Organic compounds

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is an international application claiming priority to and the benefit of U.S. Provisional Application Serial No. 63 / 269,305, filed on March 14, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to specific substituted heterocyclic fused γ-carbolines as described herein in free, solid, pharmaceutically acceptable salt and / or substantially pure form, pharmaceutical compositions thereof and use thereof in the treatment of 5-HT-related diseases. 2A Receptor, serotonin transporter (SERT), involved in dopamine D 1 and D 2 The method of treating a disease of a pathway of a receptor signal transduction system and / or a μ-opioid receptor, such as a disease or disorder such as anxiety, psychosis, schizophrenia, sleep disorders, sexual dysfunction, migraine, pain-related conditions (including headache, neuropathic pain and as an acute analgesic), fibromyalgia, chronic fatigue, social phobia, gastrointestinal disorders such as gastrointestinal motility dysfunction and obesity; depression and mood disorders, such as those associated with psychosis or Parkinson's disease; psychosis, such as schizophrenia with depression; bipolar disorder; drug dependence, such as opioid dependence and alcohol dependence, drug withdrawal symptoms; obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD) and related disorders; and other psychiatric and neurological disorders, as well as combinations with other drugs. In some embodiments, the disease or disorder may include treatment-resistant depression, cocaine dependence and / or amphetamine dependence, opioid use disorder and opioid withdrawal symptoms.

[0004] background

[0005] Substituted heterocyclic fused γ-carbolines are known to be 5-HT inhibitors in the treatment of central nervous system disorders. 2 Receptors, especially 5-HT 2A These compounds have been described in U.S. Pat. Nos. 6,548,493, 7,238,690, 6,552,017, 6,713,471, 7,183,282, USRE39,680 and USRE39,679 as agents useful in the treatment of 5-HT 2ANovel compounds for treating disorders related to receptor modulation such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual dysfunction, migraine, headache-related disorders, social phobia, gastrointestinal disorders such as gastrointestinal motility dysfunction and obesity are disclosed. U.S. Patent No. 8,309,722 and U.S. Patent No. 7,081,455 also disclose methods for preparing substituted heterocyclic fused γ-carbolines and the use of these γ-carbolines as serotonin agonists and antagonists that can be used to control or prevent central nervous system disorders such as addictive behavior and sleep disorders.

[0006] In addition, U.S. Pat. No. 8,598,119 discloses specific substituted heterocyclic fused γ-carbolines for treating combinations of psychotic and depressive disorders and sleep, depression and / or mood disorders in patients with psychotic or Parkinson's disease. In addition to disorders associated with psychotic and / or depression, the patent also discloses or claims that low doses of these compounds selectively antagonize 5-HT 2A receptors without affecting dopamine D 2 dopamine D 2 The effects on dopamine D receptors are minimal, thus making the compounds useful for treating sleep disorders without interacting with dopamine D 2 Side effects associated with high occupancy of pathways or other pathways (e.g., GABA) associated with conventional sedatives and hypnotics (e.g., benzodiazepines) A The side effects of the present invention include, but are not limited to, drug dependence, hypotonia, weakness, headache, blurred vision, dizziness, nausea, vomiting, epigastric distress, diarrhea, joint pain and chest pain. U.S. Patent No. 8,648,077 also discloses a method for preparing toluenesulfonic acid addition salt crystals of these substituted heterocyclic fused γ-carboline compounds.

[0007] In addition, recent evidence shows that the above-mentioned substituted fused heterocyclic γ-carbolines may act in a manner similar to ketamine, in part, through NMDA receptor antagonism, via mTOR1 signaling. Ketamine is a selective NMDA receptor antagonist. Ketamine acts through a system unrelated to common psychoactive monoamines (serotonin, norepinephrine and dopamine), which is the main reason for its much faster action in the treatment of depression or anxiety. Ketamine directly antagonizes extrasynaptic glutamatergic NMDA receptors, which also indirectly leads to the activation of AMPA-type glutamate receptors. Downstream effects involve brain-derived neurotrophic factor (BDNF) and mTORC1 kinase pathways. Similar to ketamine, recent evidence suggests that those compounds related to the compounds of the present disclosure increase both NMDA and AMPA-induced currents in rat medial prefrontal cortex pyramidal neurons via activation of D1 receptors, and this is accompanied by increased mTORC1 signaling. WO 2019 / 178484 and US 2021 / 0060009 (each of which is incorporated herein by reference in its entirety) disclose such effects of certain substituted fused heterocyclic γ-carbolines and useful therapeutic indications associated therewith.

[0008] Publication US2017 / 319580 and U.S. Patents 10,245,260 and 10,799,500 (each of which is incorporated herein by reference in its entirety) disclose new oxo-metabolites of the compounds disclosed in the above-mentioned publications. These new oxo-metabolites retain most of the unique pharmacological activities of the parent compound, including serotonin receptor inhibition, SERT inhibition, and dopamine receptor regulation. However, it was found that these oxo-metabolites unexpectedly also showed significant activity to μ-opioid receptors. Other indications and treatment methods for such compounds have also been disclosed in, for example, US11,376,249, US 2021 / 0093634, US 2022 / 0088014, US 2022 / 0184072, and PCT / US2022 / 078177, the contents of which are each incorporated herein by reference in their entirety.

[0009] Analogs of these novel compounds have also been disclosed, for example, in US 10,961,245, US 10,906,906, US 11,427,587, US 2021 / 0009592, and US 2022 / 0048910, each of which is incorporated herein by reference in its entirety.

[0010] The compound of formula A shown below is, for example, a potent serotonin 5-HT 2AReceptor antagonists and μ-opioid receptor partial agonists or biased agonists. The compounds also interact with dopamine receptors, particularly dopamine D1 receptors.

[0011]

[0012] It is also believed that the compounds of formula A can also enhance NMDA and AMPA mediated signaling through the mTOR pathway via D1 receptor activity. The compounds of formula A are therefore useful for treating or preventing central nervous system disorders, but there is a need in the art for additional compounds with unique biochemical and pharmacological properties, especially those with subtly altered pharmacological or pharmacokinetic properties compared to the compounds of formula A.

[0013] Obsessive-compulsive disorder (OCD) and related disorders have become extremely common and difficult to treat. OCD is estimated to affect approximately 2.3% of people at some stage in their lives, and it is estimated that more than 1.2% of people worldwide suffer from the disease during a given year. Half of OCD patients begin to experience symptoms before the age of 20, which can seriously affect their ability to obtain a full and effective education. However, without effective treatment, the disease can persist for decades. The main approach to medication OCD treatment is the use of selective serotonin reuptake inhibitors (SSRIs). Second-line treatment is the use of antipsychotic drugs such as clomipramine, risperidone, quetiapine, and olanzapine. A large number of patients either do not respond to these drugs or cannot handle the side effects caused by these drugs. Recently, it has been reported that the opioid analgesic tramadol may be effective in treating OCD. Opioids work through completely different pathways than traditional OCD treatment drugs, so they offer a treatment possibility for people who cannot take traditional serotonergic drugs or for whom these drugs are ineffective. However, potent opioids can be addictive and may be contraindicated for some patients. Therefore, there is still a pressing need for new treatments for pain, OCD, and other conditions.

[0014] Drug dependence disorders, such as opioid use disorder (OUD), are another group of diseases that are difficult to successfully treat. Opioid overdose claims approximately 100 lives in the United States every day, and the opioid epidemic continues to grow in the United States. Methadone, buprenorphine, and naltrexone are the most commonly used treatments for OUD. Methadone is a μ-opioid receptor (MOP) agonist, buprenorphine is a MOP partial agonist, and naltrexone is a MOP antagonist. These medications have each had limited success, and long-term compliance with prescription treatments for OUD remains low. In addition, these treatments often exacerbate common comorbidities associated with OUD, such as mood and anxiety disorders, which further increases the risk of remission. Abruptly stopping opioid abuse (i.e., "cold turkey") is also accompanied by serious side effects, including irritability, depression, and anxiety, and common treatment medications do not address these problems and may make them worse.

[0015] Therefore, there is a pressing need for new compounds that possess a combination of pharmacological activities at one or more of the serotonin 5-HT2A, dopamine D1, dopamine D2, and μ-opioid receptors and / or serotonin transporters.

[0016] Brief description

[0017] In a first aspect, the present disclosure relates to compounds of formula I (Compound I):

[0018]

[0019] in:

[0020] R 1 It is H, C 1-6 Alkyl, -C(O)-OC(R a )(R b )(R c )、-C(O)-O-CH 2 -OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 ;

[0021] R 2 and R 3 Independently selected from H, D, C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g. methoxy), halo (e.g. F), cyano or hydroxy;

[0022] or where R 2 and R 3 Together with the carbon they are attached to form the group -CH2 CH 2 -, or where R 2 and R 3 The carbons to which they are attached do not exist;

[0023] L is C 1-6 Alkylene (e.g. ethylene, propylene or butylene), C 1-6 Alkoxy (such as propoxy or butoxy), C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH 2 CH 2 OCH 2 ), C 1-6 Alkylamino or N-(C 1-6 Alkyl)-C 1-6 Alkylamino (e.g. propylamino or N-methylpropylamino), C 1-6 Alkylthio (e.g. -CH 2 CH 2 CH 2 S-), C 1-6 Alkylsulfonyl (e.g. -CH 2 CH 2 CH 2 S(O) 2 -), or -C 1-6 alkyl-C(O)- (e.g. 4-butyryl), each of which is optionally substituted by one or more R 4 Partial replacement;

[0024] R 4 Each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), halo (e.g., F), cyano, hydroxy, amino (-NH 2 ), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl);

[0025] Z is selected from aryl (e.g. phenyl) and heteroaryl (e.g. thienyl, furanyl, pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), methyl or OH, each optionally substituted by one or more R 4 Partially substituted, optionally wherein Z is unsubstituted

[0026] replaced;

[0027] R 8 Yes-C(R a )(R b )(R c )、-OC(R a )(R b )(R c ), or -N(R d )(R e );

[0028] R a , R b and R c Each independently selected from H and C 1-24 alkyl;

[0029] R d and R e Each independently selected from H and C 1-24 alkyl;

[0030] R 6 and R 7 Each independently selected from H, C 1-6 Alkyl, carboxyl and C 1-6 Alkoxycarbonyl;

[0031] Provided that, if Z is aryl or heteroaryl, at least one radical R 4 Selected from amino (-NH 2 ), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl);

[0032] In free form or in salt form (eg, a pharmaceutically acceptable salt form), for example, in isolated or purified free form or in salt form (eg, a pharmaceutically acceptable salt form).

[0033] The present disclosure provides additional exemplary embodiments of compounds of Formula I in free form or salt form (eg, pharmaceutically acceptable salt form), eg, isolated or purified free form or salt form (eg, pharmaceutically acceptable salt form), including:

[0034] 1.1 Compound I, wherein R 1 It is H;

[0035] 1.2 Compound I, wherein R 1 It is C 1-6 Alkyl groups, such as methyl;

[0036] 1.3 Compound I, wherein R 1 Yes-C(O)-OC(R a )(R b )(R c );

[0037] 1.4 Compound 1.3, wherein R a is H, and R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0038] 1.5 Compound 1.3, wherein R a and R b is H, and R c It is C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0039] 1.6 Compound 1.3, wherein R a , R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16alkyl;

[0040] 1.7 Compound 1.3, wherein R a , R b and R c Each is H;

[0041] 1.8 Compound 1.3, wherein R a and R b is H, and R c It is C 10-14 Alkyl (such as R c Yes CH 3 (CH 2 ) 10 or CH 3 (CH 2 ) 14 );

[0042] 1.9 Compound I, wherein R 1 Yes -C(O)-O-CH 2 -OC(R a )(R b )(R c );

[0043] 1.10 Compound 1.9, wherein R a is H, and R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0044] 1.11 Compound 1.9, wherein R a and R b is H, and R c It is C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0045] 1.12 Compound 1.9, wherein R a , R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0046] 1.13 Compound 1.9, wherein R a , R b and R c Each is H;

[0047] 1.14 Compound I, wherein R 1 Yes-C(R 6 )(R 7 )-OC(O)-R 8 , and R 8 Yes-C(R a )(R b )(R c );

[0048] 1.15 Compound I, wherein R 1 Yes-C(R 6 )(R 7 )-OC(O)-R 8 , and R 8 Yes-OC(R a )(R b )(R c );

[0049] 1.16 Compound 1.14 or 1.15, wherein R a is H, and R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0050] 1.17 Compound 1.14 or 1.15, wherein R a and R b is H, and R c It is C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0051] 1.18 Compound 1.14 or 1.15, wherein R a , R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0052] 1.19 Compound 1.14 or 1.15, wherein R a , R b and R c Each is H;

[0053] 1.20 Any of compounds 1.14-1.19, wherein R 6 is H, and R 7 It is C 1-3 Alkyl (such as R 7 is methyl or isopropyl), and R 8 It is C 10-14 Alkyl (such as R 8 Yes CH 3 (CH 2 ) 10 or CH 3 (CH 2 ) 14 );

[0054] 1.21 Compound I, wherein R 1 Yes-C(R 6 )(R7 )-OC(O)-R 8 , and R 8 Yes-N(R d )(R e );

[0055] 1.22 Compound 1.21, wherein R d is H, and R e Independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0056] 1.23 Compound 1.21, wherein R d and R e Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0057] 1.24 Compound 1.21, wherein R d and R e Each is H;

[0058] 1.25 Any of compounds 1.14-1.24, wherein R 6 is H, and R 7 It is H;

[0059] 1.26 Any of compounds 1.14-1.24, wherein R 6 It is C 1-6 Alkyl, and R 7 It is C 1-6 alkyl;

[0060] 1.27 Any of compounds 1.14-1.24, wherein R 6 is H, and R 7 It is C 1-6 alkyl;

[0061] 1.28 Any of compounds 1.14-1.24, wherein R 6 is H, and R 7 It is a carboxyl group;

[0062] 1.29 Any of compounds 1.14-1.24, wherein R 6 is H, and R 7 It is C 1-6 Alkoxycarbonyl, for example ethoxycarbonyl or methoxycarbonyl;

[0063] 1.30 Compound I or any one of 1.1-1.29, wherein R 2 and R 3 It is H;

[0064] 1.31 Compound I or any one of 1.1-1.29, wherein R 2 is H, and R 3 It is D;

[0065] 1.32 Compound I or any one of 1.1-1.29, wherein R 2 and R 3 It is D;

[0066] 1.33 Compound I or any one of 1.1-1.32, wherein L is C 1-6 Alkylene (e.g. ethylene, propylene or butylene), C 1-6 Alkoxy (e.g. propoxy), C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH 2 CH 2 OCH 2 ), C 1-6 Alkylamino (e.g. propylamino or N-methylpropylamino), or C 1-6 Alkylthio (e.g. -CH 2 CH 2 CH 2 S-), each of which is optionally replaced by one or more R 4 Partial replacement;

[0067] 1.34 Compound 1.33, wherein L is unsubstituted C 1-6 Alkylene (e.g., ethylene, propylene, or butylene);

[0068] 1.35 Compound 1.33, where L is C 1-6 Alkylene (e.g. ethylene, propylene or butylene), with one or more R 4 Partial replacement;

[0069] 1.36 Compound 1.33, wherein L is unsubstituted C1-6 Alkoxy (eg, propoxy or butoxy);

[0070] 1.37 Compound 1.33, where L is C 1-6 Alkoxy (eg, propoxy or butoxy), with one or more R 4 Partial replacement;

[0071] 1.38 Compound 1.33, wherein L is unsubstituted C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH 2 CH 2 OCH 2 );

[0072] 1.39 Compound 1.33, where L is C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH 2 CH 2 OCH 2 ), by one or more R 4 Partial replacement;

[0073] 1.40 Compound I or any one of 1.1-1.39, wherein R 1 , R 2 and R 3 Each is H;

[0074] 1.41 Compound I or any one of 1.1-1.40, wherein L is -(CH 2 ) n -X-, and wherein n is an integer selected from 2, 3 and 4, and X is selected from -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, -CH 2 -, and -C(O)-;

[0075] 1.42 Compound 1.41, where L is –(CH 2 ) n -X-, and wherein n is an integer selected from 2, 3 and 4, and X is -O-;

[0076] 1.43 Compound 1.41, where L is –(CH 2 ) n -X-, and wherein n is 3, and X is selected from -O-, -S-, -NH-, -N(C 1-6 alkyl)-(e.g. -N(CH 3 )-), and -C(O)-;

[0077] 1.44 Compound 1.41, where L is –(CH 2 ) n-X-, and wherein n is 3, and X is O;

[0078] 1.45 Compound 1.41, where L is –(CH 2 ) n -X-, and wherein n is 3, and X is -C(O)-;

[0079] 1.46 Compound I or any one of 1.1-1.45, wherein Z is aryl (eg, phenyl), optionally substituted with one or more R 4 Partial replacement;

[0080] 1.47 Compound 1.46, wherein Z is an aryl group (eg, phenyl), is replaced by one or more R 4 Partial replacement;

[0081] 1.48 Compound 1.47, wherein Z is phenyl, is replaced by one, two, three or four R 4 Partial replacement;

[0082] 1.49 Compound 1.47 or 1.48, wherein one, two, three or four R 4 The moieties are independently selected from methyl, methoxy, hydroxy, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ), and C(O)N(CH 3 )(CH 3 );

[0083] 1.50 Compound 1.48 or 1.49, wherein Z is phenyl, is replaced by one R 4 Partially substituted, the R 4 The moiety is selected from methyl, methoxy, hydroxyl, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0084] 1.51 Compound 1.48 or 1.49, wherein Z is phenyl, surrounded by two R 4 Partially substituted, the R 4 The moieties are each independently selected from methyl, amino (-NH 2 ), halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0085] 1.52 Compound I or any one of 1.1-1.45, wherein Z is heteroaryl (eg, thienyl, furanyl, pyridinyl, indazolyl, benzimidazolyl, benzisoxazolyl), optionally substituted by one or more R 4 Partial replacement;

[0086] 1.53 Compound 1.52, wherein the heteroaryl is a monocyclic 5-membered or 6-membered heteroaryl (e.g., pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolyl, thienyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl);

[0087] 1.54 Compound 1.53, wherein the heteroaryl group is selected from pyridyl, pyrimidinyl and pyrazinyl;

[0088] 1.55 Compound 1.53, wherein the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl and tetrazolyl;

[0089] 1.56 Compound 1.53, wherein the heteroaryl group is selected from thienyl and furanyl;

[0090] 1.57 Compound 1.53, wherein the heteroaryl is thienyl (eg, 5-substituted-2-thienyl or 4-substituted-3-thienyl);

[0091] 1.58 Compound 1.53, wherein the heteroaryl is a bicyclic 9-membered or 10-membered heteroaryl (e.g., indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, benzodioxolyl, or 2-oxo-tetrahydroquinolyl);

[0092] 1.59 Compound 1.58, wherein the heteroaryl is selected from indazolyl, benzisoxazolyl, quinolyl, quinazolinyl, benzodioxolyl and 2-oxo-tetrahydroquinolyl;

[0093] 1.60 Compound 1.58, wherein the heteroaryl group is selected from indazolyl, benzisoxazolyl, quinolyl, quinazolinyl;

[0094] 1.61 Compound 1.60, wherein the heteroaryl is indazolyl (eg, 5-substituted or 6-substituted-3-indazolyl, 1-substituted-3-indazolyl, or 1,5- or 1,6-disubstituted-3-indazolyl);

[0095] 1.62 Compound 1.61, wherein the indazolyl group is 1-(C 1-3 alkyl)-5-halogeno-3-indazolyl, or 1-(C1-3 alkyl)-6-halo-3-indazolyl), optionally wherein the C 1-3 Alkyl is methyl and / or said halo is fluoro;

[0096] 1.63 Compounds 1.52 to 1.62, wherein the heteroaryl group is replaced by one, two, three or four R 4 Partial replacement;

[0097] 1.64 Compound 1.63, wherein one, two, three or four R 4 The moieties are independently selected from methyl, methoxy, ethoxy, hydroxy, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0098] 1.65 Compound 1.63, wherein the heteroaryl group is replaced by one R 4 Partially substituted, the R 4 The moiety is selected from methyl, methoxy, hydroxyl, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy), phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0099] 1.66 Compound I or any one of 1.1-1.65, wherein R 2 and R 3 Together with the carbon they are attached to form the group -CH 2 CH 2 -, for example, wherein the compound I is a compound of the formula:

[0100]

[0101] In free or pharmaceutically acceptable salt form, wherein R 1 , L and Z are as defined in any of the preceding embodiments;

[0102] 1.67 Compound I or any one of 1.1-1.65, wherein R 2 and R 3and the carbon to which they are attached are absent, for example, wherein the compound I is a compound of the formula:

[0103]

[0104] In free or pharmaceutically acceptable salt form, wherein R 1 , L and Z are as defined in any of the preceding embodiments;

[0105] 1.68 Compound 1 or any one of 1.1-1.67, wherein the compound is selected from:

[0106]

[0107]

[0108] Each is independently in free form or in pharmaceutically acceptable salt form;

[0109] 1.69 Compound I or any one of 1.1-1.68 in free form;

[0110] 1.70 Compound I or any one of 1.1-1.68, in the form of a salt, such as a pharmaceutically acceptable salt;

[0111] 1.71 Compound 1 or any one of 1.1-1.68, wherein the compound is in the form of an acid addition salt, such as a hydrochloric acid or toluenesulfonic acid addition salt;

[0112] 1.72 Compound 1 or any one of 1.1-1.71 in substantially pure stereoisomer form (ie, substantially free of other stereoisomers);

[0113] 1.73 Compound I or any one of 1.1-1.71 having a stereoisomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%;

[0114] 1.74 Compound I or any one of 1.1-1.73 in solid form, for example in crystalline form;

[0115] 1.75 Compound I or any of 1.1-1.74 in isolated or purified form (eg, in at least 90% pure form, or at least 95% or at least 98% or at least 99%).

