Combination drug therapy

Abstract

Combination drug therapy is provided that includes a 5-HTZA receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist (e.g., nitrous oxide, ketamine, etc.). Pharmaceutical compositions and methods are also described that use combination drug therapy to treat central nervous system (CNS) disorders or psychiatric disorders, for example, via aerosol inhalation.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 241,891, filed September 8, 2021, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to combination drug therapy, particularly 5-HT 2A The present invention relates to combination medications including a receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist, pharmaceutical compositions containing the combination medications, and methods of treating diseases or conditions, including central nervous system (CNS) disorders or psychiatric disorders. [Background technology]

[0003] The "Background Art" discussion provided herein is for purposes of generally presenting the contents of the present disclosure. To the extent described in this Background section, the work of the currently named inventors, as well as aspects of the description that may not have been admitted as prior art at the time of filing, are not expressly or impliedly admitted as prior art to the present disclosure.

[0004] Mood disorders, such as depression, are ubiquitous psychiatric illnesses. Treatments for such disorders were first discovered in the 1940s and included first-generation medications, such as monoamine oxidase inhibitors. These medications were followed by tricyclic antidepressants, followed by second-generation antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. The latter revolutionized the treatment of depression and remain a staple of therapy to this day. However, current therapies can take weeks or months to reach full efficacy after initiation of treatment, and fewer than 50% of patients respond to such medications.

[0005] Emerging strategies for the treatment of central nervous system (CNS) disorders focus on serotonin (5-HT) receptor subfamily 5-HT2 receptor agonists and glutamate N-methyl-D-aspartate (NMDA) receptor antagonists, such as psilocybin, psilocin, N,N-dimethyltryptamine (DMT), phenethylamine, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), and ketamine, through the actions of hallucinogenic compounds. These serotonin 5-HT2 receptor agonists and glutamate N-methyl-D-aspartate (NMDA) receptor antagonists are used to affect the serotonin pathway and glutamate pathway, respectively, and have shown promising results in early-phase clinical trials and clinical settings. These receptors are believed to be important in the treatment and pathology of depression, schizophrenia, anxiety, and several other psychiatric disorders. As an example, (S)-ketamine (Spravato®) has recently been approved for the treatment of suicidal ideation and treatment-resistant depression (TRD) when combined with an oral (conventional) antidepressant. Psilocybin is currently in Phase II clinical trials for TRD and major depressive disorder (MDD).

[0006] Hallucinogens are so named because of their experiential effects on the user. The hallucinogenic experience, in most cases, acts to elevate the user's mood upon use. However, administration of hallucinogens can also cause negative experiences in patients, presenting with acute hallucinogenic crises known as "bad trips" in which the patient experiences feelings of regret or distress, or presenting with other symptoms such as agitation, confusion, intense anxiety, and psychotic episodes that may be transient or prolonged in nature. 5-HT 2A Overstimulation of receptors is thought to increase the risk of adverse tripping experiences, which may lead to therapy interruption, therapy discontinuation, or even adverse treatment events.

[0007] In clinical settings, during supervised hallucinatory experiences, medical professionals, treatment monitors, or other session participants may attempt to reduce acute hallucinatory crisis events by shifting the patient's perspective, providing reassurance, or reducing anxiety through other specialized psychological means. If the acute hallucinatory crisis rises to a significant level, the medical professional supervising the hallucinatory experience may administer benzodiazepines or other anti-anxiety drugs. Unfortunately, this administration may counteract the desired therapeutic results of administering hallucinogens. This problem is exacerbated in populations being treated for generalized anxiety disorder, social anxiety disorder, forms of depression, or alcohol use disorder or other addiction disorders, as these conditions are associated with increased psychological stressors and therefore increase the risk of acute hallucinatory crisis.

[0008] Furthermore, NMDA receptor antagonists are dissociative anesthetics with a wide range of effects in humans. At high doses (e.g., anesthetic and subanesthetic doses), a significant number of patients experience dissociative effects, such as adverse psychiatric symptoms, including out-of-body experiences, dissociation of the mind from the body, perceptual distortions, and hallucinations. Summary of the Invention

[0009] In light of the foregoing, there is a need for new psychedelic therapies with robust therapeutic efficacy that minimize adverse psychological effects.

[0010] Therefore, it is an object of the present disclosure to provide novel combination drug therapies that meet these criteria.

[0011] Another object of the present disclosure is to provide novel pharmaceutical compositions for delivering the combination drug therapies of the present disclosure.

[0012] It is yet another object of the present disclosure to provide a subject in need thereof with a novel method of treating a central nervous system (CNS) disorder or psychiatric illness with the combination drug therapy of the present disclosure.

[0013] These and other objects, which will become apparent during the course of the following detailed description, are achieved by the use of 5-HT 2A This was achieved through the inventors' discovery that the combination of a 5-HT receptor agonist with an N-methyl-D-aspartate (NMDA) receptor antagonist unexpectedly yields a combination pharmacotherapeutic regimen that exhibits beneficial therapeutic activity by modulating the uptake of both serotonin and glutamate, while improving the patient experience, e.g., increasing safety and / or reducing acute hallucinatory crises. In particular, 5-HT 2A The combination of a 5-HT receptor agonist and an NMDA receptor antagonist 2A It enhances the patient experience by providing therapeutic benefits while reducing or eliminating adverse psychotic effects such as acute hallucinogenic crises and dissociative effects that can be caused by taking only receptor agonists or NMDA receptor antagonists.

[0014] Thus, the present disclosure provides: (1)5-HT 2A receptor agonists, and Concomitant medications, including N-methyl-D-aspartate (NMDA) receptor antagonists. (2)5-HT 2A The combination drug therapy according to (1), wherein the receptor agonist is a tryptamine derivative. (3) Tryptamine derivatives include psilocybin, psilocin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ), and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 (2) The combination drug therapy according to (2), wherein the combination drug therapy is at least one selected from the group consisting of: (4) Tryptamine derivatives include N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ), and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 (2) or (3), wherein the combined drug therapy is at least one selected from the group consisting of: (5)5-HT 2A The combination drug therapy according to (1), wherein the receptor agonist is a phenethylamine derivative. (6) The combination drug therapy according to (5), wherein the phenethylamine derivative is at least one selected from the group consisting of 3,4-methylenedioxymethamphetamine (MDMA) and 2,5-dimethoxy-4-bromophenethylamine (2C-B), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (7)5-HT 2A The combination drug therapy according to any one or more of (1) to (6), wherein the receptor agonist is a tryptamine derivative containing at least one deuterium atom, or a phenethylamine derivative containing at least one deuterium atom. (8) The combination drug therapy according to any one or more of (1) to (7), wherein the NMDA receptor antagonist is at least one selected from the group consisting of ketamine, nitrous oxide, memantine, and dextromethorphan, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (9) The combination drug therapy according to any one or more of (1) to (8), wherein the NMDA receptor antagonist is nitrous oxide. (10)5-HT 2A The combination drug therapy according to (1), wherein the receptor agonist is N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is nitrous oxide. (11)5-HT2A The combination drug therapy of (1), wherein the receptor agonist is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is nitrous oxide. (12)5-HT 2A The receptor agonist is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is nitrous oxide. (13)5-HT 2A The receptor agonist is 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is nitrous oxide. (14) The combination drug therapy according to any one or more of (1) to (8), wherein the NMDA receptor antagonist is ketamine, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (15)5-HT 2A The combination drug therapy of (1), wherein the receptor agonist is N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (16)5-HT 2A 10. The combination drug therapy of claim 1, wherein the receptor agonist is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (17)5-HT 2A The receptor agonist is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (18)5-HT 2A The receptor agonist is 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (19)5-HT 2A The combination drug therapy according to any one or more of (1) to (18), wherein the receptor agonist and the NMDA receptor antagonist are combined in a single pharmaceutical composition. (20)5-HT 2A 19. The combination drug therapy of claim 18, wherein the receptor agonist and the NMDA receptor antagonist are combined in an aerosol for administration via inhalation. (21) The combination drug therapy according to (20), wherein the aerosol is in the form of a mist. (22) The aerosol was prepared by dissolving 5-HT in the liquid phase of the aerosol. 2A The combination drug therapy according to (20) or (21), which comprises a receptor agonist. (23) The combination drug therapy according to any one or more of (20) to (22), wherein the aerosol comprises an NMDA receptor antagonist in the gas phase of the aerosol. (24)5-HT 2A 19. The combination drug therapy of claim 19, wherein the receptor agonist and the NMDA receptor antagonist are combined in a transdermal patch. (25)5-HT 2A The combination drug therapy according to any one or more of (1) to (18), wherein the receptor agonist and the NMDA receptor antagonist are provided as separate pharmaceutical compositions. (26)5-HT 2A25. The combination drug therapy of claim 25, wherein the receptor agonist is provided as an intravenous injection and the NMDA receptor antagonist is provided as a therapeutic gas mixture. (27)5-HT 2A 25. The combination drug therapy of claim 25, wherein the receptor agonist is provided as an aerosol and the NMDA receptor antagonist is provided as a therapeutic gas mixture. (28) The combination drug therapy according to any one or more of (25) to (27), wherein the separate pharmaceutical compositions are administered sequentially. (29) The combination drug therapy according to any one or more of (25) to (27), wherein the separate pharmaceutical compositions are administered simultaneously. (30) A pharmaceutical composition comprising the combination drug therapy according to any one or more of (1) to (24) and a pharmaceutically acceptable excipient. (31) The pharmaceutical composition according to (30), which is formulated for administration via inhalation. (32) A method for treating a subject having a central nervous system (CNS) disorder or a psychiatric disorder, the method comprising: Therapeutic doses of 5-HT 2A The method includes administering to a subject a receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist. (33) CNS disorders or psychiatric disorders include post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), obsessive-compulsive behavior and other related symptoms, generalized anxiety disorder (GAD), acute hallucinatory crisis, social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder, and nicotine 32. The method of claim 32, wherein the neurological disorder is selected from the group consisting of: use disorder, cocaine use disorder, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease, gambling disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, pedophilic disorder, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, cross-dressing disorder, sexual dysfunction, peripheral neuropathy, and obesity. (34) The method according to (32) or (33), wherein the CNS disorder or psychiatric disease is major depressive disorder (MDD). (35) The method according to (32) or (33), wherein the CNS disorder or psychiatric disease is treatment-resistant depression (TRD). (36) The method according to (32) or (33), wherein the CNS disorder or psychiatric disease is generalized anxiety disorder (GAD). (37) The method according to (32) or (33), wherein the CNS disorder or psychiatric disease is social anxiety disorder. (38) The method according to (32) or (33), wherein the CNS disorder or psychiatric disease is obsessive-compulsive disorder (OCD). (39) The method according to (32) or (33), wherein the CNS disease or psychiatric disease is alcohol use disorder. (40)5-HT 2A The method according to any one or more of (32) to (39), wherein the receptor agonist is administered at a dose of about 0.01 mg / kg to about 3 mg / kg. (41)5-HT 2AThe method according to any one or more of (32) to (40), wherein the receptor agonist and the NMDA receptor antagonist are administered 1 to 8 times over the course of treatment. (42)5-HT 2A The method according to any one or more of (32) to (41), wherein the receptor agonist and the NMDA receptor antagonist are administered simultaneously as a single pharmaceutical composition. (43)5-HT 2A The method according to any one or more of (32) to (42), wherein the receptor agonist and the NMDA receptor antagonist are administered to the patient as an aerosol by inhalation. (44) The method according to (43), wherein the aerosol is in the form of a mist. (45) The aerosol was prepared by dissolving 5-HT in the liquid phase of the aerosol. 2A The method according to (43) or (44), comprising a receptor agonist. (46) Aerosols are 2A The method according to any one of (43) to (45), wherein the composition is prepared by nebulizing the receptor agonist. (47) The method according to (46), wherein the nebulization is carried out using a device selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, an exhalation-actuated nebulizer, and a vibrating mesh nebulizer. (48) The method according to any one of (32) to (47), wherein the NMDA receptor antagonist is nitrous oxide. (49) The method according to (48), wherein the aerosol contains nitrous oxide in the gas phase of the aerosol. (50) The method according to (49), wherein the gas phase of the aerosol comprises a therapeutic gas mixture containing nitrous oxide. (51) The method of (50), wherein the therapeutic gas mixture is a mixture of nitrous oxide and O2, a mixture of N2O and air, a mixture of N2O and medical air, a mixture of N2O, N2, and O2, a mixture of N2O O2 enriched medical air, or a mixture of N2O, He, and O2. (52) The method according to (50) or (51), wherein the nitrous oxide is present in the therapeutic gas mixture at a concentration of 5 to 50% by volume, based on the total volume of the therapeutic gas mixture. (53) The method according to any one or more of (50) to (52), wherein the therapeutic gas mixture acts as a driving gas for generating the aerosol. (54) The method according to any one or more of (50) to (53), wherein the therapeutic gas mixture acts as a carrier gas for generating the aerosol. (55) The method according to any one of (43) to (54), wherein the aerosol is administered for 20 to 60 minutes. (56)5-HT 2A The method according to any one or more of (32) to (55), wherein the receptor agonist is N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is nitrous oxide. (57)5-HT 2A The method according to any one or more of (32) to (55), wherein the receptor agonist is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is nitrous oxide. (58)5-HT 2A The receptor agonist is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is nitrous oxide. (59)5-HT 2A The receptor agonist is 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is nitrous oxide. (60)5-HT 2A The method according to any one or more of (32) to (42), wherein the receptor agonist and the NMDA receptor antagonist are administered transdermally to the patient by a transdermal patch. (61)5-HT2A The method of (60), wherein the receptor agonist is N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (62)5-HT 2A 60. The method of claim 60, wherein the receptor agonist is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (63)5-HT 2A The receptor agonist is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (64)5-HT 2A The receptor agonist is 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ) or a pharmaceutically acceptable salt or solvate thereof, and the NMDA receptor antagonist is ketamine or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. (65)5-HT 2A The method according to any one or more of (32) to (41), wherein the receptor agonist and the NMDA receptor antagonist are administered sequentially as separate pharmaceutical compositions. (66)5-HT 2A The method according to any one or more of (32) to (41), wherein the receptor agonist and the NMDA receptor antagonist are administered simultaneously as separate pharmaceutical compositions. (67)5-HT 2AThe method of any one or more of (32) to (41), or (65), or (66), wherein the receptor agonist is administered intravenously and the NMDA receptor antagonist is administered via inhalation. (68)5-HT 2A 67. The method of claim 67, wherein the receptor agonist is administered intravenously to the subject as a single bolus. (69)5-HT 2A The method according to (68), wherein the receptor agonist is administered at a dose of about 0.1 mg / kg to about 0.8 mg / kg. (70)5-HT 2A The method of (67), wherein the receptor agonist is administered intravenously to the subject as a perfusion. (71)5-HT 2A The method according to (70), wherein the receptor agonist is administered at a dose of about 0.1 mg / kg to about 0.8 mg / kg. (72) The method according to (70) or (71), wherein the perfusion is administered for a duration of about 5 minutes to about 1 hour. (73)5-HT 2A The method according to any one or more of (67) to (72), wherein the receptor agonist is administered intravenously to the subject as a bolus and then perfused. (74) 5-HT administered via bolus and perfusion 2A The method of (73), wherein the doses of the receptor agonists are each independently in the range of about 0.1 mg / kg to about 0.8 mg / kg. (75) The method according to any one or more of (32) to (41) or (65) to (74), wherein the NMDA antagonist is nitrous oxide, which is administered via inhalation as a therapeutic gas mixture containing nitrous oxide. (76) The method of (75), wherein the therapeutic gas mixture is a mixture of nitrous oxide and O2, a mixture of N2O and air, a mixture of N2O and medical air, a mixture of N2O, N2, and O2, a mixture of N2O O2 enriched medical air, or a mixture of N2O, He, and O2. (77) The method according to (75) or (76), wherein the nitrous oxide is present in the therapeutic gas mixture at a concentration of 5 to 50% by volume, based on the total volume of the therapeutic gas mixture. (78)5-HT2A The method according to any one or more of (32) to (55), (60), or (65) to (77), wherein the receptor agonist is N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or solvate thereof. (79)5-HT 2A The method according to any one or more of (32) to (55), (60), or (65) to (77), wherein the receptor agonist is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt or solvate thereof. (80)5-HT 2A The receptor agonist is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ) or a pharmaceutically acceptable salt or solvate thereof. (81)5-HT 2A The receptor agonist is 2-(5-methyl-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ) or a pharmaceutically acceptable salt or solvate thereof. (82)5-HT 2A The method according to any one or more of (32) to (81), wherein the receptor agonist and the NMDA receptor antagonist are administered in amounts effective to reduce or inhibit an acute hallucinatory crisis. (83)5-HT 2A The method according to any one or more of (32) to (82), wherein the receptor agonist and the NMDA receptor antagonist are administered in amounts effective to reduce or inhibit the dissociative effect. (84) Nitrous oxide and 5-HT 2A 1. An inhalation delivery device for delivering a combination of a steroid and a receptor agonist by inhalation to a patient in need thereof, comprising: Nitrous oxide and 5-HT for patients 2Aan inhalation exit portal for administration of a combination with a receptor agonist; a container configured to deliver nitrous oxide to an inhalation outlet portal; and 5-HT 2A and a device configured to generate and deliver an aerosol comprising the receptor agonist to an inhalation outlet portal. (85) The inhalation delivery device of (84), wherein the inhalation outlet portal is a mouthpiece or mask that covers the patient's nose and mouth. (86) The inhalation delivery device according to (84) or (85), wherein the device configured to generate and deliver an aerosol to the inhalation outlet portal is a nebulizer. (87) The inhalation delivery device of (86), wherein the nebulizer is a jet nebulizer and nitrous oxide gas acts as a driving gas for the jet nebulizer. (88) An inhalation delivery device according to any one or more of (84) to (87), further comprising electronics configured to provide remote actuation and operational control of the inhalation delivery device. (89) A fast-acting therapeutic combination comprising: 5-HT with an elimination half-life of up to 2 hours 2A receptor agonists, and Nitrous oxide, a fast-acting therapeutic combination. (90)5-HT 2A A fast-acting therapeutic combination according to (89), wherein the elimination half-life of the receptor agonist is less than 30 minutes. (91)5-HT 2A Receptor agonists include N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ), or 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ) (89) or (90). (92) A rescue medicine kit comprising, in one or more containers packaged separately or together, a fast-acting therapeutic combination according to any one or more of (89) to (91). (93) A method for treating a subject having an acute psychiatric condition, the method comprising: 5-HT 2A A method comprising administering to a subject a therapeutically effective amount of a fast-acting therapeutic combination according to any one of (89) to (91) for a period of time equal to or less than the elimination half-life of the receptor agonist. [Brief explanation of the drawings]

[0015] The foregoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the claims that follow. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings.

