Organic compounds

Abstract

The present invention relates to specific deuterium-substituted heterocycle fused gamma-carbolines in free, solid, pharmaceutically acceptable salt and / or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of preparing the same. And methods of use in the treatment of diseases involving 5-HT2A receptor, serotonin transporter (SERT) and / or pathways involving dopamine D1 and D2 receptor signaling systems, and / or [mu]-opioid receptors.

Description

[0001] This application is a divisional application of Chinese patent application 201980029046.7. The filing date of the original application is March 21, 2019, and the name is “Organic Compounds”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 647,488, filed on March 23, 2018, the contents of which are hereby incorporated by reference in their entirety. Field of the Invention

[0004] The present invention relates to specific deuterated heterocyclic fused γ-carbolines as described herein in free form, solid form, pharmaceutically acceptable salt form and / or substantially pure form, pharmaceutical compositions thereof and methods for treating diseases involving: 5-HT 2A Receptors, serotonin transporters (SERTs), pathways involving dopamine D1 / D2 receptor signaling systems and / or μ-opioid receptors, such as diseases or disorders such as anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders, migraines, pain-related conditions (including head pain, neuropathic pain, and as emergency analgesics), fibromyalgia, chronic fatigue, social phobia, gastrointestinal disorders such as gastrointestinal motility disorders and obesity; depression and mood disorders such as those associated with psychosis or Parkinson's disease; psychosis such as schizophrenia associated with depression; bipolar disorder; drug dependence such as opioid dependence and alcohol dependence, drug withdrawal symptoms, obsessive-compulsive personality disorder (OCD) and related disorders; and other psychiatric and neurological disorders; and the present invention also relates to combinations with other active agents. In some embodiments, the disease or disorder may include treatment-resistant depression, cocaine dependence, and / or amphetamine dependence. Background of the Invention

[0006] Substituted heterocyclic fused γ-carbolines are known to be active agents for the treatment of central nervous system disorders such as 5-HT2 receptors, especially 5-HT 2A These compounds have been described in U.S. Patent Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; USRE39680 and USRE39679 as agents useful in the treatment of 5-HT 2ANovel compounds for diseases related to receptor modulation, such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, headache-related disorders, social phobia, gastrointestinal diseases, such as gastrointestinal dysmotility and obesity. U.S. Patent Publication Nos. 2010 / 113781 and 2004 / 209864 also disclose methods for preparing substituted heterocyclic fused γ-carbolines, and the use of these γ-carbolines as serotonin agonists and antagonists, which can be used to control and prevent central nervous system disorders, such as addictive behaviors and sleep disorders.

[0007] Furthermore, US 2011 / 071080 discloses the use of specific substituted heterocyclic fused γ-carbolines in the treatment of psychosis and depression and a combination of sleep, depression and / or mood disorders in patients with psychotic Parkinson's disease. In addition to diseases associated with psychosis and / or depression, the patent application also discloses and claims that these compounds selectively antagonize 5-HT at low doses. 2A The invention relates to the use of a novel sedative-hypnotic drug that inhibits dopamine D2 without affecting or minimizing the effect on dopamine D2, thereby treating sleep disorders without the side effects associated with high occupancy of the dopamine D2 pathway or other pathways (e.g., GABA) associated with conventional sedative-hypnotic drugs (e.g., benzodiazepines). A The side effects of the present invention include, but are not limited to, drug dependence, low muscle tone, weakness, headache, blurred vision, dizziness, nausea, vomiting, upper abdominal discomfort, diarrhea, joint pain and chest pain. US 2011 / 112105 also discloses a method for preparing the toluenesulfonic acid addition salt crystals of these substituted heterocyclic fused γ-carbolines.

[0008] Related publications WO 2017 / 132408 and US2017 / 319586 disclose novel oxo-metabolites of the compounds disclosed in the above publications. These new oxo-metabolites retain many unique pharmacological activities of the parent compounds, including serotonin receptor inhibition, SERT inhibition, and dopamine receptor modulation. However, it was found that these oxo-metabolites also unexpectedly have significant activity on μ-opioid receptors.

[0009] Obsessive-compulsive disorder (OCD) and related disorders have become highly prevalent and difficult to treat. OCD is estimated to affect approximately 2.3% of people at some point, and in a given year, an estimated 1.2% of people worldwide suffer from the disorder. Half of people with OCD begin to experience symptoms before the age of 20, which can severely impact their ability to obtain an adequate and effective education. However, without effective treatment, the disorder can persist for decades. Treatment of OCD with selective serotonin reuptake inhibitors (SSRIs) is the mainstay of treatment. Second-line treatment is with antipsychotics such as clomipramine, risperidone, quetiapine, and olanzapine. A large number of patients do not respond to these medications or are unable to cope with the side effects caused by these medications. Recently, there have been reports that the opioid analgesic tramadol may be effective in treating OCD. Opioids work in a completely different way than traditional OCD treatments, so they offer the possibility of treatment for people who cannot take traditional serotonergic medications or for whom they do not work. However, strong opioids can be addictive and may be contraindicated for some patients. Therefore, new treatments for OCD and related disorders are urgently needed. SUMMARY OF THE INVENTION

[0011] The compounds of formula A and B shown below are potent serotonin 5-HT 2A Receptor antagonists and μ-opioid receptor partial agonists. These compounds also interact with dopamine receptors, especially dopamine D1 receptors.

[0012]

[0013] Compounds of formula A and B and their analogs are used to treat or prevent central nervous system diseases, but there is a need in the art for analogs, such as isotopic analogs, of compounds of formula A and B that can provide improved therapeutic concentrations or improved pharmacokinetic profiles or kinetics of these compounds when administered to patients. The present disclosure meets this need by providing compounds of formula I and II, etc., which are deuterated analogs of compounds of formula A and B. Due to their useful metabolic and pharmacokinetic properties, the compounds of the present disclosure are particularly suitable for formulation as long-acting or extended release compositions that can provide improved therapeutic dosage concentrations of compounds A and B and their analogs over an extended period of time when administered to patients.

[0014] In a first aspect, the present disclosure relates to compounds of Formula I (Compound I):

[0015]

[0016] in:

[0017] R 1 C 1-4 Alkyl (e.g. methyl);

[0018] Z is O or -C(O)-;

[0019] R 2 and R 3 are each independently H and D (deuterium); and

[0020] R 4 -R 14 Each independently is H and D;

[0021] The compound is in free form or in salt form, e.g., in isolated or purified free or salt form, provided that R 2 -R 14 At least one of them is D.

[0022] The present disclosure provides additional exemplary embodiments of compounds of Formula I in free or salt form, e.g., isolated or purified free or salt form, including:

[0023] 1.1 Compound I, wherein Z is O;

[0024] 1.2 Compound I, wherein Z is -C(O);

[0025] 1.3 Compound I, 1.1 or 1.2, wherein R 1 is methyl;

[0026] 1.4 Any one of the compounds 1.1-1.3, wherein R 2 is H, and R 3 is D;

[0027] 1.5 Any compound of 1.1-1.3, wherein R 2 is D, and R 3 is D;

[0028] 1.6 Any compound of 1.1-1.3, wherein R 2 is H, and R 3 is H;

[0029] 1.7 Any compound of 1.1-1.6, wherein R 4 -R 7 Any one of is D;

[0030] 1.8 Any compound of 1.1-1.6, wherein R 4 -R 7 Any two of are D;

[0031] 1.9 Any compound of 1.1-1.6, wherein R 4 -R 7 Any three of are D;

[0032] 1.10 Any compound of 1.1-1.6, wherein R 4 -R 7 All four of them are D;

[0033] 1.11 Any of the compounds 1.1-1.10, wherein R 8 -R 14 All six of them are H;

[0034] 1.12 Any compound of 1.1-1.10, wherein R 8 -R 14 Any one or two of is D;

[0035] 1.13 Any one of the compounds 1.1-1.10, wherein R 8 -R 14 Any three or four of them are D;

[0036] 1.14 Any one of the compounds 1.1-1.10, wherein R 8 -R 14 Any five or six of the following are D;

[0037] 1.15 Any compound of 1.1-1.10, wherein R 8 -R 14 All six of them are D;

[0038] 1.16 Compound I or any one of 1.1-1.15, in free form;

[0039] 1.17 Compound I or any one of 1.1-1.15, in the form of a salt, such as a pharmaceutically acceptable salt;

[0040] 1.18 Compound I or any one of 1.1-1.15, in solid form;

[0041] 1.19 Compound 1 or any one of 1.1-1.18 in substantially pure diastereomeric form (i.e., substantially free of other enantiomers);

[0042] 1.20 Compound I or any one of 1.1-1.18 having a diastereomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90%, most preferably greater than 95%.

[0043] 1.21 Compound I or any one of 1.1-1.20 having greater than 50% (i.e., greater than 50% atomic D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99% deuterium incorporation at one or more of the indicated positions of the structure.

[0044] 1.22 Compound I or any one of 1.1-1.21, in isolated or purified form.

[0045] 1.23 Compound I or any one of 1.1-1.22, wherein the compound is selected from:

[0046]

[0047]

[0048] 1.24 Compound I or any one of 1.1-1.22, wherein the compound is selected from:

[0049]

[0050] 1.25 Compound I or any one of 1.1-1.22, wherein the compound is selected from:

[0051]

[0052] In a second aspect, the present disclosure provides each of the above-mentioned compounds I or 1.1-1.25 (hereinafter collectively referred to as "compounds of Formula I, etc." or "compounds of the present disclosure") in the form of a pharmaceutically acceptable salt. The present disclosure provides additional exemplary embodiments of compounds of Formula I, etc.:

[0053] 2.1 Compounds of formula I-II, etc., wherein the salt is an acid addition salt selected from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, isethionic acid, etc.;

[0054] 2.2 Compounds of formula I-II, etc., wherein the salt is a fumaric acid addition salt;

[0055] 2.3 Compounds of formula I-II, etc., wherein the salt is a phosphoric acid addition salt;

[0056] 2.4 Compounds of formula I-II, etc., wherein the salt is a toluenesulfonic acid addition salt;

[0057] 2.5 Any of 2.1-2.4 wherein the salt is in solid form.

[0058] In a third aspect, the present disclosure provides a pharmaceutical composition (pharmaceutical composition 3), which comprises, for example, compound 1 or any one of 1.1-1.25 and a pharmaceutically acceptable diluent or carrier. The present disclosure provides another exemplary embodiment of pharmaceutical composition 1, comprising:

[0059] 3.1 Pharmaceutical composition 3, wherein the compound of formula I, etc., is in solid form;

[0060] 3.2 Pharmaceutical composition 3 or 3.1, wherein the compound of formula I etc. is in the form of a pharmaceutically acceptable salt as described in compounds 2.1-2.5;

[0061] 3.3 Pharmaceutical composition 3 or any one of 3.1-3.3, wherein the composition is a depot formulation as described herein (eg, wherein the composition is formulated as a long-acting injectable, eg, for intramuscular or subcutaneous injection).

[0062] 3.4 Pharmaceutical composition 3 or any one of 3.1-3.4, wherein the compound of Formula I etc. is in a polymer matrix.

[0063] In another embodiment, the pharmaceutical composition of the present disclosure is used for sustained or delayed release, such as a depot formulation. In one embodiment, the depot formulation (depot formulation 3.3) is a pharmaceutical composition preferably in free form or a pharmaceutically acceptable salt form of any one of 3.1-3.3, and preferably it is mixed with a pharmaceutically acceptable diluent or carrier, for example, to provide sustained or delayed release as an injectable depot.

[0064] In a specific embodiment, the depot formulation 3.3 comprises a compound of any one of Compound I or 1.1-1.25, which is a free base or a pharmaceutically acceptable salt form, optionally in a crystalline form, wherein the compound is ground to or crystallized to a microparticle or nanoparticle size, for example, particles or crystals having a volume-based particle size (e.g., diameter or Dv50) of 0.5-100 microns, for example, 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 pharmaceutically acceptable diluent or carrier, such as water, to form a depot formulation for injection. For example, the depot formulation can be formulated for intramuscular or subcutaneous injection, with a drug dose suitable for 4-6 weeks of treatment. In some embodiments, the particles or crystals have a volume-based particle size (e.g., diameter or Dv50) of 0.1-5 microns. 2 / g, for example 0.5-3.3m 2 / g or 0.8-1.2m 2 / g of surface area.

[0065] In another embodiment, the present disclosure provides pharmaceutical composition 3.4, any one of pharmaceutical compositions 3 or 3.1-3.3, wherein the compound of formula I, etc. is in a polymer matrix. In one embodiment, the compound of the present disclosure is dispersed or dissolved in a polymer matrix. In another embodiment, the polymer matrix comprises a standard polymer for a depot formulation, such as a polymer selected from the following: polyesters of hydroxy fatty acids and their derivatives, or polymers of α-cyanoacrylate alkyl esters, polyalkylene oxalates, polyorthoesters, polycarbonates, polyortho-carbonates, polyamino acids, hyaluronates, and mixtures thereof. In another embodiment, the polymer is selected from polylactide, poly d, l-lactide, polyglycolide, PLGA 50:50, PLGA 75:25, PLGA 85:15, and PLGA 90:10 polymers. In another embodiment, the polymer is selected from poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers thereof, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxonones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes such as glycerol monostearate and distearate, etc. In a preferred embodiment, the polymer matrix comprises poly(d,l-lactide-co-glycolide).