[0116] In other embodiments of the first aspect, the present disclosure provides a compound of Formula II (Compound 2):

[0117]

[0118]

[0119] in:

[0120] R 1 It is H, C 1-6 Alkyl, -C(O)-OC(R a )(R b )(R c )、-C(O)-O-CH 2 -OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 ;

[0121] R 2 and R 3 Independently selected from H, D, C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g. methoxy), halo (e.g. F), cyano or hydroxy;

[0122] or where R 2 and R 3 Together with the carbon they are attached to form the group -CH 2 CH 2 -, or where R 2 and R 3 The carbons to which they are attached do not exist;

[0123] L is C 3 Alkylene (e.g. propylene), C 3 Alkoxy (e.g. propoxy), C 3 Alkylsulfonyl (e.g. -CH 2 CH 2 CH 2 S(O) 2 -), or -C 2-4 Alkyl-C(O)- (eg, 4-butyryl); and

[0124] Z is selected from aryl (eg, phenyl, naphthyl) and heteroaryl (eg, bicyclic heteroaryl or monocyclic 5-membered heteroaryl), each of which is optionally substituted by one or more R 4 partially substituted, optionally wherein Z is unsubstituted;

[0125] Provided that LZ is selected from:

[0126] -CH 2 CH 2 CH 2 O-Ph;

[0127] -CH 2 CH 2CH 2 -(heteroaryl), wherein the heteroaryl is separated by two R 4 Partially disubstituted bicyclic heteroaryl;

[0128] -CH 2 CH 2 CH 2 -(heteroaryl), wherein the heteroaryl is separated by one, two or three R 4 Partially substituted quinazolinyl;

[0129] -CH 2 CH 2 CH 2 O-(aryl), wherein the aryl is phenyl or naphthyl and the aryl is monosubstituted with a hydroxyl group;

[0130] -CH 2 CH 2 CH 2 O-(aryl), wherein the aryl is phenyl or naphthyl and the aryl is surrounded by two or more R 4 Partial replacement;

[0131] -(CH 2 )nC(O)-(heteroaryl), wherein n is an integer selected from 2, 3 and 4, and wherein the heteroaryl is substituted by one to three R 4 Partially substituted monocyclic 5-membered heteroaryl;

[0132] -CH 2 CH 2 CH 2 S(O) 2 -(aryl), and wherein the aryl is phenyl or naphthyl and the aryl is replaced by one or two R 4 Partial replacement; and

[0133] -CH 2 CH 2 CH 2 O-(aryl), wherein the aryl is phenyl or naphthyl and the aryl is replaced by one or more R 4 Partially substituted, provided that R 2 and R 3 It is F;

[0134] and among them

[0135] R 4 Each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), halo (e.g., F), cyano, hydroxy, amino (-NH 2 ), C 1-6Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl);

[0136] R 8 Yes-C(R a )(R b )(R c )、-OC(R a )(R b )(R c ), or -N(R d )(R e );

[0137] R a , R b and R c Each independently selected from H and C 1-24 alkyl;

[0138] R d and R e Each independently selected from H and C 1-24 alkyl;

[0139] R 6 and R 7 Each independently selected from H, C 1-6 Alkyl, carboxyl and C 1-6 Alkoxycarbonyl;

[0140] In free form or in salt form (eg, a pharmaceutically acceptable salt form), for example, in isolated or purified free form or in salt form (eg, a pharmaceutically acceptable salt form).

[0141] The present disclosure provides additional exemplary embodiments of compounds of Formula II in free form or salt form (eg, pharmaceutically acceptable salt form), eg, isolated or purified free form or salt form (eg, pharmaceutically acceptable salt form), including:

[0142] 2.1 Compound II, wherein R 1 It is H;

[0143] 2.2 Compound II, wherein R 1 It is C 1-6 Alkyl groups, such as methyl;

[0144] 2.3 Compound II, wherein R 1Yes-C(O)-OC(R a )(R b )(R c );

[0145] 2.4 Compound 2.3, wherein R a is H, and R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0146] 2.5 Compound 2.3, wherein R a and R b is H, and R c It is C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0147] 2.6 Compound 2.3, wherein R a , R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0148] 2.7 Compound 2.3, wherein R a , R b and R c Each is H;

[0149] 2.8 Compound 2.3, wherein R a and R b is H, and R c It is C 10-14 Alkyl (such as R c Yes CH 3 (CH 2 ) 10 or CH 3 (CH 2 ) 14 );

[0150] 2.9 Compound II, wherein R 1 Yes -C(O)-O-CH 2 -OC(R a )(R b )(R c );

[0151] 2.10 Compound 2.9, wherein R a is H, and R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0152] 2.11 Compound 2.9, wherein R a and R b is H, and R c It is C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0153] 2.12 Compound 2.9, wherein R a , R b and R c Each independently selected from C 1-24 Alkyl groups, such as C1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0154] 2.13 Compound 2.9, wherein R a , R b and R c Each is H;

[0155] 2.14 Compound II, wherein R 1 Yes-C(R 6 )(R 7 )-OC(O)-R 8 , and R 8 Yes-C(R a )(R b )(R c );

[0156] 2.15 Compound II, wherein R 1 Yes-C(R 6 )(R 7 )-OC(O)-R 8 , and R 8 Yes-OC(R a )(R b )(R c );

[0157] 2.16 Compound 2.14 or 2.15, wherein R a is H, and R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0158] 2.17 Compound 2.14 or 2.15, wherein R a and R b is H, and R c It is C1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0159] 2.18 Compound 2.14 or 2.15, wherein R a , R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0160] 2.19 Compound 2.14 or 2.15, wherein R a , R b and R c Each is H;

[0161] 2.20 Any of compounds 2.14-2.19, wherein R 6 is H, and R 7 It is C 1-3 Alkyl (such as R 7 is methyl or isopropyl), and R 8 It is C 10-14 Alkyl (such as R 8 Yes CH 3 (CH 2 ) 10 or CH 3 (CH 2 ) 14 );

[0162] 2.21 Compound II, wherein R 1 Yes-C(R 6 )(R 7 )-OC(O)-R 8 , and R 8 Yes-N(R d )(R e );

[0163] 2.22 Compound 2.21, wherein R d is H, and R e Independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0164] 2.23 Compound 2.21, wherein R d and R e Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0165] 2.24 Compound 2.21, wherein R d and R e Each is H;

[0166] 2.25 Any of compounds 2.14-2.24, wherein R 6 is H, and R 7 It is H;

[0167] 2.26 Any of compounds 2.14-2.24, wherein R 6 It is C 1-6 Alkyl, and R 7 It is C 1-6 alkyl;

[0168] 2.27 Any of compounds 2.14-2.24, wherein R 6 is H, and R 7 It is C 1-6 alkyl;

[0169] 2.28 Any of compounds 2.14-2.24, wherein R 6 is H, and R 7 It is a carboxyl group;

[0170] 2.29 Any of compounds 2.14-2.24, wherein R 6 is H, and R 7 It is C 1-6 Alkoxycarbonyl, for example ethoxycarbonyl or methoxycarbonyl;

[0171] 2.30 Compound II or any one of 2.1-2.29, wherein R 2 and R 3 It is H;

[0172] 2.31 Compound II or any one of 2.1-2.29, wherein R 2 is H, and R 3 It is D;

[0173] 2.32 Compound II or any one of 2.1-2.29, wherein R 2 and R 3 It is D;

[0174] 2.33 Compound II or any one of 2.1-2.32, wherein L is -CH 2 CH 2 CH 2 O-Ph;

[0175] 2.34 Compound II or any one of 2.1-2.32, wherein L is -CH 2 CH 2 CH 2 -(heteroaryl), wherein the heteroaryl is separated by two R 4 A partially disubstituted bicyclic heteroaryl, or wherein the heteroaryl is substituted by one, two or three R 4 Partially substituted quinazolinyl;

[0176] 2.35 Compound 2.34, wherein the heteroaryl is a bicyclic 9-membered or 10-membered heteroaryl (e.g., indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, benzodioxolyl, 2-oxo-tetrahydroquinolyl);

[0177] 2.36 Compound 2.34, wherein the heteroaryl is selected from indazolyl, benzisoxazolyl, quinolyl, benzodioxolyl and 2-oxo-tetrahydroquinolyl;

[0178] 2.37 Compound 2.34, wherein the heteroaryl group is selected from indazolyl, benzisoxazolyl and quinolinyl;

[0179] 2.38 Compound 2.34, wherein the heteroaryl is indazolyl (eg, 1,5- or 1,6-disubstituted-3-indazolyl);

[0180] 2.39 Any of compounds 2.34-2.38, wherein R 4 The moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0181] 2.40 Compound 2.39, where R 4 moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, halo (e.g., fluorine, chlorine, bromine or iodine) and cyano;

[0182] 2.41 Compound 2.39, where R 4 The moieties are each independently selected from methyl, hydroxy, amino (-NH 2 ), halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0183] 2.42 Compound 2.38, wherein the indazolyl group is 1-(C 1-3 alkyl)-5-halogeno-3-indazolyl, or 1-(C 1-3 alkyl)-6-halo-3-indazolyl), optionally wherein the C 1-3 Alkyl is methyl and / or said halo is fluoro;

[0184] 2.43 Compound II or any one of 2.1-2.32, wherein L is -CH 2 CH 2 CH 2 O-(aryl), wherein the aryl is phenyl or naphthyl and the aryl is monosubstituted with a hydroxyl group;

[0185] 2.44 Compound 2.43, wherein the aryl group is phenyl which is monosubstituted by a hydroxy group (eg, substituted at the ortho, meta or para position);

[0186] 2.45 Compound II or any one of 2.1-2.32, wherein L is -CH 2 CH 2 CH 2O-(aryl), wherein the aryl is phenyl or naphthyl and the aryl is surrounded by two or more R 4 Partial replacement;

[0187] 2.46 Compound 2.45, wherein the aryl group is phenyl;

[0188] 2.47 Compound 2.45 or 2.46, wherein R 4 The moieties are each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), halo (e.g., F), cyano, hydroxy, amino (-NH 2 ), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl);

[0189] 2.48 Compound 2.47, where R 4 The moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ), and C(O)N(CH 3 )(CH 3 );

[0190] 2.49 Compound 2.47, where R 4 moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, halo (e.g., fluorine, chlorine, bromine or iodine) and cyano;

[0191] 2.50 Compound 2.47, where R 4 moieties are each independently selected from methyl, ethyl, hydroxy, halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0192] 2.51 Any of compounds 2.45-2.50, wherein there are two or three R 4 part;

[0193] 2.52 Compound 2.51, one of which R 4 The moiety is halogenated (e.g., fluorine, chlorine, bromine or iodine) and one or more other R 4 The moiety is selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, halo (e.g., fluorine, chlorine, bromine or iodine), methoxy, ethoxy, hydroxy and cyano;

[0194] 2.53 Compound 2.51, one of which R 4 The moiety is halogenated (e.g., fluorine, chlorine, bromine or iodine) and one or more other R 4 The moiety is selected from methyl, ethyl, hydroxy, halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0195] 2.54 Compound 2.51, which has three R 4 moiety, two are methyl and one is halo (e.g., fluoro, chloro, bromo or iodo);

[0196] 2.55 Compound 2.51, which has two R 4 moieties, one is methyl or ethyl and one is halo (e.g., fluoro, chloro, bromo or iodo) or cyano;

[0197] 2.56 Compound 2.51, which has three R 4 moieties, each independently selected from cyano, fluorine, chlorine, bromine and iodine;

[0198] 2.57 Compound 2.51, which has two R 4 moieties, each independently selected from cyano, fluorine, chlorine, bromine and iodine;

[0199] 2.58 Compound 2.51, which has two R 4 moieties, each of which is fluorine, or one is fluorine and one is chlorine, or one is fluorine and one is cyano;

[0200] 2.59 Any of compounds 2.51-2.58, wherein there are three R 4 moiety, which are located at the two ortho and para positions of the phenyl ring (relative to the carbon atom to which the group L is attached);

[0201] 2.60 Any of compounds 2.51-2.58, wherein there are two R 4 moieties, which are located in an ortho and a para position of the phenyl ring (relative to the carbon atom to which the group L is attached);

[0202] 2.61 Any of compounds 2.51-2.58, wherein there are two R 4 moiety, which are located in an ortho position and a meta position of the phenyl ring (relative to the carbon atom to which the group L is attached);

[0203] 2.62 Compound II or any one of 2.1-2.32, wherein L is -(CH 2 )nC(O)-(heteroaryl), wherein n is an integer selected from 2, 3 and 4, and wherein the heteroaryl is substituted by one to three R 4 Partially substituted monocyclic 5-membered heteroaryl;

[0204] 2.63 Compound 2.62, wherein n is 2;

[0205] 2.64 Compound 2.62, wherein n is 3;

[0206] 2.65 Compound 2.62, wherein n is 4;

[0207] 2.66 Any of compounds 2.62-2.65, wherein the heteroaryl is selected from thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl and tetrazolyl;

[0208] 2.67 Compound 2.66, wherein the heteroaryl group is selected from thienyl and furanyl;

[0209] 2.68 Compound 2.66, wherein the heteroaryl is thienyl (eg, 5-substituted-2-thienyl or 4-substituted-3-thienyl);

[0210] 2.69 Compounds 2.62-2.68, wherein the heteroaryl group is replaced by one R 4 Partial replacement;

[0211] 2.70 Any of compounds 2.62-2.68, wherein the heteroaryl group is separated by two R 4 Partial replacement;

[0212] 2.71 Any of compounds 2.62-2.68, wherein the heteroaryl group is replaced by three R 4 Partial replacement;

[0213] 2.72 Any of compounds 2.62-2.71, wherein R 4 The moieties are each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), halo (e.g., F), cyano, hydroxy, amino (-NH 2 ), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(C 1-6alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl);

[0214] 2.73 Compound 2.72, where R 4 The moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0215] 2.74 Compound 2.72, where R 4 moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, halo (e.g., fluorine, chlorine, bromine or iodine) and cyano;

[0216] 2.75 Compound 2.72, where R 4 moieties are each independently selected from methyl, hydroxy, halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0217] 2.76 Compound 2.72, where R 4 moieties are each fluorine or chlorine (e.g. chlorine);

[0218] 2.77 Any of compounds 2.62-2.65, wherein n is 3, the heteroaryl is thienyl and the thienyl is replaced by one or two R 4 Partial substitution, and R 4 The moieties are each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), halo (e.g., F), cyano, hydroxy, amino (-NH 2 ), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl);

[0219] 2.78 Compound 2.77, where R 4 The moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0220] 2.79 Compound 2.77, where R 4 moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, halo (e.g., fluorine, chlorine, bromine or iodine) and cyano;

[0221] 2.80 Compound 2.77, where R 4 moieties are each independently selected from methyl, hydroxy, halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0222] 2.81 Compound 2.77, where R 4 moieties are each fluorine or chlorine (e.g. chlorine);

[0223] 2.82 Any of compounds 2.77-2.81, wherein the thienyl group is 5-substituted-2-thienyl or 4-substituted-3-thienyl;

[0224] 2.83 Compound II or any one of 2.1-2.32, wherein L is -CH 2 CH 2 CH 2 S(O) 2 -(aryl), and wherein the aryl is phenyl or naphthyl and the aryl is replaced by one or two R 4 Partial replacement;

[0225] 2.84 Compound 2.83, wherein the aryl group is unsubstituted phenyl or unsubstituted naphthyl;

[0226] 2.85 Compound 2.83, wherein the aryl group is phenyl or naphthyl, and R 4 The moieties are each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), halo (e.g., F), cyano, hydroxy, amino (-NH 2 ), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl);

[0227] 2.86 Compound 2.85, where R 4 The moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0228] 2.87 Compound 2.85, where R 4 moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, halo (e.g., fluorine, chlorine, bromine or iodine) and cyano;

[0229] 2.88 Compound 2.85, where R 4 moieties are each independently selected from methyl, hydroxy, halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0230] 2.89 Any of compounds 2.85-2.88, wherein there are two or three R 4 part;

[0231] 2.90 Compound 2.89, one of which R 4 The moiety is halogenated (e.g., fluorine, chlorine, bromine or iodine) and one or more other R 4 The moiety is selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, halogenated (e.g., fluorine, chlorine, bromine or iodine) methoxy, ethoxy, hydroxy and cyano;

[0232] 2.91 Compound 2.89, one of which R 4 The moiety is halogenated (e.g., fluorine, chlorine, bromine or iodine) and one or more other R 4 The moiety is selected from methyl, hydroxy, halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0233] 2.92 Compound 2.89, with one, two or three R 4 moieties are each independently selected from fluorine, chlorine, bromine and iodine;

[0234] 2.93 Compound 2.89, which has an R 4 The moiety is selected from fluorine, chlorine, bromine and iodine;

[0235] 2.94 Compound II or any one of 2.1-2.32, wherein L is CH 2 CH 2 CH 2 O-(aryl), wherein the aryl is phenyl or naphthyl and the aryl is replaced by one or more R 4 Partially substituted, provided that R 2 and R 3 It is F;

[0236] 2.95 Compound 2.94, wherein the aryl group is unsubstituted phenyl or unsubstituted naphthyl;

[0237] 2.96 Compound 2.94, wherein the aryl group is phenyl or naphthyl and R 4 The moieties are each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), halo (e.g., F), cyano, hydroxy, amino (-NH 2 ), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl);

[0238] 2.97 Compound 2.96, where R 4 The moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0239] 2.98 Compound 2.96, where R 4 moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, halo (e.g., fluorine, chlorine, bromine or iodine) and cyano;

[0240] 2.99 Compound 2.96, where R 4 moieties are each independently selected from methyl, hydroxy, halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0241] 2.100 Any of compounds 2.96-2.99, wherein there are two or three R 4 part;

[0242] 2.101 Compound 2.100, one of which is R 4 The moiety is halogenated (e.g., fluorine, chlorine, bromine or iodine) and one or more other R 4 The moiety is selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, halogenated (e.g., fluorine, chlorine, bromine or iodine) methoxy, ethoxy, hydroxy and cyano;

[0243] 2.102 Compound 2.100, one of which is R 4 The moiety is halogenated (e.g., fluorine, chlorine, bromine or iodine) and one or more other R 4 The moiety is selected from methyl, hydroxy, halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0244] 2.103 Compound 2.100, with one, two or three R 4 moieties are each independently selected from cyano, fluoro, chloro, bromo and iodo;

[0245] 2.104 Compound 2.100, which has an R 4 The moiety is selected from fluorine, chlorine, bromine and iodine;

[0246] 2.105 Compound II or any one of 2.1-2.104, wherein the compound is selected from:

[0247]

[0248]

[0249]

[0250] Each is independently in free form or in pharmaceutically acceptable salt form;

[0251] 2.106 Compound II or any one of 2.1-2.105 in free form;

[0252] 2.107 Compound II or any one of 2.1-2.105, in the form of a salt, such as a pharmaceutically acceptable salt;

[0253] 2.108 Compound II or any one of 2.1-2.105, wherein the compound is in the form of an acid addition salt, such as a hydrochloric acid or toluenesulfonic acid addition salt;

[0254] 2.109 Compound II or any one of 2.1-2.106 in substantially pure stereoisomeric form (ie, substantially free of other stereoisomers);

[0255] 2.110 Compound II or any one of 2.1-2.109 having a stereoisomeric excess of higher than 70%, preferably higher than 80%, more preferably higher than 90% and most preferably higher than 95%;

[0256] 2.111 Compound II or any one of 2.1-2.110 in solid form, such as crystalline form;

[0257] 2.112 Compound II or any of 2.1-2.111, in isolated or purified form (eg, at least 90% pure form, or at least 95% or at least 98% or at least 99%).

[0258] In a third embodiment of the first aspect, the present disclosure relates to a compound of formula III (Compound III):

[0259]

[0260] in:

[0261] R 1 It is H, C 1-6 Alkyl, -C(O)-OC(R a )(R b )(R c )、-C(O)-O-CH 2 -OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 ;

[0262] L is C 1-6 Alkylene (e.g. ethylene, propylene or butylene), C 1-6 Alkoxy (such as propoxy or butoxy), C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH 2 CH 2 OCH2 ), C 1-6 Alkylamino or NC 1-6 Alkyl C 1-6 Alkylamino (e.g. propylamino or N-methylpropylamino), C 1-6 Alkylthio (e.g. -CH 2 CH 2 CH 2 S-), C 1-6 Alkylsulfonyl (e.g. -CH 2 CH 2 CH 2 S(O) 2 -), -C 1-6 Alkyl-C(O)- (e.g. 4-butyryl), or -C 1-6 Alkyl-C(OH)- (e.g. 4-butanol), each of which is optionally substituted by one or more R 4 Partial replacement;

[0263] R 4 Each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), halo (e.g., F), cyano, hydroxy, amino (-NH 2 ), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl);

[0264] Z is selected from aryl (e.g. phenyl) and heteroaryl (e.g. thienyl, furanyl, pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), methyl or OH, each optionally substituted by one or more R 4 partially substituted, optionally wherein Z is unsubstituted;

[0265] R 8 Yes-C(R a )(R b )(R c )、-OC(R a )(R b )(R c ), or -N(R d )(R e );

[0266] Ra , R b and R c Each independently selected from H and C 1-24 alkyl;

[0267] R d and R e Each independently selected from H and C 1-24 alkyl;

[0268] R 6 and R 7 Each independently selected from H, C 1-6 Alkyl, carboxyl and C 1-6 Alkoxycarbonyl;

[0269] In free form or in salt form (eg, a pharmaceutically acceptable salt form), for example, in isolated or purified free form or in salt form (eg, a pharmaceutically acceptable salt form).