[0016] [Figure 1A] Figures 1A-1B show a directed flow exposure chamber housed within a secondary containment chamber (top view, Figure 1A), and a depiction of a rat held within a restraining tube with its nose protruding from the end of the restraining tube into the exposure chamber (Figure 1B). [Figure 1B] Same as above. [Figure 2] FIG. 2 shows DMT and DMT-d10 plasma concentration-time profiles after IV administration (1 mg / kg) in rats. [Figure 3] FIG. 3 shows DMT and DMT-d10 plasma concentration-time profiles after inhalation administration (14.7 mg / kg and 15.3 mg / kg, respectively) in rats. [Figure 4] FIG. 4 shows DMT and DMT-d10 plasma concentration-time profiles after PO (oral gavage, OG) administration (10 mg / kg) in rats. [Figure 5] Figure 5 shows DMT plasma concentration-time profiles after IV, inhaled, and PO (OG) administration, dose normalized to 1 mg / kg. [Figure 6] Figure 6 shows DMT-d10 plasma concentration-time profiles after IV, inhaled, and PO (OG) administration, dose normalized to 1 mg / kg. [Figure 7] Figure 7 shows a transparent airtight Plexiglas anesthesia induction chamber setup for preclinical rodent studies. [Figure 8] Figure 8 shows the general experimental design for a human study probing the synergistic interaction between DMT and nitrous oxide (NO). DETAILED DESCRIPTION OF THE INVENTION

[0017] In the following detailed description, it is understood that other embodiments may be utilized and structural and operational changes may be made without departing from the scope of the present embodiments disclosed herein.

[0018] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0019] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 carbon atoms. This term includes, by way of example, straight-chain and branched hydrocarbyl groups such as methyl (CH-), ethyl (CHCH-), n-propyl (CHCHCH-), isopropyl ((CH)CH-), n-butyl (CHCHCHCH-), isobutyl ((CH)CHCH-), sec-butyl ((CH)(CHCH)CH-), t-butyl (t-Bu) ((CH)C-), n-pentyl (CHCHCHCHCHCH-), and neopentyl ((CH)CCH-).

[0020] The term "substituted alkyl" refers to an alkyl group, as defined herein, wherein one or more carbon atoms in the alkyl chain are optionally substituted with -O-, -N-, -S-, -S(O) n -(n is 0 to 2), -NR- (R is hydrogen or alkyl), and substituted with a heteroatom such as deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO 2- Heteroaryl, and -NR ’ R ’’ , where R ’ and R ’ ’ may be the same or different and have 1 to 10 substituents selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic groups.

[0021] "Alkylene" is -O-, -NR 10 -, -NR 10 C(O), -C(O)NR 10- refers to a divalent aliphatic hydrocarbyl group having from 1 to 6 carbon atoms, either straight or branched, including from 1 to 3 carbon atoms, optionally interrupted by one or more groups selected from, for example, methylene (-CH-), ethylene (-CHCH-), n-propylene (-CHCHCH-), iso-propylene (-CHCH(CH)-), (-C(CH)CHCH-), (-C(CH)CHC(O)-), (-C(CH)CHC(O)NH-), (-CH(CH)CH-), and the like.

[0022] "Substituted alkylene" refers to an alkylene group having 1 to 3 hydrogens replaced with a substituent, as described for carbon in the definition of "substituted" below.

[0023] The term "alkane" refers to alkyl and alkylene groups as defined herein.

[0024] The terms "alkylaminoalkyl," "alkylaminoalkenyl," and "alkylaminoalkynyl" refer to R ’ NHR ” - refers to the group R ’ is an alkyl group as defined herein, and R ” is an alkylene, alkenylene, or alkynylene group as defined herein.

[0025] The terms "alkaryl" or "aralkyl" refer to the groups -alkylene-aryl and -substituted alkylene-aryl, where alkylene, substituted alkylene, and aryl are defined herein.

[0026] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0027] The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O-, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0028] The term "alkoxyamino" refers to the group --NH-alkoxy, where alkoxy is as defined herein.

[0029] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group and includes, by way of example, groups such as trifluoromethoxy.

[0030] The term "haloalkyl" refers to an alkyl group substituted as described above, in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0031] The term "alkylalkoxy" refers to the group -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0032] The term "alkylthioalkoxy" refers to -alkylene-S-alkyl groups, alkylene-S-substituted alkyl groups, substituted alkylene-S-alkyl groups, and substituted alkylene-S-substituted alkyl groups, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0033] "Alkenyl" refers to a straight or branched chain hydrocarbyl group having 2 to 6 carbon atoms, e.g., 2 to 4 carbon atoms, and having at least one site of double bond unsaturation, e.g., 1 to 2. The term includes, by way of example, bivinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers.

[0034] The term "substituted alkenyl" refers to an alkenyl group, as defined herein, having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0035] "Alkynyl" refers to a straight-chain or branched monovalent hydrocarbyl group having from 2 to 6 carbon atoms, e.g., 2 to 3 carbon atoms, and having at least 1 site of triple bond unsaturation, e.g., 1 to 2. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CHC≡CH).

[0036] The term "substituted alkynyl" refers to an alkynyl group, as defined herein, having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0037] "Alkynyloxy" refers to the group -O-alkynyl, where alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0038] "Acyl" includes HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, "C(O)-," "substituted heteroaryl-C(O)-," "heterocyclyl-C(O)-," and "substituted heterocyclyl-C(O)-" groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the "acetyl" group CHC(O).

[0039] "Acylamino" is -NR 20 C(O) alkyl group, -NR 20 C(O)-substituted alkyl group, NR 20 C(O)cycloalkyl group, -NR 20 C(O)-substituted cycloalkyl groups, -NR 20 C(O) cycloalkenyl group, -NR 20 C(O)-substituted cycloalkenyl group, -NR 20 C(O) alkenyl group, -NR 20 C(O)-substituted alkenyl group, -NR 20 C(O) alkynyl group, -NR 20 C(O)-substituted alkynyl group, -NR 20 C(O) aryl group, -NR 20 C(O) substituted aryl group, -NR 20 C(O) heteroaryl group, -NR 20 C(O)-substituted heteroaryl groups, -NR 20 C(O) heterocyclic groups, and -NR 20 C(O)-substituted heterocyclic groups, R 20is hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0040] "Aminocarbonyl" or the term "aminoacyl" refers to -C(O)NR 21 R 22 R refers to the group 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 is optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0041] "Aminocarbonylamino" is -NR 21 C(O)NR 22 R 23 R refers to the group 21 , R 22 , and R 23 is independently selected from hydrogen, alkyl, aryl, or cycloalkyl, and two R groups are joined to form a heterocyclyl group.

[0042] The term "alkoxycarbonylamino" refers to the group -NRC(O)OR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0043] The term "acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O-, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0044] "Aminosulfonyl" is -SO2NR 21 R 22 R refers to the group 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 is optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0045] "Sulfonylamino" is -NR 21 SO2R 22 R refers to the group 21 and R 22is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 is optionally joined together with the atom(s) bound to it to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0046] "Aryl" or "ar" refers to a monovalent aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (e.g., as in a phenyl group) or a ring system having multiple fused rings, which may or may not be aromatic, provided that the point of attachment is through an aromatic ring atom (examples of such aromatic ring systems include naphthyl, anthryl, and indanyl). This term includes, by way of example, phenyl and naphthyl. Unless constrained by the definition of an aryl substituent, such aryl groups may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamido, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl.

[0047] "Aryloxy" refers to the group --O-aryl, where aryl is as defined herein and includes, for example, phenoxy, naphthoxy, etc., and includes optionally substituted aryl groups, also as defined herein.

[0048] "Amino" refers to the group NH2.

[0049] The term "substituted amino" refers to the group -NRR, where if at least one R is not hydrogen, then each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl.

[0050] The term "azido" refers to the group -N3.

[0051] "Carboxyl", "carboxy" or "carboxylate" refers to -CO2H or salts thereof.

[0052] "Carboxyl-ester" or "carboxy-ester", or the term "carboxyalkyl" or "carboxylalkyl" refers to a -C(O)O-alkyl group, a -C(O)O-substituted alkyl group, a -C(O)O-alkenyl group, a -C(O)O-substituted alkenyl group, a -C(O)O-alkynyl group, a -C(O)O-substituted alkynyl group, a -C(O)Oaryl group, a -C(O)O-substituted aryl group, a -C(O)O-cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-cycloalkenyl

[0033] This refers to the groups, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0053] "(Carboxyl-ester)oxy" or "carbonate" refers to an -OC(O)O-alkyl group, an -OC(O)O-substituted alkyl group, an -OC(O)O-alkenyl group, an -OC(O)O-substituted alkenyl group, an -OC(O)O-alkynyl group, an -OC(O)O-substituted alkynyl group, an -OC(O)O-aryl group, an -OC(O)O-substituted aryl group, an -OC(O)O-cycloalkyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-cycloalkenyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-cycloalkenyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-substituted cycloalkenyl ... refers to a cycloalkenyl group, an -OC(O)O-heteroaryl group, an -OC(O)O-substituted heteroaryl group, an -OC(O)O-heterocyclic group, and an -OC(O)O-substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0054] "Cyano" or "nitrile" refers to the group --CN.

[0055] "Cycloalkyl" refers to cyclic alkyl groups of 3 to 10 carbon atoms having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl.

[0056] The term "substituted cycloalkyl" includes but is not limited to deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It refers to a cycloalkyl group having 1 to 5 substituents, or 1 to 3 substituents, selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0057] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group of from 3 to 10 carbon atoms having single or multiple rings and at least one double bond, eg, 1 to 2 double bonds.

[0058] The term "substituted cycloalkenyl" includes but is not limited to deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO2- It refers to a cycloalkenyl group having 1 to 5 substituents selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl, or 1 to 3 substituents.

[0059] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having single or multiple rings and at least one triple bond.

[0060] "Cycloalkoxy" refers to -O-cycloalkyl.

[0061] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0062] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0063] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0064] "Heteroaryl" refers to an aromatic group of 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl, imidazolyl, or furyl) or multiple condensed rings within the ring system (e.g., in groups such as indolizinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), provided that at least one ring within the ring system is aromatic and the point of attachment is through an aromatic ring atom. In certain embodiments, the nitrogen and / or sulfur ring atoms of a heteroaryl group are optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless constrained by the definition of a heteroaryl substituent, such heteroaryl groups may be acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamido, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl, and trihalomethyl.

[0065] The term "heteroaralkyl" refers to the group alkylene-heteroaryl, where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

[0066] "Heteroaryloxy" refers to -O-heteroaryl.

[0067] "Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings, including fused bridges and spiro ring systems, and having 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen; in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided the point of attachment is through a non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0068] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine. These include benzo[b]thiophene, ...

[0069] Unless otherwise constrained by the definition of a heterocyclic substituent, such heterocyclic groups may include deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents selected from substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycle.

[0070] "Heterocyclyloxy" refers to the group --O-heterocyclyl.

[0071] The term "heterocyclylthio" refers to the group heterocyclic -S-.

[0072] The term "heterocyclene" refers to a diradical group formed from a heterocycle, as defined herein.

[0073] The term "hydroxyamino" refers to the group --NHOH.

[0074] "Nitro" refers to the NO2 group.

[0075] "Oxo" refers to the (=O) atom.

[0076] "Sulfonyl" refers to an SO2 alkyl group, an SO2-substituted alkyl group, or a SO 2- Alkenyl group, SO2-substituted alkenyl group, SO 2- Cycloalkyl groups, SO2-substituted cycloalkyl groups, SO 2- Cycloalkenyl groups, SO2-substituted cycloalkenyl groups, SO 2- Aryl groups, SO2-substituted aryl groups, SO 2- Heteroaryl groups, SO2-substituted heteroaryl groups, SO 2- Sulfonyl refers to heterocyclic and SO-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.

[0077] "Sulfonyloxy" refers to an OSO2 alkyl group, an OSO2-substituted alkyl group, or an OSO 2- Alkenyl group, OSO2-substituted alkenyl group, OSO2- Cycloalkyl groups, OSO2-substituted cycloalkyl groups, OSO 2- Cycloalkenyl group, OSO2-substituted cycloalkenyl group, OSO 2- Aryl group, OSO2-substituted aryl group, OSO 2- Heteroaryl groups, OSO2-substituted heteroaryl groups, OSO 2- refers to heterocyclic groups, and OSO2-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0078] The term "aminocarbonyloxy" refers to the group -OC(O)NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

[0079] "Thiol" refers to the group --SH.

[0080] The term "thioxo" or "thioketo" refers to the atom (=S).

[0081] The term "alkylthio" or "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In certain embodiments, sulfur can be oxidized to -S(O)-. Sulfoxides can exist as one or more stereoisomers.

[0082] The term "substituted thioalkoxy" refers to an --S-substituted alkyl group.

[0083] The term "thioaryloxy" refers to an aryl-S- group, where aryl is as defined herein, including an optionally substituted aryl group, as defined herein.

[0084] The term "thioheteroaryloxy" refers to the group --S-heteroaryl, where heteroaryl is as defined herein, including an optionally substituted aryl group, as defined herein.

[0085] The term "thioheterocyclooxy" refers to the group -S-heterocyclyl, where heterocyclyl is as defined herein, including optionally substituted heterocyclyl groups, as defined herein.

[0086] Further to the disclosure herein, when used to modify a particular group or radical, the term "substituted" can also mean that one or more hydrogen atoms of the particular group or radical are each, independently of one another, replaced with the same or different substituents as defined below.

[0087] In addition to the groups disclosed for individual terms herein, substituents to replace one or more hydrogens on a saturated carbon atom in a particular group or radical (any two hydrogens on a single carbon can be ═O, ═NR, etc.) are also included. 70 , =N-OR 70 , =N2 or =S) is, unless otherwise specified, deuterium, -R 60 , halo, =O, -OR 70 , ‐SR 70 , ‐NR 80 R 80 , trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R 70 , -SO2O - M + , -SO2OR 70 , ‐OSO2R 70 , ‐OSO2O - M + , -OSO2OR 70 , -P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, ‐C(O)R 70 , ‐C(S)R 70, -C(NR 70 )R 70 , -C(O)O - M + , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , ‐OC(O)R 70 , ‐OC(S)R 70 , ‐OC(O)O‐M + , -OC(O)OR 70 , -OC(S)OR 70 , ‐NR 70 C(O)R 70 , ‐NR 70 C(S)R 70 , ‐NR 70 CO2 - M + , ‐NR 70 CO2R 70 , -NR 70 C(S)OR 70 , ‐NR 70 C(O)NR 80 R 80 , ‐NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 and R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups; and each R 70 are independently hydrogen or R 60 and each R 80 are independent, R 70 or alternatively, two R taken together with the nitrogen atom to which they are attached 80’forming a 5-, 6-, or 7-membered heterocycloalkyl, which optionally contains 1 to 4 additional heteroatoms, which may be the same or different, selected from the group consisting of O, N, and S, wherein N may have —H or C1-C3 alkyl substitution, and each M + is a counter ion with a net single positive charge. + are independent, e.g., K + , Na + , Li + Alkaline ions such as + N(R 60 )4, or ammonium ions such as [Ca 2+ 〕 0.5 , [Mg 2+ 〕 0.5 , or [Ba 2+ 〕 0.5 (The subscript 0.5 means that one of the counterions of such divalent alkaline earth ions is the ionized form of the compounds of the present disclosure, and the other typical counterion, such as chloride, or a doubly ionized compound disclosed herein, can serve as the counterion of such divalent alkaline earth ion, or a doubly ionized compound disclosed herein can serve as the counterion of such divalent alkaline earth ion.) A specific example is -NR 80 R 80 is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-1-yl and N-morpholinyl.