[0066] (Drug) Compositions 3 and 3.1-3.4 are particularly useful for sustained release or delayed release, wherein the compounds of the present disclosure are released when the polymer matrix degrades. These compositions can be formulated to control the release and / or sustained release of the compounds of the present disclosure over a period of up to 180 days, such as about 14 days to about 30 days to about 180 days (e.g., formulated as a reservoir composition). For example, the polymer matrix can degrade and release the compounds of the present disclosure over a period of about 30 days, about 60 days, or about 90 days. In another example, the polymer matrix can degrade and release the compounds of the present disclosure over a period of about 120 days or about 180 days.

[0067] In yet another embodiment, a pharmaceutical composition of the disclosure, eg, a depot composition of the disclosure, eg, pharmaceutical composition 3.3 or 3.4, is formulated for administration by injection.

[0068] In a fourth aspect, the present disclosure provides a compound of formula I, etc. as described above in an osmotic controlled release oral delivery system (OROS), the osmotic controlled release oral delivery system being described in WO 2000 / 35419 (US 2001 / 0036472) and EP 1 539 115 (US Publication No. 2009 / 0202631), the contents of each of which are incorporated herein by reference in their entirety. Therefore, in one embodiment of the seventh aspect, the present disclosure provides a pharmaceutical composition or device comprising: (a) a gelatin capsule comprising a compound of formula I, etc. or a pharmaceutical composition of the present invention in free form or in pharmaceutically acceptable salt form as described above; (b) a multi-layer wall superimposed on the gelatin capsule, comprising, in order from the capsule to the outside: (i) a barrier layer, (ii) an expandable layer, and (iii) a semipermeable layer; and (c) and a hole formed or formable through the wall. (Pharmaceutical composition P.1)

[0069] In another embodiment, the present invention provides a pharmaceutical composition comprising a gelatin capsule containing a liquid, free form or pharmaceutically acceptable salt form of a compound of formula I, etc. or a pharmaceutical composition of the present invention, such as any one of pharmaceutical compositions 3 or 3.1-3.4, wherein the gelatin capsule is surrounded by a composite wall, the composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, a swellable layer in contact with the barrier layer, a semi-permeable layer surrounding the swellable layer, and an exit hole formed in the wall or can be formed in the wall. (Pharmaceutical composition P.2)

[0070] In still another embodiment of the fourth aspect, the present invention provides a composition comprising a gelatin capsule containing a compound of formula I, etc., or a pharmaceutical composition of the present invention, such as any one of pharmaceutical compositions 3 or 3.1-3.4, in liquid, free form or in pharmaceutically acceptable salt form, the gelatin capsule being surrounded by a composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, a swellable layer in contact with the barrier layer, a semi-permeable layer surrounding the swellable layer, and an exit hole formed or formable in the wall, wherein the barrier layer forms a seal between the swellable layer and the environment at the exit hole. (Pharmaceutical composition P.3)

[0071] In still another embodiment of the fourth aspect, the present invention provides a composition comprising a gelatin capsule, the gelatin capsule containing a compound of formula I, etc., or a pharmaceutical composition of the present invention, such as any one of pharmaceutical compositions 3 or 3.1-3.4, in liquid, free form or pharmaceutically acceptable salt form, the gelatin capsule being surrounded by the following layers: a barrier layer in contact with the outer surface of the gelatin capsule, a swellable layer in contact with a portion of the barrier layer, a semi-permeable layer at least surrounding the swellable layer, and an exit hole formed or formable in the dosage form, the exit hole extending from the outer surface of the gelatin capsule to the use environment. (Pharmaceutical composition P.4). The swellable layer can be formed in one or more discrete parts, such as two parts located at opposite sides or opposite ends of the gelatin capsule.

[0072] In a specific embodiment of the fourth aspect, the compound of the present disclosure in the osmotic-controlled release oral delivery system (i.e., in pharmaceutical compositions P.1-P.4) is a liquid formulation, which can be a pure liquid active agent, a liquid active agent in a solution, suspension, emulsion or self-emulsifying composition, etc.

[0073] More information on osmotic-controlled release oral delivery system compositions including gelatin capsules, barrier layers, swellable layers, semi-permeable layers and pore features can be found in WO 2000 / 35419 (and equivalent patent US 2001 / 0036472), the contents of which are incorporated herein by reference in their entirety.

[0074] Other osmotic-controlled release oral delivery system compositions of compounds or pharmaceutical compositions of Formula I disclosed herein can be found in EP 1 539 115 (U.S. Publication No. 2009 / 0202631), the contents of which are incorporated herein by reference in their entirety. Therefore, in another embodiment of the seventh aspect, the present invention provides a composition or device comprising: (a) two or more layers, the two or more layers comprising a first layer and a second layer, the first layer comprising a compound of Formula I, etc. or the pharmaceutical composition described above in free form or in the form of a pharmaceutically acceptable salt, and the second layer comprising a polymer; (b) an outer wall surrounding the two or more layers; and (c) holes on the outer wall. (Pharmaceutical composition P.5)

[0075] Pharmaceutical composition P.5 preferably utilizes a semipermeable membrane surrounding a three-layer core: in these embodiments, the first layer is referred to as the first drug layer and contains a small amount of drug (e.g., a compound of Formula I, etc.) and an osmotic agent such as a salt, the middle layer referred to as the second drug layer contains a higher amount of drug, excipients, and no salt; the third layer referred to as the push layer contains an osmotic agent and no drug. At least one hole is drilled through the membrane at the end of the first drug layer of the capsule-shaped tablet. (Pharmaceutical composition P.6)

[0076] Pharmaceutical composition P.5 or P.6 may comprise: a membrane defining a compartment, the membrane surrounding an inner protective base coat, in which at least one exit hole is formed or can be formed, and at least a portion of the membrane is semipermeable; a swellable layer in a compartment away from the exit hole in fluid communication with the semipermeable portion of the membrane; a first drug layer adjacent to the exit hole; and a second drug layer in a compartment between the first drug layer and the swellable layer, the drug layer comprising a compound of the present invention in free form or in pharmaceutically acceptable salt form. Different release characteristics are obtained depending on the relative viscosities of the first drug layer and the second drug layer. The optimal viscosity of each layer must be identified. In the present invention, the viscosity is adjusted by adding the salt sodium chloride. The delivery characteristics from the core depend on the weight, formulation and thickness of the respective drug layers. (Pharmaceutical composition P.7)

[0077] In a specific embodiment, the present invention provides pharmaceutical composition P.7, wherein the first drug layer comprises a salt and the second drug layer does not contain a salt. Pharmaceutical compositions P.5-P.7 may optionally comprise a flow-promoting layer between the membrane and the drug layer.

[0078] Pharmaceutical compositions P.1-P.7 are collectively referred to as osmotic-controlled release oral delivery system compositions.

[0079] In a fifth aspect, the present invention provides a method for treating or preventing a central nervous system disorder (method I), comprising administering to a patient in need thereof a compound or pharmaceutical composition 3 or 3.1-3.4 or P.1-P.7 of formula I, etc., such as method 1, wherein the compound or composition administered is:

[0080] 1.1 Compound I or any one of 1.1-1.25 in free form or in pharmaceutically acceptable salt form;

[0081] 1.2 A compound of any one of formulas 2.1-2.5;

[0082] 1-3 A pharmaceutical composition as described in any one of Pharmaceutical Composition 3 or 3.1-3.4;

[0083] 1.4 Pharmaceutical compositions P.1-P.7;

[0084] 1.5 The osmotic-controlled release oral delivery system composition as described above;

[0085] In another embodiment of the fifth aspect, the present disclosure provides method 1 or any one of methods 1.1-1.5, wherein the method is further described as follows:

[0086] 1.6 Method 1 or any one of Methods 1.1-1.5, wherein the central nervous system disorder is a disorder selected from the following: obesity, anxiety disorders (including general anxiety, social anxiety and panic disorder), depression (such as refractory depression and MDD), psychosis (including psychosis associated with dementia, such as hallucinations in advanced Parkinson's disease or paranoid delusions), schizophrenia, sleep disorders (especially sleep disorders associated with schizophrenia and other psychiatric and neurological diseases), sexual disorders, migraine, pain and pain-related disorders, idiopathic pain, chronic pain (such as moderate to moderately severe chronic pain, such as in the need for 24 hours of prolonged treatment) (e.g., in patients being treated for other conditions), neuropathic pain, dental pain, fibromyalgia, chronic fatigue, agoraphobia, social phobia, agitation in dementia (e.g., agitation in Alzheimer's disease), agitation in autism and related autistic disorders, gastrointestinal disorders such as gastrointestinal dysmotility, and dementia, such as dementia in Alzheimer's disease or Parkinson's disease; mood disorders; drug dependence, such as opioid dependence and / or alcohol dependence and withdrawal from drug or alcohol dependence (e.g., opioid dependence); comorbidities associated with drug dependence, such as depression, anxiety, and psychosis; binge eating disorder; and obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), and related disorders;

[0087] 1.7 Method 1 or any one of methods 1.1-1.6, wherein the central nervous system disorder is a disorder involving the serotonin 5-HT2A, dopamine D1 and / or D2 receptor system and / or the serotonin reuptake transporter (SERT) pathway similarly as described in US2011 / 071080, the contents of which are incorporated herein by reference in their entirety;

[0088] 1.8 Method 1 or any one of methods 1.1-1.7, wherein the central nervous system disorder is a disorder involving μ-opioid receptors;

[0089] 1.9 Method 1 or any one of Methods 1.1-1.8, wherein the central nervous system disorder is a disorder selected from the following: (i) psychosis, such as schizophrenia, in a patient suffering from depression; (2) depression in a patient suffering from psychosis, such as schizophrenia; (3) mood disorders and / or drug dependence associated with psychosis, such as schizophrenia or Parkinson's disease; (4) sleep disorders associated with psychosis, such as 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;

[0090] 1.10 Method 1 or any one of methods 1.1-1.9, wherein the central nervous system disorder is a psychotic disorder, such as schizophrenia, and the patient is a patient suffering from depression;

[0091] 1.11 Method 1 or any one of methods 1.1-1.10, wherein the patient cannot tolerate the side effects of conventional antipsychotic drugs, such as chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, epiriprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone;

[0092] 1.12 Method 1 or any one of Methods 1.1-1.11, wherein the patient cannot tolerate non-narcotic analgesics and opioids and the side effects of opioids, or wherein the use of opioids is contraindicated in the patient due to prior drug abuse or a high potential for drug abuse, such as opioids including, for example, codeine, thebaine, C3-northebaine, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, hydroxycodone fentanyl, alpha-methylfentanyl, tetrazofentanyl, trefantinil, bufentanil, remifentanil, octfentanil, sufentanil, carfentanil, pethidine, anadolu, trimeridine, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol and anileridine or any combination thereof.

[0093] 1.13 Method 1 or any one of methods 1.1-1.12, wherein the patient cannot tolerate the side effects of conventional antipsychotic drugs such as haloperidol, epiprazole, cariprazine, asenapine, lurasidone, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone;

[0094] 1.14 Method 1 or any one of Methods 1.1-1.13, wherein the disorder is depression and the patient is a patient suffering from a psychotic disorder such as schizophrenia or Parkinson's disease;

[0095] 1.15 Method 1 or any one of methods 1.1-1.13, wherein the disorder is a sleep disorder and the patient suffers from depression;

[0096] 1.16 Method 1 or any one of methods 1.1-1.13, wherein the one or more disorders are sleep disorders and the patient suffers from a psychotic disorder such as schizophrenia;

[0097] 1.17 Method 1 or any one of methods 1.1-1.13, wherein the one or more disorders are sleep disorders and the patient suffers from Parkinson's disease;

[0098] 1.18 Method 1 or any of Methods 1.1-1.13, wherein the one or more disorders are sleep disorders and the patient suffers from depression and a psychotic disorder such as schizophrenia or Parkinson's disease.

[0099] 1.19 Any one of method 1 or 1.1-1.18, wherein the patient suffers from drug dependence, optionally in combination with any of the above disorders, for example, wherein the patient suffers from opiate dependence, cocaine dependence, amphetamine dependence and / or alcohol dependence or withdrawal from drug or alcohol dependence (e.g., cocaine or amphetamine dependence), and optionally wherein the patient suffers from a comorbidity, such as anxiety, depression or residual symptoms of anxiety or depression and / or mood changes (e.g., depression);

[0100] 1.20 Any of the above methods, wherein the effective amount is 1 mg-1000 mg, such as 2.5 mg-50 mg, or for a long-acting preparation, 25 mg-1500 mg, such as 50 mg-500 mg or 250 mg-1000 mg or 250 mg-750 mg or 75 mg-300 mg;

[0101] 1.21 Any of the above methods, wherein the effective amount is 1 mg-100 mg / day, such as 2.5 mg-50 mg / day;

[0102] 1.22 Any of the above methods, wherein the condition treated is dyskinesia, e.g. dyskinesia in a patient receiving a dopaminergic agent, e.g. an agent selected from the group consisting of levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists and anticholinergics, e.g. levodopa;

[0103] 1.23 Any of the above methods, wherein the patient suffers from Parkinson's disease.

