)-4-fluorobenzene (90 μL, 0.57 mmol) and KI (166 mg, 1.0 mmol) in DMF (2 mL) is purged with argon for 3 min and DIPEA (110 μL, 1.0 mmol) is added. The resulting mixture is heated to 76 °C and stirred at this temperature for 2 h. After cooling to room temperature, the reaction mixture is evaporated to dryness. The resulting residue is purified by silica gel column chromatography eluting with a gradient of 0-100% ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v / v) in ethyl acetate to give the title product (8aS,12aR)-11-(3-(4-fluorophenoxy)propyl)-6,7,8a,9,10,11,12,12a-octahydro-[1,4]diazepino-[3,2,1-hi]pyrido[4,3-b]indol-5(4H)-one as a yellow solid (50 mg, 28% yield). 1 HNMR (500 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.10 (t, J = 8.8 Hz, 2H), 6.93 (dd, J = 9.1,4.4 Hz, 2H), 6.75-6.85 (m, 2H), 6.60-6.67 (m, 1H), 4.02 (b, 2H), 3.45-3.32 (m, 3H), 3.16 (b, 1H), 3.03 (m, 2H), 2.72 (m, 3H), 2.36 (b, 2H), 2.07 (b, 3H), 1.90 (b, 2H). MS (ESI) m / z 396.1 [M+1] + .

[0360] Example 28: (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-1,1-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0361] Step 1: Sodium hydride (0.796 g, 19.9 mmol) is added to a solution of ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (2 g, 6.64 mmol) in DMF (20 mL) at 0°C. The mixture is stirred at this temperature for 30 min and 1-(chloromethyl)-4-methoxybenzene (1.35 mL, 9.96 mmol) is added. The reaction mixture is allowed to warm to room temperature and stirred overnight. Water (40 mL) is added and the mixture is extracted with ethyl acetate (3 x 40 ml). The combined organic phase is dried over anhydrous Na2SO4. The mixture is filtered and the filtrate is evaporated to dryness. The residue is purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexane. The product (6bR,10aS)-3-(4-methoxybenzyl)-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate is obtained as a white solid (1.01 g, 36% yield). MS (ESI) m / z 422.2 [M+H] + .

[0362] Step 2: To a solution of (6bR,10aS)-3-(4-methoxybenzyl)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxaline-8(7H)-ethyl carboxylate (0.994 g, 2.36 mmol) in THF (9 mL) at -78°C, lithium bis(trimethylsilyl)amide (7.07 mL, 7.07 mmol) is added. The reaction mixture is stirred at -78°C for 1 hour, and then iodomethane (0.441 mL, 7.07 mmol) is added slowly via syringe. After stirring at -78°C for 5 minutes, the reaction mixture is warmed to 0°C and stirred at this temperature for 2 hours. Water (50 mL) is added and the mixture is extracted with ethyl acetate (3 x 40 ml). The combined organic phases are dried over anhydrous Na2SO4. The mixture is filtered and the filtrate is evaporated to dryness. The residue is purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexane. The product (6bR,10aS)-3-(4-methoxybenzyl)-1-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate is obtained as a white solid (1.14 g, 99% yield). MS (ESI) m / z 436.2 [M+H] + .

[0363] Step 3: To a solution of (6bR,10aS)-3-(4-methoxybenzyl)-1-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-ethyl carboxylate (1.01 g, 2.32 mmol) in THF (10 mL) at -78°C, lithium bis(trimethylsilyl)amide (4.64 mL, 9.28 mmol) is added. The reaction mixture is stirred at -78°C for 1 hour, and then iodomethane (0.578 mL, 9.28 mmol) is added slowly via syringe. After stirring at -78°C for 5 minutes, the reaction mixture is allowed to warm to room temperature and stirred at this temperature for 2 days. Water (30 mL) is added and the mixture is extracted with ethyl acetate (3 x 20 ml). The combined organic phase is dried over anhydrous Na2SO4. The mixture is filtered and the filtrate is evaporated to dryness. The residue is purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexane. The product (6bR,10aS)-3-(4-methoxybenzyl)-1,1-dimethyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate is obtained as a white solid (260 mg, 25% yield).