[0270] The present disclosure provides additional exemplary embodiments of compounds of Formula III in free form or salt form (eg, pharmaceutically acceptable salt form), eg, isolated or purified free form or salt form (eg, pharmaceutically acceptable salt form), including:

[0271] 3.1. Compound III, wherein R 1 It is H;

[0272] 3.2. Compound III, wherein R 1 It is C 1-6 Alkyl groups, such as methyl;

[0273] 3.3. Compound III, wherein R 1 Yes-C(O)-OC(R a )(R b )(R c );

[0274] 3.4. Compound 3.3, wherein R a is H, and R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0275] 3.5. Compound 3.3, wherein Ra and R b is H, and R c It is C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0276] 3.6. Compound 3.3, wherein R a , R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0277] 3.7. Compound 3.3, wherein R a , R b and R c Each is H;

[0278] 3.8. Compound 3.3, wherein R a and R b is H, and R c It is C 10-14 Alkyl (such as R c Yes CH 3 (CH 2 ) 10 or CH 3 (CH 2 ) 14 );

[0279] 3.9. Compound III, wherein R 1 Yes -C(O)-O-CH 2 -OC(R a )(R b )(R c );

[0280] 3.10. Compound 3.9, wherein R ais H, and R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0281] 3.11. Compound 3.9, wherein R a and R b is H, and R c It is C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0282] 3.12. Compound 3.9, wherein R a , R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0283] 3.13. Compound 3.9, wherein R a , R b and R c Each is H;

[0284] 3.14. Compound III, wherein R 1 Yes-C(R 6 )(R 7 )-OC(O)-R 8 , and R8 Yes-C(R a )(R b )(R c );

[0285] 3.15. Compound III, wherein R 1 Yes-C(R 6 )(R 7 )-OC(O)-R 8 , and R 8 Yes-OC(R a )(R b )(R c );

[0286] 3.16. Compound 3.14 or 3.15, wherein R a is H, and R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0287] 3.17. Compound 3.14 or 3.15, wherein R a and R b is H, and R c It is C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0288] 3.18. Compound 3.14 or 3.15, wherein R a , R b and R c Each independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0289] 3.19. Compound 3.14 or 3.15, wherein R a , R b and R c Each is H;

[0290] 3.20. Any of compounds 3.14-3.19, wherein R 6 is H, and R 7 It is C 1-3 Alkyl (such as R 7 is methyl or isopropyl), and R 8 It is C 10-14 Alkyl (such as R 8 Yes CH 3 (CH 2 ) 10 or CH 3 (CH 2 ) 14 );

[0291] 3.21. Compound III, wherein R 1 Yes-C(R 6 )(R 7 )-OC(O)-R 8 , and R 8 Yes-N(R d )(R e );

[0292] 3.22. Compound 3.21, wherein R d is H, and R e Independently selected from C 1-24 Alkyl groups, such as C 1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0293] 3.23. Compound 3.21, wherein R d and R e Each independently selected from C 1-24 Alkyl groups, such as C1-20 Alkyl, C 5-20 Alkyl, C 9-18 Alkyl, C 10-16 Alkyl, or C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 14 Alkyl, C 15 Alkyl or C 16 alkyl;

[0294] 3.24. Compound 3.21, wherein R d and R e Each is H;

[0295] 3.25. Any of compounds 3.14-3.24, wherein R 6 is H, and R 7 It is H;

[0296] 3.26. Any of compounds 3.14-3.24, wherein R 6 It is C 1-6 Alkyl, and R 7 It is C 1-6 alkyl;

[0297] 3.27. Any of compounds 3.14-3.24, wherein R 6 is H, and R 7 It is C 1-6 alkyl;

[0298] 3.28. Any of compounds 3.14-3.24, wherein R 6 is H, and R 7 It is a carboxyl group;

[0299] 3.29. Any of compounds 3.14-3.24, wherein R 6 is H, and R 7 It is C 1-6 Alkoxycarbonyl, for example ethoxycarbonyl or methoxycarbonyl;

[0300] 3.30. Compound III or any one of 3.1-3.29, wherein L is C 1-6 Alkylene (e.g. ethylene, propylene or butylene), C 1-6 Alkoxy (e.g. propoxy), C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH 2 CH 2 OCH 2 ), C 1-6 Alkylamino (e.g. propylamino or N-methylpropylamino), or C 1-6Alkylthio (e.g. -CH 2 CH 2 CH 2 S-), optionally with one or more R 4 Partial replacement;

[0301] 3.31. Compound 3.30, wherein L is unsubstituted C 1-6 Alkylene (e.g., ethylene, propylene, or butylene);

[0302] 3.32. Compound 3.30, wherein L is C 1-6 Alkylene (e.g. ethylene, propylene or butylene), with one or more R 4 Partial replacement;

[0303] 3.33. Compound 3.30, wherein L is unsubstituted C 1-6 Alkoxy (eg, propoxy or butoxy);

[0304] 3.34. Compound 3.30, wherein L is C 1-6 Alkoxy (eg, propoxy or butoxy), with one or more R 4 Partial replacement;

[0305] 3.35. Compound 3.30, wherein L is unsubstituted C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH 2 CH 2 OCH 2 );

[0306] 3.36. Compound 3.30, wherein L is C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH 2 CH 2 OCH 2 ), by one or more R 4 Partial replacement;

[0307] 3.37. Compound III or any one of 3.1-3.36, wherein L is -(CH 2 ) n -X-, and wherein n is an integer selected from 2, 3 and 4, and X is selected from -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, -CH 2 -, -CH(OH)-, and -C(O)-;

[0308] 3.38. Compound 3.37, wherein L is –(CH 2 ) n-X-, and wherein n is an integer selected from 2, 3 and 4, and X is -O-;

[0309] 3.39. Compound 3.37, wherein L is –(CH 2 ) n -X-, and wherein n is an integer selected from 2, 3 and 4, and X is -C(O)-;

[0310] 3.40. Compound 3.37, wherein L is –(CH 2 ) n -X-, and wherein n is 3, and X is selected from -O-, -S-, -NH-, -N(C 1-6 alkyl)-(e.g. -N(CH 3 )-), -CH(OH) and -C(O)-;

[0311] 3.41. Compound 3.37, wherein L is –(CH 2 ) n -X-, and wherein n is 3, and X is selected from the group consisting of -O-, -S-, -CH(OH) and -C(O)-;

[0312] 3.42. Compound 3.37, wherein L is –(CH 2 ) n -X-, and wherein n is 3, and X is O;

[0313] 3.43. Compound 3.37, wherein L is –(CH 2 ) n -X-, and wherein n is 3, and X is S;

[0314] 3.44. Compound 3.37, wherein L is –(CH 2 ) n -X-, and wherein n is 3, and X is -CH(OH)-;

[0315] 3.45. Compound 3.37, wherein L is –(CH 2 ) n -X-, and wherein n is 3, and X is -C(O)-;

[0316] 3.46. Compound III or any one of 3.1-3.45, wherein Z is aryl (eg, phenyl), optionally substituted with one or more R 4 Partial replacement;

[0317] 3.47. Compound 3.46, wherein Z is an aryl group (eg, phenyl) and is surrounded by one or more R 4 Partial replacement;

[0318] 3.48. Compound 3.47, wherein Z is phenyl, is replaced by one, two, three or four R 4 Partial replacement;

[0319] 3.49. Compound 3.47 or 3.48, wherein the one, two, three or four R 4 The moieties are independently selected from methyl, methoxy, hydroxy, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0320] 3.50. Compound 3.47 or 3.48, wherein Z is replaced by an R 4 Partially substituted phenyl, the R 4 The moiety is selected from methyl, methoxy, hydroxyl, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0321] 3.51. Compound 3.47 or 3.48, wherein Z is separated by two R 4 Partially substituted phenyl, the R 4 moieties are each independently selected from methyl, halo (e.g., fluoro, chloro, bromo or iodo) and cyano;

[0322] 3.52. Compound III or any one of 3.1-3.45, wherein Z is heteroaryl (eg, thienyl, furanyl, pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), optionally substituted with one or more R 4 Partial replacement;

[0323] 3.53. Compound 3.52, wherein the heteroaryl is a monocyclic 5-membered or 6-membered heteroaryl (eg, pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolyl, thienyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl);

[0324] 3.54. Compound 3.53, wherein the heteroaryl group is selected from pyridinyl, pyrimidinyl and pyrazinyl;

[0325] 3.55. Compound 3.53, wherein the heteroaryl is selected from thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl and tetrazolyl;

[0326] 3.56. Compound 3.53, wherein the heteroaryl group is selected from thienyl and furanyl;

[0327] 3.57. Compound 3.53, wherein the heteroaryl is thienyl (eg, 5-substituted-2-thienyl or 4-substituted-3-thienyl);

[0328] 3.58. Compound 3.53, wherein the heteroaryl is a bicyclic 9-membered or 10-membered heteroaryl (e.g., indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, benzodioxolyl, 2-oxo-tetrahydroquinolyl);

[0329] 3.59. Compound 3.58, wherein the heteroaryl is selected from indazolyl, benzisoxazolyl, quinolinyl, quinazolinyl, benzodioxolyl and 2-oxo-tetrahydroquinolinyl;

[0330] 3.60. Compound 3.58, wherein the heteroaryl group is selected from indazolyl, benzisoxazolyl, quinazolinyl and quinolinyl;

[0331] 3.61. Compound 3.60, wherein the heteroaryl is indazolyl (eg, 5-substituted or 6-substituted-3-indazolyl, 1-substituted-3-indazolyl, or 1,5- or 1,6-disubstituted-3-indazolyl);

[0332] 3.62. Compound 3.61, wherein the indazolyl group is 1-(C 1-3 alkyl)-5-halogeno-3-indazolyl, or 1-(C 1-3 alkyl)-6-halo-3-indazolyl), optionally wherein the C 1-3 Alkyl is methyl and / or said halo is fluoro;

[0333] 3.63. Any of compounds 3.52-3.62, wherein the heteroaryl group is replaced by one, two, three or four R 4 Partial replacement;

[0334] 3.64. Compound 3.63, wherein the one, two, three or four R 4 The moieties are independently selected from methyl, methoxy, ethoxy, hydroxy, amino (-NH 2), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0335] 3.65. Compound 3.63, wherein the heteroaryl group is replaced by one R 4 Partially substituted, the R 4 The moiety is selected from methyl, methoxy, hydroxyl, amino (-NH 2 ), halo (e.g., fluorine, chlorine, bromine or iodine), cyano, benzyl, benzyloxy), phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH 2 、-C(O)NH(CH 3 ) and C(O)N(CH 3 )(CH 3 );

[0336] 3.66. Compound III or any of 3.1-3.65, wherein the compound is selected from:

[0337]

[0338] Each is independently in free form or in pharmaceutically acceptable salt form;

[0339] 3.67. Compound III or any one of 3.1-3.66 in free form;

[0340] 3.68. Compound III or any one of 3.1-3.66 in the form of a salt, such as a pharmaceutically acceptable salt;

[0341] 3.69. Compound III or any one of 3.1-3.66, wherein the compound is in the form of an acid addition salt, such as a hydrochloric acid or toluenesulfonic acid addition salt;

[0342] 3.70. Compound III or any one of 3.1-3.69 in substantially pure stereoisomeric form (ie, substantially free of other stereoisomers);

[0343] 3.71. Compound III or any one of 3.1-3.69, having a stereoisomeric excess of greater than 70%, preferably greater than 80%, more preferably greater than 90% and most preferably greater than 95%;

[0344] 3.72. Compound III or any one of 3.1-3.71 in solid form, such as crystalline form;

[0345] 3.73. Compound III or any of 3.1-3.72, in isolated or purified form (eg, at least 90% pure form, or at least 95% or at least 98% or at least 99%).

[0346] As used hereinafter, a "compound of the invention" refers to a compound of formula I or any one of 1.1-1.75, or a compound of formula II or any one of 2.1-2.112, or a compound of formula III or any one of 3.1-3.73.

[0347] In a second aspect, the disclosure provides a pharmaceutical composition (pharmaceutical composition 1), which comprises a compound of the present invention, for example, mixed with a pharmaceutically acceptable diluent or carrier. In a specific embodiment, the compound of the present invention is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule, for example, for gastrointestinal absorption (i.e., absorption by the stomach and / or large intestine and small intestine). In some embodiments, the pharmaceutical composition is an oral transmucosal composition, such as an oral dissolving tablet, a wafer, a film, a gel or a spray. For example, the composition can be a rapidly dissolving sublingual or buccal tablet, a wafer, a film or a gel. In some embodiments, the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (for example, as an aerosol, a mist or a powder for inhalation). In some embodiments, the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous or intraperitoneal injection. In particular, the pharmaceutical composition for intramuscular or subcutaneous injection can be in the form of a long-acting injection composition or a reservoir composition, for example, providing a compound of the present invention to be continuously or delayed released into the bloodstream and body tissues. Alternatively, particularly when formulated for intravenous, intrathecal, intraperitoneal or subcutaneous injection, the composition may be a rapid-acting composition, eg, providing rapid release of most or all of the dose into body fluids.

[0348] In a further embodiment, the pharmaceutical composition of the present disclosure is for sustained-release or delayed-release preparations (pharmaceutical composition 1-A), such as depot preparations. In some embodiments, the compound of the present invention mixed with a pharmaceutically acceptable diluent or carrier is provided in the form of an injection depot providing sustained-release or delayed-release of the compound, preferably in free form or in pharmaceutically acceptable salt form.

[0349] In a specific embodiment, pharmaceutical composition 1-A comprises a compound of the present invention in the form of a free base or a pharmaceutically acceptable salt, optionally in a crystalline form, wherein the compound has been ground or the compound is crystallized into 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 preparation for injection. For example, a depot preparation can be formulated into an intramuscular or subcutaneous injection with a drug dose suitable for 4-6 weeks of treatment. In some embodiments, the particles or crystals have a particle size of 0.1-5 μm. 2 / g, for example 0.5-3.3m 2 / g or 0.8-1.2m 2 / g of surface area.

[0350] In another embodiment, the present disclosure provides pharmaceutical composition 1-B, which is pharmaceutical composition 1, wherein the compound of the present invention is in a polymer matrix. In one embodiment, the compound of the present disclosure is dispersed or dissolved in the polymer matrix. In a further embodiment, the polymer matrix includes a standard polymer used in a depot formulation, such as a polymer selected from the following: polyesters of hydroxy fatty acids and their derivatives, or α-cyanoacrylate alkyl ester polymers, polyalkylene oxalates, polyorthoesters, polycarbonates, polyorthocarbonates, polyamino acids, hyaluronates, and mixtures thereof. In a further embodiment, the polymer is selected from polylactide, poly d, l-lactide, polyglycolide, PLGA 50:50, PLGA85:15, and PLGA 90:10 polymers. In another embodiment, the polymer is selected from polyglycolic acid, poly-D, L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly(orthocarbonates), polyacetals, 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 includes poly(d, l-lactide-co-glycolide), such as PLGA having a molar ratio of 50:50 to 90:10. In some embodiments, PLGA is mixed with a solvent carrier, such as an aqueous solvent, an aqueous emulsion, or a non-aqueous organic solvent (preferably a pharmaceutically acceptable organic solvent). Depending on the amount used in the injection, suitable organic solvents may include propylene glycol, polyethylene glycol, ethanol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycofurol, solketal, glyceryl formate, acetone, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether, dimethylisosorbide, ethyl lactate or a mixture thereof.

[0351] Pharmaceutical composition 1-B can be particularly used for sustained release or delayed release, wherein the compound of the present disclosure is released by degradation of the polymer matrix. These compositions can be formulated for controlled release or sustained release of the compound of the present disclosure (e.g., as a reservoir composition) over 180 days, such as about 14 to about 30 days to about 180 days. For example, the polymer matrix can degrade and release the compound of the present disclosure over about 30, about 60 or about 90 days. In another example, the polymer matrix can degrade and release the compound of the present disclosure over about 120 or about 180 days.

[0352] In yet another embodiment, Pharmaceutical Composition 1 or 1-A or 1-B can be formulated for administration by injection, for example, as a sterile solution, such as a sterile aqueous solution or a sterile non-aqueous solution.

[0353] In another embodiment, the present disclosure provides a pharmaceutical composition (Pharmaceutical Composition 1-C) comprising a compound of the present invention as described above in an osmotic controlled release oral delivery system (OROS), the OROS being described in US2001 / 0036472 and US2009 / 0202631, the contents of each of which are incorporated herein by reference in their entirety. Thus, in one embodiment, the present disclosure provides a pharmaceutical composition or device comprising (a) a gelatin capsule containing a compound of the present invention in free or pharmaceutically acceptable salt form, optionally mixed with a pharmaceutically acceptable diluent or carrier; (b) a multilayer wall superimposed on the gelatin capsule, which comprises, in order from the capsule outward: (i) a barrier layer, (ii) a swellable layer, and (iii) a semipermeable layer; and (c) an orifice formed or formable through the wall (Pharmaceutical Composition P.1).

[0354] In another embodiment, the present invention provides a pharmaceutical composition comprising a gelatin capsule containing a liquid, optionally in free or pharmaceutically acceptable salt form of a compound of the present invention mixed with a pharmaceutically acceptable diluent or carrier, wherein the gelatin capsule is surrounded by a composite wall comprising a barrier layer in contact with the outer surface of the gelatin capsule, a swellable layer in contact with the barrier layer, a semipermeable layer encapsulating the swellable layer, and an outflow orifice formed or formable in the wall (pharmaceutical composition P.2).

[0355] In yet another embodiment, the present invention provides a composition comprising a gelatin capsule containing a liquid, optionally in free or pharmaceutically acceptable salt form of a compound of the present invention mixed with a pharmaceutically acceptable diluent or carrier, 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 semipermeable layer encapsulating the swellable layer, and an outflow orifice formed or formable in the wall, wherein the barrier layer forms a seal between the swellable layer and the environment at the outflow orifice (pharmaceutical composition P.3).

[0356] In yet another embodiment, the present invention provides a composition comprising a gelatin capsule containing a liquid, optionally in free or pharmaceutically acceptable salt form of a compound of the present invention mixed with a pharmaceutically acceptable diluent or carrier, the gelatin capsule being surrounded by 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 semipermeable layer at least encapsulating the swellable layer, and an egress opening formed or formable in the dosage form 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 separate parts, such as two parts located at opposite sides or ends of the gelatin capsule.

[0357] In a specific embodiment, the compound of the present invention in the osmotic controlled release oral delivery system (i.e., in compositions P.1-P.4) is in a liquid formulation, which can be a neat liquid active agent, a liquid active agent in a solution, suspension, emulsion or self-emulsifying composition, etc.

[0358] Additional information regarding the composition of osmotic controlled release oral delivery systems, including characteristics of the gelatin capsule, barrier layer, swellable layer, semipermeable layer, and orifice, can be found in US 2001 / 0036472, the contents of which are incorporated herein by reference in their entirety.

[0359] Other osmotic controlled release oral delivery systems for compounds of the present invention or pharmaceutical compositions of the present disclosure can be found in US2009 / 0202631, the contents of which are incorporated herein by reference as a whole. Therefore, in another embodiment, 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 the present invention in free or pharmaceutically acceptable salt form optionally mixed with a pharmaceutically acceptable diluent or carrier, the second layer comprising a polymer; (b) an outer wall surrounding the two or more layers; and (c) an orifice in the outer wall (pharmaceutical composition P.5).

[0360] Pharmaceutical composition P.5 preferably uses a semipermeable membrane surrounding a three-layer core: in these embodiments, the first layer is called the first drug layer, containing a small amount of drug (e.g., a compound of the present invention) and an osmotic agent such as a salt, the middle layer is called the second drug layer, containing a higher amount of drug, excipients, and no salt; and the third layer is called the push layer, containing an osmotic agent and no drug (pharmaceutical composition P.6). The membrane on the first drug layer end of the capsule-shaped tablet is drilled with at least one orifice.

[0361] Pharmaceutical composition P.5 or P.6 may comprise a membrane defining a compartment, the membrane surrounding an inner protective base coating, in which at least one hole is formed or can be formed, and at least a portion of the membrane is semipermeable; a swellable layer located within the compartment, which is away from the egress orifice and can communicate fluid with the semipermeable portion of the membrane; a first drug layer located near the egress orifice; and a second drug layer located within the compartment between the first drug layer and the swellable layer, the drug layer comprising a compound of the present invention in free or pharmaceutically acceptable salt form (pharmaceutical composition P.7). Different release properties are obtained depending on the relative viscosity of the first drug layer and the second drug layer. The optimal viscosity of each layer must be determined. In the present invention, the viscosity is adjusted by adding the salt sodium chloride. The delivery properties from the core depend on the weight, formulation and thickness of each drug layer.

[0362] 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.

[0363] Pharmaceutical compositions P.1-P.7 will generally be referred to as osmotic controlled release oral delivery system compositions.

[0364] In a third aspect, the present invention provides a method for treating or preventing a central nervous system disorder or more than one central nervous system disorder (method 1), the method comprising administering to a patient in need thereof an effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, such as any one of pharmaceutical compositions 1, 1-A, 1-B, 1-C or P.1-P.7. In a particular embodiment, method 1 comprises administering:

[0365] 1.1 The compounds of the present invention in free form;

[0366] 1.2 The compounds of the present invention in the form of pharmaceutically acceptable salts;

[0367] 1.3 Compounds of the present invention in the form of acid addition salts;

[0368] 1.4 Pharmaceutical composition 1;

[0369] 1.5 Any one of pharmaceutical compositions 1-A, 1-B or 1-C;

[0370] 1.6 Any one of the pharmaceutical compositions P.1 to P.7; or

[0371] 1.7 Any osmotic controlled-release oral delivery system composition as described above.

[0372] Substance use disorders and substance-induced disorders are two types of substance-related disorders defined in the fifth edition of the DSM (Diagnostic and Statistical Manual of Mental Disorders, DSM-5). Substance use disorders are symptom patterns resulting from the use of a substance for which the individual continues to use the substance despite having problems with it. Substance-induced disorders are disorders that result from the use of the substance. Substance-induced disorders include intoxication, withdrawal, substance-induced psychotic disorders, including substance-induced psychosis, substance-induced bipolar disorder and related disorders, substance-induced depressive disorders, substance-induced anxiety disorders, substance-induced obsessive-compulsive disorder and related disorders, substance-induced sleep disorders, substance-induced sexual dysfunction, substance-induced delirium, and substance-induced neurocognitive disorders.

[0373] DSM-5 includes classification criteria for mild, moderate, or severe substance use disorders. 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.

[0374] Anxiety and depression are highly prevalent comorbid disorders among patients undergoing substance use or substance abuse treatment. A common treatment for substance abuse disorders is a combination of the partial opioid agonist buprenorphine and the opioid antagonist naloxone, but these medications do not have any significant effect on either anxiety or depression, with the common result that a third medication, such as a benzodiazepine, must also be prescribed. The compounds of the present disclosure provide opioid antagonism as well as serotonin antagonism and dopamine modulation. This can significantly enhance the treatment of patients with substance use or abuse disorders and anxiety and / or depression.

[0375] The compounds of the present invention may have anxiolytic properties, which improves the need for treating patients with anxiolytic agents, wherein the patients suffer from anxiety comorbidity. Thus, in some embodiments, the present disclosure provides methods of treating substance addiction, substance use disorder, and / or substance-induced disorder or substance abuse disorder, for example, in patients suffering from anxiety symptoms or diagnosed with anxiety as a comorbid or residual disorder, wherein the methods do not include further administration of anxiolytic agents, such as benzodiazepines. Benzodiazepines The class of drugs are GABA modulating compounds.

[0376] The compounds of the present invention are particularly effective and useful for treating pain in patients with gastrointestinal disorders and / or lung disease. Traditional opioid analgesics have two major side effects: gastrointestinal disturbances (including nausea, vomiting and constipation) and respiratory depression. 90% to 95% of patients using opioids as long-term pain treatment experience severe constipation, requiring long-term use of laxatives and / or enemas. Stronger opioids, such as morphine, oxycodone and hydromorphone, produce more severe constipation than other opioids. Respiratory depression is the most serious adverse reaction to opioid therapy because it poses a risk of death, especially when patients (intentionally or unintentionally) combine prescribed opioid analgesics with other legal or illegal respiratory depressants (including alcohol). Therefore, patients who need pain treatment, especially long-term pain treatment, are particularly susceptible to adverse reactions if they suffer from pre-existing gastrointestinal disorders or lung diseases. Unlike traditional opioid analgesics, the compounds of the present invention provide analgesic relief without significant gastrointestinal adverse reactions and without significant respiratory depression. Thus, such compounds will provide improved safety and efficacy to patients in need of pain treatment and suffering from these pre-existing GI disorders and pulmonary diseases. In further embodiments, the compounds of the invention can be combined with traditional opioids to provide improved pain control and a dose-sparing effect (and concurrently reduced risk of adverse reactions) relative to traditional opioids.

[0377] In some embodiments, the pain is caused by postherpetic neuralgia. Postherpetic neuralgia (PHN) is a neuropathic pain that occurs due to damage to peripheral nerves caused by reactivation of the varicella zoster virus.

[0378] In some embodiments, the pain is caused by fibromyalgia, e.g., the pain is a symptom of fibromyalgia. Fibromyalgia is a complex syndrome of unknown cause or origin. It is classified as a pain processing disorder, specifically the processing of pain signals within the central nervous system. As such, it is similar to central neuropathic pain syndromes and is generally considered an example of "central sensitization." Fibromyalgia is characterized by chronic, widespread pain that often includes allodynia. In the United States, only pregabalin and duloxetine have been approved for the management of fibromyalgia, and existing analgesics are generally ineffective.

[0379] Neurological patients who may be treated with opioid analgesics or other drugs with a high risk of abuse may be contraindicated for such treatment if they suffer from a substance use disorder or substance abuse disorder, or have a history of opioid addiction, opioid withdrawal, or opioid overdose, or have a history of substance or alcohol abuse. Therefore, there is a need for alternative, non-addictive treatments, such as the methods described herein, particularly for such patients.

[0380] In some embodiments of the methods described below, a pharmaceutical composition comprising a compound of the invention can be administered to control and / or sustain release of the compound of the invention over a period of about 14 days, about 30 to about 180 days, preferably over a period of about 30 days, about 60 days, or about 90 days. Controlled and / or sustained release is particularly useful for avoiding premature discontinuation of treatment, particularly for antipsychotic drug therapy, where non-compliance or non-adherence to drug treatment regimens is a common phenomenon.

[0381] In some embodiments of the methods described below, the pharmaceutical composition comprising the compound of the invention may be a depot composition of the disclosure, which is administered for controlled and / or sustained release of the compound of the invention over a period of time.