[0104] Substance use disorders and substance-induced disorders are two types of substance-related disorders defined by the DSM, fifth edition (Diagnostic and Statistical Manual of Mental Disorders). Substance use disorders are symptom patterns from the use of a substance that an individual continues to take, but, as a result, still experiences problems. Substance-induced disorders are disorders induced as a result of the use of the substance. Substance-induced disorders include intoxication, withdrawal, substance-induced psychiatric disorders, including substance-induced psychosis, substance-induced bipolar and related disorders, substance-induced depression, substance-induced anxiety disorders, substance-induced obsessive-compulsive and related disorders, substance-induced sleep disorders, substance-induced sexual dysfunction, substance-induced delirium, and substance-induced neurocognitive disorders.

[0105] DSM-V includes criteria for classifying substance use disorders as mild, moderate, or severe. In some embodiments of the methods disclosed 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.

[0106] Anxiety and depression are highly prevalent comorbidities in patients undergoing treatment for drug use or drug abuse. A common treatment for drug abuse disorders is a combination of the partial opioid agonist buprenorphine and the opioid antagonist naloxone, but neither of these drugs has any significant effect on anxiety or depression, resulting in a common outcome that a third drug, such as a benzodiazepine anxiolytic or SSRI antidepressant, must also be prescribed. This makes treatment regimens and patient compliance more difficult. In contrast, the compounds of the present disclosure provide opioid antagonism along with serotonin antagonism and dopamine modulation. This may result in significantly enhanced treatment of drug use or abuse patients who also suffer from anxiety and / or depression.

[0107] The compounds of the present disclosure may have anxiolytic properties, thereby improving the need for treating patients with anxiolytics, wherein the patients suffer from co-existing anxiety. Thus, in some embodiments, the present disclosure provides a method according to any one of methods 1 or 1.1-1.23, wherein the central nervous system disorder is a substance addiction, a substance use disorder and / or a substance-induced disorder or a substance abuse disorder, such as in a patient suffering from anxiety symptoms or diagnosed with anxiety as a co-existing disorder or as a residual disorder, wherein the method does not comprise further administration of anxiolytics, such as benzodiazepines. Benzodiazepines are compounds that modulate GABA, including those discussed with reference to methods 3.1 and 3.2 below.

[0108] In another embodiment of the fifth aspect, the present disclosure provides method 1 or any one of methods 1.1-1.7, wherein the method is further described as follows:

[0109] 1.24 Method 1 or any one of Methods 1.1-1.23, wherein the central nervous system disorder is a disorder selected from the following: obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), general anxiety, social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, delusional disorder, pathological grooming disorder, kleptomania, pyromania, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorders, and related disorders and combinations thereof.

[0110] 1.25 Method 1 or any one of Methods 1.1-1.23, 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.

[0111] 1.26 Method 1 or any one of Methods 1.1-1.23, wherein the central nervous system disorder is obsessive compulsive disorder (OCD) or obsessive compulsive personality disorder (OCPD).

[0112] 1.27 Any of the above methods, wherein the patient is unresponsive to or cannot tolerate the side effects of a selective serotonin reuptake inhibitor (SSRI) such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline.

[0113] 1.28 Any of the above methods, wherein the patient is unresponsive to or cannot tolerate the side effects of treatment with a serotonin-norepinephrine reuptake inhibitor (SNRI), such as venlafaxine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran.

[0114] 1.29 Any of the above methods, wherein the patient is unresponsive to treatment with, or cannot tolerate the side effects of, an antipsychotic drug such as clomipramine, risperidone, quetiapine and olanzapine.

[0115] 1.30 Any of the above methods, wherein the effective amount is 1 mg-1000 mg, preferably 2.5 mg-50 mg, or for long-acting preparations, 25 mg-1500 mg, such as 50 mg-500 mg or 250 mg-1000 mg or 250 mg-750 mg or 75 mg-300 mg;

[0116] 1.31 Any of the above methods, wherein the effective amount is 1 mg-100 mg / day, preferably 2.5 mg-50 mg / day.

[0117] In yet another embodiment, the present disclosure provides any one of Method 1 or 1.1-1.31 as described above, wherein the disorder is schizophrenia or a sleep disorder. In some embodiments, the schizophrenia is associated with depression.

[0118] In yet another embodiment, the disclosure provides any of methods 1.1-1.31, wherein pharmaceutical composition 3 or 3.1-3.4 or pharmaceutical composition P.1-P.7 is administered for controlled- and / or sustained-release of a compound of the invention over a period of about 14 days, about 30 to about 180 days, preferably about 30 days, about 60 days, or about 90 days. Controlled- and / or sustained-release is particularly useful for avoiding premature termination of therapy, especially for antipsychotic drugs, where non-compliance or non-adherence to the dosing regimen is a common occurrence.

[0119] In yet another embodiment, the invention provides any one of Methods 1 or 1.1-1.31 as described above, wherein a depot composition of the present disclosure is administered for controlled- and / or sustained-release of a compound of the invention over a period of time.

[0120] In a sixth aspect, the present invention provides a method for preventing or treating one or more sleep disorders (Method 2), comprising administering to a patient in need thereof a compound or pharmaceutical composition 3 or 3.1-3.4 or P.1-P.7 of Formula I, etc. (Method 2), for example, Method 2, wherein the compound or composition administered is:

[0121] 2.1 Compound I or 1.1-1.25 in free form or in pharmaceutically acceptable salt form;

[0122] 2.2 Compounds 5.1-5.5;

[0123] 2.3 A pharmaceutical composition as described in any one of Pharmaceutical Composition 3 or 3.1-3.4;

[0124] 2.4 Pharmaceutical compositions P.1-P.7;

[0125] 2.5 The osmotic-controlled release oral delivery system composition described above;

[0126] In an embodiment of the sixth aspect, the present invention provides method 2 or 2.1-2.5, wherein the sleep disorder comprises sleep maintenance insomnia, frequent awakening, and waking up feeling unrefreshed; for example:

[0127] 2.6 Any one of the above methods, wherein the sleep disorder is sleep maintenance insomnia;

[0128] 2.7 Any of the above methods, wherein the effective amount is 1 mg-5 mg / day, preferably 2.5-5 mg / day;

[0129] 2.8 Any of the above methods, wherein the effective amount is 2.5 mg or 5 mg / day;

[0130] 2.9 Any of the above methods, wherein the sleep disorder is a sleep disorder in a patient suffering from or at risk of movement disorders, such as a patient receiving a drug selected from levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists and anticholinergics, such as a patient receiving levodopa;

[0131] 2.10 Any of the above methods, wherein the patient suffers from Parkinson's disease.

[0132] In another embodiment of the sixth aspect, the present invention provides any one of Method 2 or 2.1-2.10, wherein the sleep disturbance comprises sleep maintenance insomnia, frequent awakenings, and awakenings that do not feel rested.

[0133] The compounds of the present disclosure, the pharmaceutical compositions of the present disclosure, or the reservoir compositions of the present disclosure can be used in combination with a second therapeutic agent, particularly at a dose lower than that of a single drug used as a monotherapy, so as to enhance the therapeutic activity of the combination without causing undesirable side effects that typically occur in conventional monotherapy. Thus, the compounds of the present disclosure can be administered simultaneously, sequentially, or together with other antidepressants, antipsychotics, other hypnotics, and / or drugs for the treatment of Parkinson's disease or mood disorders. In another example, side effects can be reduced or minimized by administering a compound of the present disclosure with one or more second therapeutic agents in free form or salt form, or (ii) the side effects of the combination of a compound of the present disclosure and a second therapeutic agent are lower than the side effects of the drug / compound when administered as a monotherapy. In a specific embodiment, the compounds of the present disclosure are useful for treating dyskinesias in patients receiving dopaminergic drugs, e.g., selected from levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics, e.g., for treating Parkinson's disease, and anticholinergics are used to treat the side effects of Parkinson's disease medications.

[0134] Thus, in a seventh aspect, the present disclosure provides method I or any one of methods 1.1-1.31 or method 2 or any one of 2.1-2.10, further comprising administering to the patient one or more therapeutic agents, wherein the one or more therapeutic agents are selected from compounds that modulate GABA activity (e.g., enhance activity and facilitate GABA transmission), GABA-B agonists, 5-HT modulators (e.g., 5-HT 1A Agonists, 5-HT 2A Antagonists, 5-HT 2A inverse agonists, etc.), melatonin receptor agonists, ion channel modulators (e.g., blockers), serotonin-2 receptor antagonists / reuptake inhibitors (compounds with 5-HT2 antagonism and serotonin reuptake inhibition, i.e., SARI), orexin receptor antagonists, H3 agonists or antagonists, noradrenergic agonists or antagonists, galanin agonists, CRH antagonists, human growth hormone, growth hormone agonists, estrogens, estrogen agonists, neurokinin-1 drugs, antidepressants and opioid agonists and / or partial opioid agonists (e.g., μ-, κ- or δ-opioid receptor agonists or partial agonists), pain-sensitive peptide agonists and antipsychotics, such as atypical antipsychotics, wherein the therapeutic agent is in free form or in the form of a pharmaceutically acceptable salt (Methods IA and II-A, respectively; collectively referred to as "Method 3").

[0135] In one embodiment of the seventh aspect, the present disclosure provides method I or any one of methods 1.1-1.31 or method 2 or any one of 2.1-2.10, further comprising administering to the patient one or more therapeutic agents selected from those described above and further selected from μ-opioids, κ-opioids or δ-opioids and / or agonists or partial agonists of pain-sensitive peptide / orphanin receptors. In another embodiment of the tenth aspect, the present disclosure also provides method I or any one of methods 1.1-31 or method 2 or any one of 2.1-2.10, further comprising one or more therapeutic agents selected from serotonin HT6 receptor antagonists and mGluR-2, -3 or -5 receptor agonists or antagonists (including positive and negative modulators and partial agonists).

[0136] In another embodiment of the seventh aspect, the present invention provides method 3 (ie, method IA or II-A), wherein the method further comprises administering to the patient one or more of the following therapeutic agents in free form or in pharmaceutically acceptable salt form:

[0137] 3.1 Method IA or II-A, wherein the therapeutic agent is a compound that modulates GABA activity (e.g., enhances activity and facilitates GABA transmission);

[0138] 3.2 Method IA or II-A or 3.1, wherein the GABA compound is selected from one or more of doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepam, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, indiprolon, zopiclone, eszopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;

[0139] 3.3 Method IA or II-A, wherein the therapeutic agent is another 5HT2a receptor antagonist;

[0140] 3.4 Method IA or II-A or 3.3, wherein the additional 5HT2a receptor antagonist is selected from one or more of pimasserin, ketanserin, risperidone, eliserin, fluriserin (Sanofi-Aventis, France), pravanserin, MDL 100907 (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego, CA) and AVE8488 (Sanofi-Aventis, France);

[0141] 3.5 Method IA or II-A, wherein the therapeutic agent is a melatonin receptor agonist;

[0142] 3.6 Method IA or II-A or 3.5, wherein the melatonin receptor agonist is selected from melatonin, ramelteon ( Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II discovery), and agomelatine;

[0143] 3.7 Method IA or II-A, wherein the therapeutic agent is an ion channel blocker;

[0144] 3.8 Method IA or II-A or 3.7, wherein the ion channel blocker is one or more of lamotrigine, gabapentin and pregabalin.

[0145] 3.9 Method IA or II-A, wherein the therapeutic agent is an orexin receptor antagonist;

[0146] 3.10 Method IA or II-A or 3.9, wherein the orexin receptor antagonist is selected from orexin, 1,3-biaryl urea, SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline) and benzamide derivatives;

[0147] 3.11 Method IA or II-A, wherein the therapeutic agent is a serotonin-2 receptor antagonist / reuptake inhibitor (SARI);

[0148] 3.12 Method IA or II-A or 3.11, wherein the serotonin-2 receptor antagonist / reuptake inhibitor (SARI) is selected from one or more of Org 50081 (Organon-Netherlands), ritanserin, nefazodone, nefazodone and trazodone;

[0149] 3.13 Method IA or II-A, wherein the therapeutic agent is a 5HTIa agonist;

[0150] 3.14 Method IA or II-A or 3.13, wherein the 5HTIa agonist is selected from one or more of repinotan, sarizotan, elepidotan, buspirone and MN-305 (MediciNova, San Diego, CA);

[0151] 3.15 Method IA or II-A, wherein the therapeutic agent is a neurokinin-1 drug;

[0152] 3.16 Method IA or II-A or 3.15, wherein the neurokinin-1 drug is casopitant (GlaxoSmithKline);

[0153] 3.17 Method IA or II-A, wherein the therapeutic agent is an antipsychotic drug;

[0154] 3.18 Method IA or II-A or 3.17, wherein the antipsychotic drug is selected from chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, epiriprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone;

[0155] 3.19 Method IA or II-A, wherein the therapeutic agent is an antidepressant;

[0156] 3.20 Method IA or II-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;

[0157] 3.21 Method IA or II-A, 3.17 or 3.18, wherein the antipsychotic drug is an atypical antipsychotic drug;

[0158] 3.22 Any of Methods IA or II-A or 3.17-3.21, wherein the atypical antipsychotic is selected from epiriprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone;