[0364] Step 4: To ethyl (6bR,10aS)-3-(4-methoxybenzyl)-1,1-dimethyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (0.6 g, 1.33 mmol) is added TFA (1 mL, 13.3 mmol) at room temperature, followed by TfOH (0.47 mL, 5.32 mmol). The reaction mixture is stirred at room temperature for 1 h. The solvent is evaporated and the residue is dissolved in DCM (20 mL). The pH of the mixture is adjusted to 9 with 1N NaOH. The DCM phase is separated and evaporated to dryness. The residue is purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexane. The product (6bR,10aS)-ethyl 1,1-dimethyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate is obtained as a brown solid (300 mg, 68% yield). MS (ESI) m / z 330.2 [M+H] + .

[0365] Step 5: (6bR,10aS)-1,1-dimethyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate ethyl (330 mg, 1 mmol) is added at room temperature with hydrobromic acid solution (33% in HOAc, 2.4 mL, 13 mmol). The mixture is stirred at 50°C for 15 hours and then cooled to room temperature. Ethyl acetate (12 mL) is added and the mixture is neutralized with concentrated ammonium chloride and then filtered. The filtrate is evaporated and the residue is dried under high vacuum. The product (6bR,10aS)-1,1-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one is obtained as a pale solid (302 mg, 99% yield). MS (ESI) m / z 258.2 [M+H] + .

[0366] Step 6: (6bR,10aS)-1,1-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (155 mg, 0.603 mmol), 1-(3-chloropropoxy)-4-fluorobenzene (0.114 mL, 0.724 mmol) and KI (200 mg, 1.2 mmol) in a suspension in DMF (0.6 mL) are purged with argon for 3 min and DIPEA (0.21 mL, 1.2 mmol) is added. The resulting mixture is heated to 80° C. and stirred at this temperature for 2 h. The solvent is removed and the residue is purified by silica gel column chromatography eluting with 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate. The title product is obtained as a white solid (40 mg, 16% yield). MS (ESI) m / z 410.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.13 - 7.06 (m, 2H), 6.95 - 6.89 (m, 2H), 6.74 (d, J = 7.3 Hz, 1H), 6.62 (dd, J = 7.6 Hz, 1H), 6.57 - 6.53 (m, 1H), 3.95 (t, J = 6.4 Hz, 2H), 3.88 - 3.78 (m, 1H), 3.30 - 3.20 (m, 1H), 2.88 - 2.78 (m, 1H), 2.72 - 2.59 (m, 1H), 2.44 - 2.31 (m, 2H), 2.27 - 2.09 (m, 2H), 1.96 - 1.79 (m, 3H), 1.73 (t, J = 11.0 Hz, 1H), 1.54 (s, 3H), 1.07 (s, 3H).

[0367] Example 29: (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-1-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0368] Step 1: A mixture of (4aR,9bS)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (3.2 g, 9.8 mmol), 2-bromopropanamide (4.5 g, 30 mmol) and KI (5.0 g, 30 mmol) in dioxane (10 mL) is purged with argon for 8 min and heated to 105° C. under vigorous stirring. The mixture is stirred at this temperature for 24 h. After cooling to room temperature, the reaction mixture is evaporated to dryness. The residue is suspended in DCM (200 mL) and washed with water (150 mL). The DCM phase is separated, dried over MgSO4 and filtered. The filtrate is concentrated and purified by silica gel column chromatography (gradient: 0% to 100% ethyl acetate in hexane). The product (4aS,9bR)-ethyl 5-(1-amino-1-oxopropan-2-yl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate is obtained as a light green oil (2.7 g, 69% yield). MS (ESI) m / z 396.0, 398.0 [M+H] + .