[0382] In a further embodiment of the third aspect, the present disclosure provides a further embodiment of method 1 as shown below:

[0383] 1.8 Method 1 or any of Methods 1.1-1.7, wherein the central nervous system disorder is a disorder involving serotonin 5-HT 2A receptors, dopamine D1 receptor and / or D2 receptor system and / or serotonin reuptake transporter (SERT) pathway and / or μ-opioid receptor pathway;

[0384] 1.9 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a disorder selected from the group consisting of obesity, anxiety (including generalized anxiety, social anxiety, and panic disorder), depression (e.g., refractory depression and MDD), psychosis (including psychosis with dementia, such as hallucinations or paranoid delusions in advanced Parkinson's disease), schizophrenia, sleep disorders (particularly sleep disorders with schizophrenia and other psychiatric and neurological diseases), sexual dysfunction, migraine, pain and pain-related conditions, including headache, idiopathic pain, chronic pain (e.g., moderate to moderately severe chronic pain, such as in patients requiring a 24-hour delay in treatment for other minor illnesses), neuropathic pain, toothache, 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 motility dysfunction, and dementia, such as Alzheimer's disease dementia or Parkinson's disease dementia; mood disorders; drug dependence, such as opioid dependence and / or alcohol dependence, and drug or alcohol dependence (e.g., opioid dependence) withdrawal; opioid overdose; 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; or opioid use disorder (OUD), or any combination thereof;

[0385] 1.10 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a disorder selected from the following: (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 with a psychotic disorder and / or drug dependence, such as schizophrenia or Parkinson's disease; (4) a sleep disorder with a psychotic disorder, such as schizophrenia or Parkinson's disease; and (5) a substance addiction, substance use disorder, and / or a 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;

[0386] 1.11 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a psychotic disorder, such as schizophrenia, and the patient is a patient suffering from depression;

[0387] 1.12 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is depression, and the patient is a patient suffering from a psychotic disorder, such as schizophrenia or Parkinson's disease;

[0388] 1.13 Any of method 1 or 1.1-1.8, wherein the disorder is a drug dependence disorder, optionally in combination with any of the foregoing disorders, for example, wherein the disorder is opioid dependence, cocaine dependence, amphetamine dependence, alcohol dependence, or any drug or alcohol dependence withdrawal (e.g., opioid, cocaine or amphetamine dependence withdrawal), or wherein the disorder is opioid use disorder or opioid overdose; or wherein the method is a method for treating or preventing relapse of opioid addiction (e.g., for detoxification and opioid addiction maintenance treatment or prevention of relapse of opioid addiction);

[0389] 1.14 Method 1.13, wherein the patient also suffers from a comorbidity, such as anxiety, depression or psychosis, or residual symptoms of anxiety or an anxiety disorder and / or mood changes (e.g., depression); further optionally wherein the patient suffers from an opioid overdose;

[0390] 1.15 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a disorder selected from the group consisting of obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, hypochondriasis, pathological grooming disorder, kleptomania, pyromania, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorders and related disorders, and combinations thereof;

[0391] 1.16 Method 1 or any of Methods 1.1-1.8, 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;

[0392] 1.17 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is obsessive-compulsive disorder (OCD) or obsessive-compulsive personality disorder (OCPD);

[0393] 1.18 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a pain disorder, e.g., a pain-related condition, such as headache, idiopathic pain, neuropathic pain, chronic pain (e.g., moderate to moderately severe chronic pain, e.g., in patients requiring a 24-hour delay in treatment for other minor illnesses), fibromyalgia, dental pain, traumatic pain, or long-term fatigue;

[0394] 1.19 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is opioid use disorder, opioid withdrawal, or opioid dependence, and / or wherein the method provides relief from withdrawal-induced symptoms (e.g., gastrointestinal symptoms such as diarrhea, anxiety, depression, pain, sleep disturbances, or any combination thereof);

[0395] 1.20 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is chronic pain and / or neuropathic pain;

[0396] 1.21 Method 1.20, wherein the pain is caused by a peripheral neuropathy (e.g., mononeuropathy, plexopathy, radiculopathy, or polyneuropathy), or by a central neuropathy (e.g., deafferentation pain or sympathetically maintained pain, such as complex regional pain syndrome (CRPS));

[0397] 1.22 Any of Methods 1.20-1.21 wherein the pain is chronic pain.

[0398] 1.23 Any of Methods 1.20-1.21 wherein the pain is neuropathic pain.

[0399] 1.24 Method 1.22 or 1.23 wherein the pain is chronic neuropathic pain.

[0400] 1.25 Any of methods 1.20-1.24, wherein the pain is caused by a mononeuropathy (e.g., mononeuropathy in solitary form), such as a focal mononeuropathy, a compressive mononeuropathy, or an entrapment mononeuropathy (e.g., carpal tunnel syndrome);

[0401] 1.26 Any of methods 1.20-1.24, wherein the pain is caused by radiculopathy, such as caused by a herniated disc or caused by diabetic ischemia;

[0402] 1.27 Any of Methods 1.20-1.24, wherein the pain is caused by a plexopathy, such as a plexopathy caused by nerve compression, such as nerve compression by a neuroma, tumor, or herniated disk;

[0403] 1.28 Any of methods 1.20-1.24, wherein the pain is caused by multiple mononeuropathy or by a polyneuropathy, such as diabetic polyneuropathy;

[0404] 1.29 Any of Methods 1.20-1.24, wherein the pain is caused by a central neuropathic pain condition, such as deafferentation pain or complex regional pain syndrome (CRPS), or by fibromyalgia;

[0405] 1.30 Any of methods 1.20-1.24, wherein the pain is caused by postherpetic neuralgia (PHN) or by fibromyalgia;

[0406] 1.31 Any of methods 1.20-1.24, wherein the pain is caused by neurotoxicity induced by a drug (e.g., doxorubicin, etoposide, gemcitabine, ifosfamide, interferon alpha, platinum chemotherapeutics (e.g., cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin, phenanthriplatin, picoplatin, satraplatin) or vinca alkaloids (e.g., vinblastine, vincristine, vindesine, vinorelbine or vinpocetine) or antiretroviral nucleosides (e.g., didanosine, stavudine, zalcitabine));

[0407] 1.32 Any of methods 1.20-1.31, wherein the neuropathy is an axonal neuropathy (ie, axonal neuropathy);

[0408] 1.33 Any of methods 1.20-1.32, wherein the patient suffers from fibromyalgia, diabetes, human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), or cancer;

[0409] 1.34 Any of methods 1.20-1.32, wherein the patient is receiving concurrent treatment with, or has undergone prior treatment with, an antiretroviral nucleoside, a platinum-based antineoplastic agent, or a vinca alkaloid antineoplastic agent;

[0410] 1.35 Any of methods 1.20-1.34, wherein the pain is associated with allodynia and / or hyperalgesia;

[0411] 1.36 Any of methods 1.20-1.35, wherein the patient also suffers from anxiety (including generalized anxiety, social anxiety, and panic disorder), depression (e.g., refractory depression and MDD), psychosis (including psychosis with dementia, such as hallucinations or paranoid delusions in advanced Parkinson's disease), schizophrenia, migraine, substance abuse disorder, substance use disorder, opioid use disorder or other drug dependence, such as stimulant dependence and / or alcohol dependence.

[0412] 1.37 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a sleep disorder;

[0413] 1.38 Method 1.37, wherein the sleep disorder is selected from sleep maintenance insomnia, frequent awakenings, and waking up feeling tired;

[0414] 1.39 Method 1.37, wherein the sleep disorder is in a patient with or at risk for movement disorders, such as in a patient receiving a dopaminergic medication, such as selected from levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics, such as receiving levodopa;

[0415] 1.40 Any of methods 1.37-1.39 wherein the patient also has Parkinson's disease.

[0416] 1.41 Method 1 or any of Methods 1.1-1.8, wherein the disorder is a sleep disorder and the patient is suffering from depression;

[0417] 1.42 Method 1 or any of Methods 1.1-1.8, wherein the disorder is a sleep disorder and the patient is suffering from a psychotic disorder, such as schizophrenia;

[0418] 1.43 Method 1 or any of Methods 1.1-1.8, wherein the disorder is a sleep disorder and the patient is suffering from Parkinson's disease;

[0419] 1.44 Method 1 or any of Methods 1.1-1.8, wherein the disorder is a sleep disorder and the patient is suffering from depression and a psychotic disorder, such as schizophrenia and / or Parkinson's disease;

[0420] 1.45 Method 1 or any of Methods 1.1-1.8, wherein the disorder is a movement disorder, for example in a patient receiving dopaminergic medication, for example, medication selected from levodopa and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists, and anticholinergics such as levodopa;

[0421] 1.46 Any of Method 1 or 1.1-1.46, wherein the patient suffers from any combination of the disorders described in Methods 1.1-1.45;

[0422] 1.47 Any of Method 1 or 1.1-1.46, wherein the method is a method for treating or preventing any combination of the disorders described in Methods 1.1-1.45;

[0423] 1.48 Any of Method 1 or 1.1-1.47, wherein the patient has a pre-existing or comorbid gastrointestinal disorder and / or pulmonary disease;

[0424] 1.49 Method 1.48, wherein the pre-existing or comorbid disorder is selected from irritable bowel syndrome, pelvic floor disorder, diverticulitis, inflammatory bowel disease, colon or colorectal cancer, celiac disease, non-celiac gluten sensitivity, asthma, chronic obstructive pulmonary disease (COPD), dyspnea, pneumonia, congestive heart failure, interstitial lung disease, pneumothorax, bronchitis, pulmonary embolism, and traumatic chest injury (e.g., sternum or rib fracture, intercostal muscle injury);

[0425] 1.50 Any of methods 1.1-1.49, wherein the patient has been diagnosed with a substance use disorder or substance abuse disorder, such as opioid use disorder (OUD);

[0426] 1.51 Any of methods 1.1-1.50, wherein the patient has a prior history of substance use or substance abuse of an opioid or opioid, such as morphine, codeine, thebaine, opaven, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentanyl, alfentanyl, trefafentanil, fentanyl ... ntinil, bufentanil, remifentanil, ofentanil, sufentanil, carfentanyl, meperidine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol and anileridine or any combination thereof;

[0427] 1.52 Any of method 1 or 1.1-1.51, wherein the patient is diagnosed or has been diagnosed with opiate dependence, cocaine dependence, amphetamine dependence and / or alcohol dependence, or is suffering from withdrawal from drug or alcohol dependence (e.g., opiate, cocaine, or amphetamine dependence);

[0428] 1.53 Any of Method 1 or 1.1-1.52, wherein the patient has previously suffered an opioid or opioid overdose;

[0429] 1.54 Method 1 or any of 1.1-1.53, wherein the patient is unresponsive to or cannot tolerate the side effects of non-narcotic analgesics and / or opioids and opioids, or wherein the use of opioids or opioids is contraindicated for the patient, e.g., due to previous substance abuse or a high potential for substance abuse, such as opioids and opioids, including, e.g., morphine, codeine, thebaine, opioid, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha - methylfentanyl, alfentanyl, trefantinil, bufentanil, remifentanil, ofentanil, sufentanil, carfentanyl, meperidine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol and anileridine or any combination thereof;

[0430] 1.55 Method 1 or any of Methods 1.1-1.54, 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, brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone;

[0431] 1.56 Method 1 or any of Methods 1.1-1.55, wherein the patient cannot tolerate the side effects of non-narcotic analgesics and / or opioids and opioid drugs, or wherein the use of opioid drugs is contraindicated for the patient, such as due to previous substance abuse or high potential for substance abuse, such as opioids and opioid drugs, including, for example, morphine, codeine, thebaine, opioid, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha- Methylfentanyl, alfentanyl, trefantinil, bufentanil, remifentanil, oxifentanil, sufentanil, carfentanyl, meperidine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol and anileridine or any combination thereof;

[0432] 1.57 Method 1 or any of Methods 1.1-1.56, wherein the patient is unresponsive to or cannot tolerate the side effects of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline;

[0433] 1.58 Method 1 or any of Methods 1.1-1.57, wherein the patient is unresponsive to or cannot tolerate the side effects of serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran;

[0434] 1.59 Method 1 or any of Methods 1.1-1.58, wherein the patient is unresponsive to or cannot tolerate the side effects of antipsychotic drug treatment, such as clomipramine, risperidone, quetiapine and olanzapine;

[0435] 1.60 Method 1 or any of Methods 1.1-1.59, wherein the patient has been previously treated with other pain relief medications and the patient has had an inadequate response to the medications, e.g., the patient's pain is not adequately relieved, or the patient suffers from side effects that prevent continued treatment;

[0436] 1.61 Method 1.60, wherein the patient develops an addiction to or becomes at risk of developing an addiction to the other pain relief medication;

[0437] 1.62 Method 1.60 or 1.61, wherein the other pain relief medication is selected from non-opioid analgesics (e.g., nonsteroidal anti-inflammatory drugs, such as ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, oxaprozin, meclofenamate, mefenamic acid, phenylbutazone, indomethacin, ketorolac, diclofenac, sulindac, etodolac, tolmetin, nabumetone, piroxicam, acetaminophen, aspirin, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib) , opioid analgesics (e.g., morphine, codeine, oxycodone, hydrocodone, hydromorphone, oxymorphone, buprenorphine, fentanyl, levorphanol, meperidine, nalbuphine, pentazocine, tramadol, methadone) and topical analgesics (e.g., benzocaine, lidocaine, procaine, bupivacaine, tetracaine) or other medications (e.g., tricyclic antidepressants or anticonvulsants, e.g., amitriptyline, desipramine, duloxetine, pregabalin, gabapentin, valproate, carbamazepine, phenytoin);

[0438] 1.63 Any of the preceding methods, wherein the effective amount is 1 mg-1000 mg, preferably 2.5 mg-50 mg or for a long-acting formulation 25 mg-1500 mg, for example 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg, measured as the equivalent of the free base of the compound;

[0439] 1.64 Any of the preceding methods wherein the effective amount is 1 mg to 100 mg / day, preferably 2.5 mg to 50 mg / day, measured as the equivalent of the free base of the compound.

[0440] 1.65 Any of the preceding methods, wherein the effective amount of the compound of the invention is 1 mg-1000 mg, for example 2.5 mg-50 mg or for a long-acting formulation is 25 mg-1500 mg, for example 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg, measured as the equivalent amount of the free base of the compound;

[0441] 1.66 Any of the preceding methods, wherein the effective amount of the compound of the invention is 1 mg to 100 mg / day, such as 2.5 mg to 50 mg / day, measured as the equivalent of the free base of the compound;

[0442] 1.67 Any of the preceding methods, wherein the effective amount of the compound of the invention is 1 mg to 5 mg per day, preferably 2.5 to 5 mg per day, measured as the equivalent of the free base of the compound;

[0443] 1.68 Any of the preceding methods, wherein the effective amount of the compound of the invention is 2.5 mg or 5 mg per day, measured as the equivalent of the free base of the compound;

[0444] 1.69 Method 1 or any of 1.1-1.68, wherein the compound of Formula I is administered in the form of a pharmaceutical composition comprising the compound of Formula I in admixture with a pharmaceutically acceptable diluent or carrier;

[0445] 1.70 Method 1.69, wherein the compound of formula I is in the form of a pharmaceutically acceptable salt in admixture with a pharmaceutically acceptable diluent or carrier;

[0446] 1.71 Method 1.69 or 1.70, wherein the pharmaceutical composition is a sustained-release or delayed-release formulation, for example according to pharmaceutical composition 1-A as described herein;

[0447] 1.72 Method 1.69, 1.70, or 1.71, wherein the pharmaceutical composition comprises a compound of Formula I in a polymer matrix, for example according to Pharmaceutical Composition 1-B as described herein;

[0448] 1.73 The method of any of 1.69-1.72, wherein the pharmaceutical composition is formulated as an osmotic controlled-release oral delivery system, for example according to any of pharmaceutical compositions 1-C or P.1 to P.7 as described herein;

[0449] 1.74 Any of methods 1.69-1.72, wherein the pharmaceutical composition is in the form of a tablet or capsule;

[0450] 1.75 Any of methods 1.69-1.72, wherein the pharmaceutical composition is formulated for oral, sublingual, or buccal administration;

[0451] 1.76 Any of methods 1.69-1.72, wherein the pharmaceutical composition is a rapidly dissolving oral tablet (e.g., a rapidly dissolving sublingual tablet);

[0452] 1.77 Any of methods 1.69-1.72, wherein the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (e.g., as an aerosol, mist, or powder for inhalation);

[0453] 1.78 Any of methods 1.69-1.72, wherein the pharmaceutical composition is formulated for administration by injection, for example as a sterile aqueous solution;

[0454] 1.79 Method 1.78 wherein the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous or intraperitoneal injection.

[0455] 1.80 Method 1 or any of 1.1-1.79, wherein the method further comprises concurrent administration of one or more additional therapeutic agents, such as simultaneous, separate or sequential administration;

[0456] 1.81 Method 1.80, wherein the one or more other therapeutic agents comprises an opioid or opioid-like active agent, such as an opioid agonist or partial opioid agonist, such as a μ-agonist or partial agonist, or a κ-agonist or partial agonist, including a mixed agonist / antagonist (e.g., an active agent having partial μ-agonist activity and κ-antagonist activity);

[0457] 1.82 Method 1.80, wherein the additional opioid or opioid active agent is selected from the group consisting of morphine, codeine, thebaine, opaven, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentanyl, alfentanyl, trefantinil, bufentanil, remifentanil, ocfentanil, sufentanil, carfentanyl, meperidine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol and anileridine, or any combination thereof;

[0458] 1.83 Method 1.80, wherein the additional opioid or opioid active agent is buprenorphine, optionally wherein the method does not include co-treatment with an anxiolytic agent, such as a GABA compound or a benzodiazepine;

[0459] 1.84 Method 1.80, wherein the additional opioid or opioid-like active agent is an opioid receptor antagonist or inverse agonist, such as a full opioid antagonist, for example, selected from naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime or norbinaltorphimine;

[0460] 1.85 Any of methods 1.80-1.84, wherein the additional therapeutic agent is an NMDA receptor antagonist, e.g., administered simultaneously, separately or sequentially;

[0461] 1.86 Method 1.85, wherein the NMDA receptor antagonist is selected from ketamine (e.g., S-ketamine and / or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine and agmatine, or any combination thereof;

[0462] 1.87 Any of methods 1.80-1.86, wherein the additional therapeutic agent is selected from a compound that modulates GABA receptor activity, a GABA-B receptor agonist, a 5-HT receptor modulator, a 5-HT 1A Receptor agonists, 5-HT 2A Receptor antagonists, 5-HT 2A receptor inverse agonists, melatonin receptor agonists, ion channel modulators, ion channel blockers, SARIs (serotonin-2 receptor antagonists / reuptake inhibitors), orexin receptor antagonists, H3 receptor agonists, H3 receptor antagonists, noradrenergic receptor agonists, noradrenergic receptor antagonists, galanin receptor agonists, CRH receptor antagonists, human growth hormone, growth hormone receptor agonists, estrogen, estrogen receptor agonists, neurokinin-1 drugs, antidepressants, opioid receptor agonists, partial opioid receptor agonists, opioid receptor antagonists, opioid receptor inverse agonists, nociceptive / orphanin receptor agonists, typical antipsychotics, atypical antipsychotics, serotonin HT6 receptor antagonists, and mGluR-2, -3 or -5 receptor agonists or antagonists;

[0463] 1.88 Any of methods 1.80-1.87, wherein the additional therapeutic agent is a compound that modulates GABA activity (e.g., enhances activity and promotes GABA transmission);

[0464] 1.89 Method 1.88, wherein the additional therapeutic agent is a GABA compound selected from the group consisting of doxepin, alprazolam, bromazepam, clobazam, clonazepam, clonazepam, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), and estazolam;

[0465] 1.90 Any of methods 1.80-1.89 wherein the additional therapeutic agent is 5-HT 2AA receptor antagonist, optionally selected from pimavanserin, ketanserin, risperidone, eliserin, volinanserin, pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San Diego, CA) and AVE8488 (Sanofi-Aventis, France);

[0466] 1.91 Any of methods 1.80-1.90, wherein the additional therapeutic agent is a melatonin receptor agonist, optionally selected from melatonin, ramelteon ( Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II Discovery), and agomelatine;

[0467] 1.92 Any of methods 1.80-1.91, wherein the additional therapeutic agent is an ion channel blocker, optionally selected from lamotrigine, gabapentin, and pregabalin;

[0468] 1.93 Any of methods 1.80-1.92, wherein the additional therapeutic agent is an orexin receptor antagonist, optionally selected from orexin, SB-334867-a (GlaxoSmithKline, UK) and GW649868 (GlaxoSmithKline);

[0469] 1.94 Any of methods 1.80-1.93, wherein the additional therapeutic agent is a serotonin-2 receptor antagonist / reuptake inhibitor (SARI), optionally selected from one or more of Org 50081 (Organon-Netherlands), ritanserin, nefazodone, serzone and trazodone;

[0470] 1.95 Any of methods 1.80-1.94 wherein the additional therapeutic agent is 5-HT 1A an agonist, optionally selected from one or more of repinotan, sarizotan, elepidostat, buspirone, and MN-305 (MediciNova, San Diego, CA);

[0471] 1.96 Any of methods 1.80-1.95, wherein the additional therapeutic agent is a neurokinin-1 drug, optionally wherein the drug is casopitant;

[0472] 1.97 Any of methods 1.80-1.96, wherein the additional therapeutic agent is an antipsychotic, optionally wherein the antipsychotic is selected from chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone;

[0473] 1.98 Any of methods 1.80-1.97, wherein the additional therapeutic agent is an antidepressant, optionally wherein the antidepressant is selected from amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine and venlafaxine;

[0474] 1.99 Any of methods 1.80-1.98, wherein the additional therapeutic agent is an atypical antipsychotic, optionally wherein the active agent is selected from brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone;

[0475] 1.100 Any of methods 1.80-1.99, wherein the additional therapeutic agent is an atypical stimulant, optionally selected from modafinil, adrafinil, and armofinil;

[0476] 1.101 Any of methods 1.80-1.100 wherein the additional therapeutic agent is an anti-Parkinson's drug, optionally selected from L-dopa, co-careldopa, duodopa, stalevo, Symmetrel, benztropine, biperiden, bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline and tolcapone.

[0477] 1.102 Any of methods 1.80-1.101, wherein any one or more additional therapeutic agents are administered to the patient as a single pharmaceutical composition, e.g., a depot composition as described above;

[0478] 1.103 Any of methods 1.80-1.102 wherein any one or more of the additional therapeutic agents are administered to the patient as separate pharmaceutical compositions, eg, one of which is a depot composition as described above and the other is not (eg, an oral dosage form).

[0479] As described above, the compounds of the present invention may be particularly useful because they have the potential to act as biased μ-opioid receptor ligands. Depending on the cell type, or even within the same cell type, the intracellular domain of the activated μ-opioid receptor may interact with either the inhibitory G protein or with the β-arrestin protein. Binding of a non-biased agonist to the μ-opioid receptor will result in approximately equal activation of the G-protein signal and the β-arrestin signal.