[0159] 3.23 Method IA or II-A, wherein the therapeutic agent is selected from any one of methods 3.1-3.22, for example, selected from modafinil, armofinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepam, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, indiprolon, zopiclone, eszopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam, pimaselin, ketanserin, risperidone, eliselin, fluliserin (Sanofi-Aventis, France), pravanserin, MDL 100907 (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena Pharm aceuticals, San Diego, CA), AVE8488 (Sanofi-Aventis, France), Repinotan, Sarizotane, Ecitabirone, Buspirone, MN-305 (MediciNova, San Diego, CA), Melatonin, Ramelteon ( Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II discovery), agomelatine, lamotrigine, gabapentin, pregabalin, glutathione, 1,3-biaryl urea, SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), benzamide derivatives, Org 50081 (Organon-Netherlands), ritanserin, nefazodone, nefazodone, trazodone, casopitant (GlaxoSmithKline), amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paro oximetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, epiriprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone;

[0160] 3.24 Method IA or II-A, wherein the therapeutic agent is an H3 agonist;

[0161] 3.25 Method IA or II-A, wherein the therapeutic agent is an H3 antagonist;

[0162] 3.26 Method IA or II-A, wherein the therapeutic agent is a noradrenergic agonist or antagonist;

[0163] 3.27 Method IA or II-A, wherein the therapeutic agent is a galanin agonist;

[0164] 3.28 Method IA or II-A, wherein the therapeutic agent is a CRH antagonist;

[0165] 3.29 Method IA or II-A, wherein the therapeutic agent is human growth hormone;

[0166] 3.30 Method IA or II-A, wherein the therapeutic agent is a growth hormone agonist;

[0167] 3.31 Method IA or II-A, wherein the therapeutic agent is estrogen;

[0168] 3.32 Method IA or II-A, wherein the therapeutic agent is an estrogen agonist;

[0169] 3.33 Method IA or II-A, wherein the therapeutic agent is a neurokinin-1 drug;

[0170] 3.34 Method IA or II-A, wherein a therapeutic agent is combined with the compound of formula (I), and the therapeutic agent is an anti-Parkinson's disease agent such as L-dopa, co-careldopa, duodopa, stalevo, Symmetrel, benztropine, biperiden, bromocriptine, entacapone, pergolet, pramipexole, procyclidine, ropinirole, selegiline and tolcapone;

[0171] 3.35 Method IA or II-A, wherein the therapeutic agent is an opioid agonist or partial opioid agonist, such as a μ-agonist or partial agonist or a κ-agonist or partial agonist, including mixed agonist / antagonists (e.g., a drug with partial μ-agonist activity and κ-antagonist activity);

[0172] 3.36 Method 3.35, wherein the therapeutic agent is buprenorphine, optionally wherein the method does not include co-treatment with an anxiolytic, such as a GABA compound or a benzodiazepine;

[0173] 3.37 Method IA or II-A, wherein the compound of formula (I) can be used to treat sleep disorders, depression, psychosis or any combination thereof, in patients suffering from the listed diseases and / or Parkinson's disease;

[0174] 3.38 Method IA or II-A, wherein the disorder is selected from at least one or more of a psychotic disorder such as schizophrenia, depression, a mood disorder, a sleep disorder (such as sleep maintenance and / or sleep onset), or any combination thereof;

[0175] 3.39 Any of the above methods, wherein the disorder is a sleep disorder;

[0176] 3.40 Any of the above methods wherein the disorder is a sleep disorder associated with a psychotic disorder such as schizophrenia or Parkinson's disease.

[0177] In an eighth aspect of the invention, a combination of a compound of the present disclosure and one or more second therapeutic agents as described in any of Method IA, II-A or Method 3 or 3.1-3.40 can be administered to a patient as a pharmaceutical composition or a reservoir combination as described above. The combination composition can include a mixture of combined drugs and two or more separate compositions of drugs, each of which can be administered to a patient, for example, together with each other.

[0178] In a specific embodiment, Method IA, II-A, 3 or 3.1-3.40 comprises administering to a patient in need thereof a compound of the invention and an atypical antipsychotic, e.g., a compound selected from epiriprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone or paliperidone, in free form or in pharmaceutically acceptable salt form, e.g., wherein the dosage of the atypical antipsychotic is reduced and / or the side effects are reduced.

[0179] In another embodiment, Method IA, II-A, 3 or 3.1-3.40 comprises administering to a patient in need thereof a compound of the invention and 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 the form of a pharmaceutically acceptable salt. Alternatively, the antidepressant may be used as an adjunct to the compound of the invention.

[0180] In yet another embodiment, Methods IA, II-A, 3, or 3.1-3.40 comprise administering to a patient in need thereof a compound of the invention and a compound that modulates GABA activity, such as a compound selected from the group consisting of doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepam, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, indiprolon, zopiclone, eszopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam, or any combination thereof, in free form or in pharmaceutically acceptable salt form. In additional embodiments, the methods disclosed herein do not further comprise administering a GABA compound, a benzodiazepine, or any other anxiolytic.

[0181] In another preferred embodiment, Method IA, II-A, 3 or 3.1-3.40 comprises administering to a patient in need thereof a compound of the invention and doxepin in free form or in a pharmaceutically acceptable salt form. The dose of doxepin may vary within any range known to those skilled in the art. In one example, a 10 mg dose of doxepin may be combined with any dose of a compound of the invention.

[0182] In another embodiment, Methods IA, II-A, 3, or 3.1-3.40 comprise administering to a patient in need thereof a compound of this invention with (including as part of a daily dosage regimen) an atypical stimulant such as modafinil, adrafinil, or armodafinil. Regimens incorporating a compound of this invention with such drugs promote more regular sleep and avoid side effects, such as psychosis or mania, associated with higher levels of such drugs, such as for the treatment of bipolar depression, cognition associated with schizophrenia, and excessive sleepiness and fatigue in conditions such as Parkinson's disease and cancer.

[0183] In each of the above embodiments, compounds of Formula I, etc.; pharmaceutical compositions 3 and 3.1-3.4; combinations P.1-P.7; methods 1 and 1.1-1.31; and some of methods 2 and 2.1-2.10 and 3 and 3.1-3.40; the compounds of the present disclosure are substantially free of compounds of Formula A and / or Formula B.

[0184] In a ninth aspect, the present invention provides compounds implemented as follows:

[0185] 9.1 Compound I or 1.1-1.25 in free form or in pharmaceutically acceptable salt form;

[0186] 9.2 Compound 5 or 5.1-5.5;

[0187] 9.3 Pharmaceutical composition 3 or 3.1-3.4;

[0188] 9.4 Pharmaceutical compositions P.1-P.7;

[0189] 9.5 The osmotic-controlled release oral delivery system composition described above;

[0190] Use (in the preparation of a medicament) for treating or preventing one or more disorders disclosed above, such as one or more disorders described in method 1 or any one of 1.1-1.31, method 2 and any one of 2.1-2.10 and method 3 or 3.3-3.40 or any one of the methods described in the tenth aspect of the invention.

[0191] In a tenth aspect, the present invention provides a pharmaceutical composition as described above, for example:

[0192] 10.1 Pharmaceutical composition 3 or 3.1-3.4;

[0193] 10.2 Pharmaceutical compositions P.1-P.7;

[0194] 10.3 The osmotic-controlled release oral delivery system composition described above,

[0195] It is used to treat or prevent one or more disorders as disclosed above, for example in any of Methods 1 and 1.1-1.31, Methods 2 and 2.1-2.10, Methods IA, II-A, 3 or 3.1-3.40 or in any of the methods described in the eighth or ninth aspects of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0197] As used herein, the following terms have the following meanings unless otherwise specifically or clearly defined in the context:

[0198] Without being bound by theory, the present invention provides compounds that specifically limit, slow, alter and / or prevent metabolism that has been found to occur in animals treated with Compound A and Compound B:

[0199]

[0200] Due to the difference with normal hydrogen atoms ( 1 H) compared to deuterium ( 2H) of the very similar chemical and physical properties, such as atomic charge, atomic volume, polarity, valence, etc., of the pharmaceutical compounds in which hydrogen is replaced by deuterium, it is believed that the pharmaceutical compounds in which hydrogen is replaced by deuterium usually have similar biological activity to the non-deuterated analogs, but potentially have improved pharmacokinetic properties. Of particular importance is that, although the atomic mass of the deuterium atom is almost twice the atomic mass of the protium atom, their spatial volume and charge distribution are similar, and the latter factors are crucial for the combination with biomolecules. Compared with the HD bond, the bond strength of the CD bond is significantly higher, and therefore, the energy barrier for D / H extraction during the enzymatic (metabolic) reaction is higher (kinetic isotope effect), thereby improving the pharmacokinetic properties. The degree to which this substitution will obtain improved pharmacokinetic properties without excessive loss of pharmacological activity is variable. Therefore, in some cases, the deuterated compound obtained only moderately increases the pharmacokinetic stability, while in other cases, the deuterated compound obtained may have significantly improved stability. Furthermore, it may be difficult to predict the effect of simultaneous deuteration with confidence. These changes may or may not result in additive (synergistic) improvements in metabolic stability.

[0201] Although many deuterated drug compounds have been proposed and explored to date, only one deuterated drug compound, deutetrabenazine (Teva Pharmaceuticals, April 2017), has been approved by the U.S. Food and Drug Administration, which is a deuterated form of the Huntington's disease drug tetrabenazine that has a therapeutically useful longer half-life compared to its non-deuterated counterpart.

[0202] The present disclosure provides compounds containing deuterium atoms at specific selected positions of the structure of Formula A and / or Formula B. Due to the relationship of these specific deuterated species to enzymatic pathways determined by the inventors, it is expected that these specific deuterated species will affect the metabolic degradation and clearance of the compounds, which may affect these compounds. Therefore, it is expected that these novel compounds antagonize 5-HT in a manner similar to their natural hydrogen analogs. 2A receptors, inhibit the serotonin reuptake transporter, modulate the phosphorylation of dopaminergic proteins, and regulate μ-opioid receptor activity while having unexpectedly improved metabolic stability and pharmacokinetic properties.

[0203] As used herein, "alkyl" is a saturated or unsaturated hydrocarbon moiety, e.g., 1-12 carbon atoms in length, unless otherwise indicated; any such alkyl group may be straight chain or branched (e.g., n-butyl or tert-butyl), preferably straight chain, unless otherwise specified. For example, "C 1-21 "Alkyl" means an alkyl group having 1 to 21 carbon atoms. In one embodiment, the alkyl group is optionally substituted with one or more hydroxyl groups or C 1-22In another embodiment, the alkyl group comprises 1-21 carbon atoms, preferably straight chain and optionally saturated or unsaturated, for example, in some embodiments, wherein R1 is an alkyl chain comprising 1-21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, for example, such that when cleaved from the compound of formula I, together with the attached -C(O)-, a residue of a natural or non-natural, saturated or unsaturated fatty acid is formed.

[0204] The term "D" or "deuterium" refers to the 2 H-isotope. The natural abundance of the two abundant isotopes of hydrogen is about 99.98% protium ( 1 H) and 0.02% deuterium ( 2 H). Thus, any hydrogen atom on a molecule synthesized using conventional reagents has, on average, about 0.02% deuterium at each hydrogen atom position. Thus, it will be understood by those skilled in the art that when referring to a chemical structure having a CD bond or "D" atom as described herein, this means that the enrichment of said position of the molecule has a natural abundance of deuterium exceeding 0.02%. Thus, the label "D" on the molecule indicates, for example, at least 0.1% deuterium or at least 1% deuterium or at least 10% deuterium. Preferably, any compound of the present disclosure has greater than 50% deuterium incorporation (i.e., greater than 50 atomic % D) at each designated "D" atom position of the compound structure, such as greater than 60% or greater than 70% or greater than 80% or greater than 90% or greater than 95% or greater than 96% or greater than 97% or greater than 98% or greater than 99%.

[0205] The term "pharmaceutically acceptable diluent or carrier" is intended to mean diluents and carriers used in pharmaceutical preparations and do not contain substances that are allergenic, pyrogenic or pathogenic and are known to cause or promote disease. Thus, a pharmaceutically acceptable diluent or carrier excludes body fluids, such as blood, urine, cerebrospinal fluid, saliva, etc., and their constituents, such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in several well-known works on pharmaceutical formulations, such as Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, 10th edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th edition, McGraw Hill, 2001; Remington's Pharmaceutical Sciences, 20th edition, Lippincott Williams & Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, 32nd edition (The Pharmaceutical Sciences). Press, London, 1999); all of which are incorporated herein by reference in their entirety.

[0206] The term "purified", "purified form" or "isolated and purified form" of a compound refers to the physical state of the compound after isolation from a synthetic method (e.g., from a reaction mixture) or a natural source, or a combination thereof. Thus, the term "purified", "purified form" or "isolated and purified form" of a compound refers to the physical state of the compound after obtaining it from a purification method or methods described herein or well known to those skilled in the art (e.g., chromatography, recrystallization, LC-MS and LC-MS / MS techniques, etc.), which is sufficiently pure to be characterized by standard analytical techniques described herein or well known to those skilled in the art.

[0207] Unless otherwise indicated, the compounds of the present disclosure, such as compounds I or 1.1-1.25, may exist in free form or in salt form, such as in the form of acid addition salts. Acid addition salts of compounds of the present invention having sufficient basicity are, for example, acid addition salts formed with, for example, inorganic acids or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, toluenesulfonic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. In addition, salts of compounds of the invention having sufficient acidity are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases providing physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)-amine. In a specific embodiment, the salt of the compound of the invention is an acid addition salt of toluenesulfonic acid.