[0369] Step 2: A suspension of K2CO3 (2.0 g, 14.5 mmol), CuI (268 mg, 1.7 mmol) and (4aS,9bR)-5-(1-amino-1-oxopropan-2-yl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-ethyl carboxylate (2.7 g, 6.8 mmol) in dioxane (10 mL) is purged with argon for 5 min and N,N,N',N'-tetramethylethylenediamine (610 μL, 4.1 mmol) is added. The mixture is heated to 100 °C and stirred at this temperature for 48 h. LC-MS shows that the reaction is complete. After cooling to room temperature, the reaction mixture is poured onto a silica gel pad and filtered. The gel pad is rinsed with ethyl acetate (0.2 L) and the filtrate is evaporated to dryness. The product, ethyl (6bR,10aS)-1-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate, is obtained as a white foam. MS (ESI) m / z 316.2 [M+H] + This product is used directly in the next reaction without further purification.

[0370] Step 3: The carbamate obtained from step 2 is suspended in HBr (20 mL, 33% w / w in acetic acid) at room temperature. The mixture is heated to 70° C. under stirring to form a clear solution. This clear solution gradually becomes a suspension again within 1 h due to the formation of a pale green precipitate. After stirring at 70° C. for 2 h, the reaction mixture is cooled to room temperature and ethyl acetate (100 mL) is added. The mixture is stirred for 5 min and allowed to settle upright in a hood. The precipitate is filtered and the filter cake is washed with ethyl acetate (10 mL). The filtrate is evaporated to dryness and further dried under high vacuum. The obtained residue is suspended in methanol (30 mL), cooled with isopropanol / dry ice and ammonia solution (20 mL, 7N in methanol) is added slowly with stirring. During this addition process, the temperature of the mixture is maintained below 5° C. The solution gradually changes color from pale green to brown as its pH value reaches 14. The solvent is removed and the residue is dried under high vacuum to give crude (6bR,10aS)-1-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one as a brown solid (760 mg, 100% yield). This product is used directly in the next step without further purification. MS (ESI) m / z 232.2 [M+H] + .

[0371] Step 4: A mixture of KI (700 mg, 5.4 mmol), 1-(3-chloroproxy)-4-fluorobenzene (850 μL, 8.8 mmol) and crude (6bR,10aS)-1-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (660 mg, 2.7 mmol) in DMF (4 mL) is purged with argon for 3 min and DIPEA (950 μL, 5.4 mmol) is added. The resulting mixture is heated to 78 °C and stirred at this temperature for 2 h. After cooling to room temperature, the reaction solvent is removed. The residue is suspended in dichloromethane (30 mL) and washed with water (10 mL). The organic phase is separated, dried over K2CO3, and then filtered. The filtrate is concentrated and purified by silica gel column chromatography [gradient: 0-25% methanol in ethyl acetate:ethyl acetate:methanol:7N NH3 mixture (10:1:0.1; by volume)]. The product obtained is further purified by semi-preparative HPLC using a gradient of 0-20% acetonitrile in water containing 0.1% formic acid as eluent. The title product is obtained as a green solid (78 mg, 7% yield). 1 H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.62 - 7.46 (m, 2H), 7.43 - 7.31 (m, 2H), 7.26 (s, 1H), 7.15 (s, 1H), 7.06 (s, 1H), 4.43 (t, J = 6.2 Hz, 2H), 4.00 (s, 4H), 3.59 (s, 2H), 3.32 (s, 1H), 3.16 (d, J = 0.7 Hz, 1H), 2.93 (p, J = 1.9 Hz, 2H), 2.80 (s, 1H), 2.67 - 2.55 (m, 2H), 1.91 (d, J = 6.6Hz, 3H). MS (ESI) m / z 396.2 [M+1] + .

[0372] Example 30: (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one [ka]

[0373] Step 1: (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (0.1 g, 0.262 mmol) in DMF (1 mL) at 0° C. is added with sodium hydride (60% in mineral oil, 32 mg, 0.786 mmol). The mixture is stirred at 0° C. for 30 minutes and iodomethane (19.6 μL, 0.315 mmol) is added. The reaction mixture is stirred at 0° C. for 1 hour and water (4 mL) is added. The mixture is extracted with ethyl acetate (3×4 ml) and the combined organic phase is dried over anhydrous Na2SO4. The mixture is filtered and the filtrate is evaporated to dryness. The residue is purified by column chromatography eluting with 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate. The title compound is obtained as an off-white solid (110 g, 99% yield). MS (ESI) m / z 396.2 [M+H] + . 1 H NMR (500 MHz, Chloroform-d) δ 7.02 - 6.95 (m, 2H), 6.95 - 6.85 (m, 2H), 6.85 - 6.76 (m, 3H), 4.09 - 3.99 (m, 3H), 3.93 (m, 1H), 3.44 (m, 2H), 3.36 (s, 3H), 3.16 - 2.65 (m, 4H), 2.29 (m, 3H), 2.13 (m, 1H), 1.73 (m, 2H).