[0088] Further to the disclosure herein, the substituents of hydrogen on unsaturated carbon atoms in "substituted" alkene, alkyne, aryl, and heteroaryl groups are, unless otherwise specified, deuterium, -R 60 , halo, -O - M + , -OR 70 , ‐SR 70 , -S - M + , ‐NR 80 R 80, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , ‐OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , ‐OC(S)R 70 , ‐NR 70 C(O)R 70 , ‐NR 70 C(S)R 70 , ‐NR 70 CO2 - M + , ‐NR 70 CO2R 70 , -NR 70 C(S)OR 70 , ‐NR 70 C(O)NR 80 R 80 , ‐NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 and R60 , R 70 , R 80 and M + is as previously defined, except that in the case of a substituted alkene or alkyne, the substituent is -O - M + , -OR 70 , ‐SR 70 , or -S - M + isn't it.

[0089] In addition to the groups disclosed for each individual term herein, the substituent of a hydrogen on a nitrogen in a "substituted" heteroalkyl and cycloheteroalkyl group is, unless otherwise specified, an -R 60 , -OM + , -OR 70 , -SR 70 , -SM + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 , -S(O)2O-M + , -S(O)2OR 70 , -OS(O)2R 70 , -OS(O)2O-M + , -OS(O)2OR 70 , -P(O)(O-)2(M + )2, -P(O)(OR 70 )OM + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)OR 70 , -OC(S)OR 70 , -NR70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 and R 60, R 70 , R 80 and M + is as previously defined.

[0090] Further to the disclosure herein, in some embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0091] Unless otherwise specified, it is understood that polymers defined herein are not intended to encompass any of the above-defined substituents, achieved by defining the substituent to have further substituents thereon (e.g., a substituted aryl having a substituted aryl group as a substituent itself substituted with a substituted aryl group, which in turn is substituted with a substituted aryl group, etc.). In such cases, the maximum number of such substitutions is three. For example, the sequential substitution of substituted aryl groups specifically contemplated herein is limited to substituted aryl-(substituted aryl)-substituted aryl. However, for example, a substituent defined as a polyether may have more than three sequential substitutions, e.g., -O-(CHCHO). n It may contain -H, where n can be 1, 2, 3, or more.

[0092] Unless otherwise indicated, naming of substituents not expressly defined herein is accomplished by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0093] For any of the groups disclosed herein that contain one or more substituents, it is of course understood that such groups do not include any substitutions or substitution patterns that are sterically infeasible and / or synthetically impractical. Furthermore, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0094] When a substituent or group is defined as "containing deuterium," it is to be understood that the substituent or group itself can be deuterium, or the substituent or group can contain at least one deuterium substitution in its chemical structure. For example, when the substituent "-R" is defined as "containing deuterium," it is to be understood that -R can be -D (-deuterium), or a group such as -CD consistent with the other requirements set forth for -R.

[0095] The phrases "pharmaceutically acceptable," "physiologically acceptable," and the like are used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. When referring to salts, the phrases "pharmaceutically acceptable salt," "physiologically acceptable salt," and the like mean salts that are acceptable for administration to a patient, such as a mammal (salts having counterions that have acceptable mammalian safety for a given administration regimen). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases such as sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and, where the molecule contains a basic functional group, from addition salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, sulfamate, phosphates, nitrates, perchlorates, and the like, as well as from addition salts with organic acids such as formates, tartrates, besylates, mesylates, acetates, maleates, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemixalates, hemifumarates, propionates, stearates, lactates, citrates, ascorbates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, tosylates, ethanedisulfonates, isethionates, and the like.

[0096] The term "salt thereof" refers to a compound formed when the proton of an acid is replaced by a cation, such as a metal cation or an organic cation. Where applicable, the salt is a pharmaceutically acceptable salt, but this is not required for salts of intermediate compounds that are not intended for administration to patients. For example, salts of the present compounds include those in which the compound is protonated with an inorganic or organic acid to form a cation, and has a conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0097] "Solvate" refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate can exist in an ordered and / or irregular arrangement. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Thus, exemplary solvates include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.

[0098] "Stereoisomer" and "stereoisomers" refer to compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms of the compounds, such as racemates and optically pure stereoisomers, are contemplated herein. Chemical formulas and compounds that have at least one stereocenter but are drawn without reference to stereochemistry are intended to include both the racemate and the individual stereoisomers, such as R- and / or S-stereoisomers, each permutation of the diastereomers, so long as such diastereomers are geometrically feasible.

[0099] "Tautomer" refers to alternative forms of molecules that differ only in the electronic bonding of the atoms and / or in the position of protons, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. One of ordinary skill in the art will recognize that other tautomeric ring atom configurations are possible.

[0100] It will be understood that the compounds herein may exist in different salt, solvate, and stereoisomeric forms, and the present disclosure is intended to include all permutations of salts, solvates, and stereoisomers, for example, solvates of pharmaceutically acceptable salts of the stereoisomers of the subject compounds.

[0101] A "vapor" is a solid substance in the gas phase at a temperature below its critical temperature, meaning that the vapor can be condensed to a liquid by increasing its pressure without decreasing the temperature.

[0102] As used herein, an "aerosol" is a suspension of fine solid particles or liquid droplets in a gas phase (e.g., air, oxygen, helium, nitrous oxide, and other gases, and mixtures thereof). As used herein, a "mist" is a subset of aerosol, distinct from vapor, and is a dispersion of liquid droplets (liquid phase) suspended in a gas phase (e.g., air, oxygen, helium, and mixtures thereof). The droplets of an aerosol or mist may contain a drug moiety dissolved in an aqueous liquid, an organic solvent, or a mixture thereof. The gas phase of an aerosol or mist may contain other gases, such as nitrous oxide, including air, oxygen, helium, or mixtures thereof. A mist does not contain solid particles. The aerosols and mists of the present disclosure can be generated by any suitable method and device, examples of which are described herein, for example, through the use of an inhaler or nebulizer.

[0103] As used herein, the term "sustained release" or "controlled release" describes the release period of certain formulations of the present disclosure that are formulated to increase the release period, for example, to a maximum value, which is ultimately limited by the time the gastrointestinal tract naturally expels all of the drug with food. As used herein, the term "release period" describes the time frame during which any active ingredient described herein is released from an excipient (e.g., a matrix) to achieve the plasma concentration of the active ingredient described herein. The start time of the release period is defined from the time of oral administration to a subject, which, if taken orally, is considered to be approximately equivalent to entry into the stomach and initial dissolution by gastric enzymes and acids. The end time of the release period is defined as the time when the entire loaded drug has been released. In some embodiments, the release period can be greater than about 4 hours, greater than 8 hours, greater than 12 hours, greater than 16 hours, or greater than 20 hours, greater than about 24 hours, greater than 28 hours, greater than 32 hours, greater than 36 hours, or greater than 48 hours, or less than about 48 hours, less than 36 hours, 4 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less.

[0104] As used herein, the terms "stable," "stability," and the like include chemical stability and solid-state (physical) stability. The term "chemical stability" means that a compound can be stored under normal storage conditions, either in an isolated form or in a formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein, with little or no chemical degradation or decomposition. "Solid-state stability" means that a compound can be stored under normal storage conditions, either in an isolated solid form or in a solid formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein, with little or no solid-state changes (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization, or solid-state phase transition).

[0105] As used herein, the term "composition" is equivalent to the term "formulation."

[0106] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of active ingredients and / or compositions to a desired biological site of action. Routes or modes of administration are as described herein.

[0107] As used herein, "simultaneous" administration or administration performed "simultaneously" refers to administration of two or more active ingredients that are simultaneous (e.g., at the same time, such as when administered in the same dosage form), overlapping in time (e.g., when a first active ingredient is administered continuously over a period of time, such as continuously over a 20 minute period, and a second active ingredient is administered overlapping at a point or time period within the administration period of the first active ingredient), or non-overlapping but substantially adjacent, i.e., separated by 30 seconds or less, i.e., the start of administration of a first active ingredient is separated by 30 seconds or less from the end of administration of a second active ingredient, or vice versa. For example, the administration of two injections, one following the other within 30 seconds, is considered simultaneous administration herein. "Sequential" administration or administration performed "sequentially" refers to administration of two or more active ingredients where the time interval between their non-overlapping endpoints is greater than 30 seconds (i.e., the start of administration of a first active ingredient is separated by more than 30 seconds from the end of administration of a second active ingredient, or vice versa).

[0108] As used herein, the term " inhalation session " describes the administration event that a subject inhales a given dose of drug, regardless of the number of breaths required to inhale a given dose.For example, a subject prescribed to take 10 mg of drug twice a day will perform two inhalation sessions, and each inhalation session will provide 10 mg of drug.The duration and number of breaths of each inhalation session will depend on factors such as the inhalation device used, the amount of drug inhaled per breath, the drug concentration of the dosage form, and the breathing pattern of the subject.

[0109] As used herein, the term "treating" or "treatment" refers to treating or curing a disease or medical condition in a patient, e.g., a mammal (particularly a human), including ameliorating a disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a patient; inhibiting a disease or medical condition, e.g., by slowing or arresting the onset of the disease or medical condition in a patient; or alleviating the symptoms of a disease or medical condition in a patient. Treatment may provide a therapeutic benefit, such as eradicating or ameliorating one or more of the underlying symptoms, physiological or psychological symptoms associated with a disease or disorder, such that an improvement is observed in the patient despite the fact that the patient may still be affected by the condition. In some embodiments, treatment may refer to prophylaxis, i.e., preventing the occurrence of a disease or medical condition or otherwise delaying the onset of a disease or medical condition in a patient.

[0110] A "patient" or "subject," as used interchangeably herein, may be any mammal, including, for example, a human. The patient or subject may have the condition to be treated or may be susceptible to the condition to be treated.

[0111] As used herein, unless otherwise specified, the terms "prevent" and "preventing" refer to the prevention of the onset, recurrence, or spread of a disease, disorder, or condition, or one or more symptoms thereof. The term encompasses the prevention or reduction of symptoms of a particular disease, disorder, or condition. Subjects with a family history of a disease, disorder, or condition are particularly, in some embodiments, candidates for a preventative regimen. Additionally, subjects with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term "prevention" may be used interchangeably with the term "prophylactic treatment."

[0112] As used herein, and unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease, disorder, or condition, or one or more symptoms thereof. Often, the beneficial effects a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term "managing" encompasses treating a subject afflicted with a particular disease, disorder, or condition in an effort to prevent or minimize the recurrence of the disease, disorder, or condition.

[0113] A "therapeutically effective amount" refers to an amount of a compound sufficient to treat a particular disorder or disease, or one or more symptoms thereof, and / or prevent the occurrence of a disease or disorder. As used herein, and unless otherwise specified, a "prophylactically effective amount" of an active ingredient is an amount sufficient to prevent a disease, disorder, or condition, or to prevent its recurrence. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effect of another prophylactic agent.

[0114] The term "administration schedule" refers to a plan that chronologically shows the type, amount, duration, and procedure of drug treatment, including the dosage, administration method, administration order, and administration date of each drug. The designated administration date is determined before the start of drug administration. Administration is continued by repeating a series of administration schedules, each of which is considered a "course." A "continuous" administration schedule means that the drug is administered daily without interruption during the treatment course. If the administration schedule follows an "intermittent" administration schedule, the days of administration may be followed by "rest days" or non-administration days of the drug during the course. A "drug holiday" indicates that the drug is not administered according to a predetermined administration schedule. For example, after receiving several treatment courses, a subject may be prescribed a regulated drug holiday as part of the administration schedule, for example, before resuming active treatment.

[0115] The term "toxic spike" is used herein to describe a spike in the concentration of any compound described herein that would result in side effects such as sedation or psychotomimetic effects such as hallucinations, dizziness, and nausea, which not only have an immediate effect but also affect treatment compliance. In particular, side effects may be more pronounced at blood concentration levels above about 300 ng / L (e.g., about 300, 400, 500, 600, or more ng / L).

[0116] As used herein, and unless otherwise specified, a "neuropsychiatric disease or disorder" refers to a behavioral or psychological problem associated with a known neurological condition, typically defined as a group of coexisting symptoms. Examples of neuropsychiatric disorders include, but are not limited to, schizophrenia, cognitive impairment in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, bipolar disorder and mania, depression, or any combination thereof.

[0117] As used herein, "inflammatory condition" or "inflammatory disease" refers broadly to chronic or acute inflammatory diseases. Inflammatory conditions and diseases include, but are not limited to, rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthropathies (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystal arthropathies (e.g., gout, pseudogout, calcium pyrophosphate deposition disease), multiple sclerosis, Lyme disease, polymyalgia rheumatica, connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjogren's syndrome), vasculitis (e.g., nodular polyarthritis, vasculitis, inflammatory bowel disease ... It broadly refers to chronic or acute inflammatory conditions, including, but not limited to, vascular diseases including arteritis, Wegener's granulomatosis, Churg-Strauss syndrome), inflammatory conditions resulting from trauma or ischemia, sarcoidosis, atherosclerosis, and vascular occlusive diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular stent restenosis, uveitis, corneal disease, iritis, iridocyclitis, and cataracts.

[0118] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. As used throughout this description and the claims that follow, the meaning of "a," "an," and "the" includes plural references as well as singular references, unless the context clearly indicates otherwise. The term "about" in connection with a numerical value means that the value may vary above or below 5%. For example, a value of about 100 means 95 to 105 (or any value between 95 and 105).

[0119] Combination drug therapy The present disclosure provides 5-HT as an active ingredient. 2A The present invention relates to combination drug therapies based on the administration of both a 5-HT receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist. The synergistic effects of such combinations include, but are not limited to: 1) improved efficacy and duration of response, 2) more rapid onset of action, 3) reduced systemic toxicity, 4) reduced neurotoxicity, and 5) induction of euphoric hallucinogenic events, thereby enhancing the efficacy of 5-HT. 2A It offers many benefits, including enhancing the patient's experience by reducing or eliminating adverse psychedelic effects such as acute hallucinogenic crises (bad trips) that are routinely seen when taking receptor agonists or NMDA receptor antagonists alone, and the dissociative effects (out-of-body experiences) of hallucinogens.

[0120] 5-HT 2A Receptor agonists As used herein, "5-HT 2A "Receptor agonists" are 5-HT 2A It refers to compounds that increase the activity of receptors, which are subtypes of the 5-HT2 receptor belonging to the serotonin receptor family, including both partial and full agonists.Non-limiting examples of such agonists include, but are not limited to, tryptamine derivatives and phenethylamine derivatives.5-HT used in combination drug therapy 2AThe receptor agonist may be a single compound or a mixture of compounds, e.g., a mixture of tryptamine derivatives, a mixture of phenethylamine derivatives, or a mixture of one or more tryptamine derivatives and one or more phenethylamine derivatives, including pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof.

[0121] Examples of tryptamine derivatives include, but are not limited to, psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate) and its derivatives, such as psilocin (4-hydroxy-N,N-dimethyltryptamine), N-desmethyl-psilocybin (3-[2-(methylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate), 4-HO-NMT (4-hydroxy-N-methyltryptamine), norbaeocystin ([3-(2-aminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, 3-[2-(N,N,N-trimethylamino)ethyl]-1H-indol-4-yl phosphate), dihydrogen nitrite, and 4-hydroxyTMT salts (salts of 4-hydroxy-N,N,N-trimethyltryptamine); N,N-dimethyltryptamine (DMT); 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT); 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT); lysergic acid diethylamide (LSD) (a complex tryptamine) and its derivatives, e.g., LA-SS-Az ("LSZ" or (2S,4S)-1-[[(8β)-9,10-didehydro-6-(methyl)ergolin-8-yl]carbonyl]-2,4-dimethylazetidine); ibogaine (a complex tryptamine); or its deuterated analogs, e.g., DMT-d 10 (2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), 5-MeO-DMT-d 10 (2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), and the like; and pharmaceutically acceptable salts, stereoisomers, tautomers, or solvates thereof.

[0122] In some embodiments, 5-HT 2A The receptor agonist is a tryptamine derivative, which is a compound of Formula (I), Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), or Formula (II-d), as set forth below, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a combination thereof.