[0208] The compounds of the present disclosure are intended for use as pharmaceuticals, and pharmaceutically acceptable salts are therefore preferred. Salts that are not suitable for pharmaceutical applications may be useful, for example, for isolating or purifying free compounds of the present disclosure, and are therefore also included within the scope of the compounds of the present disclosure.

[0209] The compounds of the present disclosure may contain one or more chiral carbon atoms. Therefore, the compounds exist in the form of each isomeric form, such as enantiomers or diastereomeric forms, or in the form of a mixture of each form, such as a racemic / diastereomeric mixture. There may be any isomer in which the asymmetric center is (R)-, (S)- or (R, S)-configuration. It should be understood that the present invention includes each optical isomer and a mixture thereof (e.g., a racemic / diastereomeric mixture). Therefore, the compounds of the present invention may be a racemic mixture, or it may exist mainly, for example, in a pure or substantially pure isomeric form, for example, greater than 70% enantiomeric / diastereomeric excess ("ee"), preferably greater than 80% ee, more preferably greater than 90% ee, and most preferably greater than 95% ee. The purification of the isomers and the separation of the isomeric mixtures may be carried out by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed, etc.).

[0210] Geometric isomers as substituents about double bonds or rings may exist in either cis (Z) or trans (E) form, and both isomeric forms are encompassed within the scope of the present invention.

[0211] It is also contemplated that the compounds of the present disclosure contain stable and unstable isotopes thereof. Stable isotopes are non-radioactive isotopes that contain an additional neutron compared to the abundant nuclide of the same species (i.e., element). It is expected that the activity of compounds containing such isotopes will be retained, and such compounds can also be used to measure the pharmacokinetics of non-isotopic analogs. For example, a hydrogen atom at a certain position on a compound of the present disclosure can be replaced by deuterium (a stable isotope that is non-radioactive). Examples of known stable isotopes include, but are not limited to, deuterium, 13 C. 15 N. 18 O. Alternatively, an unstable isotope containing an additional neutron compared to the abundant nuclide of the same species (i.e., element), such as 123 I. 131 I. 125 I. 11 C. 18 F can replace the corresponding abundant species of I, C and F. Another example of a useful isotope of a compound of the present invention is 11 These radioactive isotopes can be used for radioimaging and / or pharmacokinetic studies of the compounds of the invention.

[0212] Thus, in addition to the deuterated forms specifically provided within the scope of the compounds of Formula I, the present disclosure also contemplates compounds of Formula I in which one or more carbon atoms, nitrogen atoms, or oxygen atoms are replaced by stable or unstable isotopic variants (e.g. 11 C. 13 C. 15 N. 18 O. 18 F), and in addition, one or more of the hydrogen atoms are deuterated ( 3 These compounds are useful, for example, for structural determination (e.g., by nuclear magnetic resonance or mass spectrometry) and for the purpose of radioactive imaging studies to elucidate metabolic and excretion pathways and to determine the clearance rate of potential drug candidates.

[0213] The compounds of the present disclosure may be included in the form of a depot formulation, for example, by dispersing, dissolving or encapsulating the compounds of the present invention in a polymer matrix described in any one of Compositions 3 and 3.1-3.4, so that the compounds are continuously released as the polymer degrades over time. The release of the compounds of the present invention from the polymer matrix provides controlled release and / or delayed release and / or sustained release of the compounds, for example, from the drug depot composition into an individual to which it is administered, such as a warm-blooded animal, such as a human. Thus, the drug depot delivers the compounds of the present invention to an individual at a concentration effective for treating a particular disease or medical condition over a sustained period of time, such as 14-180 days, preferably about 30 days, about 60 days or about 90 days.

[0214] The polymer matrix used in the composition of the present invention (e.g., the depot composition of the present invention) may 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), polymers of α-cyanoacrylate alkyl esters (e.g., poly(2-cyanoacrylate butyl ester)), polyalkylene oxalate (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyoxyethylene oxalate (e.g., polyoxypropylene oxalate or polyoxybutylene oxalate), polyoxyethylene oxalate (e.g., polyoxypropylene oxalate or polyoxybutylene oxalate), polyoxyethylene oxalate (e.g., polyoxypropylene oxalate or polyoxybutylene oxalate), polyoxyethylene oxalate (e.g., polyoxyethylene oxalate or polyoxyethylene ... Poly(oxalate)), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene propylene carbonate), polyorthocarbonates, polyamino acids (e.g., poly-γ-L-alanine, poly-γ-benzyl-L-glutamic acid or poly-y-methyl-L-glutamic acid), hyaluronates, etc., and one or more of these polymers can be used.

[0215] If the polymer is a copolymer, they can be any of random, block and / or graft copolymers. When the above-mentioned α-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity in their molecules, any of the D-isomers, L-isomers and / or DL-isomers can be used. Among them, α-hydroxycarboxylic acid polymers (preferably lactic acid-glycolic acid polymers), their esters, poly-α-cyanoacrylates, etc. can be used, preferably lactic acid-glycolic acid copolymers (also known as poly (lactide-α-glycolide) or poly (lactic acid-co-glycolic acid), and hereinafter referred to as PLGA). Therefore, in one aspect, the polymer used for the polymer matrix is ​​PLGA. The term PLGA used herein includes polymers of lactic acid (also known as polylactide, poly (lactic acid) or PLA). Most preferably, the polymer is a biodegradable poly (d, l-lactide-co-glycolide) polymer.

[0216] In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymer material. The term "biocompatibility" is defined as a polymer material that is non-toxic, non-carcinogenic and does not significantly induce inflammation in body tissues. The matrix material should be biodegradable, wherein the polymer material should be degraded into products that are easily disposed of by the body through body processes and should not accumulate in the body. Since the polymer matrix is ​​biocompatible with the body, the biodegradable product should also be biocompatible with the body. Examples of particularly useful polymer matrix materials include poly (glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid, copolymers of the above substances, poly (aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly (orthocarbonates), poly (acetals), poly (lactic acid-caprolactone), polyorthoesters, poly (glycolic acid-caprolactone), polyanhydrides and natural polymers, including albumin, casein and waxes, such as glycerol monostearate and distearate, etc. The preferred polymer for use in the practice of the present invention is dl-(polylactide-co-glycolide). Preferably, the molar ratio of lactide to glycolide in such copolymers is from about 75:25 to about 50:50.

[0217] Useful PLGA polymers can have a weight average molecular weight of about 5,000-500,000 daltons, preferably about 150,000 daltons. Depending on the degradation rate to be achieved, polymers of different molecular weights can be used. For the diffusion mechanism of drug release, the polymer should remain intact until all drugs are released from the polymer matrix and then degraded. Drugs can also be released from the polymer matrix along with the bioerosion of the polymer excipient.

[0218] PLGA can be prepared by any conventional method or can be commercially available. For example, PLGA can be produced from cyclic lactide, glycolide, etc. by ring-opening polymerization using a suitable catalyst (see EP-0058481B2; Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

[0219] It is believed that PLGA is biodegradable by degradation of the entire solid polymer composition due to the hydrolyzable and enzymatically cleavable ester bonds breaking down under biological conditions (e.g., in the presence of water and biological enzymes found in warm-blooded animals such as humans) to form lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic normal metabolites that can be further biodegraded into carbon dioxide and water. In other words, it is believed that PLGA degrades by hydrolysis of its ester groups in the presence of water, such as in the presence of water in warm-blooded animals such as the human body, thereby producing lactic acid and glycolic acid and generating an acidic microenvironment. Lactic acid and glycolic acid are byproducts of different metabolic pathways under normal physiological conditions in warm-blooded animals such as humans, and are therefore well tolerated and produce minimal systemic toxicity.

[0220] In another embodiment, the polymer matrix used for the present invention can include star polymers, wherein the structure of the polyester is star-shaped. These polyesters have a single polyol residue, which, as a central part, is surrounded by an acid residue chain. The polyol moiety can be, for example, glucose or, for example, mannitol. These esters are known and are described in GB 2,145,422 and U.S. Patent No. 5,538,739, the contents of which are incorporated herein by reference.

[0221] Star polymers can be prepared using polyhydroxy compounds, such as polyols, such as glucose or mannitol as starting materials. The polyol contains at least 3 hydroxyl groups and has a molecular weight of up to about 20,000 Daltons, wherein at least 1, preferably at least 2, for example an average of 3 hydroxyl 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 portion with radial linear polylactide chains.

[0222] The depot compositions of the invention described above (e.g., compositions 6 and 6.1-6.10, in a polymer matrix) may comprise a polymer in microparticle or nanoparticle form or in liquid form, in which the compound of the invention is dispersed or encapsulated. "Microparticles" means containing the compound of the invention in solution or in solid form, wherein such compound is dispersed or dissolved in a polymer used as a particle matrix. By appropriate selection of polymer materials, microparticle formulations may be prepared in which the resulting microparticles exhibit both diffusional release and biodegradation release properties.

[0223] When the polymer is in the form of microparticles, any suitable method can be used, such as by solvent evaporation or solvent extraction method to prepare microparticles. 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., ketones such as acetone, halogenated hydrocarbons such as chloroform or dichloromethane, halogenated aromatic hydrocarbons, cyclic ethers such as dioxanes, esters such as ethyl acetate, nitriles such as acetonitrile, or alcohols such as ethanol) and dispersed in an aqueous phase containing a suitable emulsion stabilizer (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 generated to obtain microparticles in which the compound of the present invention is encapsulated. Spray drying is an alternative production technology for preparing microparticles.

[0224] Another method for preparing microparticles of the present invention is also described in US Pat. No. 4,389,330 and US Pat. No. 4,530,840.

[0225] Microparticles of the present invention can be prepared by any method that can produce microparticles with acceptable size ranges for use in injectable compositions. A preferred preparation method is the method described in U.S. Patent No. 4,389,330. In this method, the activating agent is dissolved in or dispersed in a suitable solvent. A polymer matrix material is added to the medium containing the activating agent in an amount that provides a product with a desired activating agent load relative to the active ingredient. Optionally, all ingredients of the microparticle product can be mixed in a solvent medium.

[0226] Solvents for the compounds and polymer matrix materials of the present invention that can be used to implement the present invention include organic solvents such as acetone; halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols such as benzyl alcohol; ethyl acetate, etc. In one embodiment, the solvent used to implement the present invention can be a mixture of benzyl alcohol and ethyl acetate. Additional information for preparing microparticles that can be used in the present invention can be found in U.S. Patent Publication No. 2008 / 0069885, the contents of which are incorporated herein by reference in their entirety.

[0227] The amount of the compound of the present invention incorporated into the microparticles is generally in the range of about 1 wt% to about 90 wt%, preferably 30-50 wt%, more preferably 35-40 wt%. wt% refers to the fraction of the compound of the present disclosure per total weight of the microparticles.

[0228] The drug reservoir may comprise a pharmaceutically acceptable diluent or carrier, such as a water-miscible diluent or carrier.

[0229] A detailed description of osmotic-controlled release oral delivery system compositions can be found in EP 1 539 115 (US Publication No. 2009 / 0202631) and WO 2000 / 35419 (US 2001 / 0036472), the contents of each of which are incorporated herein by reference in their entirety.

[0230] A "therapeutically effective amount" is any amount of a compound of the invention (eg, contained in a drug depot) that when administered to a subject suffering from a disease or disorder is effective to cause reduction, alleviation or regression of the disease or disorder over the intended treatment period.

[0231] The dosage for implementing the present invention will of course vary according to, for example, the specific disease or condition to be treated, the specific compound of the present invention used, the mode of administration and the desired treatment. Unless otherwise indicated, the amount of the compounds of the present invention (whether used as free alkali or salt) refers to or is based on the amount of the compounds of the present invention in free alkali form (i.e., an amount calculated based on the amount of the free alkali).

[0232] The compounds of the invention may be administered by any satisfactory route, including oral administration, parenteral (intravenous, intramuscular or subcutaneous) administration or transdermal administration, but oral administration is preferred. In some embodiments, the compounds of the invention, such as the compounds of the invention in a depot formulation, are preferably administered parenterally, such as by injection.

[0233] In general, satisfactory results are shown for methods 1 and 1.1-1.31, methods 2 and 2.1-2.10 and methods 3 and 3.1-3.40 or the use of the compounds of the present disclosure as described above, e.g., for use in treating a combination of diseases, e.g., a combination of at least depression, psychosis, e.g., (1) psychosis in patients suffering from depression, e.g., schizophrenia; (2) depression in patients suffering from psychosis, e.g., schizophrenia; (3) mood disorders associated with psychosis, 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 as listed above, at a dosage of about 1 mg-100 mg (once daily), preferably about 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg (once daily), when administered orally (preferably orally).

[0234] It is indicated that oral administration of a compound of the invention in a dosage of about 2.5 mg to 5 mg, e.g., 2.5 mg, 3 mg, 4 mg or 5 mg, in free form or in pharmaceutically acceptable salt form, gives satisfactory results for Method 2 or 2.1 to 2.10, or the use of a compound of the invention as described above, e.g., as a single agent for the treatment of sleep disorders, once a day, preferably by oral administration, is obtained.

[0235] For any one of Method IA or Method II-A or 3.1-3.40, satisfactory results are shown to be obtained at less than 100 mg, preferably less than 50 mg, for example 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 a day). For any one of Method II-A or 3.1-3.40, satisfactory results are shown to be obtained at less than 5 mg, preferably less than 2.5 mg.