[0374] Example 31: ((6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-2-oxo-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-3(2H)-yl)methyl dodecanoate [ka]

[0375] Step 1: To a stirred suspension of zinc(II) chloride (294 mg, 2.16 mmol) in anhydrous acetonitrile (4 mL) at 0° C. under argon, add lauroyl chloride (5.0 mL, 21.6 mmol) dropwise. The suspension is stirred at 0° C. for 10 min, at room temperature for 10 min, then heated to 70° C. and stirred at this temperature for 24 h. The reaction mixture is cooled to room temperature and poured into a flask containing dichloromethane (100 mL). The resulting suspension is filtered under vacuum and the filter cake is washed with dichloromethane (2×10 mL). Saturated NaHCO3 (10 mL) is added to the combined filtrate and stirred at room temperature for 1.5 h. The dichloromethane phase is separated, washed with saturated NaHCO3 (2×60 mL) and evaporated to dryness under reduced pressure. The residue is further dried under high vacuum to give the product chloromethyl dodecanoate as a light orange oil (4.523 g, 84% yield), which crude product is used directly in the next reaction without further purification.

[0376] Step 2: A suspension of potassium iodide (131 mg, 0.786 mmol), potassium carbonate (181 mg, 1.31 mmol), N,N-diisopropylethylamine (137 mL, 0.786 mmol), N,N-dimethylpyridin-4-amine (64 mg, 0.524 mmol), chloromethyl dodecanoate (522 mg, 2.10 mmol), and (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (212 mg, 0.556 mmol) in anhydrous DMF (1.5 mL) is purged with argon for 5 min. The resulting suspension is heated to 125° C. by microwave and stirred at this temperature for 5 h. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The residue is purified by silica gel column chromatography using 0-100% ethyl acetate in hexane as eluent to give the title compound as a pale orange solid (150 mg, 45% yield). MS (ESI) m / z 594.4 [M + H] + . 1 H NMR (500 MHz, Chloroform-d) δ 6.96 (dd, J = 9.1, 8.2 Hz, 2H), 6.90 (s, 1H), 6.82 (d, J = 7.0 Hz, 4H), 6.16 (d, J = 10.5 Hz, 1H), 5.70 (d, J = 10.5 Hz, 1H), 4.05 (d, J = 14.5 Hz, 1H), 3.99 (d, J = 6.6 Hz, 2H), 3.42 (d, J = 14.4 Hz, 1H), 3.38 - 3.25 (m, 1H), 2.91 (d, J = 28.2 Hz, 1H), 2.74 (s, 1H), 2.50 (s, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.28 (t, J = 7.9 Hz, 1H), 1.96 (s, 3H), 1.86 (s, 1H), 1.70 - 1.59 (m, 2H), 1.54 (s, 1H), 1.35 - 1.16 (m, 17H), 0.88 (t, J = 6.9 Hz, 3H).

[0377] Example 32: (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-2-oxo-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-3(2H)-carboxylic acid heptadecanoic anhydride [ka]