[0123] In a preferred embodiment, 5-HT 2A Receptor agonists include psilocin, psilocybin, N,N-dimethyltryptamine (DMT), 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and DMT-d 10 (2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), and 5-MeO-DMT-d 10 (2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), or a pharmaceutically acceptable salt or solvate thereof.

[0124] Examples of phenethylamine derivatives include, but are not limited to, 3,4-methylenedioxymethamphetamine (MDMA); 2C-X phenethylamines such as 2,5-dimethoxy-4-bromophenethylamine (2C-B), (4-chloro-2,5-dimethoxyphenethyl)amine (2C-C), and 2,5-dimethoxy-4-methylphenethylamine (2C-D); 3,4-methylenedioxy-N-ethylamphetamine (MDEA); 1,3-benzyl benzoate (BDO); Trimethoxyamphetamines, such as benzodioxolyl-N-methylbutanamine (MBDB); 3,4,5-trimethoxyamphetamine (TMA), 2,4,5-trimethoxyamphetamine (TMA-2), 2,3,4-trimethoxyamphetamine (TMA-3), 2,3,5-trimethoxyamphetamine (TMA-4), 2,3,6-trimethoxyamphetamine (TMA-5), and 2,4,6-trimethoxyamphetamine (TMA-6); amphetamine (TMA); trimethoxyphenethylamines such as 3,4,5-trimethoxyphenethylamine (mescaline) and isomescaline (2,3,4-trimethoxyphenethylamine); 2,5-dimethoxy-4-methylamphetamine (DOM); 2,5-dimethoxy-4-ethylamphetamine (DOET); 1-(2,5-dimethoxyphenyl)-2-aminopropane; 2,5-dimethoxy-4-iodoamine, including (R)-DOI amphetamine (DOI); 4-chloro-2,5-dimethoxy-amphetamine (DOC); 4-bromo-2,5-dimethoxy-amphetamine (DOB); 4-bromo-2,5-dimethoxy-methamphetamine (MDOB); and 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (2C-BCB); or deuterated analogs thereof, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0125] In some embodiments, 5-HT 2AThe receptor agonist is a phenethylamine derivative, which is a compound of Formula (III), Formula (III-a), Formula (IV), Formula (IV-a), Formula (IV-b), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VI-a), Formula (VI-b), as set forth below, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a combination thereof.

[0126] In a preferred embodiment, 5-HT 2A The receptor agonist is at least one phenethylamine derivative selected from the group consisting of 3,4-methylenedioxymethamphetamine (MDMA) and 2,5-dimethoxy-4-bromophenethylamine (2C-B), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0127] As used herein, 5-HT 2A The receptor agonist may be a compound having at least one deuterium atom. For example, 5-HT 2A The receptor agonist may be a tryptamine derivative of the following formula (I), (II), (II-a), (II-b), (II-c), or (II-d), which contains at least one deuterium atom, or a combination thereof. Alternatively, or in addition, 5-HT 2A The receptor agonist may be a phenethylamine derivative of the following formula (III) or formula (III-a), an N-substituted phenethylamine (NSP) containing at least one deuterium atom of the following formula (IV), formula (IV-a), formula (IV-b), formula (V), formula (Va), formula (Vb), formula (VI), formula (VI-a), formula (VI-b), or a combination thereof.

[0128] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from hydrogen, deuterium, and unsubstituted or substituted alkoxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; and R9 and R 10 are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0129] X1 and X2 can be the same or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is hydrogen or deuterium, and X2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, X2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X2 is a substituted C1-C6 alkyl. The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, one of X1 and X2 is deuterium and the other is hydrogen. In some embodiments, one or more of X and X is a substituted or unsubstituted C-C 10 In some embodiments, one or more of X and X is an unsubstituted C-C 10 In some embodiments, one or more of X and X are substituted C-C alkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10 It is cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0130] Y1 and Y2 can be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0131] In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R2 is substituted C1-C6 alkyl. When R2 is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R2 is substituted or unsubstituted C3-C6 alkyl. 10 In some embodiments, R2 is an unsubstituted C3-C 10 In some embodiments, R2 is a substituted C3-C6 alkyl group, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10 In some embodiments, R2 is cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R2 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0132] R4 and R5 can be the same or different. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R4 is hydroxy. In some embodiments, R4 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R4 is a substituted alkoxy. When R4 is a substituted alkoxy, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkoxy group may contain one or more substituents. For example, if the alkoxy group is a C1 alkoxy group (ie, a methoxy group), the substituted C1 alkoxy group can be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, and the like.

[0133] In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxy. In some embodiments, R5 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R5 is a substituted alkoxy. When R5 is a substituted alkoxy, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkoxy group may contain one or more substituents. For example, when the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the substituted C1 alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc.

[0134] R6 and R7 can be the same or different. R6 and R7 can independently be hydrogen, deuterium, or halogen, such as -Br, -F, -Cl, or -I.

[0135] R9 and R 10 can be the same or different. In some embodiments, R and R 10 In some embodiments, R and R 10 is hydrogen. In some embodiments, R and R 10 In some embodiments, R is hydrogen and R 10 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 10 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R 10 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R9 and R 10 One or more of the following may be substituted or unsubstituted C3-C 10 In some embodiments, R and R are cycloalkyl. 10 One or more of the following is an unsubstituted C3-C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R and R 10 One or more of the following may be substituted C3-C 10Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R and / or R 10 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0136] In some embodiments, X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R 10 At least one of the atoms contains deuterium.

[0137] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R is [ka] and; R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted phosphoryloxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; and R9, R 10 and R 11are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0138] Y1 and Y2 can be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0139] In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R2 is substituted C1-C6 alkyl. When R2 is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R2 is substituted or unsubstituted C3-C6 alkyl. 10 In some embodiments, R2 is an unsubstituted C3-C 10 In some embodiments, R2 is a substituted C3-C6 alkyl group, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10In some embodiments, R2 is cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R2 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0140] R4 and R5 can be the same or different. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R4 is hydroxy. In some embodiments, R4 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R4 is a substituted alkoxy. When R4 is a substituted alkoxy, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkoxy group may contain one or more substituents. For example, when the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the substituted C1 alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc. In some embodiments, R4 is an unsubstituted phosphoryloxy group (i.e., -OP(O)(OH)2 or its deprotonated form). In some embodiments, R4 is a substituted phosphoryloxy group in which one or more of the hydrogen atoms in -OP(O)(OH)2 is replaced with a substituent such as unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or other substituents described herein. When both hydrogen atoms in -OP(O)(OH)2 are replaced with substituents, the substituents can be the same or different.

[0141] In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxy. In some embodiments, R5 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R5 is a substituted alkoxy. When R5 is a substituted alkoxy, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkoxy group may contain one or more substituents. For example, when the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the substituted C1 alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc. In some embodiments, R5 is an unsubstituted phosphoryloxy group (i.e., -OP(O)(OH)2 or its deprotonated form). In some embodiments, R5 is a substituted phosphoryloxy group in which one or more of the hydrogen atoms in -OP(O)(OH)2 is replaced with a substituent such as unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or other substituents described herein. When both hydrogen atoms in -OP(O)(OH)2 are replaced with substituents, the substituents can be the same or different.

[0142] R6 and R7 can be the same or different. R6 and R7 can independently be hydrogen, deuterium, or halogen, such as -Br, -F, -Cl, or -I.

[0143] In some embodiments, R is [ka] R9 and R 10 can be the same or different. In some embodiments, R and R 10 In some embodiments, R and R 10 is hydrogen. In some embodiments, R and R 10 In some embodiments, R is hydrogen and R 10 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 10 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R 10 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R9 and R 10 One or more of the following may be substituted or unsubstituted C3-C 10 In some embodiments, R and R are cycloalkyl. 10 One or more of the following is an unsubstituted C3-C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R and R 10 One or more of the following may be substituted C3-C 10 Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R and / or R 10 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0144] In some embodiments, R is [ka] R9 and R 10 are described above. R9, R 10 , and R 11 can be the same or different. In some embodiments, R, R 10 , and R 11 are the same. In some embodiments, R, R 10 , and R 11 In some embodiments, R, R 10 , and R 11 are the same. 11 is hydrogen. In some embodiments, R 11 is the unsubstituted C 1- C alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R 11 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 11 is a substituted or unsubstituted C3-C 10 In some embodiments, R 11 is unsubstituted C3-C 10 and cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 11 is substituted C3-C 10 Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R11 is unsubstituted or substituted alkenyl, e.g., unsubstituted or substituted allyl. In some embodiments, R is a quaternary ammonium cation (where R, R 10 , and R 11 In some embodiments, R is a protonated ammonium cation, where R, R 10 , and R 11wherein one, two, or three are hydrogen. Examples of acids that may be used to prepare the pharmaceutically acceptable (acid addition) salts disclosed herein include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthyl 2-sulfonic acid, benzoic ... toluene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, gallataric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycerin, Cholic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid (e.g. For example, they include, but are not limited to, DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid, thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di-acids, e.g., adipic (hexanedio) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.).

[0145] In some embodiments, 5-HT 2AThe receptor agonist is a compound of formula (II-a) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are hydrogen; R is [ka] and R2, R4, R5, R6, R7, R9, R 10 , and R 11 is as defined above for formula (II).

[0146] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (II-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are hydrogen; R is [ka] and R2, R4, R5, R6, R7, R9, and R 10 is as defined above for formula (II).

[0147] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (II-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are hydrogen; R is [ka] and R2, R4, R5, R6, R7, R9, R 10 , and R 11 is as defined above for formula (II).

[0148] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (II-d) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] X1 and X2 are deuterium; Y1 and Y2 are hydrogen; R is [ka] and R2, R4, R5, R6, R7, and R 11 is as defined above for formula (II).

[0149] In a preferred embodiment, 5-HT 2A Receptor agonists are [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0150] In some embodiments, 5-HT 2AThe receptor agonist is a compound of formula (III) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen and deuterium; R 2 and R 3 are independently hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6 alkyl, and -OR a selected from the group consisting of: R 4 and R 5 are independently hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a or R 4 and R 5 together with the atom to which they are attached optionally form an unsubstituted or substituted heterocycloalkyl or an unsubstituted or substituted heteroaryl; R 6 and R 7 are independently selected from the group consisting of hydrogen and unsubstituted or substituted C1-C6 alkyl; and Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0151] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. 1 and X2 is deuterium. 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is a substituted or unsubstituted C1-C6 alkyl. 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0152] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. 1 and X 2 In some embodiments, Y 1 and Y 2 One of the atoms is deuterium and the other is hydrogen.

[0153] In some embodiments, R 2 is deuterium. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen, e.g., —Br, —F, —Cl, or —I. In some embodiments, R 2is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 2 is a substituted C1-C6 alkyl. 2 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 2 -OR a is.

[0154] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a halogen, e.g., —Br, —F, —Cl, or —I. In some embodiments, R 3 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 3 is a substituted C1-C6 alkyl. 3 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R3 -OR a is.

[0155] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen, e.g., —Br, —F, —Cl, or —I. In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、 -SEt, -Sn-Pr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -Me, -CD3, -CF3, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br. 4 is hydrogen, deuterium, halogen, -OR a , or -SR a and R ais a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0156] In some embodiments, R 5 is deuterium. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halogen, e.g., —Br, —F, —Cl, or —I. In some embodiments, R 5 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 5 is a substituted C1-C6 alkyl. 5 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 5 -OR a In some embodiments, R 5 -SR a In some embodiments, R 5 is hydrogen, -OMe, or -OCD. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is -OMe. In some embodiments, R 5 is -OCD3. In some embodiments, R 5 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms. 4is -OCH3, -OCD3, -Br, -SCH3, -SCH2CH3, or -SCH2CH2CH3, and / or R 5 is hydrogen, -OMe, or -OCD3.

[0157] In some embodiments, R 4 and R 5 R, together with the atoms to which it is attached, forms a heterocycloalkyl or heteroaryl, and specifically includes a benzo[d][1,3]oxathiol group or a benzo[d][1,3]dioxole group. 4 and R 5 In embodiments where is bonded together with the atoms to which it is attached to form a heterocycloalkyl or heteroaryl (e.g., a benzo[d][1,3]oxathiol group, a benzo[d][1,3]dioxole group, etc.), the heterocycloalkyl or heteroaryl ring (e.g., an oxathiol ring, a dioxole ring, etc.) may be further substituted with substituents as defined herein, e.g., one or more halogen (e.g., fluorine) or deuterium substituents.

[0158] R 6 and R 7 can be the same or different. R 6 and R 7 can independently be hydrogen, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl), or C1-C6 alkyl substituted with one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0159] Each R amay independently be hydrogen, deuterium, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C1-C6 alkyl with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. a is a substituted or unsubstituted C1-C6 alkyl, preferably C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3. In some embodiments, each R a is —CH. In some embodiments, each R a is -CD3. In some embodiments, multiple R a In such a case, each R a may be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one Ra is -CH3 and the other R a is -CD3. In line with the above, -OR a or -SR a Examples include ‐SMe, ‐SCD 3、 -SCF 3、 These may include, but are not limited to, -SEt, -Sn-Pr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2CFH2.

[0160] In some embodiments, X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6, and R 7 At least one of the atoms contains deuterium.

[0161] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (III-a) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, Z 1 and Z 2 are independently selected from the group consisting of hydrogen, deuterium, or fluorine; and X 1 , X 2 , Y 1 , Y 2 , R 3 , R 6 , R 7 , and R a is as defined for formula (III).

[0162] Z 1 and Z 2 may be the same or different. In some embodiments, Z 1 and Z 2 are the same. In some embodiments, Z 1 and Z 2 is hydrogen. 1 and Z 2 is deuterium. 1 and Z 2 is fluorine. 1 and Z 2 are different. In some embodiments, Z 1 and Z 2 One of them is deuterium and the other is hydrogen.

[0163] In some embodiments, Z 1 , Z 2 , X 1 , X 2 , Y 1 , Y2 , R 3 , R 6 , and R 7 At least one of the atoms contains deuterium.

[0164] In some embodiments, R 6 and R 7 are independently hydrogen, -CH3, or -OCD3.

[0165] In a preferred embodiment, 5-HT 2A Receptor agonists are [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0166] In some embodiments, 5-HT 2A The receptor agonists are N-substituted phenethylamines (NSPs).

[0167] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] R 2 and R 3 are independently hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a、 and -SR a or R 2 and R 3 optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; R 4is hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and S.R. a is selected from the group consisting of R 5 and R 6 are independently hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a、 and -SR a or R 5 and R 6 optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; W 1 and W 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl, or X 2 and W 1 taken together with the atom to which they are attached form an optionally unsubstituted or substituted heterocycloalkyl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 7 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 8 , R 9 , and R 10 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a is selected from the group consisting of R 11 and R 12 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -ORa、 and -SR a or R 11 and R 12 optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, and Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0168] In some embodiments, R 2 is deuterium. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 2 is cyano. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 2 is a substituted C1-C6 alkyl. 2 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 2 -OR a In some embodiments, R 2 -SR a is.

[0169] In some embodiments, R 3 is deuterium. In some embodiments, R3 is hydrogen. In some embodiments, R 3 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 3 is cyano. In some embodiments, R 3 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 3 is a substituted C1-C6 alkyl. 3 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 3 -OR a In some embodiments, R 3 -SR a is.

[0170] In some embodiments, R 2 and R 3 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0171] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 4 is cyano. In some embodiments, R 4is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、 -SEt, -Sn-Pr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -Me, -CD3, -CF3, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br. 4 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0172] In some embodiments, R 5 is deuterium. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 5 is cyano. In some embodiments, R5 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 5 is a substituted C1-C6 alkyl. 5 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 5 -OR a In some embodiments, R 5 -SR a In some embodiments, R 5 is hydrogen, -OMe, or -OCD. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is -OMe. In some embodiments, R 5 is -OCD3. In some embodiments, R 5 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0173] In some embodiments, R 6 is deuterium. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 6 is cyano. In some embodiments, R 6is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 6 is a substituted C1-C6 alkyl. 6 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 6 -OR a In some embodiments, R 6 -SR a In some embodiments, R 6 is hydrogen, -OMe, or -OCD. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is -OMe. In some embodiments, R 6 is -OCD3. In some embodiments, R 6 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0174] In some embodiments, R 5 and R 6 together with the atom to which they are attached form an optionally unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0175] W 1 and W 2 may be the same or different. In some embodiments, W1 and W 2 are the same. In some embodiments, W 1 and W 2 is hydrogen. In some embodiments, W 1 and W 2 is deuterium. In some embodiments, W 1 and W 2 are different. In some embodiments, W 1 is hydrogen or deuterium, and W 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, W 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, W 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, W 1 and W 2 One of the atoms is deuterium and the other is hydrogen.