[0236] For treatment of the disorders disclosed herein where a depot formulation is used to achieve a longer duration of action, the dosage is higher than for shorter acting compositions, e.g., above 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or above 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 particle size. In the case where the composition of the invention is a depot composition, it is preferably administered by injection.

[0237] The pharmaceutically acceptable salt of the disclosed compounds can be synthesized by a parent compound containing an alkaline or acidic part by conventional chemical methods. Generally, such salts can be prepared by reacting the free alkali form of these compounds with a stoichiometric appropriate acid in water or an organic solvent or in two mixtures (usually a non-aqueous medium, preferably such as ether, ethanol, ethyl acetate, isopropanol or acetonitrile). The further details of preparing these salts, such as tosylate in amorphous or crystalline form, can be found in PCT / US08 / 03340 and / or U.S. Provisional Application No. 61 / 036,069 (each equivalent to US 2011 / 112105).

[0238] Pharmaceutical compositions comprising the compounds of the present disclosure may be prepared using conventional diluents or excipients (examples include, but are not limited to, sesame oil) and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.

[0239] Preparation method of the compound of the present invention:

[0240] The synthesis methods of compounds of formula A and B including intermediates thereof have been disclosed in International Application PCT / US2017 / 15178 published as WO 2017 / 132408 and U.S. Patent Publication No. US 2017 / 319580.

[0241] The basic parent core of other compounds of the present disclosure can be made by similar methods disclosed in the above-mentioned reference publications and known to those skilled in the art. When deuterated reagents are available, specific deuterated compounds of the present disclosure can usually be prepared in a similar manner by replacing non-deuterated reagents with commercially available deuterated reagents.

[0242] The separation or purification of diastereoisomers of the compounds of the present invention can be achieved by conventional methods known in the art, such as column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving bed and the like.

[0243] Salts of the disclosed compounds may be prepared in a manner similar to that described in U.S. Patent Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; USRE39680; USRE39679; and WO 2009 / 114181 (US 2011 / 112105), the contents of each of which are incorporated by reference in their entirety.

[0244] The diastereomers of the compounds can be prepared, for example, by using AY-H, 5μ, 30x250mm was separated by HPLC and eluted with 10% ethanol / 90% hexane / 0.1% dimethylethylamine. A peak could be detected at 230nm, yielding diastereomers with 98-99.9% ee.

[0245] Example 1: Synthesis of (6bR, 10aS)-1,1-d2-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0246]

[0247] Step 1: To a degassed mixture of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (1.60 g, 8.0 mmol), 2-chloro-2,2-bis-deuteroacetamide (2.5 g, 26 mmol) and KI (2.68 g, 16 mmol) in dioxane (30 mL) was added diisopropylethylamine (3.0 mL, 16 mmol) at room temperature. The reaction mixture was then heated to 104°C with vigorous stirring for 5 days. The solvent was removed in vacuo and the residue was suspended in dichloromethane (50 mL) and extracted with water (20 mL). The organic phase was separated, dried over anhydrous K2CO3 and concentrated to give a residue. The product was purified by silica gel column chromatography using a 0-100% ethyl acetate gradient in hexanes to give (4aS,9bR)-ethyl 5-(2-amino-1,1-d2-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate as a brown oil (1.26 g, 41% yield). MS (ESI) m / z 384.1 [M+1]. The synthesis of the starting material is disclosed in US 2010 / 113781. The reaction scheme is shown below:

[0248]

[0249] Step 2: To a degassed mixture of the product from step 1 (1.26 g, 3.3 mmol), K2CO3 (1.0 g, 6.0 mmol), CuI (132 mg, 0.69 mmol) in dioxane (6 mL) was added N,N,N,N'-tetramethylethylenediamine (0.3 mL, 12.0 mmol) at room temperature. The reaction mixture was heated to 99°C and stirred at this temperature for 20 h. After cooling to room temperature, the mixture was directly applied to a silica gel column. The product was purified by silica gel column chromatography using 100% ethyl acetate to give (6bR,10aS)-ethyl 1,1-d2-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(9H)-carboxylate as a light red solid (680 mg, 68% yield). MS (ESI) m / z 318.2 [M+1] + The reaction scheme is shown below:

[0250]

[0251] Step 3: The product from step 2 (680 mg, 2.24 mmol) was suspended in HBr solution (33% in acetic acid, 10 ml) at room temperature. The mixture was heated to 70°C and stirred at 70°C for another 2 h. LC-MS confirmed the completion of the reaction. The reaction mixture was cooled to room temperature and then ice-cooled. Ethyl acetate (60 mL) was added to precipitate the product salt. The solid was filtered and dried in vacuo. The HBr salt of the product was suspended in methanol (20 mL) and cooled with dry ice and 2-propanol. Ammonia (7N in methanol) was slowly added until the pH was at or above 14. The solvent was then removed in vacuo to give the crude product (6bR,10aS)-1,1-d2-6b,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 (227 mg, yield 44%). The crude product was used in the next step without any further purification. MS (ESI) m / z 232.2 [M+1] + The reaction scheme is shown below:

[0252]

[0253] Step 4: A mixture of the crude product from step 3 (227 mg, 0.98 mmol), 1-(3-chloropropoxy)-4-fluorobenzene (320 μL, 2.0 mmol) and KI (330 mg, 2.0 mmol) in DMF (4 mL) was bubbled with argon for 3 min and DIPEA (350 μL, 2 mmol) was added. The resulting mixture was heated to 76° C. and stirred at this temperature for 2 h. After cooling to room temperature, the solvent was removed and the residue was purified by silica gel column chromatography using a 0-100% mixed solvent gradient [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate to give the title product as a brown solid (110 mg, 28% yield). 1 HNMR (500MHz, DMSO-d6) δ10.34 (s, 1H), 7.14-7.06 (m, 2H), 6.97-6.89 (m, 2H), 6.77 (d, J=6.7Hz, 1H), 6.64 (td, J=7.5, 1.1Hz, 1H), 6.58 (d, J=7.8Hz, 1H), 3.97 (t, J=6.4 Hz, 2H), 3.30-3.17(m, 2H), 2.92-2.81(m, 1H), 2.70-2.58(m, 1H), 2.47-2.28(m, 2H ), 2.10 (t, J=11.6Hz, 1H), 1.99-1.90 (m, 1H), 1.90-1.75 (m, 3H), 1.74-1.61 (m, 1H). MS(ESI)m / z 384.2[M+1]+ The reaction scheme is shown below:

[0254]

[0255] Example 2: Synthesis of (6bR,10aS)-8-(1,1,2,2,3,3-d6-3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0256]

[0257] Step 1: p-Fluorophenol (442 mg, 4.0 mmol), 1,3-dibromopropane-d6 (1.02 g, 4.9 mmol) and K2CO3 (608 mg, 4.4 mmol) were added to degassed CH3CN (5 mL) with stirring. The resulting mixture was heated to 80°C and stirred at 80°C overnight. After cooling to room temperature, the solvent was removed, the residue was suspended in dichloromethane (50 mL) and extracted with water (20 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL). The combined organic phases were dried over anhydrous Na2CO3 and concentrated to give a crude product of 1-(3-bromo-1,1,2,2,3,3-d6-propoxy)-4-fluorobenzene as a colorless oil. 0.98 g of crude product was obtained, which was used directly in the next step without further purification. The reaction scheme is shown below:

[0258]

[0259] 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 HBr salt (900 mg, 2.9 mmol), 1-(3-bromo-1,1,2,2,3,3-d6-propoxy)-4-fluorobenzene (500 mg, 2.1 mmol) and potassium iodide (500 mg, 3.6 mmol) in DMF (5 mL) was bubbled with argon for 3 min and di-isopropylethylamine (550 μL, 3.16 mmol) was added. The resulting mixture was heated to 78° C. and stirred at this temperature for 2 h. After cooling to room temperature, the solvent was removed and the residue was suspended in dichloromethane (50 mL) and extracted with water (20 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL). The organic phase was dried and concentrated using anhydrous NaCO. The final product was purified by silica gel column chromatography using a 0-80% mixed solvent gradient [ethyl acetate / methanol / 7N NH (10: 1: 0.1 v / v)] in ethyl acetate to obtain the title product as a light brown solid (400 mg, 49% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.73 (s, 1H), 7.00-6.90 (m, 2H), 6.89-6.77 (m, 3H), 6.77-6.69 (m, 1H), 6.61 (d, J = 7.7 Hz, 1H), 3.95 (d, J = 14.5 Hz, 1H), 3.59-3.19 (m, 3H), 3.10-2.59 (m, 2H), 2.28 (s, 1H), 2.01 (t, J = 16.0 Hz, 3H). MS (ESI) m / z 388.2 [M+1] + The reaction scheme is shown below:

[0260]

[0261] Example 3: Synthesis of (6bR,10aS)-8-(1,1,3,3-d4-3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0262]

[0263] Step 1: Add p-fluorophenol (546 mg, 4.9 mmol), 1,3-dibromo-1,1,3,3-d4-propane (1.1 g, 5.4 mmol) and K2CO3 (730 mg, 5.4 mmol) to degassed CH3CN (5 mL) with stirring. The resulting mixture was heated to 80°C and stirred at 80°C for 21 h. After cooling to room temperature, the solvent was removed, and the residue was suspended in dichloromethane (50 mL) and extracted with water (20 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL). The combined organic phases were dried over anhydrous MgSO4 and concentrated to give the crude product 1-(3-bromo-1,1,3,3-d4-propoxy)-4-fluorobenzene as a light yellow oil (0.82 g). It was used directly in the next step without further purification. The reaction scheme is shown below:

[0264]

[0265] Step 2: A mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-d1-quinoxalin-2(3H)-one (930 mg, 4.1 mmol), 1-(3-bromo-1,1,3,3-d4-propoxy)-4-fluorobenzene (500 mg, 2.1 mmol) and potassium iodide (560 mg, 3.4 mmol) in DMF (5 mL) was purged with argon for 3 min and dipropylethylamine (550 μL, 3.2 mmol) was added. The resulting mixture was heated to 78°C and stirred at this temperature for 2 h. After cooling to room temperature, the solvent was removed and the residue was suspended in dichloromethane (50 mL) and extracted with water (20 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL x 2). Use anhydrous MgSO4 dry the combined organic phase, concentrate.By silica gel column chromatography purification final product, use 0-80% mixed solvent gradient [ethyl acetate / methanol / 7N NH3 (10: 1: 0.1 v / v)] in ethyl acetate, use basic alumina column chromatography to further purify product, use 0-100% mixed solvent gradient [ethyl acetate / methanol (20: 1 v / v)] in ethyl acetate.Obtain title product, be white solid (248mg, yield 31%). 1H NMR (500MHz, chloroform-d) δ7.80 (s, 1H), 7.01-6.88 (m, 2H), 6.87-6.77 (m, 3H), 6.73 (t, J=7.6Hz, 1H), 6.59 (dd, J=7.8, 1.0Hz, 1H), 3.96 (d, J=14.6H z, 1H), 3.39 (d, J=14.5Hz, 1H), 3.37-3.24 (m, 2H), 2.92 (d, J=9.9Hz, 1H), 2.74 (s, 1H), 2.25 (d, J=14.3Hz, 1H), 1.98 (dd, J=37.6, 12.2Hz, 5H). MS(ESI)m / z 386.2[M+1] + The reaction scheme is shown below:

[0266]

[0267] Example 4: 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]quinoxaline-2(3H)-one (compound of formula A) and 4-((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-yl-1-(4-fluoro-phenyl)-butan-1-one (compound of formula B)

[0268] US 2017 / 319580 discloses therein the synthesis of compounds of formula A and B as Examples 3 and 1, respectively:

[0269]

[0270] Compounds of Formula A and B are prepared from ethyl (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-carboxylate. The carbamate is first deprotected using HBr / acetic acid solution. The resulting amine is then reacted with a suitable alkylating agent (1-(3-chloropropoxy)-4-fluorobenzene for compounds of Formula A; 4-chloro-4′-fluorobutyrophenone for compounds of Formula B) to give the desired product.

[0271] Example 5: Experimental characterization 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 (compound of formula A) and 4-((6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl-1-(4-fluoro-phenyl)-butan-1-one (compound of formula B)

[0272] US2017 / 319580 discloses several experimental data, and the pharmacological properties of compounds of formula A and B are evaluated in Examples 1-10 therein. In addition, U.S. Provisional Application No. 62 / 639,244 (and WO 2019 / 023062) disclose additional properties of these compounds. These disclosures are summarized as follows.

[0273] The compound of formula B was subjected to cellular and nuclear receptor functional assays to determine the agonist and antagonist effects of the compound on the human μ-opioid receptor. The compound was found to have an antagonist effect of IC 50 1.3x10 -6 M and K B 1.4x10 -7 M.

[0274] Compounds of Formula B were subjected to receptor binding characterization studies, where results were expressed as a percentage of control specific binding and IC was determined by nonlinear regression analysis. 50 Value and Hill coefficient (nH). The following receptor affinity results were obtained:

[0275]

[0276] In addition, in the agonist and antagonist functional receptor activity assay, the compounds of formula A and B were compared with buprenorphine (μ-opioid partial agonist), naloxone (μ-opioid antagonist) and DAMGO (μ-opioid full agonist) using CHO-K1 cells expressing human μ-opioid receptors (μ1 subtype). The results are shown in the table below. The results show that the compound of formula A is a weak antagonist of the μ receptor, which shows a much higher IC than naloxone. 50 , and moderately high affinity, while being a partial agonist, showing only about 22% agonist activity relative to DAMGO (compared to about 79% activity of buprenorphine relative to DAMGO). The compound of formula B was also demonstrated to have moderately potent partial agonist activity.