[0480] In contrast, when a biased agonist binds to the μ opioid receptor, its binding mode is biased toward the intracellular domain of the receptor so as to interact with the G protein rather than the β-arrestin. Therefore, the compounds of the present invention can act as partial or full agonists of the G protein-coupled signal of the μ-opioid receptor, but as antagonists of the β-arrestin signal of the receptor. This is in contrast to traditional opioid agonists, such as morphine and fentanyl, which tend to strongly activate both G protein signaling and β-arrestin signaling pathways. The activation of β-arrestin signaling by such drugs is believed to mediate gastrointestinal dysfunction, addiction, and respiratory depression that are usually mediated by opioids, while the analgesic and anesthetic effects of μ-opioid receptor agonists are mediated through the G protein signaling pathway.

[0481] Furthermore, because biased agonists antagonize the beta-arrestin pathway, they are known to be useful in treating opioid overdose in general—by reversing opioid-induced respiratory depression. Advantageously, however, they will do this while also providing pain relief. Biased beta-arrestin antagonists are expected to be useful in treating opioid overdose because they will suppress the most severe opioid adverse effects but still provide pain relief.

[0482] The opioid abuse epidemic began in the late 1990s and was driven by a combination of overprescribed prescription opioids (e.g., oxycodone sold by Purdue Pharma as OxyContin), cheap imported illegal heroin, and legal and illegal fentanyl. While heroin and oxycodone (as well as codeine, hydrocodone, hydromorphone, oxymorphone, and several other drugs) are natural or semi-synthetic analogs of morphine, fentanyl is the first and most prominent of the newer classes of synthetic opioids. Unlike natural and semi-synthetic opioids, fentanyl and fentanyl analogs do not have the complete classical five-ring core skeleton of morphine. Instead, fentanyl and fentanyl analogs have a common 4-aminophenyl (piperidine) core. The most common fentanyl analogs are sufentanil, alfentanyl, remifentanil, and carfentanil.

[0483] Fentanyl and its analogs are substantially more potent than morphine and heroin because they have stronger μ-opioid receptor binding, greater lipophilicity, or both. These drugs have a greater lipophilicity than morphine and heroin, allowing them to cross the blood-brain barrier more quickly and thus be more potent even with comparable receptor binding. Fentanyl is generally considered to be about 50 times more potent than heroin and 100 times more potent than morphine (some sources state it is 150 times more potent than morphine). Sufentanil is considered 5 to 10 times more potent than fentanyl, and carfentanil is considered to be about 100 times more potent than fentanyl (and therefore 10,000 times more potent than morphine).

[0484] Due to its extremely high efficacy and wide and cheap supply, it is becoming increasingly common to mix different and unpredictable amounts of fentanyl in amphetamine, heroin and other street drugs. Due to this trend and other trends, fentanyl has become the main cause of opioid overdose and especially opioid-related deaths in the United States. By 2016, fentanyl was the cause of at least 50% of opioid deaths, rising to more than 70% of the causes of death in 2017 and 2018. See Torralva & Janowsky, J.Pharmacol.Exp.Ther.371:453-475 (2019). In fact, the rate of amphetamine overdose has increased significantly in the past few years, mainly due to the mixing of fentanyl in amphetamine. In just 5 years, the amphetamine mortality rate has risen 4 times, which is mainly related to the mixing of fentanyl.

[0485] Only three fentanyl analogs are approved for use in humans (sufentanil, alfentanyl, remifentanil), and one is only approved for veterinary use (carfentanil). However, these and many other new synthetic fentanyl analogs have been found as adulterants in a variety of street drugs, including amphetamine, heroin, cocaine, alprazolam (Xanax) and hydrocodone / acetaminophen (Norco). See Armenian et al., Neuropharmacology (2017). Until 2013, only sporadic cases of fentanyl or fentanyl analog contamination occurred in the US heroin supply, but since then, such compounds have been widely infiltrated in North America, contaminating heroin and cocaine. From 2012 to 2014, deaths caused by heroin and cocaine adulterated with fentanyl doubled. From 2015 to 2016, counterfeit Xanax and Norco purchased on the street caused two outbreaks in California. Adulteration of non-opioid substances with fentanyl and fentanyl analogs is particularly concerning because users of such drugs are likely to have never used opioids (and therefore have little or no established drug tolerance) and therefore have significantly worse clinical outcomes. As testing for standard fentanyl analogs became more common (in both medical and forensic settings), illicit manufacturers began to switch to novel synthetic fentanyl derivatives to evade detection, and today, a wide variety of such illicit compounds are known. Currently, the U.S. Drug Enforcement Administration has placed at least 21 synthetic opioid compounds on its control list.

[0486] Due to its high potency and high lipophilicity, fentanyl overdose is much more difficult to treat than morphine, heroin, or oxycodone overdose. Fentanyl has an extremely rapid onset of action, which makes reversal with treatment with a μ-receptor antagonist such as naloxone or naltrexone difficult in an outpatient setting (EMS or police response times are often longer than the time it takes for severe respiratory depression to develop). Reversal of a fentanyl overdose also requires larger doses of a μ-receptor antagonist, and there are limits to the rate and dose of a μ-opioid antagonist that can be safely administered. Morphine takes an average of 19 minutes to reach 80% of its peak effect, whereas fentanyl produces severe respiratory depression much more quickly.

[0487] More worryingly, however, fentanyl and its analogs have an additional mechanism of action, which has become extremely important in the ongoing opioid epidemic. Although all opioids cause respiratory depression through activation of the μ-opioid receptor of the β-arrestin signaling pathway in the brain, fentanyl and its analogs can also cause rapid closure of the vocal cords (laryngospasm) and severe muscle stiffness of the chest wall and diaphragm for reasons that are not fully understood. This can result from intravenous, transdermal or inhaled administration of fentanyl and fentanyl analogs. Morphine, heroin or any other opioid with a classic morphine skeleton do not have this property. This severe chest wall stiffness is called fentanyl-induced respiratory muscle rigidity (FIRMR) (or simply fentanyl-induced muscle rigidity FIMR), and the combination of FIRMR and laryngospasm is clinically known as wooden chest syndrome (WCS). WCS can occur only 1-2 minutes after injection of fentanyl, fentanyl analogs or heroin or other drugs containing fentanyl or its analogs. It has been demonstrated that WCS occurs after intravenous injection of 50 micrograms of fentanyl.

[0488] The main cause of death in WCS has been shown to be interruption of mechanical ventilation due to closure of the glottic structures and upper airway. Laryngospasm is defined as involuntary closure or obstruction of the glottic opening, which is controlled by the intrinsic muscles of the larynx. These muscles are innervated by both sympathetic (adrenergic) and parasympathetic (cholinergic) nerve fibers, so the ultimate activity of these muscles is determined by the balance of sympathetic and parasympathetic input.

[0489] While FIRMR and WCS have long been known in the surgical anesthesia community (because it typically occurs within the therapeutic dose range of surgical anesthesia), these conditions are not well known to first responders or the emergency medical community. This often results in rapid death in drug abusers because those treating them are unaware of these effects of fentanyl (and often because the patient is unaware that a substance containing fentanyl has been ingested). Many witnesses and survivors of overdose report cyanosis, loss of consciousness, severe muscle rigidity, and seizure-like behavior immediately following drug injection. The rapid onset of death is very different from the respiratory depression commonly associated with overdose of morphine, heroin, and oxycodone. Indeed, mechanical respiratory failure in overdose with fentanyl or fentanyl analogs typically occurs in less than 2 minutes after administration and precedes centrally mediated respiratory depression (7-9 minutes are required for a 50% decline in respiratory mechanics).

[0490] More worrisome is that the standard first-line treatments for opioid overdose—naloxone, naltrexone, and nalmefene—are ineffective in reversing fentanyl-induced effects. Severe chest wall stiffness also impairs the effectiveness of chest compressions during cardiopulmonary resuscitation. Thus, while the ratio of emergency room visits to deaths due to heroin-related overdoses is reported to be approximately 10:1, the ratio for fentanyl-related overdoses is only 1:1.

[0491] The standard dose of intravenous naloxone for opioid overdose is 0.4 to 2 mg, with additional doses administered at 2 to 3 minute intervals, up to a maximum dose of 10 mg. However, the recommended maximum total dose of intranasal naloxone, widely used by first responders, is only 4 mg. See, e.g., Williams et al., Prehospital Emergency Care 23(6):749-63 (2019). However, in one study, while the upper respiratory tract effects of morphine can be completely blocked by a 0.1 mg / kg naloxone dose (e.g., 7 mg for a 70 kg person), to completely block the upper respiratory tract effects of fentanyl, 0.8 to 1.6 mg / kg naloxone (56 to 112 mg for a 70 kg person) is required. A study investigating the 2006 fentanyl overdose outbreak reported that of patients given 0.4 to 12 mg naloxone in a hospital emergency room, only 15% responded to the 0.4 mg dose, and 6 of 26 patients required at least 6 mg to reverse respiratory depression. In another study of 18 patients who overdosed with counterfeit hydrocodone / acetaminophen contaminated with fentanyl, 0.4 to 8 mg of naloxone were required as an IV push, with four patients requiring a naloxone infusion for 26–40 hours.

[0492] Unfortunately, however, high-dose naloxone is not practical for therapeutic use because rapid injection of as little as 0.4 mg of naloxone (0.0057 mg / kg for a 70 kg adult) in an active opioid user often results in laryngospasm, pulmonary edema, hemodynamic instability, and cardiac arrhythmias (all caused by catecholamine release). Therefore, high-dose naloxone therapy is contraindicated, especially in the field. As a result, it is often difficult or even impossible to use naloxone to reverse fentanyl-induced overdose before it leads to fatal consequences without additional medical and pharmacological support.

[0493] Clearly, WCS is not simply a result of μ-opioid receptor agonism, because other potent μ-opioid receptor agonists do not induce WCS (e.g., morphine), and because potent μ-opioid antagonists (e.g., naloxone) do not reverse WCS within the normal dose range. Therefore, fentanyl and its analogs must induce WCS through some other mechanism involving other neurotransmitter systems.

[0494] There is evidence from in vitro studies and from various animal models that fentanyl exerts these effects by stimulating noradrenergic activity and possibly cholinergic activity in the locus coeruleus (LC) region of the brain. Without being bound by theory, it is believed that in the LC, fentanyl acts as an agonist at the μ-opioid receptors and the resulting hyperpolarization of LC neurons results in output noradrenergic neuronal activity, particularly in coerulospinal fibers that connect to spinal motor neurons terminating in the chest wall and abdomen, and in laryngeal nerve fibers that contribute to the vagus nerve via the superior and middle cervical ganglia. These laryngeal nerve fibers directly innervate the intrinsic muscles of the larynx.

[0495] The role of α1-adrenergic receptors has been suggested in particular by animal studies demonstrating that intravenous administration of the selective α1-adrenergic antagonist prazosin ten minutes before fentanyl inhibits the development of FIMR, as does ablation of the LC region of the brain. Other studies have shown that intrathecal administration of prazosin at the L3 spinal level also inhibits FIMR, but administration of the α2-adrenergic antagonist yohimbine does not. There is also some animal evidence that fentanyl itself is an antagonist of α1-adrenergic receptors, albeit a weaker one and selective for α1B and α1A receptors (but not α1D receptors). Unfortunately, these studies do not directly predict the beneficial use of α1-adrenergic antagonists in the treatment of opioid overdose, as the corresponding human doses used in the animal studies result in lethal hypotension in humans.

[0496] There is also increasing evidence that GABA interneurons play an intermediate role in the pathogenesis of WCS. GABA interneurons are part of an inhibitory network throughout the brain, and they are particularly abundant in the LC. The LC is responsible for maintaining basal skeletal muscle tone of the trunk through noradrenergic activation of spinal motor neurons, but GABA efferent signals inhibit noradrenaline release from LC presynaptic terminals. Therefore, inhibition of GABA interneurons leads to increased skeletal muscle tone via increased LC noradrenergic activity. Without being bound by theory, it is believed that fentanyl binds to μ-opioid receptors on GABA interneurons, which results in inhibition of GABA interneuron afferents, which results in the release of LC sympathetic neurons.

[0497] There is also evidence that LC neurons are also high in muscarinic and nicotinic acetylcholine receptors. It is believed that because the LC receives cholinergic input from other brain areas (such as the pontine reticular formation), fentanyl-induced μ-receptor agonism in these neighboring areas can stimulate acetylcholine release, which leads to further stimulation of norepinephrine release from the LC. There is also some evidence that fentanyl acts directly as an M3 muscarinic receptor antagonist, which can lead to a suppression of parasympathetic tone in the intrinsic muscles of the larynx, thereby further increasing the spasm caused by sympathetic activation of these muscles.

[0498] NMDA and non-NMDA glutamate receptor activity has also been implicated in the pathogenesis of WCS.

[0499] Since these other neurotransmitters (e.g., norepinephrine, acetylcholine, GABA, etc.) play intermediate roles in the pathogenesis of WCS, another reason why WCS is unresponsive to μ-opioid antagonist treatment may be that once these indirect fentanyl stimulatory effects are initiated (via μ-receptor agonism), simple μ-receptor antagonism cannot reverse the effects that have already been initiated.

[0500] Finally, there is also evidence that fentanyl, but not morphine, has some norepinephrine reuptake inhibitor activity. This effect has been shown to be unantagonized by naloxone in various neural cell lines, suggesting that it is not an indirect effect of μ-receptor agonism. Therefore, fentanyl may also directly affect neurons in the LC, stimulating hyperactivity of muscles involved in FIMR and WCS.

[0501] Therefore, there remains a need for therapeutic agents that are particularly suitable for reversing the effects of acute fentanyl overdose or fentanyl analog overdose. Fentanyl analogs include, but are not limited to, the compounds sufentanil, alfentanyl, remifentanil, carfentanil, and derivatives of these compounds, as further explained herein. Fentanyl and fentanyl analogs are referred to herein as "F / FA".

[0502] Without being bound by theory, it is believed that the compounds of the present invention have potent 5-HT 2A , D 1The compounds are unexpectedly effective in reversing the symptoms of F / FA overdose, especially respiratory depression, chest wall stiffness and laryngospasm, due to their preferential μ-opioid receptor activity. This is particularly believed to be due to the activity of these compounds as μ-receptor antagonists through β-arrestin signaling. The compounds are also believed to be active as α1-adrenergic antagonists, indirect NMDA and AMPA antagonists, and possibly due to indirect effects on GABA-expressing neurons. These properties are very unique and are not possessed by traditional μ-opioid receptor antagonists such as naloxone, which are used for the treatment of opioid overdose and surgical reversal of opioid agonism.

[0503] The compounds disclosed herein are also very beneficial in treating acute overdose and chronic opioid addiction because they do not cause opioid withdrawal symptoms like opioid cessation or opioid antagonist treatment. Opioid withdrawal syndrome can be very serious for addicted patients and can include symptoms such as tachycardia, nausea, vomiting, diarrhea, extreme anxiety, restless legs, muscle pain and heavy sweating. These withdrawal symptoms are the result of the body's adaptation to the presence of opioids, leading to tolerance and physical dependence. In severe cases, abrupt cessation of opioid abuse or treatment with opioid antagonists can lead to withdrawal symptoms lasting for weeks or months. Administration of opioid antagonists, such as naloxone or naltrexone, especially high doses, can trigger acute withdrawal effects, especially for patients with acute F / FA overdose. For patients with overdose of weaker opioid agonists such as heroin, small repeated doses of antagonists can be used to avoid or minimize such withdrawal syndromes. However, in acute F / FA overdose, such small doses of antagonists are ineffective, and thus it is often impossible to avoid severe withdrawal from traditional antagonist therapy in order to have any chance of reversing the overdose.

[0504] In a further embodiment of the third aspect, the present disclosure provides other embodiments of method 1, wherein the method is a method for one or more of the following aspects (method 1-A):

[0505] (a) Treat or reverse F / FA overdose;

[0506] (b) treating or reversing F / FA-induced respiratory depression;

[0507] (c) treating or reversing F / FA-induced muscle stiffness;

[0508] (d) treating or reversing F / A-induced laryngospasm;

[0509] (e) reversing or inhibiting the binding of F / FA to μ-opioid receptors in the central nervous system (e.g., in the macula ceruleus);

[0510] (f) inhibiting F / FA-induced β-arrestin signaling in the central nervous system (e.g., in the macula ceruleus);

[0511] (g) prevention of death from F / FA overdose; and

[0512] (h) sedation recovery (e.g. after surgery);

[0513] The method comprises administering to a patient in need thereof an effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.

[0514] Further exemplary embodiments of this aspect of Method 1 include the following:

[0515] 1.104 Method 1 or any one of 1.1-1.103, wherein the method is Method 1-A;

[0516] 1.105 Method 1-A or 1.104, wherein the patient is unconscious;

[0517] 1.106 Method 1-A or 1.104 or 1.105, wherein the patient is suspected of having an acute F / FA overdose;

[0518] 1.107 Method 1-A or any of Methods 1.104-1.106, wherein the patient exhibits chest wall stiffness;

[0519] 1.108 Method 1-A or any of Methods 1.104-1.107, wherein the patient exhibits laryngospasm;

[0520] 1.109 Method 1-A or any of Methods 1.104-1.08, wherein the patient is diagnosed with or suspected of having wooden chest syndrome (WCS);

[0521] 1.110 Method 1-A or any of Methods 1.104-1.08, wherein the patient is diagnosed with or suspected of having fentanyl-induced muscle rigidity (FIMR) or fentanyl-induced respiratory muscle rigidity (FIRMR) (wherein the FIMR or FIRMR is caused by fentanyl or by a fentanyl analog);

[0522] 1.111 Method 1-A or any of Methods 1.104-1.110, wherein the patient is in a non-hospital setting or a non-emergency room setting;

[0523] 1.112 Method 1-A or any of Methods 1.104-1.111, wherein the patient is suspected of having an opioid use disorder or has a history of an opioid use disorder;

[0524] 1.113 Method 1-A or any of Methods 1.104-1.112, wherein the patient is suspected to be a previous user of opioids;

[0525] 1.114 Method 1-A or any of Methods 1.104-1.113, wherein the patient has or is suspected of having an overdose of a legal or illegal drug contaminated with or mixed with F / FA, such as morphine, heroin, codeine, hydrocodone, oxycodone, hydromorphone, marijuana or cannabis products, tetrahydrocannabinol, cocaine, amphetamine, methamphetamine, MDMA, alprazolam, or other illegal or legal drugs;

[0526] 1.115 Method 1-A or any of Methods 1.104-1.114, wherein the F / FA is or was administered as systemic analgesia (e.g., surgical analgesia);

[0527] 1.116 Method 1.115, wherein the systemic analgesia also includes or has included one or more of the following: inhaled anesthetics (e.g., isoflurane, sevoflurane, desflurane, nitrous oxide, halothane, methoxyflurane), other opioid agonists (e.g., morphine, oxycodone), sedatives or hypnotic agents (e.g., propofol, midazolam, ketamine, etomidate), or muscle relaxants (e.g., atracurium, mevacurium, pancuronium, rocuronium, vecuronium, cistracurium, succinylcholine);

[0528] 1.117 Method 1.115 or 1.116, wherein the patient has difficulty emerging from anesthesia, for example due to persistent respiratory depression;

[0529] 1.118 Method 1-A or any of Methods 1.104-1.117, wherein the patient does not respond or does not respond adequately (e.g., with respect to signs or symptoms of respiratory depression) to a single dose of a mu-opioid antagonist (e.g., naloxone or naltrexone, e.g., 0.1-4 mg) administered by any route (e.g., intranasally, intravenously, subcutaneously, or intramuscularly);

[0530] 1.119 Method 1-A or any of Methods 1.104-1.117, wherein the patient does not respond or does not respond adequately (e.g., with respect to signs or symptoms of respiratory depression) to multiple doses of a mu-opioid antagonist (e.g., naloxone or naltrexone, e.g., 0.4-20 mg total) administered by any route (e.g., intranasally, intravenously, subcutaneously, or intramuscularly);

[0531] 1.120 Method 1-A or any of Methods 1.104-1.119, wherein the patient has experienced a recurrence of respiratory depression following administration of a single or multiple doses of a mu-opioid antagonist (e.g., naloxone or naltrexone) by any route, e.g., intranasally, intravenously, subcutaneously, or intramuscularly;

[0532] 1.121 Method 1-A or any of Methods 1.104-1.120, wherein the patient has experienced one or more opioid withdrawal symptoms or other adverse events (e.g., agitation, irritability, laryngospasm, pulmonary edema, hemodynamic instability, or cardiac arrhythmia) following administration of a single or multiple doses of a μ-opioid antagonist (e.g., naloxone or naltrexone) by any route, e.g., intranasally, intravenously, subcutaneously, or intramuscularly;

[0533] 1.122 Any of methods 1.118-1.121, wherein the μ-opioid antagonist is naloxone, naltrexone, or nalmefene;

[0534] 1.123 Any of methods 1.118-1.121, wherein the μ-opioid antagonist is naloxone;

[0535] 1.124 Method 1-A or any of 1.104-1.123, wherein the patient has been administered at least one dose of naloxone and has suffered one or more opioid withdrawal symptoms or adverse events such that further doses of naloxone are contraindicated;

[0536] 1.125 Any of Methods 1-A or 1.104-1.124, wherein the use of naloxone is contraindicated for any reason;

[0537] 1.126 Any of Method 1-A or 1.104-1.125, wherein the patient has previously suffered an opioid overdose;

[0538] 1.127 Any of Method 1-A or 1.104-1.126, wherein the patient is confirmed by toxicological or forensic methods to have suffered an F / FA overdose (e.g., by confirming the presence of F / FA in the patient's blood or in the patient's medications or drug paraphernalia);

[0539] 1.128 Any of Methods 1-A or 1.104-1.127, wherein the effective amount of the compound of Formula I is an amount effective to reverse one or more of: respiratory arrest, respiratory depression, skeletal muscle spasm, chest wall rigidity, laryngospasm, pupil constriction, cardiac arrest, bradycardia, or unconsciousness;

[0540] 1.129 Any of Methods 1-A or 1.104-1.128, wherein the effective amount of the compound of the invention is 0.1 mg-200 mg, such as 1-200 mg, or 10-150 mg, or 25-100 mg, or 50-100 mg, or 75-100 mg, or 25-75 mg, or 25-50 mg, or 1-50 mg, or 1-25 mg, 0.1 to 50 mg, 2.5 mg-50 mg, or for a long-acting formulation is 25 mg-1500 mg, such as 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg;

[0541] 1.130 Method 1.129, wherein the effective amount is administered as a single dose;

[0542] 1.131 Method 1.129, wherein the effective amount is administered in two or more doses over a period of less than 30 minutes (e.g., less than 20 minutes, or less than 15 minutes, or less than 10 minutes);

[0543] 1.132 Any of Methods 1-A or 1.104-1.131, wherein an effective amount of a compound of the invention is administered by intranasal administration (eg, as an aerosol, mist or powder for inhalation);

[0544] 1.133 Any of Method 1-A or 1.104-1.131, wherein an effective amount of the compound of the invention is administered across the oral mucosa, for example, by a rapidly dissolving oral tablet (eg, a rapidly dissolving sublingual tablet);

[0545] 1.134 Any of Method 1-A or 1.104-1.131, wherein an effective amount of the compound of the invention is administered by injection (eg, intravenous, intramuscular, intrathecal, intraperitoneal or subcutaneous injection);

[0546] 1.135 Method 1-A or any of 1.104-1.134, wherein the method does not include concurrent administration of any other opioid antagonist (e.g., naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime, or norbinaltorphimine);