[0378] A mixture of N,N-diisopropylethylamine (219 mL, 1.572 mmol), N,N-dimethylpyridin-4-amine (64 mg, 0.524 mmol), chloromethyl dodecanoate from Example 31 (522 mg, 2.10 mmol) and (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (200 mg, 0.524 mmol) in anhydrous DMF (3 mL) is purged with argon for 5 min. The mixture is stirred at room temperature for 5 h and the solvent is removed under reduced pressure. The resulting residue is purified by silica gel column chromatography using 0-100% ethyl acetate in hexane as a gradient. The title product is obtained as a pale orange solid (197 mg, 58% yield). MS (ESI) m / z 650.4970 [M + H] + . 1H NMR (500 MHz, Chloroform-d) δ 7.04 (d, J = 8.2 Hz, 1H), 6.96 (dd, J = 9.2, 8.2 Hz, 2H), 6.91 (d, J = 7.3 Hz, 1H), 6.86 - 6.76 (m, 3H), 4.40 (t, J = 6.7 Hz, 2H), 4.04 - 3.94 (m, 3H), 3.35 (d, J = 14.1 Hz, 2H), 3.26 (d, J = 5.3 Hz, 1H), 2.92 (s, 1H), 2.74 (s, 1H), 2.50 (s, 2H), 2.24 (d, J = 14.8 Hz, 1H), 2.00 - 1.86 (m, 4H), 1.83 - 1.74 (m, 2H), 1.48 - 1.38 (m, 2H), 1.26 (s, 25H), 0.88 (t, J = 6.9 Hz, 3H).

[0379] Example 33: Receptor Binding Profile Using the same receptor binding assay procedure described in Example 7, the following additional data is obtained for the following compounds: [Table 18] The present application also includes the following aspects. [Aspect 1] A compound of formula I: in free form or in salt form (e.g., a pharma- ceutically acceptable salt form), e.g., isolated or purified free form or in salt form (e.g., a pharma- ceutically acceptable salt form). [ka] [In the formula, R 1 , H, C 1-6 Alkyl, -C(O)-OC(R a )(R b )(R c ), -C(O)-O-CH 2 -OC(R a )(R b )(R c ) or -C(R6 )(R 7 )-OC(O)-R 8 and; R 2 and R 3 are independently H, D, and C 1-6 Alkyl (e.g., methyl), C 1-6 is selected from alkoxy (e.g., methoxy), halo (e.g., F), cyano, or hydroxy; or R 2 and R 3 and the carbons to which they are attached, collectively, -CH 2 CH 2 -forming a group, or R 2 and R 3 and the carbon to which they are attached is absent; L is for C 1-6 Alkylene (e.g., ethylene, propylene or butylene), C 1-6 Alkoxy (e.g., propoxy or butoxy), C 2-3 Alkoxy C 1-3 Alkylene (e.g., -CH 2 CH 2 OCH 2 -)、C 1-6 Alkylamino or NC 1-6 Alkyl C 1-6 Alkylamino (e.g., propylamino or N-methylpropylamino), C 1-6 Alkylthio (e.g., -CH 2 CH 2 CH 2 S-), C 1-6 Alkylsulfonyl (e.g., -CH 2 CH 2 CH 2 S(O) 2 -), each of which contains one or more R 4 may be substituted with a moiety; Each R 4 is independently 1-6 Alkyl (e.g., methyl), C 1-6 selected from alkoxy (e.g., methoxy), halo (e.g., F), cyano, or hydroxy; Z is selected from aryl (e.g., phenyl) and heteroaryl (e.g., pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), where the aryl or heteroaryl is selected from one or more R 4 may be substituted with a moiety; R8 is -C(R a )(R b )(R c ), -OC(R a )(R b )(R c ), or -N(R d )(R e ) and; R a 、R b and R c are each independently H and C 1-24 alkyl; R d and R e are each independently H and C 1-24 alkyl; R 6 and R 7 are each independently H, C 1-6 Alkyl, carboxy and C 1-6 alkoxycarbonyl; with the proviso that the LZ moiety is not 1-(4-(4-fluorophenyl)-4-oxobutyl), 1-(4-(4-fluorophenyl)-4-hydroxybutyl, or 1-(4-fluoro-1-phenoxy)propyl). A compound represented by the formula: [Aspect 2] R 1 The compound of embodiment 1, wherein [Aspect 3] R 1 But, C 1-6 The compound according to embodiment 1, wherein the alkyl is methyl. [Aspect 4] R 1 But -C(O)-OC(R a )(R b )(R c ), -C(O)-O-CH 2 -OC(Ra )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 2. The compound of embodiment 1, wherein [Aspect 5] L is unsubstituted C 1-6 alkylene (e.g., ethylene, propylene, or butylene) or L is one or more R 4 C substituted with moiety 1-6 The compound of any one of embodiments 1 to 4, wherein the alkylene is ethylene, propylene, or butylene. [Aspect 6] L is unsubstituted C 1-6 alkoxy (e.g., propoxy or butoxy) or L is one or more R 4 C substituted with moiety 1-6 The compound according to any one of embodiments 1 to 4, which is alkoxy (eg, propoxy or butoxy). [Aspect 7] R 1 、R 2 and R 3 The compound of any one of embodiments 1-6, wherein each is H. [Aspect 8] R with 1 or more Zs 4 The compound according to any one of embodiments 1 to 7, wherein the aryl is optionally substituted with a moiety (eg, phenyl). [Aspect 9] Z is one R selected from halo (e.g., fluoro, chloro, bromo, or iodo) and cyano. 4 The compound according to any one of embodiments 1-7, wherein Z is phenyl substituted with a moiety (eg, Z is 4-fluorophenyl, or 4-chlorophenyl, or 4-cyanophenyl). [Aspect 10] R with 1 or more Zs 4 The compound according to any one of Aspects 1 to 7, which is an optionally substituted heteroaryl moiety (eg, pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl). [Aspect 11] The compound according to embodiment 10, wherein the heteroaryl is a monocyclic 5- or 6-membered heteroaryl (eg, pyridyl, pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, thiophenyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl). [Aspect 12] The compound of embodiment 10, wherein the heteroaryl is a bicyclic 9- or 10-membered heteroaryl (e.g., indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzodioxolyl, 2-oxo-tetrahydroquinolinyl). [Aspect 13] heteroaryl is one R selected from halo (e.g., fluoro, chloro, bromo, or iodo) and cyano; 4 The compound according to embodiment 10, wherein the heteroaryl is substituted with a moiety (eg, heteroaryl is 6-fluoro-3-indazolyl, 6-chloro-3-indazolyl, 6-fluoro-3-benzisoxazolyl, or 5-chloro-3-benzisoxazolyl). [Aspect 14] The compounds each independently are in free form or in pharma- ceutically acceptable salt form:

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Claims

1. A compound of formula I, in free form or in pharma- ceutically acceptable salt form: 【Chemistry 1】 [In the formula, R 1 is H or C 1-6 is alkyl; R 2 and R 3 is independently selected from H, D and hydroxy; L is ethylene, propylene, butylene, propoxy, butoxy, propylamino, N-methylpropylamino, -CH 2 CH 2 CH 2 S- and -CH 2 CH 2 CH 2 S (O) 2 -, each of which is selected from one or more R 4 may be substituted with a moiety; Each R 4 is independently 1-6 Alkyl, C 1-6 selected from alkoxy, halo, cyano, and hydroxy; Z is selected from aryl and heteroaryl selected from pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and bicyclic 9- or 10-membered heteroaryl selected from indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzodioxolyl, and 2-oxo-tetrahydroquinolinyl, wherein the aryl or heteroaryl is selected from one or more R 4 may be substituted with a moiety; with the proviso that when L is unsubstituted propylene, Z is not fluoro-substituted isoindolyl, 6-fluoro-3-benzoisoxazolyl, or 6-fluoro-3-indazolyl; With the proviso that the L-Z moiety is not 1-(4-(4-fluorophenyl)-4-oxobutyl), 1-(4-(4-fluorophenyl)-4-hydroxybutyl, or 1-(4-fluoro-1-phenoxy)propyl). A compound represented by the formula:

2. R 1 The compound of claim 1 , wherein

3. R 1 But, C 1-6 The compound of claim 1 , which is alkyl.

4. R 1 The compound of claim 1 , wherein is methyl.

5. The compound of any one of claims 1 to 4, wherein L is unsubstituted ethylene, propylene or butylene.

6. The compound of any one of claims 1 to 4, wherein L is unsubstituted propoxy or butoxy.

7. R 1 , R 2 and R 3 The compound of any one of claims 1, 2, 5 and 6, wherein each is H.

8. Z is one or more R 4 The compound according to any one of claims 1 to 7, which is an aryl optionally substituted with a moiety.

9. Z is one R selected from fluoro, chloro, bromo, iodo and cyano. 4 The compound of any one of claims 1 to 7, which is a phenyl substituted with a moiety.