[0176] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. 1 and X 2 is deuterium. 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is a substituted or unsubstituted C1-C6 alkyl. 2is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0177] In some embodiments, X 2 and W 1 together with the atom to which they are attached form an unsubstituted or substituted heterocycloalkyl, for example, piperidine or pyrrolidine, which may be substituted or unsubstituted.

[0178] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. In some embodiments, Y 1 and Y 2 In some embodiments, Y 1 is hydrogen or deuterium, and Y 2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, Y 2is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, Y 1 and Y 2 One of the atoms is deuterium and the other is hydrogen.

[0179] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl) or C1-C6 alkyl substituted with one or more substituents such as one or more deuterium (e.g., -CDH2, -CD2H, -CD3).

[0180] R 8 , R 9 , and R 10 can be the same or different. In some embodiments, R 8 , R 9 , and R 10 are the same. In some embodiments, R 8 , R 9 , and R 10 are different. In some embodiments, R 8 , R 9 , and R 10 The two are the same.

[0181] In some embodiments, R 8 is deuterium. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 8 is hydroxyl. In some embodiments, R 8 is cyano. In some embodiments, R8 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 8 is a substituted C1-C6 alkyl. 8 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 8 -OR a In some embodiments, R 8 -SR a In some embodiments, R 8 is hydrogen, -OMe, or -OCD. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -OMe. In some embodiments, R 8 is -OCD3. In some embodiments, R 8 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0182] In some embodiments, R 9 is deuterium. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 9 is hydroxyl. In some embodiments, R 9 is cyano. In some embodiments, R9 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 9 is a substituted C1-C6 alkyl. 9 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 9 -OR a In some embodiments, R 9 -SR a In some embodiments, R 9 is hydrogen, -OMe, or -OCD. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -OMe. In some embodiments, R 9 is -OCD3. In some embodiments, R 9 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0183] In some embodiments, R 10 is deuterium. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 10 is hydroxyl. In some embodiments, R 10 is cyano. In some embodiments, R10 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 10 is a substituted C1-C6 alkyl. 10 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 10 -OR a In some embodiments, R 10 -SR a In some embodiments, R 10 is hydrogen, -OMe, or -OCD. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -OMe. In some embodiments, R 10 is -OCD3. In some embodiments, R 10 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0184] R 11 and R 12 can be the same or different. In some embodiments, R 11 is deuterium. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 11is hydroxyl. In some embodiments, R 11 is cyano. In some embodiments, R 11 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 11 is a substituted C1-C6 alkyl. 11 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 11 -OR a In some embodiments, R 11 -SR a In some embodiments, R 11 is hydrogen, -OMe, or -OCD. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is -OMe. In some embodiments, R 11 is -OCD3. In some embodiments, R 11 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0185] In some embodiments, R 12 is deuterium. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 12is hydroxyl. In some embodiments, R 12 is cyano. In some embodiments, R 12 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 12 is a substituted C1-C6 alkyl. 12 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 12 -OR a In some embodiments, R 12 -SR a In some embodiments, R 12 is hydrogen, -OMe, or -OCD. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is -OMe. In some embodiments, R 12 is -OCD3. In some embodiments, R 12 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0186] In some embodiments, R 11 and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0187] Each R a may independently be hydrogen, deuterium, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C1-C6 alkyl with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. a is a substituted or unsubstituted C1-C6 alkyl, preferably C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3. In some embodiments, each R a is —CH. In some embodiments, each R a is -CD3. In some embodiments, multiple R a In such a case, each R a may be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one Ra is -CH3 and the other R a is -CD3. In line with the above, -OR a or -SR a Examples include ‐SMe, ‐SCD 3、 -SCF 3、 These may include, but are not limited to, -SEt, -Sn-Pr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2CFH2.

[0188] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 At least one of the atoms contains deuterium.

[0189] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (IV-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X 1 and X 2 is deuterium; and W 1 , W 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R a is as defined above for formula (IV).

[0190] In some embodiments, W 1 , W 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0191] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (IV-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, W 1 and W 2 is deuterium, and X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R a is as defined above for formula (IV).

[0192] In some embodiments, X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 At least one of the atoms contains deuterium.

[0193] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (V), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 3 and R 6 -OR a and R 4 is hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and S.R. a is selected from the group consisting of W 1 and W 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 7 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 8 , R 9 , and R 10 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a is selected from the group consisting of R 11 and R 12 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a、 and -SR a or R 11 and R 12 optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, and Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0194] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 4 is cyano. In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、 -SEt, -Sn-Pr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -Me, -CD3, -CF3, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br. 4 is hydrogen, deuterium, halogen, -OR a , or -SR a and R ais a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0195] W 1 and W 2 may be the same or different. In some embodiments, W 1 and W 2 are the same. In some embodiments, W 1 and W 2 is hydrogen. In some embodiments, W 1 and W 2 is deuterium. In some embodiments, W 1 and W 2 are different. In some embodiments, W 1 is hydrogen or deuterium, and W 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, W 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, W 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, W 1 and W 2 One of the atoms is deuterium and the other is hydrogen.

[0196] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. 1 and X 2 is deuterium. 1 and X 2are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is a substituted or unsubstituted C 1~ In some embodiments, X is a C alkyl. 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0197] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. In some embodiments, Y 1 and Y 2 In some embodiments, Y 1 is hydrogen or deuterium, and Y 2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, Y 2is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, Y 1 and Y 2 One of the atoms is deuterium and the other is hydrogen.

[0198] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl) or C1-C6 alkyl substituted with one or more substituents such as one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0199] R 8 , R 9 , and R 10 can be the same or different. In some embodiments, R 8 , R 9 , and R 10 are the same. In some embodiments, R 8 , R 9 , and R 10 are different. In some embodiments, R 8 , R 9 , and R 10 The two are the same.

[0200] In some embodiments, R 8 is deuterium. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 8 is hydroxyl. In some embodiments, R 8 is cyano. In some embodiments, R8 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 8 is a substituted C1-C6 alkyl. 8 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 8 -OR a In some embodiments, R 8 -SR a In some embodiments, R 8 is hydrogen, -OMe, or -OCD. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -OMe. In some embodiments, R 8 is -OCD3. In some embodiments, R 8 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0201] In some embodiments, R 9 is deuterium. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 9 is hydroxyl. In some embodiments, R 9 is cyano. In some embodiments, R9 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 9 is a substituted C1-C6 alkyl. 9 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 9 -OR a In some embodiments, R 9 -SR a In some embodiments, R 9 is hydrogen, -OMe, or -OCD. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -OMe. In some embodiments, R 9 is -OCD3. In some embodiments, R 9 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0202] In some embodiments, R 10 is deuterium. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 10 is hydroxyl. In some embodiments, R 10 is cyano. In some embodiments, R10 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 10 is a substituted C1-C6 alkyl. 10 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 10 -OR a In some embodiments, R 10 -SR a In some embodiments, R 10 is hydrogen, -OMe, or -OCD. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -OMe. In some embodiments, R 10 is -OCD3. In some embodiments, R 10 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0203] R 11 and R 12 can be the same or different. In some embodiments, R 11 is deuterium. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 11is hydroxyl. In some embodiments, R 11 is cyano. In some embodiments, R 11 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 11 is a substituted C1-C6 alkyl. 11 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 11 -OR a In some embodiments, R 11 -SR a In some embodiments, R 11 is hydrogen, -OMe, or -OCD. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is -OMe. In some embodiments, R 11 is -OCD3. In some embodiments, R 11 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0204] In some embodiments, R 12 is deuterium. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 12is hydroxyl. In some embodiments, R 12 is cyano. In some embodiments, R 12 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 12 is a substituted C1-C6 alkyl. 12 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 12 -OR a In some embodiments, R 12 -SR a In some embodiments, R 12 is hydrogen, -OMe, or -OCD. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is -OMe. In some embodiments, R 12 is -OCD3. In some embodiments, R 12 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0205] In some embodiments, R 11 and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0206] Each R a may independently be hydrogen, deuterium, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C1-C6 alkyl with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. a is a substituted or unsubstituted C1-C6 alkyl, preferably C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3. In some embodiments, each R a is —CH. In some embodiments, each R a is -CD3. In some embodiments, multiple R a In such a case, each R a may be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one Ra is -CH3 and the other R a is -CD3. In line with the above, -OR a or -SR a Examples include ‐SMe, ‐SCD 3、 -SCF 3、 These may include, but are not limited to, -SEt, -Sn-Pr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2CFH2.

[0207] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0208] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (Va) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 8 , R 9 , R 10 , and R 11 are independently selected from the group consisting of hydrogen and deuterium; R 12 is hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a and W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , and R a is as defined above for formula (V).

[0209] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 , and R 12 At least one of the atoms contains deuterium.

[0210] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (Vb), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrogen and deuterium; R 11 and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, and W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , and R a is as defined above for formula (V).

[0211] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0212] In some embodiments, 5-HT 2AThe receptor agonist is a compound of formula (VI) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 2 and R 5 -OR a and R 4 is hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and S.R. a is selected from the group consisting of W 1 and W 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 7 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 8 , R 9 , and R 10 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a is selected from the group consisting of R 11 and R 12 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a、 and -SR a or R 11 and R 12optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, and Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0213] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 4 is cyano. In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、-SEt, -Sn-Pr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -Me, -CD3, -CF3, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br. 4 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0214] W 1 and W 2 may be the same or different. In some embodiments, W 1 and W 2 are the same. In some embodiments, W 1 and W 2 is hydrogen. In some embodiments, W 1 and W 2 is deuterium. In some embodiments, W 1 and W 2 are different. In some embodiments, W 1 is hydrogen or deuterium, and W 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, W 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, W 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, W 1 and W 2 One of the atoms is deuterium and the other is hydrogen.

[0215] X 1 and X2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. 1 and X 2 is deuterium. 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is a substituted or unsubstituted C 1~ In some embodiments, X is a C alkyl. 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0216] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. In some embodiments, Y 1 and Y 2 In some embodiments, Y 1 is hydrogen or deuterium, and Y 2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, Y 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, Y 1 and Y 2 One of the atoms is deuterium and the other is hydrogen.

[0217] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl) or C1-C6 alkyl substituted with one or more substituents such as one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0218] R 8 , R 9 , and R 10 can be the same or different. In some embodiments, R 8 , R 9 , and R 10 are the same. In some embodiments, R 8 , R 9 , and R 10 are different. In some embodiments, R 8 , R 9 , and R 10 The two are the same.

[0219] In some embodiments, R 8 is deuterium. In some embodiments, R 8 is hydrogen. In some embodiments, R 8is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 8 is hydroxyl. In some embodiments, R 8 is cyano. In some embodiments, R 8 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 8 is a substituted C1-C6 alkyl. 8 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 8 -OR a In some embodiments, R 8 -SR a In some embodiments, R 8 is hydrogen, -OMe, or -OCD. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -OMe. In some embodiments, R 8 is -OCD3. In some embodiments, R 8 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0220] In some embodiments, R 9 is deuterium. In some embodiments, R 9 is hydrogen. In some embodiments, R 9is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 9 is hydroxyl. In some embodiments, R 9 is cyano. In some embodiments, R 9 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 9 is a substituted C1-C6 alkyl. 9 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 9 -OR a In some embodiments, R 9 -SR a In some embodiments, R 9 is hydrogen, -OMe, or -OCD. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -OMe. In some embodiments, R 9 is -OCD3. In some embodiments, R 9 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0221] In some embodiments, R 10 is deuterium. In some embodiments, R 10 is hydrogen. In some embodiments, R 10is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 10 is hydroxyl. In some embodiments, R 10 is cyano. In some embodiments, R 10 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 10 is a substituted C1-C6 alkyl. 10 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 10 -OR a In some embodiments, R 10 -SR a In some embodiments, R 10 is hydrogen, -OMe, or -OCD. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -OMe. In some embodiments, R 10 is -OCD3. In some embodiments, R 10 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0222] R 11 and R 12 can be the same or different. In some embodiments, R 11is deuterium. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 11 is hydroxyl. In some embodiments, R 11 is cyano. In some embodiments, R 11 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 11 is a substituted C1-C6 alkyl. 11 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 11 -OR a In some embodiments, R 11 -SR a In some embodiments, R 11 is hydrogen, -OMe, or -OCD. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is -OMe. In some embodiments, R 11 is -OCD3. In some embodiments, R 11 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0223] In some embodiments, R 12is deuterium. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 12 is hydroxyl. In some embodiments, R 12 is cyano. In some embodiments, R 12 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 12 is a substituted C1-C6 alkyl. 12 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 12 -OR a In some embodiments, R 12 -SR a In some embodiments, R 12 is hydrogen, -OMe, or -OCD. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is -OMe. In some embodiments, R 12 is -OCD3. In some embodiments, R 12 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0224] In some embodiments, R 11and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0225] Each R a may independently be hydrogen, deuterium, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C1-C6 alkyl with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. a is a substituted or unsubstituted C1-C6 alkyl, preferably C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3. In some embodiments, each R a is —CH. In some embodiments, each R a is -CD3. In some embodiments, multiple R a In such a case, each R a may be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one Ra is -CH3 and the other R a is -CD3. In line with the above, -OR a or -SR a Examples include ‐SMe, ‐SCD 3、 -SCF 3、 These may include, but are not limited to, -SEt, -Sn-Pr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2CFH2.

[0226] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0227] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (VI-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 8 , R 9 , R 10 , and R 11 are independently selected from the group consisting of hydrogen and deuterium; R 12 is hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a and W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 7 , and R a is as defined above for formula (VI).

[0228] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1, Y 2 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0229] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (VI-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrogen and deuterium; R 11 and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, and W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 7 , and R a is as defined above for formula (VI).

[0230] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0231] In a preferred embodiment, 5-HT 2A The receptor agonist is at least one N-substituted phenethylamine (NSP) having at least one deuterium atom, which is [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0232] Also, 5-HT 2APharmaceutically acceptable salt forms of the compounds disclosed herein as receptor agonists are disclosed herein.The acid used to form the pharmaceutically acceptable salt may be a mono-, di-, tri-, tetra-, or more acid group.The acid group may be, for example, a carboxylic acid, a sulfonic acid, a phosphonic acid, or other acidic moiety that contains at least one replaceable hydrogen atom.Examples of acids that may be used in the preparation of pharmaceutically acceptable (acid addition) salts disclosed herein include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-3-sulfonic acid, naphthalene-4-sulfonic acid, naphthalene-5-sulfonic acid, naphthalene-6-sulfonic acid, naphthalene-7-sulfonic acid, naphthalene-8-sulfonic acid, naphthalene-9-sulfonic acid, naphthalene-10 ... benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, Cholic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid (e.g. For example, they include, but are not limited to, DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid, thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di-acids, e.g., adipic (hexanedio) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.).

[0233] In some embodiments, the salt is N,N-dimethyltryptamine (DMT), 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), DMT-d 10 (2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), or 5-MeO-DMT-d 10 It is formed from (2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4).

[0234] In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate. In terms of providing desirable physical and pharmaceutical characteristics such as those described above, preferred pharmaceutically acceptable salts are the fumarate, benzoate, salicylate, and succinate salts of the compounds disclosed herein, for example, 5-HT, including fumarate, benzoate, and salicylate. 2A It is a receptor agonist.

[0235] In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate of N,N-dimethyltryptamine (DMT). In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate of 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT). In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). In some embodiments, the pharmaceutically acceptable salt is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d10 In some embodiments, the pharmaceutically acceptable salt is 5-MeO-DMT-d 10 The fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt of (2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4).

[0236] In some embodiments, the pharmaceutically acceptable salt is a fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (DMT). In some embodiments, the salt is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.7°, 22.5°, 23.9°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuKα radiation source.

[0237] In some embodiments, the pharmaceutically acceptable salt is the benzoate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (DMT). In some embodiments, the salt is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 9.6°, 11.1°, 12.6°, 13.5°, 15.8°, 16.1°, 17.1°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.7°, 23.8°, 24.6°, 26.9°, 29.2°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source.

[0238] In some embodiments, the pharmaceutically acceptable salt is the salicylate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (DMT). In some embodiments, the salt is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.7°, 21.0°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuKα radiation source.

[0239] In some embodiments, the pharmaceutically acceptable salt is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 In some embodiments, the salt is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.7°, 22.5°, 23.9°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuKα radiation source.

[0240] In some embodiments, the pharmaceutically acceptable salt is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10In some embodiments, the salt is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 9.6°, 11.1°, 12.6°, 13.5°, 15.8°, 16.1°, 17.1°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.7°, 23.8°, 24.6°, 26.9°, 29.2°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source.

[0241] In some embodiments, the pharmaceutically acceptable salt is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 In some embodiments, the salt is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from the group consisting of 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.7°, 21.0°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuKα radiation source.