[0277] Compound Antagonist IC50 (nM) Agonist EC50 (nM) KB(nM) Naloxone 5.80 - 0.65 DAMGO - 1.56 - Buprenorphine - 0.95 - Formula A 641 64.5 71.4 Formula B - 140 -

[0278] Compounds of formula A and B were also studied in a mouse DOI-induced head twitch model. R-(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) is a serotonin 5-HT2 receptor family agonist. When administered to mice, it produces behavioral characteristics associated with frequent head twitches. The frequency of these head twitches during a predetermined time period can be considered as an estimate of the 5-HT2 receptor agonism or antagonism in the brain. When administered orally to mice 30 minutes after subcutaneous injection of DOI, the following results were obtained, which show that both compounds can effectively block DOI-induced head twitches:

[0279] Compound <![CDATA[EC 50 (mg / kg,p.o.)]]> Formula B 0.23 Formula A 0.44

[0280] Compounds of formula A and B are also studied in the mouse tail-flick test, which is an analgesic measure indicated by the pain reflex threshold of constrained mice. The tail of male CD-1 mice is placed under a focused beam of a high-intensity infrared heat source, causing the tail to heat up. The time (latency) from turning on the heating apparatus to the tail of the mouse being separated from the path of the heat source is recorded. The use of morphine can cause analgesia, and this can delay the reaction of mice to heating (increase the latency). Prior application of morphine (MOR) antagonists, i.e. naloxone (NAL), can reverse this effect and cause normal latency. The test is used as a functional assay for the antagonism of μ-opioid receptors. The first group of mice was a negative control, receiving a vehicle 60 minutes and 30 minutes before the test. The second and third groups of mice were positive controls, receiving a vehicle before the test, followed by morphine, or naloxone, followed by morphine. Groups 4, 5 and 6 of mice were study subjects and received one of three doses of the compound of formula A or B 60 minutes before the test and morphine 30 minutes before the test. The results of the study are shown as the following average tail-flick latency in seconds:

[0281]

[0282] A second similar mouse tail-flick study was performed to examine the effects on mice treated with naloxone prior to treatment with three different doses of the compound of Formula A. The results are shown in the table below as mean latency in seconds:

[0283]

[0284] The first study showed that both compounds of formula A and B had a dose-dependent blocking effect on morphine-induced μ-opioid receptor activity. The second study showed that higher doses of the compound of formula A exerted dose-dependent μ-opioid agonist activity. Therefore, these compounds are partial agonists and partial antagonists of the μ-opioid receptor.

[0285] Compounds of formula A and B were also evaluated in a mouse CNS phosphoprotein characterization assay. The extent of protein phosphorylation of selected key central nervous system proteins in the mouse nucleus accumbens was determined. The proteins examined included ERK1, ERK2, Glu1, NR2B, and TH (tyrosine hydroxylase), and the results were compared with the antipsychotic drugs risperidone and haloperidol. The results showed that the compound of formula A and the compound of formula B had no significant effect on TH phosphorylation or NR2B phosphorylation, and they had no marginal effect on GIuR1 and ERK2 phosphorylation. In contrast, haloperidol increased TH phosphorylation by 400-500%, suggesting that the compounds of formula A and B do not disrupt dopamine metabolism.

[0286] Compounds of formula A were also studied in the mouse marble burying model of OCD. The marble burying test is used to measure repetitive and anxiety-related behaviors in rodents. Based on observation, rats and mice bury harmful or harmless objects in their bedding, and have been used as animal models to measure the effects of pharmacological interventions in the treatment of repetitive behavior disorders (such as OCD). A selective mGluR5 glutamate receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) was used as a positive control. The desired drug was administered to mice and placed in a cage filled with marbles and bedding, and the number of marbles buried by the mice was measured after 30 minutes. The results are shown in the table below, and demonstrate the dose-dependency of the reduction of compound of formula A in OCD symptoms.

[0287] Group Buried Marble (1) Solvent 13.2 (2) 0.3 mg / kg Formula A 9.3 (3) 1.5 mg / kg Formula A 4.7 (4)MPEP 0.2

[0288] The compound of formula A was further evaluated during the daily repetition (28 days) subcutaneous administration of male Sprague-Dawley rats to monitor the effect of the drug on the dosage and determine whether pharmacological tolerance occurs.Morphine was used as a positive control to ensure the verifiability of the model and as a reference comparator of similar pharmacological categories.The results show that the compound of Example 3 was repeatedly administered 4 times at 0.3 and 3 mg / kg, and no tolerance was produced during 28 days of subcutaneous administration.In addition, after drug withdrawal, similar but gradually decreasing characteristics of behavior and physical symptoms were observed at the highest dose, but this was not considered to be clinically significant.Therefore, it was found that the compound of Example 3 generally does not produce a syndrome of physical dependence when administration is stopped.On the contrary, in this study, repeated administration of morphine showed obvious signs of tolerance and dependence, wherein the changes in body weight, food and water intake, rectal temperature and clinical signs were consistent with the dependence induced by tolerance and withdrawal.

[0289] The compound of formula A was also evaluated in an oxycodone-dependent withdrawal study in mice. Oxycodone was administered to mice in increasing doses over 8 days to induce physical dependence. At night, the compound of formula A was administered to the mice at one of two doses, followed by injection of vehicle or naloxone. The mice were then monitored for signs and symptoms of opioid withdrawal. The results showed that the compound of formula A reduced the signs and symptoms of opioid withdrawal in a dose-dependent manner after opioid-dependent rats suddenly stopped administering opioids.

[0290] The compounds of formula A were also evaluated in the mouse formalin paw test, a model of inflammatory pain. Subcutaneous injection of a 2.5% formalin solution into the mouse hind paw results in a biphasic response: an acute pain response and a delayed inflammatory response. Thirty minutes prior to formalin challenge, the same paw was pretreated with one of three doses of vehicle, morphine, or a compound of formula A subcutaneously. The results showed that the compounds of formula A attenuated both the early acute pain response and the late delayed inflammatory response in a dose-dependent manner, to an extent comparable to that of the morphine positive control.

[0291] Example 6: (6bR, 10aS)-8-(3-(2,3,5,6-tetradeuterated-4-fluorophenoxy)propyl)-

[0292] 6b,7,8,9,10,10a-Hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0293]

[0294] Under stirring, p-fluorophenol-d5 (250 mg, 2.13 mmol) was added to degassed DMF (2 mL). The obtained solution was cooled and 5 min. NaH (≈70 mg, 95%) was added to the above solution at one time, and the mixture was stirred at room temperature for 10 min. A solution of 1,3-dibromopropane (650 μL) in DMF (2 mL) was added dropwise. The mixture was stirred at room temperature for 3.5 hours and then stirred at 75 ° C overnight. The reaction mixture was cooled and then filtered. The filtrate was concentrated and the crude product obtained was purified by silica gel column chromatography using a gradient of 0-10% ethyl acetate in hexane to obtain 1- (3-bromopropoxy) -4-fluoro-2,3,5,6-d4-benzene as a colorless oil (60 mg, yield 12%).

[0295] 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 (230 mg, 1.0 mmol), 1-(3-bromopropoxy)-4-fluoro-2,3,5,6-d4-benzene (60 mg, 0.25 mmol) and KI (49 mg, 0.35 mmol) in DMF (4 mL) was bubbled with argon for 3 min, then DIPEA (50 μL, 0.28 mmol) was added. The resulting mixture was heated to 76° C. and stirred at this temperature for 2 h. After cooling to room temperature, the solvent was removed and the residue was purified by silica gel column chromatography using a 0-100% mixed solvent gradient [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate to give the title product as a white solid (35 mg, yield 9.1%). 1 H NMR (500MHz, DMSO-d6) δ10.34 (s, 1H), 6.77 (dd, J=7.2, 1.0Hz, 1H), 6.63 (t, J=7. 5Hz, 1H), 6.58 (dd, J=7.8, 1.1Hz, 1H), 3.97 (t, J=6.4Hz, 2H), 3.80 (d, J=14.6Hz, 1 H), 3.30-3.14(m, 3H), 2.92-2.80(m, 1H), 2.70-2.59(m, 1H), 2.46-2.30(m, 2H), 2.16-2.04 (m, 1H), 2.01-1.90 (m, 1H), 1.90-1.74 (m, 3H), 1.68 (t, J=11.0Hz, 1H). MS(ESI)m / z 386.2[M+1] + .

[0296] Example 7: Synthesis of (6bR,10aS)-8-(3,3-dideuterated-3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0297]

[0298] Step 1: 3-(Benzyloxy)propionic acid (3.2 g, 17.7 mmol) was added in portions to a mixture of LiAID4 (850 mg, 20.2 mmol) in THF (25 mL) at 0°C with vigorous stirring. The mixture temperature was kept below 5°C during the addition. The mixture was then stirred at room temperature overnight and cooled to 0°C. Water (0.85 mL) and NaOH (15%, 0.85 mL) were slowly added to stop the reaction. The solvent was removed, the residue was diluted with dichloromethane (100 mL) and dried over MgSO4. MgSO4 was filtered and the filtrate was evaporated to dryness. The product 3-(benzyloxy)-1,1-dideuterated propan-1-ol was obtained as a light yellow solid (2.86 g, 96% yield). The product was used directly in the next step without further purification.

[0299] Step 2: The crude product 3-(benzyloxy)-1,1-bis-deuterated propan-1-ol (2.4 g, 14.3 mmol) from step 1 was dissolved in THF (30 mL), p-fluorophenol (1.6 g, 14.3 mmol) was added, and then PPh3 (3.75 g, 14.3 mmol) was added. Diethyl azodicarboxylate (2.3 mL, 14.6 mmol) was slowly added dropwise to the mixture under stirring. The mixture temperature was maintained at 40-50° C. during the addition. After stirring at room temperature overnight, the reaction mixture was evaporated to dryness. The residue was purified by silica gel column chromatography using a gradient of 0-15% ethyl acetate in hexane as the eluent. The product 1-(3-(benzyloxy)-1,1-bis-deuterated propoxy)-4-fluorobenzene was obtained as a light yellow solid (1.89 g, 50% yield).

[0300] Step 3: Palladium on activated carbon (10%, 0.5 g) was added to a solution of 1-(3-(benzyloxy)-1,1-bis-deuterated propoxy)-4-fluorobenzene (1.89 g, 7.2 mmol) in methanol (45 mL) at room temperature. The mixture was degassed, backfilled with hydrogen three times, and then stirred at room temperature in a hydrogen atmosphere for 12 h. After the reaction was complete, the solid was filtered and the filtrate was evaporated to dryness. The residue was dissolved in dichloromethane (40 mL) and N,N-diisopropylethylamine (1.7 mL, 11 mmol). The reaction mixture was cooled to 0°C and methanesulfonyl chloride (0.65 mL, 7.9 mmol) was added dropwise over 1 minute. The reaction mixture was then gradually warmed to room temperature with stirring. After stirring at room temperature for 0.5 h, the reaction was stopped with water (20 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was evaporated to dryness to obtain the crude product 3,3-dideuterated-3-(4-fluorophenoxy)propyl methanesulfonate (1.93 g, yield 100%). The product was used directly in the next step without further purification. MS (ESI) m / z 251.2 [M+H] + .

[0301] Step 4: A mixture of crude methanesulfonic acid (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (520 mg, 2.3 mmol) and 3,3-dideutero-3-(4-fluorophenoxy)propyl ester (530 mg, 2.1 mmol) in DMF (4 mL) was bubbled with argon for 3 min and DIPEA (500 μL, 2.6 mmol) was added. The resulting mixture was heated to 78°C and stirred at this temperature for 2 h. The mixture was then cooled to room temperature and the DMF was removed. The residue was treated with dichloromethane (30 mL) and extracted with water (10 mL). The organic phase was separated, dried over K2CO3 and filtered. The filtrate was concentrated and purified by semi-preparative HPLC using a gradient of 0-20% acetonitrile in water containing 0.1% formic acid as eluent to afford the title product as a green solid (121 mg, 14% yield). 1 H NMR (500MHz, DMSO-d6) δ10.35 (s, 1H), 7.09 (dd, J=9.8, 7.9Hz, 2H), 6.97-6.88 (m, 2H), 6.77 (dd, J=7.2, 1.1Hz, 1H), 6.63 (t, J=7.6Hz, 1H), 6.57 (dd, J=7.8, 1.2Hz, 1H), 3.80 (d, J=14.6Hz, 1H), 3.33-3.27 (m, 1 H), 3.27-3.16 (m, 2H), 2.86 (dd, J=11.5, 6.3Hz, 1H), 2.69-2.57 (m, 1H), 2.45-2.26 (m, 2H), 2.09 (td, J= 11.8, 2.5Hz, 1H), 1.94 (dt, J=14.2, 2.5Hz, 1H), 1.89-1.73 (m, 3H), 1.67 (t, J=11.0Hz, 1H).MS (ESI) m / z 396.2[M+1] + .