10. Z is one or more R 4 The compound according to any one of claims 1 to 7, which is selected from optionally substituted pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl and thiazolyl.

11. 11. The compound of claim 10, wherein heteroaryl is pyrimidyl, pyrazinyl, thiophenyl, furanyl, oxazolyl, isoxazolyl, thiazolyl.

12. 11. The compound of claim 10, wherein heteroaryl is a bicyclic 9- or 10-membered heteroaryl selected from indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzodioxolyl, and 2-oxo-tetrahydroquinolinyl.

13. Heteroaryl is one R selected from fluoro, chloro, bromo, iodo, and cyano. 4 The compound of any one of claims 10 to 12, substituted with a moiety.

14. The compound of any one of claims 10 to 12, wherein heteroaryl is 6-fluoro-3-indazolyl, 6-chloro-3-indazolyl, 6-fluoro-3-benzisoxazolyl, or 5-chloro-3-benzisoxazolyl.

15. The compounds each independently are in free form or in pharma- ceutically acceptable salt form: 【Chemistry 2】 The compound according to any one of claims 1 to 13, selected from the group consisting of:

16. The compounds each independently are in free form or in pharma- ceutically acceptable salt form: 【Chemistry 3】 The compound according to any one of claims 1 to 15, selected from the group consisting of:

17. A compound according to any one of claims 1 to 16 in the form of a pharma- ceutically acceptable salt.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 in free form or in a pharma- ceutically acceptable salt form in admixture with a pharma- ceutically acceptable diluent or carrier.

19. 19. A pharmaceutical composition according to claim 18 for the treatment or prevention of a central nervous system disorder.

20. 20. The pharmaceutical composition of claim 19, wherein the disorder is selected from the group consisting of disorders selected from the group consisting of obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, pain, chronic fatigue, agoraphobia, social phobia, agitation in dementia, autism and autistic disorders, gastrointestinal disorders, dementia; mood disorders; substance dependence, binge eating disorder; obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, hypochondriasis, pathological grooming disorder, kleptomania, pyromania, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorder, and combinations thereof.

21. 21. The pharmaceutical composition of claim 20, wherein the disorder is selected from generalized anxiety, social anxiety, panic disorder, treatment-refractory depression, major depressive disorder, treatment-resistant depression, headache, idiopathic pain, neuropathic pain, chronic pain, fibromyalgia, opiate dependence, cocaine dependence, amphetamine dependence, alcohol dependence, withdrawal from drug or alcohol dependence and opiate overdose.

22. The disorder is serotonin 5-HT 2A , serotonin reuptake transporter (SERT), dopamine D 1 and / or D 2 20. The pharmaceutical composition of claim 19, wherein the disorder is associated with the pathway and / or the μ-opioid receptor.

23. 20. The pharmaceutical composition of claim 19, wherein the disorder is selected from: (1) psychosis in a patient suffering from depression; (2) depression in a patient suffering from psychosis; (3) mood disorders associated with psychosis; (4) sleep disorders associated with psychosis; and (5) substance addiction, substance use disorders and / or substance-induced disorders.

24. 20. The pharmaceutical composition of claim 19, wherein the central nervous system disorder is selected from obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, hypochondriasis, pathological grooming disorder, kleptomania, pyromania, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorder, and related disorders, and combinations thereof.

25. 20. The pharmaceutical composition of claim 19, wherein the central nervous system disorder is a disorder selected from headache, idiopathic pain, neuropathic pain, chronic pain, fibromyalgia, chronic fatigue, opiate dependence, cocaine dependence, amphetamine dependence, alcohol dependence, withdrawal from drug or alcohol dependence; and opiate overdose.

26. 26. The pharmaceutical composition according to any one of claims 19 to 25, wherein said treatment or prevention further comprises the administration of a μ-opiate, a κ-opiate, a δ-opiate, and / or an agonist or partial agonist, or an inverse agonist or antagonist of the nociceptin / orphanin receptor.

27. 27. The pharmaceutical composition of claim 26, wherein said treatment or prevention further comprises administration of buprenorphine, methadone, naloxone or naltrexone.

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