[0242] In some embodiments, the 5-HT 2A The receptor agonist, or any pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, is in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc., with hydrates and ethanolates being preferred. Solvates can be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. In one non-limiting example, 5-HT is present as a hydrate. 2AThe receptor agonist may be a monohydrate, a dihydrate, etc. Solvates of the compounds of the present disclosure also include solution-phase forms. Thus, in some embodiments, the present disclosure provides 5-HT 20 agonists of the present disclosure in a solvated form, preferably a fully solvated form. 2A Solution phase compositions of receptor agonists, or any pharmaceutically acceptable salts, stereoisomers, or prodrugs thereof, are provided. For example, 5-HT 2A Pharmaceutically acceptable salt forms of the receptor agonists can be prepared in solution phase, whereby the salt is preformed as a solid and then dissolved in a solvent (e.g., water). 2A Pharmaceutically acceptable salt forms of the receptor agonists include 5-HT 2A Solution-phase compositions can be prepared by mixing the receptor agonist (free base) with an appropriate acid in a solvent (e.g., water), thereby forming a solvated salt form in situ. If desired, these preparations can be stored for extended periods as solutions, such as in aqueous, organic, or mixed organic solvent-aqueous form, without significant decomposition or physical changes, such as oiling out of solution. The solvent that can be used to form the solution-phase composition can be any one or more of the solvents described herein, such as water, ethanol, etc. In some embodiments, the solution-phase composition comprises 5-HT 2A An aqueous phase composition comprising a receptor agonist, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof solvated with water.

[0243] 5-HT 2AReceptor agonists may contain stereocenters. In such cases, the chemical formula / name is drawn / written without reference to stereochemistry, but the compound may exist in different stereoisomeric forms. Therefore, the present disclosure includes all possible stereoisomers, including not only racemates but also individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and non-racemic mixtures thereof. When compounds are desired as single enantiomers, they can be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods, as known in the art. Resolution of the final product, intermediate, or starting material can be carried out by any suitable method known in the art.

[0244] In some embodiments, the compounds described herein, e.g., 5-HT 2A In some embodiments, the compounds described herein, e.g., 5-HT 2A In some embodiments, the compounds described herein, e.g., 5-HT 2A Receptor agonists are enantiomerically enriched (one enantiomer is present in a greater proportion), including enantiomerically pure. In some embodiments, the compounds described herein, e.g., 5-HT 2A In some embodiments, the compounds described herein, e.g., 5-HT receptor agonists, are provided as single diastereomers. 2A The receptor agonists are provided as mixtures of diastereomers, which, when provided as a mixture of diastereomers, can include equal mixtures or mixtures enriched in a particular diastereomer (where one diastereomer is present in a higher percentage than another).

[0245] NMDA receptor antagonists As used herein, "NMDA receptor antagonist" refers to a compound that reduces or inhibits the action of N-methyl-D-aspartate (NMDA) receptors. Non-limiting examples of NMDA receptor antagonists suitable for use in the present disclosure include, but are not limited to, ketamine, nitrous oxide, memantine, amantadine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), dizocilpine (MK-801), or combinations thereof, including pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs. In some embodiments, the NMDA receptor antagonist of the combination medication is at least one selected from the group consisting of ketamine, nitrous oxide, memantine, and dextromethorphan, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0246] In some embodiments, the NMDA receptor antagonist is ketamine, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof (e.g., (S)-ketamine).

[0247] Pharmaceutically acceptable salts of NMDA receptor antagonists are contemplated herein. The acids used to form the pharmaceutically acceptable salts are those described herein.

[0248] In some embodiments, the NMDA receptor antagonists of the present disclosure, or any pharmaceutically acceptable salts, stereoisomers, or prodrugs thereof, are in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanolate salts, ethanolate salts, isopropanolate salts, etc., with hydrates and ethanolate salts being preferred. Solvates can be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. In one non-limiting example, as a hydrate, the NMDA receptor antagonist may be a monohydrate, a dihydrate, etc. Solvates of the compounds herein also include solution-phase forms. Thus, in some embodiments, the present disclosure provides solution-phase compositions of the NMDA receptor antagonists of the present disclosure, or any pharmaceutically acceptable salts, stereoisomers, or prodrugs thereof, in a solvated form, preferably a fully solvated form. For example, the NMDA receptor antagonist can be prepared in solution phase by dissolving in a solvent (e.g., water). The solvent that can be used to form the solution phase composition can be any one or more of the solvents described herein, e.g., water, ethanol, etc. In some embodiments, the solution phase composition is an aqueous solution phase composition that includes an NMDA receptor antagonist, or any salt, stereoisomer, or prodrug thereof solvated with water.

[0249] NMDA receptor antagonists may contain a stereocenter, as in the case of ketamine, for example. In such cases, the chemical formula / name is drawn / written without reference to stereochemistry, but the compound may exist in different stereoisomeric forms. Therefore, the present disclosure encompasses all possible stereoisomers, including not only racemic compounds but also individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and non-racemic mixtures thereof. If compounds are desired as single enantiomers, they can be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatography methods, as known in the art. Resolution of the final product, intermediate, or starting material may be carried out by any suitable method known in the art.

[0250] In some embodiments, the NMDA receptor antagonist is non-stereomeric. In some embodiments, the NMDA receptor antagonist is racemic. In some embodiments, the NMDA receptor antagonist is enantiomerically enriched (one enantiomer is present in a higher percentage), including enantiomerically pure. In some embodiments, the NMDA receptor antagonist is provided as a single diastereomer. In some embodiments, the NMDA receptor antagonist is provided as a mixture of diastereomers. When provided as a mixture of diastereomers, the mixture can include an equal mixture or a mixture enriched with a particular diastereomer (one diastereomer is present in a higher percentage than another).

[0251] In some embodiments, the NMDA receptor antagonist is nitrous oxide and / or memantine, preferably nitrous oxide. In a preferred embodiment, the NMDA receptor antagonist is nitrous oxide.

[0252] Nitrous oxide, commonly known as laughing gas, is an NMDA receptor antagonist used in many medical and dental applications, primarily for pain reduction during surgical procedures. Nitrous oxide is used as a rapid, effective analgesic gas with fast-acting effects. Nitrous oxide is also a dissociative inhalant known to induce increased feelings of euphoria, elevated pain threshold, and involuntary laughter. Furthermore, unlike ketamine, nitrous oxide is not addictive. For these reasons, the use of nitrous oxide as an NMDA receptor antagonist is preferred.

[0253] In some embodiments, the combination medication is 5-HT 2A This involves providing the receptor agonist and the NMDA receptor antagonist in a single dosage form for administration to the patient (e.g., each combined to provide a single aerosol inhaled by the patient, or each combined in a single transdermal patch delivered transdermally or subcutaneously to the patient). For example, if the NMDA receptor antagonist is nitrous oxide, then 5-HT2A The receptor agonist may be present in the liquid phase of the aerosol, while nitrous oxide may be present in the gas phase of the aerosol. Nitrous oxide (or a therapeutic gas mixture containing nitrous oxide) may be used to generate the aerosol or may be used as a carrier gas used to deliver the generated aerosol to the patient. When the generated aerosol is combined with the carrier gas, the carrier gas becomes part of the gas phase of the aerosol, i.e., the liquid phase of the aerosol is entrained / diluted by the carrier gas. In some embodiments, the combination drug therapy may be administered as a separate dosage form containing 5-HT 2A This involves providing a 5-HT receptor agonist and an NMDA receptor antagonist. 2A The 5-HT receptor agonist may be provided as an aerosol, preferably a mist, while the NMDA receptor antagonist is provided separately as a therapeutic gas mixture. 2A Receptor agonists may be provided as an injectable (e.g., intravenous), bolus, infusion, perfusion, etc., while NMDA receptor antagonists are provided as a therapeutic gas mixture for inhalation delivery.

[0254] 5-HT 2A The co-action of receptor agonists with NMDA receptor antagonists (e.g., nitrous oxide, ketamine, etc.) can provide multiple benefits. For example, NMDA receptor antagonists can control and / or reduce the activation effects of 5-HT2R, thereby reducing the risk of overstimulation and the occurrence of adverse psychotic effects such as acute hallucinatory crises. Furthermore, the administration of NMDA receptor antagonists can reduce the 5-HT 2A This may allow for the use of reduced therapeutic doses of 5-HT receptor agonists, thereby reducing the likelihood of negative patient experiences or dose-dependent side effects. 2AAdministration of a receptor agonist may reduce the amount of NMDA receptor antagonist required for therapeutic effect, which may reduce certain side effects, such as induced involuntary laughter and the associated general feeling of anxiety, in the case of NMDA receptor antagonists such as nitrous oxide. Therefore, co-administration is thought to reduce the possibility of negative experiences from hallucinogen administration, either by administering less hallucinogen or by allowing the NMDA receptor antagonist (e.g., nitrous oxide, ketamine, etc.) to function more efficiently. Similarly, such co-administration reduces the time or amount of NMDA receptor antagonist (e.g., nitrous oxide, ketamine, etc.) required for therapeutic effect.

[0255] NMDA receptor antagonists (e.g., nitrous oxide) and 5-HT 2A Receptor agonists act through different pharmacological pathways. However, both pathways appear to ultimately converge on a cascade at mTOR (the mammalian target of rapamycin, or mechanistic target of rapamycin). Thus, NMDA receptor antagonists and 5-HT 2A There appears to be a common mechanism of action between mTOR and 5-HT receptor agonists. Specifically, the mTOR signaling pathway is involved in the upregulation of 5-HT 2A It can be regulated by receptor activation and NMDA antagonism.Without being bound by theory, this regulation of mTOR pathway can support the immediate and long-term therapeutic and synergistic benefits of the combined administration of both drugs.Therefore, in some embodiments, the administration of both drugs at hallucinogenic or subhallucinogenic doses allows therapeutic effectiveness with no or minimal psychotoxicity.

[0256] Furthermore, neuronal atrophy in the prefrontal cortex (PFC) has been found to play a key role in the pathophysiology of depression and related disorders. It is hypothesized that the ability to promote both structural and functional plasticity in the PFC underlies not only the rapid-acting antidepressant properties of the dissociative anesthetic ketamine, but also its long-lasting effects after a single administration. Without being bound by theory, it is believed that the combination drug therapies disclosed herein function by synergistically increasing neuritogenesis and spinogenesis, including increased dendritic spine density, thereby providing or contributing to long-term therapeutic benefits.

[0257] 5-HT administered in combination drug therapy 2A The ratio of 5-HT receptor agonist to NMDA receptor antagonist may vary depending on the patient (i.e., subject), the active ingredient selection of the combination, the dosage form, and the particular disease or condition being treated. The specific ratio of the combination for any particular patient may vary depending on the 5-HT 2A It should be understood that the activity of the specific compounds used for the receptor agonist and NMDA receptor antagonist will depend on various factors, such as the age, sex, and general health of the patient, the time of administration, the rate of excretion, and the severity of the specific disease or condition being treated. In some embodiments, the 5-HT 2A The weight ratio of receptor agonist to NMDA receptor antagonist can range from about 1:100 to about 100:1, or any range therebetween, such as from about 1:75, from about 1:50, from about 1:40, from about 1:30, from about 1:20, from about 1:10, from about 1:8, from about 1:6, from about 1:5, from about 1:4, from about 1:3, from about 1:2, from about 2:3, from about 1:1, and up to about 100:1, up to about 75:1, up to about 50:1, up to about 40:1, up to about 30:1, up to about 20:1, up to about 10:1, up to about 8:1, up to about 6:1, up to about 5:1, up to about 4:1, up to about 3:1, or up to about 2:1. Ratios outside this range can also be used in certain circumstances.

[0258] Concomitant medications include 5-HT 2AIt is intended to include sequential administration of a 5-HT receptor agonist and an NMDA receptor antagonist (e.g., nitrous oxide), i.e., each active ingredient is administered at a different time, as well as simultaneous administration of these active ingredients, or at least two of the active ingredients. Simultaneous administration can be achieved, for example, by administering to the subject a single dosage form with a fixed ratio of each active ingredient, or multiple single dosage forms for each active ingredient. 2A Administration of the 5-HT receptor agonist and the NMDA receptor antagonist (e.g., nitrous oxide), whether in a single dosage form or separate dosage forms, can be carried out by any of the routes of administration described herein. 2A Both the 5-HT receptor agonist and the NMDA receptor antagonist are administered via inhalation, preferably in aerosol (e.g., mist) form. 2A The 5-HT receptor agonist is administered intravenously (IV) and the NMDA receptor antagonist is administered via inhalation. 2A Both the receptor agonist and the NMDA receptor antagonist are administered transdermally or subcutaneously. Compositions for inhalation, including pharmaceutically acceptable excipients for single or separate dosage forms, are described herein.

[0259] The present disclosure provides a method for treating rheumatoid arthritis using 5-HT agonists disclosed herein in combination with any one or more of the NMDA receptor antagonists disclosed herein. 2AThe present invention provides a combination drug therapy utilizing any one or more of the receptor agonists. Examples of combination drug therapies include, but are not limited to, a compound of formula (I) and nitrous oxide, a compound of formula (II) and nitrous oxide, a compound of formula (II-a) and nitrous oxide, a compound of formula (II-b) and nitrous oxide, a compound of formula (II-c) and nitrous oxide, a compound of formula (II-d) and nitrous oxide, a compound of formula (III) and nitrous oxide, a compound of formula (III-a) and nitrous oxide, a compound of formula (IV) and nitrous oxide, a compound of formula (IV-a) and nitrous oxide, a compound of formula (IV-b) and nitrous oxide, a compound of formula (V) and nitrous oxide, a compound of formula (Va) and nitrous oxide, a compound of formula (Vb) and nitrous oxide, a compound of formula (VI ... Compounds of formula (VI-a) and nitrous oxide, compounds of formula (VI-b) and nitrous oxide, compounds of formula (I) and ketamine, compounds of formula (II) and ketamine, compounds of formula (II-a) and ketamine, compounds of formula (II-b) and ketamine, compounds of formula (II-c) and ketamine, compounds of formula (II-d) and ketamine, compounds of formula (III) and ketamine, compounds of formula (III-a) and ketamine, compounds of formula (IV) and ketamine, compounds of formula (IV-a) and ketamine, compounds of formula (IV-b) and ketamine, compounds of formula (V) and ketamine, compounds of formula (Va) and ketamine, compounds of formula (Vb) and ketamine, compounds of formula (VI) and ketamine, compounds of formula (VI-a) and ketamine, compounds of formula (VI-b) and ketamine.

[0260] Specific examples of combination drug therapies include, but are not limited to, psilocybin and nitrous oxide, psilocin and nitrous oxide, N,N-dimethyltryptamine (DMT) and nitrous oxide, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and nitrous oxide, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d), including pharmaceutically acceptable salts, stereoisomers, or solvates of any compound in the combination.10 ) and nitrous oxide, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ) and nitrous oxide, psilocybin and ketamine, psilocin and ketamine, N,N-dimethyltryptamine (DMT) and ketamine, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and ketamine, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ) and ketamine, and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ) and ketamine.

[0261] In the combination drug therapy disclosed herein, 5-HT 2A The 5-HT receptor agonist and NMDA receptor antagonist may be combined in a single molecule. 2A The receptor agonist and the NMDA receptor antagonist are combined via at least one linking agent. During treatment with such a single molecule, the 5-HT 2A The receptor agonist portion is 5-HT 2A Either the receptor binds, or the NMDA receptor antagonist portion of the molecule binds to the NMDA receptor, or both bind, resulting in therapy.

[0262] In some embodiments, 5-HT 2A The receptor agonist and the NMDA receptor antagonist are combined as a pharmaceutically acceptable prodrug. As used herein, "pharmaceutically acceptable prodrug" refers to a compound that is metabolized, for example, hydrolyzed or oxidized, in the host to form the combination drug therapy of the present disclosure. Typical examples of prodrugs include active compounds (e.g., 5-HT 2AProdrugs include compounds that have biologically labile protecting groups on the functional moiety of the 5-HT receptor (e.g., NMDA receptor agonists and NMDA receptor antagonists). Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. An example of a prodrug is, but is not limited to, a 5-HT agonist bond combined with a 5-HT agonist via a chemical bond such as an ester, phosphate, amide, carbamate, or urea. 2A The compound or formulation may contain a receptor agonist and an NMDA receptor antagonist.

[0263] Pharmaceutical Composition Also disclosed herein are pharmaceutical compositions for use in combination drug therapy. The pharmaceutical compositions comprise 5-HT 2A A single dosage form may contain both a 5-HT receptor agonist and an NMDA receptor antagonist, or 2A The receptor agonist and the NMDA receptor antagonist may be provided in separate pharmaceutical compositions, which are typically also formulated with a pharmaceutically acceptable excipient.

[0264] A "pharmaceutical composition" refers to a mixture of an active ingredient and other chemical components, such as pharmaceutically acceptable excipients. One purpose of the composition is to facilitate administration of the active ingredient disclosed herein in any of its embodiments to a subject in need of concomitant drug therapy. In some embodiments, 5-HT 2A The receptor agonist and / or NMDA receptor antagonist is the only active ingredient present in the pharmaceutical composition.