[0302] Example 8: Synthesis of (6bR,10aS)-1,1-dideuterated-8-(1,1,2,2,3,3-hexadeuterated-3-(2,3,5,6-tetradeuterated-4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0303]

[0304] 1,3-Dibromo-1,1,2,2,3,3-hexadeuterated propane (1.0 g, 4.8 mmol) was added to a suspension of degassed 4-fluorophenol-d5 (500 mg, 4.3 mmol) and K2CO3 (690 mg, 4.9 mmol) in acetonitrile (5 mL) under stirring. The resulting mixture was heated to 80°C and stirred overnight at this temperature. After cooling to room temperature, the reaction mixture was concentrated, the residue was suspended in water (20 mL) and extracted with dichloromethane (2×30 mL). The combined dichloromethane phases were dried over Na2CO3 and filtered. The filtrate was concentrated to give the crude product 1-(3-bromo-1,1,2,2,3,3-hexadeuterated propoxy)-2,3,5,6-tetradeuterated-4-fluorobenzene as a colorless oil (1.0 g, yield: 95%). The product was used directly in the next step without further purification.

[0305] A mixture of (6bR, 10aS)-1,1-dideutero-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, 2.2 mmol), 1-(3-bromo-1,1,2,2,3,3-hexadeuteropropoxy)-2,3,5,6-tetradeutero-4-fluorobenzene (500 mg, 2.0 mmol) and KI (380 mg, 2.3 mmol) in DMF (5 mL) was bubbled with argon for 3 min, and diisopropylethylamine (400 μL, 4.8 mmol) was added. The resulting mixture was heated to 78° C. and stirred at this temperature for 2 h. After cooling to room temperature, remove solvent, suspend the residue in dichloromethane (50mL), extract the mixture with water (20mL). Separate the aqueous phase and extract with dichloromethane (10mL). Use Na2CO3 dry the combined organic phase and filter. Concentrate the filtrate and purify it by silica gel column chromatography, using 0-100% mixed solvent gradient [ethyl acetate / methanol / 7N NH3 (10: 1: 0.1 v / v)] in ethyl acetate to obtain a brown solid (230mg). The brown product is further purified by semi-preparative HPLC, using 0-20% acetonitrile aqueous solution containing 0.1% formic acid as eluent. Obtain the title product as a white solid (80mg, 9% yield). 1H NMR (500MHz, DMSO-d6) δ10.35 (s, 1H), 6.78 (d, J=7.2Hz, 1H), 6.64 (td, J=7.5, 1.2Hz, 1H), 6.58 (dd, J=7.7, 1.1Hz, 1H), 3.30-3.25 (m, 1H), 3.22 (dt, J=10.7, 6.4Hz, 1H), 2.86 (ddt, J= 11.3, 6.2, 1.9Hz, 1H), 2.64 (ddt, J=11.4, 4.7, 2.4Hz, 1H), 2.17-2.02 (m, 1H), 1.95 (dt, J= 14.3, 2.6Hz, 1H), 1.80 (ddt, J=14.2, 12.1, 4.7Hz, 1H), 1.68 (tdd, J=10.7, 6.0, 4.4Hz, 1H). MS(ESI)m / z 394.2[M+1] + .

[0306] Example 9: Synthesis of (6bR,10aS)-1,1-dideuterated-8-(1,1,2,2,3,3-hexadeuterated-3-(4-fluorophenoxy)-propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0307]

[0308] Step 1: To a suspension of degassed 4-fluorophenol (442 mg, 4.0 mmol) and K2CO3 (608 mg, 4.4 mmol) in acetonitrile (5 mL) was added 1,3-dibromo-1,1,2,2,3,3-hexadeuterated propane (1.0 g, 4.8 mmol) under stirring. The resulting mixture was heated to 80°C and stirred at this temperature overnight. After cooling to room temperature, the reaction mixture was concentrated, the residue was suspended in water (20 mL) and extracted with dichloromethane (2×30 mL). The combined dichloromethane phases were dried over Na2CO3 and filtered. The filtrate was concentrated to give the crude product 1-(3-bromo-1,1,2,2,3,3-hexadeuterated propoxy)-4-fluorobenzene as a colorless oil (0.98 g). The product was used directly in the next step without further purification.

[0309] Step 2: A mixture of (6bR, 10aS)-1,1-dideutero-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one HBr salt (900 mg, 2.9 mmol), 1-(3-bromo-1,1,2,2,3,3-hexadeuteropropoxy)-4-fluorobenzene (500 mg, 2.1 mmol) and KI (500 mg, 3.6 mmol) in DMF (5 mL) was bubbled with argon for 3 min and diisopropylethylamine (500 μL, 3.16 mmol) was added. The resulting mixture was heated to 78° C. and stirred at this temperature for 2 h. After cooling to room temperature, the reaction mixture was evaporated to dryness. The residue was suspended in dichloromethane (50 mL) and extracted with water (20 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL). The combined organic phase was dried over NaCO and filtered. The filtrate was concentrated and purified by silica gel column chromatography using a 0-100% mixed solvent gradient [ethyl acetate / methanol / 7N NH3 (10: 1: 0.1 v / v)] in ethyl acetate to give the title compound as a light brown solid (400 mg, 49% yield). 1 H NMR (500MHz, DMSO-d6) δ10.34 (s, 1H), 7.15-7.05 (m, 2H), 6.93 (ddd, J=6.8, 5.4, 3.3H z, 2H), 6.77 (d, J=7.2Hz, 1H), 6.63 (t, J=7.5Hz, 1H), 6.58 (d, J=7.2Hz, 1H), 3.30-3.2 4 (m, 1H), 3.21 (dt, J=12.9, 6.4Hz, 1H), 2.85 (dd, J=11.1, 6.4Hz, 1H), 2.71-2.58 (m, 1 H), 2.17-2.04 (m, 1H), 1.94 (d, J=12.7Hz, 1H), 1.87-1.74 (m, 1H), 1.73-1.62 (m, 1H). MS(ESI)m / z 390.2[M+1] + .

[0310] Example 10: Receptor Binding Activity of Deuterated Compounds

[0311] The compounds of Examples 1, 3, 6, 7 and 9 and the compound of Formula A were tested in a radioligand binding assay using human recombinant ligand receptors expressed in CHO or HEK-293 cell lines. The test receptors were dopamine D1 receptor (antagonist radioligand), dopamine D 2S Receptor (agonist radioligand), μ-opioid (MOP) receptor (agonist radioligand), serotonin 5-HT 2AReceptor (agonist radioligand) and serotonin transporter (SERT) (antagonist radioligand). Binding assays were performed according to the methods described in the following table:

[0312]

[0313] 1. Zhou, QY et al., Nature 347: 76-80 (1990).

[0314] 2. Grandy, DK et al., Proc. Natl. Acad. Scis. USA, 86:9762-66 (1989).

[0315] 3. Wang, JB et al., FEBS Lett., 338: 217-22 (1994).

[0316] 4. Bryant, HU et al., Life Sci., 15: 1259-68 (1996).

[0317] 5. Tatsumi, M et al., Eur. J. Pharmacol., 368: 277-83 (1999).

[0318] For all assays performed, the detection method was scintillation counting. Results are expressed as percentage of control specific binding ([assayed specific binding] / [control specific binding]*100) and percent inhibition of control specific binding (100-[[([[assayed specific binding] / [control specific binding]*100]).

[0319] The results are shown in the following table:

[0320]

[0321]

[0322] These results indicate that the deuterated compounds of the present disclosure provide comparable in vitro pharmacological efficacy relative to their non-deuterated analogs, the compounds of Formula A. However, the data show that the pharmacological activities of the deuterated analogs, while similar, are different from those of the compounds of Formula A.

[0323] Example 11: Pharmacokinetics of Deuterated Compounds

[0324] In the first study, the compounds of Examples 2 and 8 were compared with the compound of Formula A in rats using standard methods. Each test compound was dissolved in a polyethylene glycol 400 vehicle and administered orally at a dose of 10 mg / kg or subcutaneously at a dose of 3 mg / kg. The plasma concentration of the drug was determined at time points from 0 to 72 hours after the dose. The results are summarized in the table below.

[0325]

[0326] These results indicate that improved oral pharmacokinetics were observed for the deuterated compounds of Examples 2 and 8 compared to the non-deuterated compound of Formula A. The total plasma dose obtained (as shown in AUC) was higher for the deuterated compounds, and the plasma concentration of the drug consistently showed higher levels of the deuterated compounds during the peak time period from 2 hours to 12 hours after dosing.

[0327] These results further indicate that when administered subcutaneously - a route that avoids first-pass metabolism in the liver - the differences in plasma concentration profiles between the three compounds are significantly attenuated. The deuterated compounds continue to show a slight increase in AUC when administered subcutaneously, but the difference is not significant compared to the non-deuterated compound.

[0328] Taking both the oral and subcutaneous results into account, the data suggest that deuteration limits the extent of first-pass hepatic metabolism of the claimed compounds.

Claims

1. A compound of formula I in free form or in salt form: in: R 1 C 1-4 Alkyl (e.g. methyl); Z is O or -C(O)-; R 2 and R 3 are each independently selected from H and are D (deuterium); and R 4 -R 14 Each independently is H and D; The condition is R 2 , R 14 At least one of them is D.

2. The compound according to claim 1, wherein Z is O.

3. The compound according to claim 1, wherein Z is -C(O).

4. A compound according to claim 1, 2 or 3, wherein R 1 It is methyl.

5. A compound according to any one of claims 1 to 4, wherein R 2 is H, and R 3 is D.

6. A compound according to any one of claims 1 to 4, wherein R 2 is D, and R 3 is D.

7. A compound according to any one of claims 1 to 4, wherein R 2 is H, and R 3 For H.

8. A compound according to any one of claims 1 to 7, wherein R 4 -R 7 Any one, any two, or any three of the is D.

9. A compound according to any one of claims 1 to 7, wherein R 8 -R 14 Any 1, any 2, any 3, any 4, any 5 or any 6 of the digits is D.

10. A compound according to any one of claims 1 to 7, wherein R 4 -R 7 All 4 of them are D.

11. A compound according to any one of claims 1 to 7, wherein R 8 -R 14 All 6 of them are D.

12. A compound according to any one of claims 1 to 11 in the form of a salt, such as a pharmaceutically acceptable salt.

13. A compound according to any one of claims 1 to 12 having greater than 50% (i.e., greater than 50% atomic D), such as greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99% deuterium incorporation at one or more of the indicated deuterated positions of the structure.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 in free form or in pharmaceutically acceptable salt form together with a pharmaceutically acceptable diluent or carrier.

15. The pharmaceutical composition of claim 14, wherein the composition is formulated as a long-acting injectable preparation, such as for intramuscular or subcutaneous injection.

16. A method for treating or preventing a central nervous system disorder, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 13 in free form or in pharmaceutically acceptable salt form, or a pharmaceutical composition according to any one of claims 14 to 15.

17. The method according to claim 16, wherein the disorder is selected from obesity, anxiety (including general anxiety, social anxiety and panic disorder), depression (such as refractory depression and MDD or treatment-resistant depression), psychosis (including psychosis associated with dementia, such as hallucinations in advanced Parkinson's disease or paranoid delusions), schizophrenia, sleep disorders (particularly sleep disorders associated with schizophrenia and other psychiatric and neurological diseases), sexual disorders, migraine, pain and pain-related conditions including head pain, idiopathic pain, neuropathic pain, chronic pain, fibromyalgia, chronic fatigue, agoraphobia, social phobia, agitation in dementia (such as agitation in Alzheimer's disease), autism and related autism conditions. agitation, gastrointestinal disorders, such as gastrointestinal dysmotility, and dementia, such as dementia of Alzheimer's disease and Parkinson's disease; mood disorders; drug dependence, such as opiate dependence, cocaine dependence, amphetamine dependence, and / or alcohol dependence, and withdrawal from drug or alcohol dependence (e.g., opiate dependence); comorbidities associated with drug dependence, such as depression, anxiety, and psychosis; binge eating disorder; and obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), and related disorders, such as compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, delusional disorder, pathological grooming disorder, kleptomania, pyromania, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorders, and related disorders, and combinations thereof.

18. The method according to claim 16, wherein the disorder is one involving serotonin 5-HT 2A , disorders of the serotonin reuptake transporter (SERT), dopamine D1 and / or D2 pathways, and / or μ-opioid receptors.

19. The method according to claim 16, wherein the disease is a disease selected from the group consisting of: (i) a psychotic disorder, such as schizophrenia, in a patient suffering from depression; (2) depression in a patient suffering from a psychotic disorder, such as schizophrenia; (3) a mood disorder associated with a psychotic disorder, such as schizophrenia or Parkinson's disease; (4) a sleep disorder associated with a psychotic disorder, such as schizophrenia or Parkinson's disease; and (5) a substance addiction disorder, a substance use disorder and / or a substance-induced disorder.

20. The method according to claim 16, wherein the central nervous system disorder is a disorder selected from the group consisting of obsessive compulsive disorder (OCD), obsessive compulsive personality disorder (OCPD), general anxiety, social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, delusional disorder, pathological grooming disorder, kleptomania, pyromania, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorders and related disorders, and combinations thereof.

21. Use of a compound according to any one of claims 1 to 13 in free form or in pharmaceutically acceptable salt form or a pharmaceutical composition according to any one of claims 14 to 15 for the preparation of a medicament for the treatment or prevention of a central nervous system disorder.

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