[0547] 1.136 Method 1-A or any of 1.104-1.135, wherein the method comprises administering a pharmaceutical composition comprising wherein R 1 A compound of formula I wherein R is H and a prodrug of the same compound of formula I (ie, wherein R 1 Yes-C(O)-OC(R a )(R b )(R c )、-C(O)-O-CH 2 -OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 , as described above) both;

[0548] 1.137 Any of Method 1-A or 1.104-1.136, wherein the compound of this invention is the only pharmacological treatment for the overdose (e.g., not supportive interventions such as administration of oxygen, cardiopulmonary resuscitation, chest compressions, and fluid administration);

[0549] 1.138 Method 1-A or any of 1.104-1.137, wherein the method is a method for treating or reversing F / FA overdose;

[0550] 1.139 Method 1-A or any of 1.104-1.138, wherein the method is for treating or reversing F / FA-induced respiratory depression;

[0551] 1.140 Method 1-A or any of 1.104-1.139, wherein the method is for treating or reversing F / FA-induced muscle stiffness;

[0552] 1.141 Any of Method 1-A or 1.104-1.140, wherein the method is for treating or reversing F / A-induced laryngospasm;

[0553] 1.142 Method 1-A or any of 1.104-1.141, wherein the method is for reversing or inhibiting the binding of F / FA to a μ-opioid receptor in the central nervous system (e.g., in the locus coeruleus);

[0554] 1.143 Method 1-A or any of 1.104-1.142, wherein the method is for inhibiting F / FA-induced β-arrestin signaling in the central nervous system (eg, in the locus coeruleus);

[0555] 1.144 Method 1-A or any of 1.104-1.143, wherein the method is a method for preventing death caused by F / FA overdose;

[0556] 1.145 Method 1-A or any of 1.104-1.144, wherein the method is a method for anesthesia recovery (e.g., emergence from anesthesia, e.g., after surgery);

[0557] 1.146 Any of Method 1-A or 1.104-1.145, wherein the F / FA is any F / FA disclosed herein;

[0558] 1.147 Any of Methods 1-A or 1.104-1.146, wherein the F / FA is selected from fentanyl, sufentanil, alfentanyl, remifentanil, carfentanil, thiafentanil, lofentanil, ocfentanil, trefantinil and bufentanil;

[0559] 1.148 Any of Method 1-A or 1.104-1.147, wherein the F / FA is selected from fentanyl, sufentanil, alfentanyl, and carfentanil;

[0560] 1.149 Any of Method 1-A or 1.104-1.148, wherein the F / FA is fentanyl;

[0561] 1.150 Any of method 1-A or 1.104-1.149, wherein the method does not result in precipitated withdrawal in the patient, such as withdrawal symptoms selected from the group consisting of tachycardia, nausea, vomiting, diarrhea, extreme anxiety, restless legs, muscle pain, and profuse sweating;

[0562] 1.151 Method 1-A or any of 1.104-1.150, wherein the source of the F / FA is another illicit drug, such as cocaine, heroin, oxycodone, amphetamine, methamphetamine, or marijuana, into which the F / FA is adulterated;

[0563] 1.152 Any of Method 1-A or 1.104-1.150, wherein the method is:

[0564] (a) Treat or reverse drug overdose;

[0565] (b) Treat or reverse drug-induced respiratory depression;

[0566] (c) Treat or reverse drug-induced muscle stiffness;

[0567] (d) treating or reversing drug-induced laryngospasm; or

[0568] (e) Preventing deaths from drug overdose;

[0569] The drugs in question are illegal drugs that have been adulterated with F / FA;

[0570] 1.153 Method 1.152, wherein the illicit drug is heroin, cocaine, amphetamine, methamphetamine, oxycodone, or marijuana;

[0571] 1.154 Method 1.152 or 1.153, wherein the risk of overdose, respiratory depression, muscle rigidity, laryngospasm and / or death is primarily or exclusively attributable to the F / FA adulterant in the illicit drug (e.g., other than the F / FA adulterant, the illicit drug does not cause the risk of overdose, respiratory depression, muscle rigidity, laryngospasm and / or death).

[0572] The compounds of the present disclosure (i.e., compounds of the present invention) and pharmaceutical compositions of the present disclosure can be used in combination with a second therapeutic agent, particularly at a lower dose than when the individual drugs are used as monotherapy, to enhance the therapeutic activity of the combined drug and not cause undesirable side effects common in conventional monotherapy. Thus, the compounds of the present disclosure can be administered simultaneously, sequentially or synchronously with other therapeutic agents as described above, such as opioids, opioids, analgesics, antidepressants, antipsychotics, other hypnotic agents and / or drugs used to treat Parkinson's disease or mood disorders.

[0573] In any of the embodiments of method 1 and below, wherein the compound of the present disclosure is administered together with one or more second therapeutic agents, the one or more second therapeutic agents may be administered as part of a pharmaceutical composition comprising the compound of the present disclosure. Alternatively, the one or more second therapeutic agents may be administered simultaneously, sequentially, or separately with the administration of the compound of the present disclosure in separate pharmaceutical compositions (such as pills, tablets, capsules, and injections).

[0574] In some further embodiments of the present disclosure, the pharmaceutical compositions of the present disclosure can be used in combination with a second therapeutic agent, particularly at a lower dose than when the individual drugs are used as monotherapy, to enhance the therapeutic activity of the combined drug and not cause undesirable side effects, wherein the second therapeutic agent is an opioid antagonist or inverse agonist (e.g., naloxone). The compounds of the present disclosure can be administered simultaneously, sequentially, or concurrently with such opioid antagonists or opioid inverse agonists.

[0575] In a fourth aspect, the disclosure provides the use of a compound of the invention in the preparation of a medicament for use according to Method 1 or any of Methods 1.1-1.154. In another embodiment, the disclosure provides a compound of the invention for use in treating a disease or disorder according to Method 1 or any of Methods 1.1-1.154.

[0576] Detailed Description

[0577] It will be appreciated that the terms "opioid" and "opioid" are distinct, with "opioid" referring to natural products extracted from the opium poppy, such as morphine, codeine and heroin, and "opioid" referring to these natural compounds and their semi-synthetic and synthetic derivatives, such as fentanyl and its analogs.

[0578] Formula A compounds and related compounds have been shown to have a variety of useful pharmaceutical properties, each of which is expected to be shared by a variety of compounds of the present disclosure. Such properties and data supporting such therapeutic efficacy are disclosed in, for example, US10,245,260, US11,376,249, US 2021 / 0093634, WO 2021 / 154519, US 2022 / 0088014, WO 2020 / 206391, US 2022 / 0184072, US Provisional Application No. 63 / 262,732, and PCT / US2022 / 078177, the contents of which are each incorporated herein by reference in their entirety.

[0579] For example, the compound of formula A has a potent 5-HT 2A , D 1 and μ opioid receptor antagonism and moderate D 2Receptor and SERT antagonism. In addition, it has been unexpectedly found that these compounds can act as "biased" μ opioid receptor ligands. This means that when the compounds bind to the μ opioid receptor, they can act as partial μ agonists through G-protein coupled signaling, but act as μ antagonists through β-inhibitory protein signaling. This is different from traditional opioid agonists morphine and fentanyl, which tend to strongly activate G protein signaling and β-inhibitory protein signaling. This type of drug activates β-inhibitory protein signaling, which is believed to mediate gastrointestinal dysfunction and respiratory depression that are usually mediated by opioid drugs. Therefore, compared with existing opioid analgesics, the compounds of the present invention are expected to lead to pain improvement and have gastrointestinal and respiratory side effects with reduced severity. This effect has been confirmed in preclinical studies and Phase II and Phase III clinical trials of the biased μ agonist oliceridine. Compared to morphine, oxeridine has been shown to produce biased μ agonism via G-protein coupled signaling with reduced β-arrestin signaling, which correlates with its ability to produce analgesia with reduced respiratory side effects compared to morphine. Furthermore, since these compounds antagonize the β-arrestin pathway, they are expected to be useful in treating opioid overdose, as they will suppress the most severe opioid adverse effects while still providing pain relief. Furthermore, due to their serotonergic activity, these compounds also have sleep-maintaining effects. Since many people with chronic pain have difficulty sleeping due to pain, these compounds may help such patients sleep through the night due to the synergistic effects of serotonergic and opioid receptor activity.

[0580] Thus, in some embodiments, the compounds of the present disclosure may be used alone or in combination with an opioid antagonist or inverse agonist (e.g., naloxone or naltrexone) in methods for treating opioid use disorder (OUD), opioid overdose, or opioid withdrawal. The compounds of the present disclosure are expected to show a strong ability to alleviate dysphoria and psychiatric comorbidities (e.g., mood and anxiety disorders, sleep disorders) associated with drug withdrawal, and they also provide potent analgesia without the adverse effects (e.g., GI effects and lung depression) and abuse potential seen with other opioid treatments (e.g., oxycodone, methadone, or buprenorphine). The unique pharmacological profile of these compounds should also reduce the risk of adverse drug-drug interactions (e.g., alcohol). Therefore, these compounds are particularly suitable for treating opioid use disorders and symptoms associated with opioid withdrawal. In addition to the direct effects of the compounds on μ-receptor activity, the effects of the compounds on serotonergic pathways also result in antidepressant, sleep maintenance, and antianxiety effects. Because depression and anxiety are key factors that lead susceptible patients to use opioids in the first place, the compounds of the present disclosure can alleviate opioid withdrawal symptoms while reducing psychiatric comorbidities that promote opioid use, a two-pronged strategy that can reduce the risk of remission. The sleep maintenance provided by these compounds will further improve the quality of life of patients receiving OUD treatment.

[0581] In some embodiments of the present disclosure, the compounds of the invention have one or more biologically labile functional groups located within the compound such that natural metabolic activity will remove the labile functional group to produce another compound of the invention. 1 C(O)-OC(R a )(R b )(R c )、-C(O)-O-CH 2 -OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 When the substituent is hydrolyzed under biological conditions, R 1 is the same compound as H, so prepare 1 Some of these prodrug compounds may have no or little or only moderate biological activity, but are hydrolyzed to R 1The compound may have strong biological activity after the compound is H. As such, administration of the compounds of the present disclosure to a patient in need thereof may produce immediate biological and therapeutic effects, or immediate and delayed biological and therapeutic effects, or only delayed biological and therapeutic effects, depending on the compound selected. Thus, such prodrug compounds will be used as compounds wherein R 1 In this manner, some compounds of the present disclosure are particularly suitable for formulation as long-acting injectable (LAI) or "depot" pharmaceutical compositions. Without being bound by theory, an injected "depot" containing a compound of the present disclosure will be gradually released into body tissues, where the compound will be gradually metabolized to produce R 1 The compound of the present invention is H. Such depot formulations can be further adjusted by selecting appropriate components to control the dissolution and release rate of the compound of the present invention. Such prodrug forms of compounds related to the compounds of the present invention have been previously disclosed, for example in US2021 / 0163481, the contents of which are incorporated herein by reference in their entirety.

[0582] As used herein, the following terms have the following meanings unless otherwise specified or the context is unclear.

[0583] As used herein, "alkyl" is a saturated or unsaturated hydrocarbon moiety, e.g., 1 to 21 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 indicated. 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 1-22 In another embodiment, the alkyl group contains 1-21 carbon atoms, is preferably linear, and is optionally saturated or unsaturated. For example, in some embodiments, wherein R 1 is an alkyl chain containing 1-21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, such that together with the -C(O)- to which it is attached, for example when cleaved from the compound of formula I, a residue of a natural or unnatural saturated or unsaturated fatty acid is formed.

[0584] The term "pharmaceutically acceptable diluent or carrier" is intended to refer to diluents and carriers that can be used in pharmaceutical preparations, which do not contain allergenic, pyrogenic or pathogenic substances and substances known to cause or promote disease. Thus, pharmaceutically acceptable diluents or carriers exclude body fluids such as blood, urine, cerebrospinal fluid, saliva, etc. and their constituent components such as blood cells and circulating proteins. Suitable pharmaceutically acceptable diluents and carriers can be found in a number of known treatises on pharmaceutical formulations, such as Anderson, Philip O.; Knoben, James E.; Troutman, William G, ed., Handbook of Clinical Drug Data, 10th edition, McGraw-Hill, 2002; Pratt and Taylor, ed., 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, ed., 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 Press, London, 1999); each of which is incorporated by reference in its entirety.

[0585] The terms "purified", "purified form" or "isolated and purified form" for a compound refer 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 terms "purified", "purified form" or "isolated and purified form" for a compound refer to the physical state of the compound after obtaining it from one or more purification methods described herein or well known to those skilled in the art (e.g., chromatography, recrystallization, LC-MS and LC-MS / MS techniques, etc.), and its purity is sufficient to be characterized by standard analytical techniques described herein or well known to those skilled in the art.

[0586] Unless otherwise indicated, the compounds of the present invention may exist in free form or in salt form, e.g., in pharmaceutically acceptable salt form, e.g., as acid addition salts. Acid addition salts of compounds of the present invention having sufficient basicity, e.g., acid addition salts formed with, e.g., inorganic or organic acids such as hydrochloric acid or toluenesulfonic acid, etc. In addition, salts of compounds of the present invention having sufficient acidity are alkali metal salts, e.g., sodium or potassium salts, or salts with organic bases providing physiologically acceptable cations. In a specific embodiment, the salt of a compound of the present invention is a toluenesulfonic acid addition salt.

[0587] The compounds of the invention are intended for use as pharmaceuticals and therefore pharmaceutically acceptable salts thereof are preferred. Salts which are unsuitable for pharmaceutical use may be useful, for example, for isolating or purifying free compounds of the invention and are therefore also included within the scope of the compounds of the present disclosure.

[0588] The compounds of the present invention may contain one or more chiral carbon atoms. Therefore, the compounds exist as individual isomers, such as enantiomers or diastereoisomers, or as a mixture of individual forms such as racemic / diastereomeric mixtures. Any isomers in which the asymmetric center is (R)-, (S)- or (R, S)-configuration may exist. The present invention is understood to include individual optically active isomers and mixtures thereof (e.g., racemic / diastereomeric mixtures). Therefore, the compounds of the present invention may be racemic mixtures, or they may be primarily, for example, pure or substantially pure isomeric forms, 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 accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed, etc.).

[0589] Depending on the nature of the substitution about the double bond or the ring, geometric isomers may exist in cis (Z) or trans (E) form, and both isomeric forms are included within the scope of the present invention.

[0590] The compounds of the present disclosure are intended to encompass both stable and unstable isotopes thereof. Stable isotopes are non-radioactive isotopes that contain one extra 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 will also have the utility of measuring the pharmacokinetics of non-isotopic analogs. For example, hydrogen atoms at specific positions on the compounds of the present disclosure can be replaced by deuterium (a non-radioactive stable isotope). Examples of known stable isotopes include, but are not limited to, deuterium ( 2 H or D), 13 C. 15 N. 18O. Alternatively, a radioactive isotope, an unstable isotope containing an extra neutron compared to the abundant nuclide of the same species (i.e., element), such as 123 I. 131 I. 125 I. 14 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 14 C isotopes. These radioactive isotopes can be used for radiographic and / or pharmacokinetic studies of the compounds of the invention. In addition, when heavier isotopes are substituted for atoms with natural isotopic distribution at metabolically susceptible sites, these substitutions can result in expected changes in pharmacokinetic rates. For example, when the position of hydrogen is a site of enzymatic or metabolic activity, the incorporation of deuterium ( 2 H) can replace hydrogen and slow down metabolic degradation.

[0591] The compounds of the present invention can be included as a depot formulation, for example, by dispersing, dissolving or encapsulating the compounds of the present invention in a polymer matrix as described above, so that as the polymer degrades over time, the compound is continuously released. 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 compound, for example, from a drug depot composition, into an individual to whom the drug depot is applied, such as a warm-blooded animal, such as a human. Therefore, the drug depot delivers the compounds of the present invention to an individual over a sustained period of time, for example 14-180 days, preferably about 30, about 60 or about 90 days, at a concentration effective to treat a particular disease or medical condition.

[0592] The polymer matrix that can be 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 substances, such as polylactic acid, polyglycolic acid, polyadipic acid, polymaleic acid, poly-β-hydroxybutyric acid, ε-caprolactone ring-opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid polymer, polylactic acid-polyethylene glycol copolymer or polyglycolic acid-polyethylene glycol copolymer), α-cyanoacrylate alkyl ester (e.g., poly(2-cyanoacrylate butyl ester)), polyalkylene oxalate (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoester, polycarbonate (e.g., polyethylene carbonate or polyethylene-propylene carbonate), polyorthocarbonate, polyamino acid (e.g., poly-γ-L-alanine, poly-γ-benzyl-L-glutamic acid or poly-γ-methyl-L-glutamic acid), hyaluronic acid ester, etc., and one or more of these polymers can be used.

[0593] If the polymer is a copolymer, they can be any of random, block and / or graft copolymers. When the above-mentioned α-hydroxycarboxylic acid, hydroxydicarboxylic acid and hydroxytricarboxylic acid have optical activity in their molecules, any of 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), hereinafter referred to as PLGA). Therefore, in one aspect, the polymer that can be used for the polymer matrix is ​​PLGA. The term PLGA as used herein includes lactic acid polymers (also known as polylactide, poly (lactic acid) or PLA). Most preferably, the polymer is a biodegradable poly (d, l-lactide-co-glycolide) polymer.

[0594] In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymer material. The term "biocompatible" is defined as a polymer material that is non-toxic, non-carcinogenic, and does not significantly induce inflammation of body tissues. The matrix material should be biodegradable, wherein the polymer material should be degraded into a product that is easily discarded by the body through a body process and should not accumulate in the body. The biodegradation product should also be biocompatible with the body because the polymer matrix is ​​biocompatible with the body. Particularly useful examples of polymer matrix materials include poly (glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid, the aforementioned copolymers, 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 wax, for example glycerol monostearate and distearate, etc. The polymer preferably used for the implementation of the present invention is dl (lactide-co-glycolide). Preferably, the molar ratio of lactide to glycolide in such copolymers is in the range of about 75:25 to 50:50.

[0595] The weight average molecular weight of useful PLGA polymers can be about 5000 to 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. The drug can also be released from the polymer matrix along with the bioerosion of the polymer excipient. PLGA can be prepared by any conventional method, or can be purchased. For example, PLGA can be produced by ring-opening polymerization from cyclolactide, glycolide, etc. using a suitable catalyst (see EP-0058481B2; The influence of polymerization variables on PLGA performance: molecular weight, composition and chain structure).

[0596] It is believed that PLGA is biodegradable by degradation of the entire solid polymer composition because under biological conditions (e.g., in the presence of water and biological enzymes found in warm-blooded animals such as human tissues), the hydrolyzable and enzymatically cleavable ester bonds are decomposed to form lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism that can be further biodegraded to form carbon dioxide and water. In other words, PLGA is believed to be degraded by hydrolyzing its ester groups in the presence of water, such as in the body of warm-blooded animals such as humans, producing lactic acid and glycolic acid and forming an acidic microclimate. Lactic acid and glycolic acid are byproducts of various metabolic pathways in warm-blooded animals, such as humans, under normal physiological conditions, and are therefore well tolerated and produce minimal systemic toxicity.

[0597] In another embodiment, the polymer matrix that can be 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 as the center portion surrounded by acid residue chains. The polyol moiety can be, for example, glucose or, for example, mannitol. These esters are known and are documented in GB 2,145,422 and United States Patent (USP) 5,538,739, the contents of which are incorporated herein by reference.

[0598] Star polymers can be prepared using polyhydroxy compounds, such as polyols, such as glucose or mannitol as initiators. The polyol contains at least 3 hydroxyl groups and has a molecular weight of up to about 20,000 Daltons, at least 1, preferably at least 2, for example an average of 3 of the hydroxyl groups of the polyol are in the form of ester groups, which contain polylactic acid or copolylactic acid chains. Branched polyesters, such as poly (d, l-lactide-co-glycolide), have a central glucose portion with radial linear polylactic acid chains.

[0599] The depot composition of the present invention as described above (a long-acting injectable composition having a compound of the present invention in a polymer matrix) may comprise a polymer in the form of microparticles or nanoparticles, or a polymer in liquid form, in which the compound of the present invention is dispersed or encapsulated. "Microparticles" refer to solid particles containing a compound of the present invention in solution or solid form, wherein such compound is dispersed or dissolved in a polymer as a particle matrix. By appropriately selecting a polymer material, microparticle preparations may be prepared in which the resulting microparticles exhibit diffusion release and biodegradation release characteristics.

[0600] When the polymer is in the form of microparticles, any appropriate method can be used to prepare microparticles, such as by solvent evaporation or solvent extraction. For example, in the solvent evaporation method, the compound of the present invention and the polymer can be dissolved in a volatile organic solvent (e.g., ketones such as acetone, halogenated hydrocarbons such as chloroform or methylene chloride, 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). Then, the organic solvent is evaporated to provide microparticles encapsulated with the compound of the present invention. In the solvent extraction method, the compound of the present invention and the polymer can be dissolved in a polar solvent (e.g., acetonitrile, methylene chloride, methanol, ethyl acetate or methyl formate), and then dispersed in an aqueous phase (e.g., water / PVA solution). An emulsion is prepared to provide microparticles encapsulated with the compound of the present invention. Spray drying is another manufacturing technique for preparing microparticles.

[0601] Another method of preparing the microparticles of the present invention is also described in US Pat. No. 4,389,330 and US Pat. No. 4,530,840.

[0602] Microparticles of the present invention can be prepared by any method that can produce microparticles within the size range that can be used for injection compositions. A preferred preparation method is the method of recording in U.S. Patent No. 4,389,330. In this method, the active agent is dissolved or dispersed in a suitable solvent. A polymer matrix material is added to the medium containing the active agent, and its amount can provide a product with an expected active agent load relative to the active ingredient. Optionally, all ingredients of the microparticle product can be mixed together in a solvent medium.

[0603] Solvents for preparing such compositions comprising compounds of the present invention and polymer matrix materials useful in the practice of the present invention include organic solvents such as acetone; halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aromatic compounds; halogenated aromatic compounds; cyclic ethers; alcohols such as benzyl alcohol; ethyl acetate; etc. In one embodiment, the solvent used to practice the present invention may be a mixture of benzyl alcohol and ethyl acetate. Further information on the preparation of microparticles useful in the present invention may be found in U.S. Patent Publication No. 2008 / 0069885, the contents of which are incorporated herein by reference in their entirety.

[0604] The amount of the compound of the disclosure incorporated into the microparticles is generally in the range of about 1 wt.% to about 90 wt.%, preferably 30 to 50 wt.%, more preferably 35 to 40 wt.%. The wt.% refers to the fraction of the compound of the disclosure relative to the total weight of the microparticles.

[0605] The pharmaceutical depot composition may comprise a pharmaceutically acceptable diluent or carrier, such as a water-miscible diluent or carrier.

[0606] Details of osmotic controlled release oral delivery system compositions can be found in EP1539115 (US Publication No. 2009 / 0202631) and WO 2000 / 35419 (US 2001 / 0036472), the contents of which are incorporated herein by reference in their entirety.

[0607] A "therapeutically effective amount" refers to any amount of a compound of the invention (e.g., 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.

[0608] The dosage for implementing the present invention will of course vary according to, for example, the specific disease or illness to be treated, the specific compound of the present invention used, the mode of administration and the intended treatment. Unless otherwise indicated, the amount of the compound of the present invention (whether it is administered in free alkali or salt form) refers to or is based on the amount of the compound of the present invention in free alkali form (that is, the calculation of the amount is based on the free alkali amount).