[0265] As used herein, the term "active ingredient" refers to an ingredient in a pharmaceutical composition that is biologically active, e.g., 5-HT 2A 5-HT refers to one or more of the compounds described above as receptor agonists, one or more of the compounds described above as NMDA receptor antagonists, and any mixtures thereof. 2AThe receptor agonists and NMDA receptor antagonists can be administered by themselves or as a pharmaceutical composition containing the active ingredient in combination with a pharmaceutically acceptable excipient. The pharmaceutical composition can comprise at least 0.0001% by weight, at least 0.001% by weight, at least 0.01% by weight, at least 0.05% by weight, at least 0.1% by weight, at least 0.5% by weight, at least 5% by weight, at least 10% by weight, at least 15% by weight, at least 20% by weight, at least 25% by weight, at least 30% by weight, at least 35% by weight, at least 40% by weight, at least 45% by weight, at least 50% by weight, at least 55% by weight, at least 60% by weight, at least 65% by weight, at least 70% by weight, at least 75% by weight, at least 80% by weight, at least 85% by weight, at least 90% by weight, at least 95% by weight, at least 99% by weight, or at least 99.9% by weight of the 5-HT disclosed herein, based on the total weight of the pharmaceutical composition. 2A receptor agonists and / or NMDA receptor antagonists.

[0266] 5-HT in unit dose preparations 2A The amount of receptor agonist and / or NMDA receptor antagonist may be, for example, (on an activity basis) from 0.001 mg, from 0.01 mg, from 0.1 mg, from 1 mg, from 3 mg, from 5 mg, from 10 mg, from 15 mg, from 20 mg, from 25 mg, and up to 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg of 5-HT. 2A The compositions may be modified or adjusted to provide a receptor agonist and / or NMDA receptor antagonist, or as deemed appropriate using sound medical judgment, depending on the particular use, route of administration, dosage form, and potency of the active ingredient. The compositions may also contain other compatible active ingredients, if desired.

[0267] The pharmaceutical composition comprises deuterated 5-HT 2AIn embodiments formulated with a receptor agonist, e.g., a compound of Formula (I), Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (III), Formula (III-a), Formula (IV), Formula (IV-a), Formula (IV-b), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VI-a), or Formula (VI-b), which includes at least one deuterium atom, the pharmaceutical composition may include a single isotopologue or a mixture of isotopologues of the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the subject compound of Formula (I), Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (III), Formula (III-a), Formula (IV), Formula (IV-a), Formula (IV-b), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VI-a), or Formula (VI-b) is present in the pharmaceutical composition. The compound of formula (III), (III-a), (IV), (IV-a), (IV-b), (V), (Va), (Vb), (VI), (VI-a), or (VI-b) may be present in the pharmaceutical composition with a purity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight, based on the total weight of the isotopologues of the compound of formula (III), (III-a), (IV), (IV-a), (IV-b), (V), (Va), (Vb), (VI), (VI-a), or (VI-b). For example, when the compound of interest is DMT-d 10 Pharmaceutical compositions formulated with may additionally contain isotopologues of the subject compounds, e.g., DMT-d9, DMT-d8, etc., as free base or salt forms, stereoisomers, solvates, or mixtures thereof. In some embodiments, the compositions are substantially free of other isotopologues of the compounds in either free base or salt form, e.g., the compositions have less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or 0.5 mole percent of other isotopologues of the compounds.

[0268] In some embodiments, any position in the compound having deuterium has a minimum deuterium incorporation of at least 10 atomic %, at least 20 atomic %, at least 25 atomic %, at least 30 atomic %, at least 40 atomic %, at least 45 atomic %, at least 50 atomic %, at least 60 atomic %, at least 70 atomic %, at least 80 atomic %, at least 90 atomic %, at least 95 atomic %, at least 99 atomic % at the deuteration site.

[0269] 5-HT 2A Receptor agonists, and similarly NMDA receptor antagonists, can be present in pharmaceutical compositions in enantiomerically pure form or as a racemic mixture. As described herein, a racemic active ingredient may contain about 50% of the R- and S-stereoisomers based on a molar ratio of one of the isomers (about 48 to about 52 mole %, or about a 1:1 ratio). In some embodiments, a pharmaceutical composition may be formed by combining separately produced R- and S-stereoisomers of a compound in an approximately equal molar ratio (e.g., about 48 to 52%). In some embodiments, a pharmaceutical composition may contain a mixture of separate R- and S-stereoisomers of a compound in different ratios. In some embodiments, a pharmaceutical composition contains an excess (greater than 50%) of the R-enantiomer. Suitable R / S molar ratios may be about 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or higher. In some embodiments, the pharmaceutical composition can contain an excess of S-enantiomer, reversing the provided ratio of R / S. Other suitable amounts of R / S can also be selected. For example, the R-enantiomer can be enriched, e.g., at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. In some embodiments, the S-enantiomer can be enriched, e.g., at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. Ratios between all of these exemplary embodiments, as well as larger and smaller ratios, remain within the scope of the present disclosure.

[0270] 5-HT 2A The 5-HT receptor agonist and the NMDA receptor antagonist may be combined in a single pharmaceutical composition. 2A Both the 5-HT receptor agonist and the NMDA receptor antagonist (e.g., nitrous oxide) are administered together in a single pharmaceutical composition suitable for inhalation, preferably in aerosol (e.g., mist) form. 2A Both the receptor agonist and the NMDA receptor antagonist (eg, ketamine) are administered together in a single pharmaceutical composition adapted for transdermal or subcutaneous administration, eg, a transdermal patch.

[0271] In some embodiments, 5-HT 2A The 5-HT receptor agonist and the NMDA receptor antagonist are administered as separate pharmaceutical compositions. 2A The 5-HT receptor agonist may be formulated with a first pharmaceutically acceptable excipient to form a first pharmaceutical composition, and the NMDA receptor antagonist may be formulated with a second pharmaceutically acceptable excipient to form a second pharmaceutical composition. 2A The first composition comprising a 5-HT receptor agonist and the second composition comprising an NMDA receptor antagonist may be administered simultaneously or sequentially. 2A Receptor agonists (e.g., DMT, 5-MeO-DMT, DMT-d 10 , 5-MeO-DMT-d 10 A first pharmaceutical composition containing an NMDA receptor antagonist (e.g., nitrous oxide) is adapted for parenteral delivery, such as intravenous administration, and a second pharmaceutical composition containing an NMDA receptor antagonist (e.g., nitrous oxide) is adapted for inhalation administration, such as a therapeutic gas mixture.

[0272] In some embodiments, 5-HT 2A The 5-HT receptor agonist and the NMDA receptor antagonist are formulated separately but are combined into a single pharmaceutical composition immediately prior to administration. 2AThe 5-HT receptor agonist may be formulated as a solution, while the NMDA receptor antagonist (e.g., nitrous oxide) may be formulated in a therapeutic gas mixture. 2A An aerosol, preferably a mist, containing droplets of the receptor agonist may be generated, and the droplets are dispersed in the vapor phase of a therapeutic gas mixture containing the NMDA receptor antagonist. 2A An aerosol combining both a 5-HT receptor agonist and an NMDA receptor antagonist may be administered to a patient via inhalation. 2A The 5-HT receptor agonist may be formulated as a solution, while the NMDA receptor antagonist (e.g., nitrous oxide) may be formulated in a therapeutic gas mixture. 2A An aerosol, preferably a mist, containing droplets of the receptor agonist may be generated, and the droplets dispersed in a gas phase, such as a heated heliox mixture. The 5-HT receptor agonist dispersed in the gas phase of the heated heliox mixture is then 2A An aerosol containing the receptor agonist may be administered to a patient via inhalation in combination with a therapeutic gas mixture containing an NMDA receptor antagonist.

[0273] A "pharmaceutically acceptable excipient" can be an excipient approved by a federal or state government regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in mammals, such as humans. As used herein, the term "excipient" refers to the 5-HT 2000 compound of the present disclosure. 2AThe term "excipient" refers to a vehicle, diluent, adjuvant, carrier, or any other auxiliary or supporting ingredient in which a receptor agonist and / or an NMDA receptor antagonist is formulated for administration to a mammal. Such pharmaceutical excipients may be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Pharmaceutical excipients may include water, saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Pharmaceutical excipients may include one or more gases, for example, to act as carriers for administration via inhalation. Additionally, adjuvants, stabilizers, thickeners, lubricants, taste-masking agents, colorants, and other pharmaceutical additives may be included in the disclosed compositions, such as those specified herein below. In some embodiments, the pharmaceutically acceptable excipient is a carrier useful for administration via inhalation. In some embodiments, the pharmaceutically acceptable excipient is an aerosol carrier, as described in more detail below. In some embodiments, the pharmaceutically acceptable excipient is useful for parenteral administration, such as via intravenous administration. In some embodiments, the pharmaceutically acceptable excipient is useful for transdermal or subcutaneous administration.

[0274] In some embodiments, the pharmaceutical composition contains 0.1 to 99.9999 wt%, preferably 1 to 99.999 wt%, preferably 5 to 99.99 wt%, preferably 10 to 99.9 wt%, preferably 15 to 99 wt%, preferably 20 to 90 wt%, preferably 30 to 85 wt%, preferably 40 to 80 wt%, preferably 50 to 75 wt%, preferably 60 to 70 wt% of a pharmaceutically acceptable excipient, based on the total weight of the pharmaceutical composition.

[0275] Pharmaceutical compositions can be in the form of capsules, tablets, pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions, suspensions, emulsions, suppositories, or sustained-release formulations thereof, or any other form suitable for administration to mammals. In some cases, pharmaceutical compositions are formulated for administration according to routine procedures as pharmaceutical compositions adapted for oral or intravenous administration to humans. Examples of suitable pharmaceutical excipients and their formulation methods are described in Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, Chapters 86, 87, 88, 91, and 92, which are incorporated herein by reference. The selection of excipients is determined in part by the specific active ingredient and the specific method used to administer the composition. Thus, there are a wide variety of suitable formulations of pharmaceutical compositions. Liquid form preparations include solutions and emulsions, for example, water, water / propylene glycol solution or organic solvent.When administered to mammals, the compounds and compositions of the present disclosure and pharmaceutically acceptable excipients can be sterilized.In some cases, for example, when the subject compound is administered intravenously or via inhalation, aqueous media such as water, saline, and aqueous dextrose and glycerol solution are used as vehicles.

[0276] As described below, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid, semi-solid, or liquid form, including those compatible with the following: A. Oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, films, or capsules, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue; B. Parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; C. Topical / transdermal administration, e.g., creams, ointments, or controlled-release patches or sprays applied to the skin, or to orifices and / or mucosal surfaces such as in the vagina or rectum, e.g., pessaries, creams, or foams; D. Modified-release dosage forms, such as delayed-, extended-, prolonged-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-, etc., modified-release dosage forms and gastroretentive dosage forms, can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126); and E. Inhalation administration, eg, aerosol, preferably mists.

[0277] Tamper-resistant dosage forms / packaging of any of the disclosed pharmaceutical compositions are contemplated.

[0278] A. Oral Administration The pharmaceutical compositions disclosed herein may be provided in solid, semisolid, or liquid dosage forms for oral administration, including both enteral / gastric delivery routes and oral routes such as buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, preservatives, antioxidants, lyoprotectants, stabilizers, solubilizers, complexing agents, and flavoring agents.

[0279] Binders or granulating agents impart cohesiveness to the tablet and ensure that it remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isagol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), veegum, larch arabogalactan (larch). arabogalactan), powdered tragacanth, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC); microcrystalline celluloses such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixtures thereof.

[0280] Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions disclosed herein from about 50 to about 99% by weight.

[0281] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.When present in sufficient amounts, certain diluents such as mannitol, lactose, sorbitol, sucrose, and inositol can impart the properties of some compressed tablets that can be disintegrated in the mouth by chewing.Such compressed tablets can be used as chewable tablets.

[0282] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV, citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; alain; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions disclosed herein varies depending on the type of formulation and is readily discernible by those skilled in the art. The pharmaceutical compositions disclosed herein may contain, for example, about 0.5 to about 15% by weight, or about 1 to about 5% by weight, of disintegrant.

[0283] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as glycerol behenate and polyethylene glycol (PEG), stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil, zinc stearate, ethyl oleate, ethyl laurate, agar, starch, lycopodium, silica, or silica gel, such as AEROSIL® 200 (WR Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co., Boston, Mass.), and mixtures thereof. The pharmaceutical compositions disclosed herein may contain, for example, about 0.1 to about 5% by weight of a lubricant.

[0284] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, Mass.), and asbestos-free talc. Coloring agents include any of the approved, certified, water-soluble FD&C dyes and insoluble FD&C dyes suspended on alumina hydrate, as well as color lakes and mixtures thereof. Color lakes are combinations of water-soluble dyes by adsorption onto hydrous heavy metal oxides, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste, such as peppermint and salicylic acid. Sweetening agents include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0285] It is understood that many excipients can serve multiple functions, even within the same formulation.

[0286] The pharmaceutical compositions disclosed herein may be formulated as compressed tablets, tablet crushers, chewable lozenges, rapid-dissolve tablets, multiple-compressed tablets, or enteric-coated, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredients from the acidic stomach environment. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by multiple compression cycles and include layered tablets, press coated or dry coated tablets.

[0287] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more excipients described herein, including binders, disintegrants, release-controlling polymers, lubricants, diluents, and / or coloring agents. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0288] The pharmaceutical compositions disclosed herein can be formulated as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two compartments, one sliding over the other to completely enclose the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including methylparaben, propylparaben, and sorbic acid. The liquid, semisolid, and solid dosage forms disclosed herein may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. The capsules may also be coated as known by those skilled in the art to modify or maintain dissolution of the active ingredient.

[0289] In some embodiments, the pharmaceutical compositions of the present disclosure may be orodispersible dosage forms (ODx), including orodispersible tablets (ODTs) (sometimes also referred to as rapid disintegrating tablets, orally disintegrating tablets, or rapidly dispersing tablets), or orodispersible films (ODFs) (or wafers). Such dosage forms, for example, when administered intramuscularly / transmucosally through the mucosal lining of the oral cavity, e.g., buccal, lingual, and sublingual, provide increased bioavailability, more rapid onset, and allow pregastric absorption of the active ingredient compared to oral administration via the gastrointestinal tract.

[0290] Orally disintegrating tablets can be prepared by various techniques, such as freeze-drying (lyophilization), molding, spray-drying, bulk extrusion, or compression. Preferably, orally disintegrating tablets are prepared by freeze-drying. In some embodiments, an orally disintegrating tablet refers to a form that disintegrates in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being placed in the oral cavity. In some embodiments, an orally disintegrating tablet refers to a form that dissolves in less than about 90 seconds, less than about 60 seconds, or less than about 30 seconds after being placed in the oral cavity. In some embodiments, an orally disintegrating tablet refers to a form that disperses in less than about 90 seconds, less than about 60 seconds, less than about 30 seconds, less than about 20 seconds, less than about 10 seconds, less than about 5 seconds, or less than about 2 seconds after being placed in the oral cavity. In some embodiments, the pharmaceutical composition has a disintegration test of about 30 seconds or less, about 20 seconds or less, about 10 seconds or less, about 5 seconds or less, or about 2 seconds or less in the United States Pharmacopeia (USP). <701> The disintegration time is in the form of an orodispersible dosage form such as an orally disintegrating tablet (ODT) that conforms to the United States Pharmacopeia (USP) Disintegration Test. <701> Accordingly, orodispersible dosage forms having longer disintegration times are also contemplated, such as when adapted for sustained release of, for example, 30 minutes or less, 20 minutes or less, 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, or the like.

[0291] In some embodiments, the pharmaceutical composition is in the form of a lyophilized orodispersible dosage form, such as a lyophilized ODT. In some embodiments, the lyophilized orodispersible dosage form (e.g., a lyophilized ODT) is prepared by sublimating water from a pre-frozen aqueous formulation of the drug containing a matrix-forming agent and other excipients as described herein, such as one or more lyoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc., to create a porous matrix. In some embodiments, the orodispersible dosage form comprises a two-component framework of a lyophilized matrix system that cooperates to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer such as gelatin, dextran, alginate, and maltodextrin. This component maintains shape and provides mechanical strength to the dosage form (binder). In some embodiments, the second component is a matrix support / disintegration promoter, such as sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and / or starch, which acts by adhering the porous framework provided by the water-soluble polymer and promotes disintegration of the orodispersible dosage form. In some embodiments, the freeze-dried orodispersible dosage form (e.g., freeze-dried ODT) comprises gelatin and mannitol. In some embodiments, the freeze-dried orodispersible dosage form (e.g., freeze-dried ODT) comprises gelatin, mannitol, and one or more of a cryoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, etc., with particular reference to citric acid. A non-limiting example of an ODT formulation is Zydis® orally dispersible tablets (available from Catalent). In some embodiments, the ODT formulation (e.g., Zydis® orally dispersible tablets) comprises one or more water-soluble polymers, such as gelatin, one or more matrix materials, fillers, or diluents, such as mannitol, an active ingredient, and optionally a cryoprotectant, preservative, antioxidant, stabilizer, solubilizer, and / or flavoring agent. In some embodiments, the ODT formulation (e.g., Zydis® orally dispersible tablets) comprises gelatin, mannitol, an active ingredient, and citric acid and / or tartaric acid.