[0609] The compounds of the invention can be administered by any satisfactory route, including oral, parenteral (intravenous, intramuscular or subcutaneous) or transdermal administration. 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, such as intramuscular or subcutaneous injection.

[0610] Typically, a dosage of about 1 mg to 100 mg, preferably 2.5 mg to 50 mg, e.g. 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg, once a day, preferably orally administered, is indicated to obtain satisfactory results of the methods of treatment disclosed herein as described above or of the use of the compounds of the present invention as described above.

[0611] For some disease treatments, lower doses are satisfactory, particularly for the treatment of sleep disorders, for example about 2.5mg-5mg, for example 2.5mg, 3mg, 4mg or 5mg of a compound of the invention in free or pharmaceutically acceptable salt form, once a day, preferably administered orally.

[0612] For treatment methods involving co-administration of a second therapeutic agent, satisfactory results may be obtained with less than 100 mg, preferably less than 50 mg, e.g. less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg, less than 2.5 mg once daily.

[0613] For the treatment of diseases disclosed herein where a depot composition is used to achieve a longer duration of action, the dosage will be higher relative to a shorter acting composition, e.g., greater than 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1000 mg, or greater than 1000 mg. The duration of action of the compounds of the present disclosure can be controlled by manipulating the polymer composition, i.e., polymer: drug ratio and particle size. Where the composition of the present invention is a depot composition, it is preferably administered by injection.

[0614] Pharmaceutically acceptable salts of the compounds of the present disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid in water or in an organic solvent or a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Further details of the preparation of these salts, such as tosylate salts in amorphous or crystalline form, can be found in US 8,309,722, 8.648,077, 9,199,995 and 9,586,960.

[0615] Pharmaceutical compositions containing compounds of the present disclosure can 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.

[0616] When referring to therapeutic uses, the term "concurrently" refers to the administration of two or more active ingredients to a patient as part of a treatment regimen for a disease or disorder, whether the two or more active agents are administered at the same or different times or by the same or different routes of administration. The concurrent administration of the two or more active ingredients may be performed at different times of the same day or on different days or at different frequencies.

[0617] When referring to therapeutic uses, the term "simultaneously" means that two or more active ingredients are administered at or about the same time by the same route of administration.

[0618] When referring to therapeutic uses, the term "separately" means that two or more active ingredients are administered simultaneously or about simultaneously by different routes of administration.

[0619] Methods for preparing the compounds of the present invention:

[0620] Compounds of formula A and methods for their synthesis, including the synthesis of intermediates used in the following synthetic schemes, have been disclosed in, for example, US 10,245,260 and US 2022 / 0041600 and US 2022 / 0064166, the contents of which are incorporated herein by reference in their entirety.

[0621] The synthesis of similar fused γ-carbolines has been disclosed in, for example, US8,309,722, US8,993,572, US 2017 / 0183350, WO 2018 / 126140 and WO 2018 / 126143, the contents of which are each incorporated herein by reference in their entirety. The compounds of the present disclosure can be prepared using similar methods.

[0622] The compound of the present invention, wherein R 1 It is C(O)-OC(R a )(R b )(R c )、-C(O)-O-CH 2 -OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 , can be prepared by a method similar to that disclosed in international application WO 2019 / 023063.

[0623] Other compounds of the present disclosure can be prepared by similar methods known to those skilled in the art.

[0624] 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.

[0625] Salts of compounds of the present disclosure can be prepared similarly to those described in U.S. Pat. Nos. 6,548,493, 7,238,690, 6,552,017, 6,713,471, 7,183,282, 8,648,077, 9,199,995, 9,586,860, USRE39680, and USRE39679, the contents of each of which are incorporated herein by reference in their entirety.

[0626] The diastereomers of the prepared compounds can be separated by, for example, HPLC, using AY-H, 5μ, 30×250 mm, separated at room temperature, eluted with 10% ethanol / 90% hexane / 0.1% dimethylethylamine. Peaks can be detected at 230 nm to produce diastereomers with 98-99.9% ee. Example

[0627] The compound of formula A and its synthesis method are disclosed in US10,245,260, US2022 / 0041600 and US2022 / 0064166. For example, in US2022 / 0041600, the compound of formula A is prepared according to the following process:

[0628]

[0629] Process 1

[0630] Compound 1 is disclosed in, for example, US8,309,722 and US2020 / 0102309.

[0631] A mixture of (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido-4,3-b]indole-2-carboxylic acid ethyl ester (Compound 1, 21.5 g, 66.2 mmol), 2-chloroacetamide (9.3 g, 100 mmol) and KI (17.7 g, 107 mmol) in anhydrous dioxane (60 mL) was heated at 104 ° C for 48 hours under argon atmosphere. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was suspended in dichloromethane (DCM, 200 mL) and washed with water (100 mL). The DCM phase was separated and purified by K 2 CO 3 Drying and concentration gave a brown oil. The oil product was suspended in ethyl acetate (100 mL), sonicated for 5 minutes, and then allowed to stand at room temperature for 2 hours. A precipitate was formed, which was filtered, and the filter cake was rinsed with ethyl acetate (2 mL) and dried under high vacuum. The title compound (4aS,9bR)-5-(2-amino-2-oxoethyl)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido-4,3-b]indole-2-carboxylic acid ethyl ester (Compound 2) was obtained as an off-white solid (19 g, 75% yield), which was used directly in the next reaction without further purification.

[0632] A suspension of compound 2 (12.9 g, 33.7 mmol), KI (10.6 g, 63.8 mmol) and CuI (1.34 g, 6.74 mmol) in dioxane (50 mL) was filled with argon for 5 minutes, and then N,N,N',N'-tetramethylethylenediamine (3 mL) was added. After the reaction mixture was stirred at 100 °C for 48 hours, the reaction mixture was cooled to room temperature and then poured onto a silica gel pad for filtration. The filter cake was rinsed with ethyl acetate (2×250 mL) and the filtrate was concentrated to give the title compound (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylic acid ethyl ester (compound 3) as a white solid (8 g, 79% yield). The crude product was used directly in the next step without further purification.

[0633] Compound 3 (6.4 g, 27.9 mmol) was suspended in HBr / acetic acid solution (64 mL, 33% w / w) at room temperature and heated to 50°C with stirring. After stirring at 50°C for 8 hours, the reaction was cooled to room temperature and ethyl acetate (300 mL) was added. The precipitate was filtered out, the filter cake was washed with ethyl acetate (10 mL) and dried under vacuum. The obtained HBr salt was suspended in methanol (100 mL) and cooled to a temperature below 5°C using an isopropanol / dry ice bath. Ammonia solution (20 mL, 7N in methanol) was slowly added to the cooled suspension with stirring until the solution pH was 14. The solution was evaporated to dryness and the residue was dried under high vacuum to give the title compound (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (Compound 4) (7.8 g, >99% yield). The crude product was used in the next step without any further purification.

[0634] A mixture of compound 4 (1.0 g, 4.4 mmol), 1-(3-chloropropoxy)-4-fluorobenzene (1.4 mL, 8.8 mmol) and KI (1.45 g, 8.7 mmol) in DMF (20 mL) was filled with argon for 3 minutes, and then DIPEA (1.50 mL, 8.7 mmol) was added. The mixture was heated to 78 ° C, stirred for 2 hours, and then cooled to room temperature. The solvent was removed and the residue was dissolved in DCM (30 mL) and washed with water (20 mL). The DCM phase was purified by K 2 CO 3 The crude product was purified by silica gel column chromatography using [ethyl acetate / methanol / 7N NH 3Purification was performed using a gradient of 0–55% in ethyl acetate [10:1:0.1 v / v / v in methanol] as the eluent. The eluted product was dissolved in methanol (5 mL) and allowed to stand at room temperature for 30 minutes. A precipitate formed, which was filtered and dried in vacuo to give the final product (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 5, Formula A compound) as a white solid (0.63 g, yield: 38%). 1 H NMR (500 MHz, DMSO-d 6 )δ10.3(s,1H),7.2–7.0(m,2H),7.0–6.9(m,2H),6.8–6.7(m,1H),6.6(t,J=7.55Hz ,1H),6.6(dd,J=1.04,7.77Hz,1H),4.0(t,J=6.37Hz,2H),3.8(d,J=14.53Hz,1H),3 .3(s,1H),3.3–3.1(m,2H),2.9–2.8(m,1H),2.7–2.6(m,1H),2.5–2.3(m,2H),2.2– 2.0(m,1H),1.9(dq,J=2.62,14.64Hz,1H),1.9–1.7(m,3H),1.7(t,J=10.98Hz,1H). HRMS(ESI)m / z C 22 H 25 FN 3 O 2 [M+H] + :Calculated value 382.1925; measured value: 382.1947.

[0635] Example 1: Synthesis of (6bR,10aS)-8-butyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0636]

[0637] Compounds can be prepared by methods similar to the synthesis of compound 5 in Scheme 1, wherein 1-chlorobutane is added in place of 1-(3-chloropropoxy)-4-fluorobenzene in step d. 1 H NMR (500 MHz, DMSO-d 6)δ10.34(s,1H),6.77(dd,J=7.4,1.0Hz,1H),6.64(t,J=7.5Hz,1H),6.58(dd,J=7.9,1.0Hz,1H),3.80(d,J= 14.5Hz,1H),3.30–3.22(m,2H),3.20(dt,J=10.7,6.4Hz,1H),2.83(ddd,J=11.4,6.3,1.8Hz,1H),2.61(ddd , J = 13.3, 4.7, 2.3 Hz, 1H), 2.30–2.13 (m, 2H), 2.11–2.00 (m, 1H), 1.93 (dq, J = 14.4, 2.6 Hz, 1H), 1.78 (ddt, J = 12.2, 9.6, 4.6 Hz, 1H), 1.63 (t, J = 11.0 Hz, 1H), 1.46–1.34 (m, 2H), 1.33–1.22 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). HRMS (ESI) m / z calculated value C 17 H 24 N 3 O[M+H] + :286.1914.

[0638] Example 2: Synthesis of (6bR,10aS)-8-(3-hydroxypropyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0639]

[0640] Compounds can be prepared by methods similar to the synthesis of compound 5 in Scheme 1, wherein 3-chloro-1-propanol is added in place of 1-(3-chloropropoxy)-4-fluorobenzene in step d. 1 H NMR (500 MHz, DMSO-d 6)δ10.37(s,1H),8.17(s,1H),6.81–6.74(m,1H),6.64(t,J=7.6Hz,1H),6.58(dd,J=7. 8,1.0Hz,1H),3.81(d,J=14.5Hz,1H),3.43(t,J=6.3Hz,2H),3.31(d,J=14.4Hz,1H),3 .28–3.10(m,2H),2.90(m,1H),2.74–2.62(m,1H),2.44–2.24(m,2H),2.19–2.08(m,1H ),2.01–1.87(m,1H),1.86–1.74(m,1H),1.70(t,J=11.0Hz,1H),1.59(p,J=6.8Hz,2H). HRMS(ESI)m / z C16H22N3O2[M+H] + :Calculated value: 288.1707; Measured value: 288.1722.

[0641] Example 3: Synthesis of (6bR,10aS)-8-(3-phenoxypropyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0642]

[0643] Compounds can be prepared by methods similar to the synthesis of compound 5 in Scheme 1, wherein (3-chloropropoxy)benzene is added in step d instead of 1-(3-chloropropoxy)-4-fluorobenzene. 1 H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.14 (d, J = 3.5Hz, 1H), 7.38–7.19 (m, 2H), 6.9 1(dd,J=7.9,4.4Hz,2H),6.78(d,J=7.1Hz,1H),6.61(dd,J=19.0,7.4Hz,2H),4.15–3 .92 (m, 2H), 3.81 (d, J = 14.5 Hz, 1H), 3.53–3.05 (m, 5H), 2.99–2.83 (m, 1H), 2.66 (s, 1H), 2.45–2.31 (m, 1H), 2.24–2.05 (m, 1H), 2.03–1.77 (m, 3H), 1.72 (t, J = 10.8 Hz, 1H). HRMS (ESI) m / z C22H26N3O2 [M+H] + calculated value 364.2020; found value: 364.1970.

[0644] Example 4: Synthesis of (6bR,10aS)-8-(4-(5-chlorothiophen-2-yl)-4-oxobutyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0645]

[0646] Compounds can be prepared by methods similar to the synthesis of compound 5 in Scheme 1, wherein 4-chloro-1-(5-chlorothien-2-yl)butan-1-one is added in step d instead of 1-(3-chloropropoxy)-4-fluorobenzene. 1 H NMR (500 MHz, DMSO-d 6 )δ10.35(s,1H),7.85(d,J=4.1Hz,1H),7.30(d,J=4.1Hz,1H),6.74(d,J=7.3Hz,1H),6.63(t,J=7.5Hz,1H),6 .56(d,J=7.8Hz,1H),3.77(d,J=14.5Hz,1H),3.28(d,J=14.4Hz,1H),3.17(q,J=3.9,2.1Hz,1H),3.02(dt,J= 11.0,6.5Hz,1H),2.88(t,J=6.8Hz,2H),2.76(dd,J=11.3,6.5Hz,1H),2.54(d,J=11.6Hz,1H),2.25(dp,J=25 .8, 6.3Hz, 2H), 2.10–1.96 (m, 1H), 1.94–1.83 (m, 1H), 1.78 (td, J = 12.0, 10.5, 5.4Hz, 2H), 1.67–1.48 (m, 2H). HRMS(ESI)m / z C 21 H 23 C1N 3 O 2 S[M+H] + Calculated value: 416.1194.

[0647] Example 5: Synthesis of (6bR,10aS)-8-(3-(6-fluoro-1-methyl-1H-indazol-3-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0648]

[0649] The compound can be prepared by a method similar to the synthesis of compound 5 in Scheme 1, wherein 3-(3-chloropropyl)-6-fluoro-1-methyl-1H-indazole is added in step d instead of 1-(3-chloropropoxy)-4-fluorobenzene. 1 H NMR (500 MHz, DMSO-d 6 )δ10.36(s,1H),8.16(s,1H),7.76(dd,J=8.8,5.2Hz,1H),7.43(dd,J=10.1,2.2Hz,1H),6.96(td,J=9.1,2.2 Hz,1H),6.77(dd,J=7.4,1.0Hz,1H),6.63(t,J=7.5Hz,1H),6.57(dd,J=7.9,1.0Hz,1H),3.92(s,3H),3.80(d ,J=14.5Hz,1H),3.30(d,J=14.4Hz,1H),3.28–3.16(m,2H),2.93–2.82(m,3H),2.65(d,J=11.8Hz,1H),2.34( dddd,J=19.4,12.4,7.5,5.3Hz,2H),2.11(td,J=11.9,2.8Hz,1H),2.03–1.74(m,5H),1.68(t,J=11.0Hz,1H). HRMS(ESI)m / z C 24 H 27 FN 5 O[M+H] + : Calculated value: 420.2194.

[0650] Example 6: Synthesis of (6bR,10aS)-8-(3-(4-hydroxyphenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0651]

[0652] Compounds can be prepared by methods similar to the synthesis of compound 5 in Scheme 1, wherein 4-(3-chloropropoxy)phenol is added in place of 1-(3-chloropropoxy)-4-fluorobenzene in step d. 1 H NMR (500 MHz, DMSO-d 6)δ10.33(s,1H),8.17(s,1H),6.80–6.75(m,1H),6.75–6.69(m,2H),6.68–6.60(m,3H) ,6.57(dd,J=7.8,1.0Hz,1H),3.88(t,J=6.4Hz,2H),3.80(d,J=14.6Hz,1H),3.27–3.1 5(m,3H),2.86(dt,J=10.4,5.0Hz,1H),2.69–2.59(m,1H),2.46–2.29(m,2H),2.09(t, J=12.0Hz, 1H), 1.94 (d, J=13.8Hz, 1H), 1.81 (p, J=6.4Hz, 3H), 1.67 (t, J=10.7Hz, 1H). HRMS(ESI)m / zC 22 H 26 FN 3 O 3 [M+H] + : Calculated value: 380.1969.

[0653] Example 7: Synthesis of (6bR,10aS)-8-(3-(4-(benzyloxy)phenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0654]

[0655] Compounds can be prepared by methods similar to the synthesis of compound 5 in Scheme 1, wherein 1-(benzyloxy)-4-(3-chloropropoxy)benzene is added in step d instead of 1-(3-chloropropoxy)-4-fluorobenzene. 1 H NMR (500 MHz, DMSO-d 6)δ10.34(s,1H),8.16(d,J=5.8Hz,1H),7.46–7.41(m,2H),7.38(dd,J=8.4,6.7Hz,2H),7.35–7.29(m,1H),6.9 6–6.90(m,2H),6.89–6.82(m,2H),6.78(d,J=7.2Hz,1H),6.64(t,J=7.5Hz,1H),6.61–6.56(m,1H),5.03(s,2H) ,3.93(t,J=6.4Hz,2H),3.81(d,J=14.5Hz,1H),3.28–3.19(m,3H),2.89(d,J=8.4Hz,1H),2.64(t,J=1.9Hz,1H) ,2.48–2.31(m,2H),2.09(d,J=10.7Hz,1H),1.95(d,J=14.5Hz,1H),1.89–1.75(m,3H),1.69(d,J=11.6Hz,1H). HRMS(ESI)m / z C 29 H 32 N 3 O 3 [M+H] + : Calculated value: 470.2438.

[0656] Example 8: Synthesis of 5-fluoro-2-(3-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propoxy)benzamide

[0657]

[0658] Compounds can be prepared by methods similar to the synthesis of compound 5 in Scheme 1, wherein 2-(3-chloropropoxy)-5-fluorobenzamide is added in place of 1-(3-chloropropoxy)-4-fluorobenzene in step d. 1 H NMR (500 MHz, DMSO-d 6)δ10.36(s,1H),7.72(d,J=18.6Hz,2H),7.53(dd,J=9.4,3.4Hz,1H),7.31(ddd,J=9.1,7.7,3.4Hz,1H),7.17(dd,J=9 .2,4.3Hz,1H),6.82–6.71(m,1H),6.63(t,J=7.5Hz,1H),6.57(dd,J=7.8,1.0Hz,1H),4.14(t,J=6.2Hz,2H),3.80(d, J=14.5Hz,1H),3.30(d,J=14.5Hz,1H),3.27–3.17(m,2H),2.86(ddd,J=11.4,6.4,1.8Hz,1H),2.70–2.60(m,1H),2.4 5–2.30(m,2H),2.07(td,J=11.8,2.8Hz,1H),1.93(tt,J=8.7,4.8Hz,3H),1.85–1.73(m,1H),1.65(t,J=11.0Hz,1H). HRMS(ESI)m / z C 23 H 26 FN 4 O 3 [M+H] + : Calculated value: 425.1984.

[0659] Example 9: Synthesis of (6bR,10aS)-8-(3-(3,4-difluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxalin-2(3H)-one

[0660]

[0661] Compound 5 can be prepared by a method similar to the synthesis of compound 5 in Scheme 1, wherein 4-(3-chloropropoxy)-1,2-difluorobenzene is added in step d instead of 1-(3-chloropropoxy)-4-fluorobenzene. 47% isolated yield. 1 H NMR (400 MHz, DMSO-d 6)δ10.32(s,1H),7.39–7.23(m,1H),7.11–6.99(m,1H),6.82–6.71(m,2H),6.68–6.54 (m,2H),4.00(t,J=6.3Hz,2H),3.80(d,J=14.5Hz,1H),3.23–3.17(m,1H),2.90–2.81( m,1H),2.70–2.59(m,1H),2.50(t,J=1.8Hz,2H),2.45–2.29(m,2H),2.17–2.05(m,1H) ,1.99–1.91(m,1H),1.90–1.76(m,3H),1.68(t,J=10.9Hz,1H),1.24(d,J=2.0Hz,1H). HRMS(ESI)m / z C 22 H 24 F 2 N 3 O 2 [M+H] + , calculated value 400.1831.

[0662] Example 10: Synthesis of (6bR,10aS)-8-(3-(2,4-difluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxalin-2(3H)-one

[0663]

[0664] Compound 5 can be prepared by a method similar to the synthesis of compound 5 in Scheme 1, wherein 1-(3-chloropropoxy)-2,4-difluorobenzene is added in step d instead of 1-(3-chloropropoxy)-4-fluorobenzene. 30% isolated yield. 1 H NMR (500 MHz, DMSO-d 6 )δ10.47(s,1H),9.15(s,1H),7.46–7.28(m,1H),7.27–7.18(m,1H),7.12– 6.97(m,1H),6.94–6.85(m,1H),6.80–6.62(m,2H),4.31–4.06(m,2H),4.0 2–3.84(m,1H),3.80–3.63(m,1H),3.61–3.34(m,3H),3.28–3.04(m,3H),2 .72–2.53(m,1H),2.43–2.29(m,1H),2.28–2.13(m,2H),2.11–2.00(m,2H). HRMS(ESI)m / z C 22 H24 F 2 N 3 O 2 [M+H] + , calculated value 400.1831.

[0665] Example 11: Synthesis of (6bR,10aS)-8-(3-(4-fluoro-2,6-dimethylphenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0666]

[0667] Compound 5 can be prepared by a method similar to the synthesis of compound 5 in Scheme 1, wherein 2-(3-chloropropoxy)-5-fluoro-1,3-dimethylbenzene is added in step d instead of 1-(3-chloropropoxy)-4-fluorobenzene. 66% isolated yield. 1 HNMR (400 MHz, DMSO-d 6 )δ10.61(s,1H),7.13(d,J=9.2Hz,2H),7.05(dd,J=7.3,1.1Hz,1H),6.92(dd,J=7.5Hz,1H),6.87(d d,J=7.8,1.1Hz,1H),6.03(s,0H),4.09(d,J=14.5Hz,1H),4.02(t,J=6.2Hz,2H),3.64(s,0H),3.58 (s, 3H), 3.53–3.43 (m, 1H), 3.21–3.10 (m, 1H), 2.98–2.87 (m, 1H), 2.81–2.76 (m, 2H), 2.76–2.65 (m, 2H), 2.50 (s, 6H), 2.45–2.36 (m, 1H), 2.28–2.20 (m, 1H), 2.20–2.11 (m, 2H), 2.00 (t, J = 11.0 Hz, 1H). HRMS (ESI) m / z calculated value C 24 H 29 FN 3 O 2 [M+H] + ,410.2238.

[0668] Example 12: Synthesis of (6bR,10aS)-8-(3-((4-fluorophenyl)sulfonyl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo-[1,2,3-de]quinoxalin-2(3H)-one

[0669]

[0670] The compound can be prepared by a method similar to the synthesis of compound 5 in Scheme 1, wherein 1-(4-chlorobutyl)-4-fluorobenzene is added in step d instead of 1-(3-chloropropoxy)-4-fluorobenzene. 1 H NMR (400 MHz, DMSO-d 6 )δ10.31(s,1H),8.14(s,1H),8.04–7.93(m,2H),7.52(dd,J=8.8Hz,2H),6.73(dd,J=7. 4,1.1Hz,1H),6.63(dd,J=7.5Hz,1H),6.57(dd,J=7.8,1.1Hz,1H),5.75(s,0H),3.78(d, J=14.5Hz,1H),3.37–3.29(m,3H),3.27(s,1H),3.20–3.11(m,1H),2.72–2.63(m,1H),2 .46(s,1H),2.36–2.20(m,2H),2.13–2.01(m,1H),1.96–1.84(m,1H),1.82–1.58(m,4H). HRMS(ESI)m / zC 22 H 25 FN 3 O 3 S[M+H] + Calculated value: 430.1595; measured value: 430.1513.

[0671] Example 13: Synthesis of (6bR,10aS)-1,1-difluoro-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

[0672]

[0673] The compound can be prepared according to the following process:

[0674]

[0675] A mixture of compound 6 (5.0 g, 19.7 mmol), 1-(3-chloropropoxy)-4-fluoro-benzene (3.73 mL, 23.7 mmol) and KI (6.56 g, 39.5 mmol) in DMF (12 mL) was filled with argon for 3 minutes and DIPEA (6.88 mL, 39.5 mmol) was added. The mixture was heated to 80 °C, stirred for 2 hours, and then cooled to room temperature. The solvent was removed and the residue was further purified by flash column chromatography to give (4aS,9bR)-6-bromo-2-(3-(4-fluorophenoxy)propyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (compound 7) (7.6 g, 95% yield) as a pale solid. 1 H NMR (500 MHz, DMSO-d 6 )δ7.17–7.07(m,3H),7.03(d,J=7.1Hz,1H),6.98–6.87(m,2H),6.51(t,J=8.1,1H),5.55(d,J=2.4Hz,1H),3.96(t,J=6.3Hz,2H),3.73(m,1H ),3.17(m,1H),2.82(d,J=79.5Hz,1H),2.65(m,1H),2.45–2.33(m,3H),2.32–2.22(m,1H),2.08(dd,J=11.5,8.8Hz,1H),1.92–1.70(m,3H). HRMS(ESI)m / z C 20 H 23 BrFN 2 O[M+H] + : Calculated value 405.0972; Measured value: 405.0992.

[0676] N,N-dimethylacetamide (6.0 mL) was added to a mixture of copper iodide (0.376 g, 1.97 mmol), cesium carbonate (6.43 g, 19.7 mmol) and compound 7 (4.0 g, 9.87 mmol) at room temperature, and then the reaction mixture was filled with argon for 5 minutes and sealed. 2,2,6,6-tetramethyl-3,5-heptanedione (2.06 mL, 9.87 mmol) and ammonium hydroxide solution (7.0 mL, 59.2 mmol) were added via a syringe. The mixture was then allowed to react under microwave irradiation at 95°C, 20 W for 4.5 hours. After the mixture was cooled to room temperature, the solvent was evaporated and the residue was directly purified by silica gel column chromatography to give the expected product (4aS,9bR)-2-(3-(4-fluorophenoxy)propyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido4,3-b]indol-6-amine (Compound 8). (2.1 g, 62% yield) as a black solid.1 H NMR (500 MHz, DMSO-d 6 )δ8.19(d,J=1.8Hz,2H),7.15–7.04(m,2H),6.98–6.88(m,2H),6.40(d,J=5.6Hz,2H),6.37–6.33(m,1H),3.97(m,2H),3.67( m,1H),3.05–3.00(m,1H),2.69(m,1H),2.59–2.52(m,1H),2.48–2.34(m,4H),2.12(t,J=11.8,1H),1.87(m,3H),1.73(m,1H). HRMS(ESI)m / z C 20 H 25 FN 3 O[M+H] + :Calculated value 342.1976; measured value: 342.1984.

[0677] 2-Bromo-2,2-difluoroacetyl chloride (0.474 g, 2.45 mmol) was added to a solution of compound 8 (0.760 g, 2.23 mmol) in DCM (8 ml) at 0°C, and the mixture was stirred at 0°C for 1 hour. The reaction was quenched with water (6 ml) and extracted with DCM (15 mL). The separated organic phase was washed with water (10 ml) and evaporated to dryness. The resulting product, 2-bromo-2,2-difluoro-N-((4aS,9bR)-2-(3-(4-fluorophenoxy)propyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-6-yl)acetamide (Compound 9) (0.980 mg, 88% yield) was used directly in the next reaction without further purification. HRMS (ESI) m / zC 22 H 24 F 3 N 3 O 2 [M+H] + Calculated value: 498.0999; measured value: 498.1027.

[0678] Compound 9 (0.042 g, 0.085 mmol) and toluene (0.8 mL) were added to a 25 mL round bottom flask under argon atmosphere. A 1 M toluene solution of lithium bis(trimethylsilyl)amide (0.13 mL, 0.13 mmol) was added dropwise to the suspension and the mixture was stirred at 0°C for 2 hours and then at room temperature for 16 hours. The reaction was cooled to 0°C, quenched with water (0.5 mL) and evaporated to dryness. The residue was purified on HPLC to give the title compound (6bR,10aS)-1,1-difluoro-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 10) as an off-white solid (0.007 g, 19% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ10.36(s,1H),8.19(s,1H),7.16–7.03(m,2H),6.96–6.85(m,2H),6.16–5 .99(m,1H),5.82(d,J=3.0Hz,1H),4.00–3.89(m,2H),3.77(t,J=5.9Hz,1H), 3.00–2.85(m,2H),2.74–2.61(m,2H),2.40–2.23(m,2H),2.23–2.10(m,1H), 2.07–1.93(m,1H),1.91–1.76(m,2H),1.76–1.64(m,1H),1.54–1.37(m,1H). HRMS (ESI) m / z C 21 H 23 FN 3 O 2 [M+H] + Calculated value: 418.1737; measured value: 418.2122.

[0679] Example 14: Synthesis of N-((4aS,9bR)-2-(3-(4-fluorophenoxy)propyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-6-yl)acetamide

[0680]

[0681] N,N-dimethylacetamide (DMA) (10.0 mL) was added to a mixture containing compound 7 (1.13 g, 2.8 mmol), CuI (0.49 g, 2.8 mmol), Cs 2 CO 3(1.8 g, 5.6 mmol) and acetamide (1.65 g, 28 mmol) were placed in a 100 mL flask. Argon was filled into the mixture for 5 minutes, and then 1,2-dimethylethylenediamine (0.60 mL, 5.6 mmol) was added via a syringe. The mixture was stirred at 100 ° C for 1 hour and then cooled to room temperature. The solvent was evaporated and the residue was directly purified by semi-preparative HPLC to give the title compound as a formate salt (176 mg, 14% yield). 1 H NMR (500 MHz, DMSO-d 6 )δ9.44(s,1H),7.18–7.03(m,3H),6.94–6.89(m,2H),6.88(d,J=7.2Hz,1H),6.64–6.50(m,1H) ,5.15(s,1H),3.96(t,J=6.3Hz,2H),3.72(dt,J=7.2,4.6Hz,1H),3.10(dt,J=8.5,6.3Hz,1H),2 .68 (dd, J = 11.6, 6.0 Hz, 1H), 2.49–2.45 (m, 1H), 2.43 (q, J = 6.6 Hz, 2H), 2.34 (td, J = 10.8, 3.4 Hz, 1H), 2.13 (dd, J = 11.5, 8.7 Hz, 1H), 2.03 (s, 3H), 1.92–1.79 (m, 3H), 1.74 (dq, J = 9.5, 4.1 Hz, 1H). HRMS (ESI) m / z calculated value C 22 H 27 FN 3 O 2 [M+H] + :384.2082.

[0682] Example 15: N-((4aS,9bR)-2-(4-(4-fluorophenyl)-4-oxobutyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-6-yl)acetamide

[0683]

[0684] 4-((4aS,9bR)-6-Bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)-1-(4-fluorophenyl)butan-1-one can be prepared following the procedure described above for compound 7, but substituting 4-chloro-(4'-fluorobutyrophenone) for 1-(3-chloropropoxy)-4-fluoro-benzene.

[0685] N,N-dimethylacetamide (10.0 mL) was added to a mixture of copper iodide (0.460 g, 2.4 mmol), cesium carbonate (1.56 g, 4.80 mmol), acetamide (1.42 g, 24 mmol) and 4-((4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)-1-(4-fluorophenyl)butan-1-one (1.0 g, 2.40 mmol) at room temperature, and then argon was charged into the reaction mixture for 5 minutes. 1,2-Dimethylethylenediamine (0.52 mL, 4.79 mmol) was added via syringe. The mixture was stirred at 100°C for 1 hour and then cooled to room temperature. The solvent was evaporated and the residue was directly purified by silica gel column chromatography. The product was purified again by semi-preparative HPLC to give the desired product (0.137 g, 14% yield). 1 H NMR (500 MHz, DMSO-d 6 )δ9.47(s,1H),8.06(dd,J=8.8,5.6Hz,2H),7.37(t,J=8.8Hz,2H),7.22–7.02(m ,1H),6.91(d,J=7.1Hz,1H),6.61(t,J=7.6Hz,1H),5.17(s,1H),3.72(dt,J=6.8, 4.5Hz,1H),2.68(dd,J=11.7,5.8Hz,1H),2.50(dt,J=10.2,4.6Hz,1H),2.37(tt ,J=13.4,6.9Hz,3H),2.18–2.12(m,1H),2.06(s,3H),1.84(m,2H),1.76(m,2H).

[0686] Example 16: Synthesis of N-((4aS,9bR)-2-(4-(4-fluorophenyl)-4-hydroxybutyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-6-yl)acetamide

[0687]

[0688] Sodium borohydride (0.028 g, 0.76 mmol) was added to a solution of the compound of Example 15 (0.050 g, 0.126 mmol) in methanol (2 ml). After completion, the reaction mixture was stirred at room temperature for 30 minutes, and then the reaction was quenched with methanol. The solvent was evaporated and the residue was purified by semi-preparative HPLC to obtain the desired product (0.036 g, 72% yield). 1 H NMR (500 MHz, DMSO-d 6)δ9.45(s,1H),7.47–7.26(m,2H),7.21–6.96(m,3H),6.95–6.76(m,1H),6.59(t,J=7 .6Hz,1H),5.15(s,1H),4.53(q,J=5.3,3.7Hz,1H),3.83–3.57(m,1H),3.20–2.88(m, 1H),2.78–2.54(m,1H),2.49–2.39(m,1H),2.36–2.23(m,3H),2.15–2.06(m,1H),2.0 3(s,3H),1.90–1.78(m,1H),1.77–1.67(m,1H),1.63–1.47(m,3H),1.46–1.33(m,1H).

[0689] Examples 17-26: Additional compounds

[0690] Using essentially the procedures described above, the following additional compounds were prepared by reacting intermediate compound 4 with an appropriate alkyl halide to provide the target compound in generally good yields:

[0691]

[0692]

[0693]

[0694] Example 27: Receptor Binding Properties

[0695] The receptor binding properties of the compound of Example 1 (compound of Formula A) and the compounds of Examples 2-6 were determined. The following procedures were used, each of which is incorporated herein by reference in its entirety: 5-HT 2A : Bryant, HU et al. (1996), Life Sci., 15: 1259-1268; D2: Hall, DA and Strange, PG (1997), Brit. J. Pharmacol., 121: 731-736; D1: Zhou, QY et al. (1990), Nature, 347: 76-80; SERT: Park, YM et al. (1999), Anal. Biochem., 269: 94-104; μ-opioid receptor: Wang, JB et al. (1994), FEBS Lett., 338: 217-222.

[0696] Typically, results are expressed as a percentage of control specific binding obtained in the presence of the test compound:

[0697]

[0698] Percent inhibition of specific binding to control:

[0699]

[0700] IC was determined by nonlinear regression analysis of competition curves generated from averaged replicates using Hill equation curve fitting. 50 Value (concentration causing half-maximal inhibition of control specific binding) and Hill coefficient (nH):

[0701]

[0702] Where Y = specific binding, A = left asymptote of the curve, D = right asymptote of the curve, C = compound concentration, C 50 =IC 50 , and nH = slope factor. The analysis was performed using in-house software and was combined with commercial software 4.0 ( 1997, SPSS Inc.) were used for comparison and validation. The inhibition constant (Ki) was calculated using the Cheng Prusoff equation:

[0703]

[0704] where L = concentration of radioligand in the assay, and K D = affinity of the radioligand for the receptor. Use Scatchard plotting to determine K D .

[0705] The following receptor affinity results were obtained (compound of formula A was used as comparison; all percentage values ​​are maximal inhibition; other values ​​are Ki):

[0706]

[0707]

[0708]

[0709]

[0710] The foregoing embodiments are merely exemplary and are not intended to limit the scope of the present disclosure in any way.

Claims

1. Compounds of Formula I in: R 1 It is H, C 1-6 Alkyl, -C(O)-OC(R a )(R b )(R c )、-C(O)-O-CH2-OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 ; R 2 and R 3 Independently selected from H, D, C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g. methoxy), halo (e.g. F), cyano or hydroxy; or where R 2 and R 3 Together with the carbon to which they are attached, they form the group -CH2CH2-, or Where R 2 and R 3 The carbons to which they are attached do not exist; L is C 1-6 Alkylene (e.g. ethylene, propylene or butylene), C 1-6 Alkoxy (such as propoxy or butoxy), C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH2CH2OCH2), C 1-6 Alkylamino or NC 1-6 Alkyl C 1-6 Alkylamino (e.g. propylamino or N-methylpropylamino), C 1-6 Alkylthio (e.g. -CH2CH2CH2S-), C 1-6 Alkylsulfonyl (e.g., -CH2CH2CH2S(O)2-), or -C 1-6 Alkyl-C(O)- (e.g. 4-butyryl), each of which is optionally substituted by one or more R 4 Partial replacement; R 4 Each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g. methoxy), halo (e.g. F), cyano, hydroxy, amino (-NH2), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl); Z is selected from aryl (e.g. phenyl) and heteroaryl (e.g. thienyl, furanyl, pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), methyl or OH, each optionally substituted by one or more R 4 partially substituted, optionally wherein Z is unsubstituted; R 8 Yes-C(R a )(R b )(R c )、-OC(R a )(R b )(R c ), or -N(R d )(R e ); R a , R b and R c Each independently selected from H and C 1-24 alkyl; R d and R e Each independently selected from H and C 1-24 alkyl; R 6 and R 7 Each independently selected from H, C 1-6 Alkyl, carboxyl and C 1-6 Alkoxycarbonyl; Provided that, if Z is aryl or heteroaryl, at least one radical R 4 Selected from amino (-NH2), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH2, -C(O)NH(C 1-6 alkyl) and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl); in free form or in salt form (eg, in pharmaceutically acceptable salt form), e.g., in isolated or purified free form or in salt form (eg, in pharmaceutically acceptable salt form).

2. The compound according to claim 1, wherein R 1 , R 2 and R 3 It's H.

3. A compound according to claim 1 or 2, wherein L is -(CH2) n -X-, and wherein n is an integer selected from 2, 3 and 4, and X is selected from -O-, -S-, -NH-, -N(C 1-6 alkyl)-, -CH2-, and -C(O)-.

4. A compound according to any one of claims 1 to 3, wherein Z is replaced by one, two, three or four R 4 Partially substituted phenyl and wherein one, two, three or four R 4 The moieties are independently selected from methyl, methoxy, hydroxy, amino (-NH2), halo (e.g., fluorine, chlorine, bromine, or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH2, -C(O)NH(CH3), and C(O)N(CH3)(CH3).

5. The compound according to claim 1, wherein the compound is selected from: Each is independently in free form or in pharmaceutically acceptable salt form.

6. Compound of formula II: in: R 1 It is H, C 1-6 Alkyl, -C(O)-OC(R a )(R b )(R c )、-C(O)-O-CH2-OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 ; R 2 and R 3 Independently selected from H, D, C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g. methoxy), halo (e.g. F), cyano or hydroxy; or where R 2 and R 3 Together with the carbon to which they are attached, they form the group -CH2CH2-, or Where R 2 and R 3 The carbons to which they are attached do not exist; L is C3 alkylene (e.g., propylene), C3 alkoxy (e.g., propoxy), C3 alkylsulfonyl (e.g., -CH2CH2CH2S(O)2-), or -C 2-4 Alkyl-C(O)- (eg, 4-butyryl); and Z is selected from aryl (eg, phenyl, naphthyl) and heteroaryl (eg, bicyclic heteroaryl or monocyclic 5-membered heteroaryl), each of which is optionally substituted by one or more R 4 partially substituted, optionally wherein Z is unsubstituted; Provided that LZ is selected from: -CH2CH2CH2O-Ph; -CH2CH2CH2-(heteroaryl), wherein the heteroaryl is separated by two R 4 Partially disubstituted bicyclic heteroaryl; -CH2CH2CH2-(heteroaryl), wherein the heteroaryl is separated by one, two or three R 4 Partially substituted quinazolinyl; -CH2CH2CH2O-(aryl), wherein the aryl is phenyl or naphthyl and the aryl is monosubstituted with a hydroxyl group; -CH2CH2CH2O-(aryl), wherein the aryl is phenyl or naphthyl and the aryl is substituted by two or more R 4 Partial replacement; -(CH2)nC(O)-(heteroaryl), wherein n is an integer selected from 2, 3 and 4, and wherein the heteroaryl is substituted by one to three R 4 Partially substituted monocyclic 5-membered heteroaryl; -CH2CH2CH2S(O)2-(aryl), and wherein the aryl is phenyl or naphthyl and the aryl is replaced by one or two R 4 partial replacement; or -CH2CH2CH2O-(aryl), wherein the aryl is phenyl or naphthyl and the aryl is replaced by one or more R 4 Partial substitution, provided that R 2 and R 3 It is F; and among them R 4 Each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g. methoxy), halo (e.g. F), cyano, hydroxy, amino (-NH2), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl); R 8 Yes-C(R a )(R b )(R c )、-OC(R a )(R b )(R c ), or -N(R d )(R e ); R a , R b and R c Each independently selected from H and C 1-24 alkyl; R d and R e Each independently selected from H and C 1-24 alkyl; R 6 and R 7 Each independently selected from H, C 1-6 Alkyl, carboxyl and C 1-6 Alkoxycarbonyl; In free form or in salt form (eg, a pharmaceutically acceptable salt form), for example, in isolated or purified free form or in salt form (eg, a pharmaceutically acceptable salt form).

7. A compound according to claim 6, wherein n is 3 and wherein R 1 , R 2 and R 3 It's H.

8. A compound according to claim 6 or 7, wherein L is -(CH2)nC(O)-(heteroaryl), wherein n is an integer selected from 2, 3 and 4, and wherein the heteroaryl is surrounded by one to three R 4 Partially substituted monocyclic 5-membered heteroaryl.

9. The compound according to any one of claims 6 to 8, wherein the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl and tetrazolyl.

10. A compound according to any one of claims 6 to 8, wherein the heteroaryl group is thienyl (eg 5-substituted-2-thienyl or 4-substituted-3-thienyl).

11. A compound according to any one of claims 6 to 10, wherein R 4 The moieties are each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g. methoxy), halo (e.g. F), cyano, hydroxy, amino (-NH2), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl).

12. A compound according to any one of claims 6 to 10, wherein R 4 The moieties are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, hydroxy, halo (eg, fluoro, chloro, bromo or iodo), and cyano.

13. The compound according to any one of claims 6 to 8, wherein the thienyl group is a 5-substituted-2-thienyl group or a 4-substituted-3-thienyl group).

14. The compound according to claim 6, wherein the compound is selected from: Each is independently in free form or in pharmaceutically acceptable salt form.

15. Compound of formula III: in: R 1 It is H, C 1-6 Alkyl, -C(O)-OC(R a )(R b )(R c )、-C(O)-O-CH2-OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 ; L is C 1-6 Alkylene (e.g. ethylene, propylene or butylene), C 1-6 Alkoxy (such as propoxy or butoxy), C 2-3 Alkoxy C 1-3 Alkylene (e.g. CH2CH2OCH2), C 1-6 Alkylamino or NC 1-6 Alkyl C 1-6 Alkylamino (e.g. propylamino or N-methylpropylamino), C 1-6 Alkylthio (e.g. -CH2CH2CH2S-), C 1-6 Alkylsulfonyl (e.g., -CH2CH2CH2S(O)2-), -C 1-6 Alkyl-C(O)- (e.g. 4-butyryl), or -C 1-6 Alkyl-C(OH)- (e.g. 4-butanol), each of which is optionally substituted by one or more R 4 Partial replacement; R 4 Each independently selected from C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g. methoxy), halo (e.g. F), cyano, hydroxy, amino (-NH2), C 1-6 Alkyl aryl (e.g. benzyl), C 1-6 Alkoxyaryl (e.g., benzyloxy), aryloxy (e.g., phenoxy), -C(O)-aryl, -C(O)-C 1-6 Alkyl, -C(O)OH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), and C(O)N(C 1-6 Alkyl)(C 1-6 alkyl); Z is selected from aryl (e.g. phenyl) and heteroaryl (e.g. thienyl, furanyl, pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), methyl or OH, each optionally substituted by one or more R 4 partially substituted, optionally wherein Z is unsubstituted; R 8 Yes-C(R a )(R b )(R c )、-OC(R a )(R b )(R c ), or -N(R d )(R e ); R a , R b and R c Each independently selected from H and C 1-24 alkyl; R d and R e Each independently selected from H and C 1-24 alkyl; R 6 and R 7 Each independently selected from H, C 1-6 Alkyl, carboxyl and C 1-6 Alkoxycarbonyl; In free form or in salt form (eg, a pharmaceutically acceptable salt form), for example, in isolated or purified free form or in salt form (eg, a pharmaceutically acceptable salt form).

16. A compound according to claim 15, wherein R 1 It's H.

17. A compound according to claim 15 or 16, wherein L is -(CH2) n -X-, and wherein n is an integer selected from 2, 3 and 4, and X is selected from -O-, -S-, -NH-, -N(C 1-6 alkyl)-, -CH2-, -CH(OH)-, and -C(O)-.

18. A compound according to any one of claims 15 to 17, wherein L is -(CH2) n -X-, and wherein n is 3, and X is O.

19. A compound according to any one of claims 15 to 18, wherein Z is replaced by one, two, three or four R 4 Partially substituted phenyl.

20. A compound according to any one of claims 15 to 19, wherein said one, two, three or four R 4 The moieties are independently selected from methyl, methoxy, hydroxy, amino (-NH2), halo (e.g., fluorine, chlorine, bromine, or iodine), cyano, benzyl, benzyloxy, phenoxy, benzoyl, acetyl, pivaloyl, -C(O)OH, -C(O)NH2, -C(O)NH(CH3), and C(O)N(CH3)(CH3).

21. According to any one of claims 15-20, the compound wherein said Z is separated by two R 4 Partially substituted phenyl, the two R 4 The moieties are each independently selected from methyl, halo (eg, fluoro, chloro, bromo or iodo) and cyano.

22. The compound according to claim 15, wherein the compound is selected from: Each is independently in free form or in pharmaceutically acceptable salt form.

23. A compound according to any one of claims 1 to 22 in salt form, eg, in pharmaceutically acceptable salt form.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 in free or pharmaceutically acceptable salt form (eg a pharmaceutically acceptable salt form) in admixture with a pharmaceutically acceptable diluent or carrier.

25. A method for treating or preventing a central nervous system disorder, which method comprises administering a compound according to any one of claims 1 to 23 or a pharmaceutical composition according to claim 24 in free or pharmaceutically acceptable salt form to a patient in need thereof.

26. Use of a compound according to any one of claims 1 to 23 in free or pharmaceutically acceptable salt form or a pharmaceutical composition according to claim 24 in free or pharmaceutically acceptable salt form for the preparation of a medicament for the treatment or prevention of a central nervous system disorder.

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