[0292] In some embodiments, the pharmaceutical composition is in the form of a freeze-dried orodispersible film (ODF) (or wafer). In some embodiments, the pharmaceutical composition is in the form of a freeze-dried ODF protected for long-term storage by special packaging that excludes moisture, oxygen, and light. In some embodiments, the freeze-dried ODF is prepared by creating a porous matrix by sublimating water from a pre-frozen aqueous formulation of the drug containing a matrix-forming agent and other solvents as described herein, such as one or more cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, etc. In some embodiments, the freeze-dried ODF comprises a thin, water-soluble film matrix. In some embodiments, the ODF comprises a two-component framework of a freeze-dried matrix system that cooperates to ensure successful formulation development. In some embodiments, the first component is a water-soluble polymer such as gelatin, dextran, alginate, and maltodextrin. This component maintains shape and provides mechanical strength to the film / wafer (binder). In some embodiments, the second component is a matrix support / disintegration promoter, such as sucrose and mannitol, which acts by adhering the porous framework provided by the water-soluble polymer and promotes disintegration of the wafer. In some embodiments, the freeze-dried ODF includes gelatin and mannitol. In some embodiments, the freeze-dried ODF includes gelatin, mannitol, and one or more of a cryoprotectant, a preservative, an antioxidant, a stabilizer, a solubilizer, a flavoring agent, etc., with particular reference to citric acid.

[0293] In some embodiments, an ODF (or wafer) can comprise a single layer, a double layer, or a triple layer. In some embodiments, a single-layer ODF comprises an active ingredient and one or more pharmaceutically acceptable excipients. In some embodiments, a double-layer ODF comprises one or more excipients, such as a solubilizer, in a first layer and the active ingredient in a second layer. This configuration allows the active ingredient to be stored separately from the excipients, increasing the stability of the active ingredient and potentially increasing the shelf life of the composition compared to when the excipients and active ingredient are contained in a single layer. For triple-layer ODFs, each layer can be different, or two layers, such as the upper and lower layers, can have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing the active ingredient. In some embodiments, the lower and upper layers can comprise one or more excipients, such as a solubilizer. In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers can comprise different excipients or different amounts of the same excipients. The core layer typically contains an active ingredient and, optionally, one or more excipients.

[0294] In some embodiments, in addition to the active ingredient, the pharmaceutical composition in the orodispersible dosage form (ODx) may include one or more pharmaceutically acceptable excipients. For example, in some embodiments, the pharmaceutical composition in the orodispersible dosage form includes one or more of a pharmaceutically acceptable cryoprotectant, preservative, antioxidant, stabilizer, solubilizer, flavoring agent, etc.

[0295] Examples of pharmaceutically acceptable cryoprotectants include, but are not limited to, disaccharides such as sucrose and trehalose, anionic polymers such as sulfobutylether-β-cyclodextrin (SBECD) and hyaluronic acid, and hydroxylated cyclodextrins.

[0296] Examples of pharmaceutically acceptable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0297] Examples of pharmaceutically acceptable antioxidants that may serve to further enhance the stability of the compositions include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​or its salts (cysteine ​​hydrochloride), sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0298] Examples of pharmaceutically acceptable stabilizers include, but are not limited to, fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, glycerin, methionine, monothioglycerin, ascorbic acid, citric acid, polysorbates, arginine, cyclodextrin, microcrystalline cellulose, modified cellulose (e.g., carboxymethylcellulose, sodium salt), sorbitol, and cellulose gels.

[0299] Examples of pharmaceutically acceptable solubilizers (or solubilizing agents) include citric acid, hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyl 40 stearate, purified shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethylethylcellulose, powdered agar, guar gum, succinic acid, copolyvidone, cellulose acetate phthalate, tartaric acid, sodium dioctyl sulfosuccinate, zein, nonfat powdered milk, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethylmethylcellulose, cellulose acetate phthal ... Examples of suitable surfactants include, but are not limited to, cellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, poly(sodium 4-styrenesulfonate), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, lauromacrogol, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogen phosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone-vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyltryptophan, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate. Of these, citric acid is preferred in some embodiments, such as ODT formulations.

[0300] Flavoring agents include natural flavors extracted from plants such as fruit, and synthetic blends of compounds that produce a pleasant taste and taste-masking effect.Examples of flavoring agents include, but are not limited to, aspartame, saccharin (as sodium, potassium, or calcium saccharin), cyclamate (as sodium, potassium, or calcium salt), sucralose, acesulfame K, thaumatin, neohisperidin, dihydrochalcone, ammoniated glycyrrhizin, glucose, maltodextrin, fructose, levulose, sucrose, glucose, wild orange peel, citric acid, tartaric acid, wintergreen oil, peppermint oil, methyl salicylate, spearmint oil, sassafras oil, clove oil, cinnamon, anethole, menthol, thymol, eugenol, eucalyptol, lemon, lime, and lemon lime.

[0301] Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin, or other solubilized derivatives, can also be advantageously used to enhance delivery of the compositions described herein.

[0302] Disclosed herein are pharmaceutical compositions in modified release dosage forms comprising an active ingredient disclosed herein and one or more controlled-release excipients or carriers described herein. Suitable controlled-release dosage excipients include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The pharmaceutical composition may also contain non-controlled-release excipients or carriers.

[0303] Further disclosed herein are enteric-coated pharmaceutical compositions comprising a compound disclosed herein and one or more controlled-release excipients or carriers for use in enteric-coated dosage forms. The pharmaceutical compositions may also include non-controlled-release excipients or carriers.

[0304] Further disclosed herein are effervescent dosage form pharmaceutical compositions comprising an active ingredient disclosed herein and one or more controlled-release excipients or carriers for use in effervescent dosage forms. The pharmaceutical compositions may also include non-controlled-release excipients or carriers.

[0305] Further disclosed are pharmaceutical compositions in dosage forms having an immediate release component and at least one delayed release component, capable of discontinuously releasing the active ingredient in at least two successive pulses separated by about 0.1 to up to about 24 hours (e.g., about 0.1, 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 10, 22, or 24 hours). 2A The compositions comprise a receptor agonist and / or an NMDA receptor antagonist and one or more controlled-release and non-controlled-release excipients or carriers, such as excipients or carriers suitable for disrupting semipermeable membranes and swelling materials.

[0306] Also disclosed herein are pharmaceutical compositions in dosage forms for oral administration to a subject, which contain the 5-HT 2A The composition comprises a receptor agonist and / or an NMDA receptor antagonist, and one or more pharmaceutically acceptable excipients encapsulated in an intermediate reactive layer comprising a gastric juice-resistant polymer layer material that is partially neutralized with alkali and has cation exchange capacity, and a gastric juice-resistant outer layer.

[0307] In some embodiments, the pharmaceutical composition is in the form of an immediate release capsule for oral administration and may further comprise cellulose, iron oxide, lactose, magnesium stearate, and sodium starch glycolate.

[0308] In some embodiments, the pharmaceutical composition is in the form of a delayed-release capsule for oral administration and may further comprise cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

[0309] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed-release tablet for oral administration and may further comprise carnauba wax, crospovidone, diacetylated monoglyceride, ethyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

[0310] In some embodiments, the pharmaceutical composition is in the form of an enteric coated delayed-release tablet for oral administration and may further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0311] The pharmaceutical compositions disclosed herein can be formulated as liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems, in which one liquid is dispersed in the form of small globules throughout another liquid, and can be oil-in-water or water-in-oil. Emulsions can contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions can contain a pharmaceutically acceptable suspending agent and optional preservative. Aqueous alcoholic solutions can contain a pharmaceutically acceptable di(lower alkyl)acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having 1 to 6 carbon atoms), e.g., acetaldehyde diethyl acetal, and a water-miscible solvent containing one or more hydroxyl groups, e.g., propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may contain a preservative. For a liquid dosage form, the solution, for example, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.

[0312] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients disclosed herein and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, and polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weights of the polyethylene glycol. These formulations may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates. In some embodiments, examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0313] Cyclodextrins, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin, or other solubilized derivatives, can also be advantageously used to enhance delivery of the compositions described herein.

[0314] The pharmaceutical compositions disclosed herein for oral administration may also be disclosed in the form of liposomes, micelles, microspheres, or nanosystems.

[0315] The pharmaceutical compositions disclosed herein can be disclosed as non-effervescent or effervescent granules and powders that can be reconstituted into liquid dosage forms. Pharmaceutically acceptable excipients used in non-effervescent granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable excipients used in effervescent granules or powders can include organic acids and carbon dioxide sources.

[0316] Coloring and flavoring agents may be used in all of the above dosage forms.

[0317] The pharmaceutical compositions disclosed herein can be co-formulated with other active ingredients that do not impair the desired therapeutic action, or with substances that supplement the desired action.

[0318] B. Parenteral Administration The pharmaceutical compositions disclosed herein can be administered parenterally by injection, infusion, perfusion, or implantation for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0319] The pharmaceutical compositions disclosed herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, supra).

[0320] Pharmaceutical compositions intended for parenteral administration may contain one or more pharmaceutically acceptable excipients including, but not limited to, aqueous solvents, water-miscible solvents, non-aqueous solvents, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0321] Suitable aqueous solvents include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous solvents include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, coconut oil, and medium-chain triglycerides of palm seed oil. Water-miscible solvents include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0322] Suitable antimicrobial or preservative agents include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propylparaben, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citric acid. Suitable antioxidants include those described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including ca-cyclodextrin, β-cyclodextrin, hydroxypropyl-3-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

[0323] The pharmaceutical compositions disclosed herein can be formulated for single or multiple dose administration.Single dose preparations are packaged in ampoules, vials or syringes.Multiple dose parenteral preparations contain antimicrobial agents at bacteriostatic or fungistatic concentrations.All parenteral preparations must be sterile, as is known and practiced in the art.

[0324] In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile solutions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry soluble products, including lyophilized powders and hypodermic tablets, which are reconstituted with a solvent before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile suspensions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry insoluble products, which are reconstituted with a solvent before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile emulsions.

[0325] The pharmaceutical composition can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot. In some embodiments, the pharmaceutical compositions disclosed herein are dispersed in a solid internal matrix that is insoluble in body fluids but is surrounded by an outer polymeric membrane that allows the active ingredient in the pharmaceutical composition to diffuse through.

[0326] Suitable inner matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0327] Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene-propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate copolymers with vinyl chloride, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers, among others.

[0328] C. Topical Administration The pharmaceutical compositions disclosed herein can be administered topically to the skin, orifices, or mucous membranes. Topical administration as described herein includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, otic, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0329] The pharmaceutical compositions disclosed herein can be formulated in any dosage form suitable for topical administration for local or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, cleansers, sprays, suppositories, bandages, and skin patches.Topical formulations of the pharmaceutical compositions disclosed herein can contain active ingredients mixed under sterile conditions with pharmaceutically acceptable excipients, and with any preservatives, buffers, absorption enhancers, and propellants that may be required.Liposomes, micelles, microspheres, nanosystems, and mixtures thereof can also be used.

[0330] Pharmaceutically acceptable excipients suitable for use in the topical formulations disclosed herein include, but are not limited to, aqueous solvents, water-miscible solvents, non-aqueous solvents, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, cryoprotectants, thickening agents, and inert gases.

[0331] The ointments, pastes, creams, and gels may contain, in addition to the active ingredient, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0332] Powders and sprays can contain, in addition to the active ingredient, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0333] Transdermal delivery devices (e.g., patches) have the additional advantage of providing controlled delivery of the active ingredient into the body. 2A Receptor agonists and / or NMDA receptor antagonists can be administered via transdermal patches at steady-state concentrations, whereby the active ingredients are administered gradually over time, avoiding the associated drug spikes and adverse events / toxicity.

[0334] The transdermal patch dosage forms herein may be formulated with varying amounts of active ingredient depending on the disease / condition being treated, the active ingredient used, the permeability and size of the transdermal delivery device, the release period, etc. For example, 5-HT 2A When formulated with a 5-HT receptor agonist, the unit dose preparation may be varied or adjusted from, for example, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, or otherwise tailored to the particular use and 5-HT 2AAccording to the efficacy of receptor agonist, it can be deemed appropriate by using sound medical judgment.In another example, when formulated with NMDA receptor antagonist, unit dose preparation can be changed or adjusted from, for example, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 5,000mg, 4,000mg, 3,000mg, 2,000mg, 1,000mg, 900mg, 800mg, 700mg, 600mg, 500mg, 400mg, 300mg, 200mg, or otherwise according to specific use and the efficacy of NMDA receptor antagonist, it can be deemed appropriate by using sound medical judgment.

[0335] Disclosed 5-HT 2A Transdermal patches formulated with 5-HT receptor agonists and / or NMDA receptor antagonists may be suitable for microdosing to achieve sustained therapeutic benefit with reduced toxicity. 2A The receptor agonist and / or NMDA receptor antagonist may be administered via a transdermal patch at sub-psychoactive concentrations, although the receptor agonist and / or NMDA receptor antagonist is serotonergic, for an extended period of time, such as, for example, an 8, 24, 48, 72, 84, 96, or 168 hour period.

[0336] Active ingredients (e.g., 5-HT 2A In addition to the NMDA receptor agonist and / or NMDA receptor antagonist) and optionally any pharmaceutically acceptable excipients, the transdermal patch may also include one or more of a pressure-sensitive adhesive layer, a backing, and a release liner, as known to those skilled in the art.

[0337] Transdermal patch dosage form is 5-HT 2A In some embodiments, the 5-HT agonist and / or NMDA receptor antagonist of the present disclosure may be prepared by dissolving or dispersing the 5-HT agonist and / or NMDA receptor antagonist in an appropriate medium. 2AThe receptor agonist and / or NMDA receptor antagonist may be directly dissolved / dispersed in the polymer matrix forming the pressure-sensitive adhesive layer. Such a transdermal patch is called a drug-in-adhesive (DIA) patch. A preferred DIA patch configuration is one in which the active ingredient is uniformly distributed throughout the pressure-sensitive adhesive polymer matrix. In some embodiments, the active ingredient may be provided in a layer containing the active ingredient and the polymer matrix, separate from the pressure-sensitive adhesive layer. In either case, the 5-HT 2A The receptor agonist and / or NMDA receptor antagonist may optionally be formulated with suitable excipients, such as carriers, permeation / absorption enhancers, moisturizers, and the like, to increase flux across the skin.

[0338] Examples of carrier agents include C8-C12 fatty acids such as oleic acid, undecanoic acid, valeric acid, heptanoic acid, pelargonic acid, capric acid, lauric acid, and eicosapentaenoic acid. 22 C8-C fatty acids, such as octanol, nonanol, oleyl alcohol, decyl alcohol, and lauryl alcohol 22 C8-C fatty alcohols such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate 22 Lower alkyl esters of fatty acids, C6-C such as diisopropyl adipate 22 C8-C di(lower) alkyl esters of diacids, such as glyceryl monolaurate 22These include, but are not limited to, monoglycerides of fatty acids, tetrahydrofuryl alcohol polyethylene glycol ethers, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monomethyl ether, alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethyl ether, polyethylene oxide dimethyl ether, glycerol, ethyl acetate, acetoacetate esters, N-alkylpyrrolidones, cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or derivatives such as 2-hydroxypropyl-β-cyclodextrin, as well as terpenes / terpenoids such as limonene, linalool, myrcene, pinenes such as α-pinene, caryophyllene, citral, eucoliptol, and mixtures thereof.

[0339] Examples of permeation agents / absorption enhancers include, but are not limited to, sulfoxides such as dodecyl methyl sulfoxide, octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxy-undecyl methyl sulfoxide, 2-hydroxydodecyl methyl sulfoxide; surfactant-lecithin organogel (PLO) formed from an aqueous phase having one or more of poloxamer, CARBOPOL, and PEMULEN, an oily phase formed from one or more of isopropyl palmitate and PPG-2 myristyl ether propionate, and lecithin; fatty acids, esters, and alcohols such as oleic acid and oleyl alcohol; keto acids such as levulinic acid; glycols and glycol ethers, for example, diethylene glycol monoethyl ether; including mixtures thereof.

[0340] Examples of humectants / crystallization inhibitors include, but are not limited to, polyvinylpyrrolidone-co-vinyl acetate, polymethacrylates, and mixtures thereof.

[0341] The pressure-sensitive adhesive layer may be formed from polymers including, but not limited to, acrylics (polyacrylates including alkyl acrylics), polyvinyl acetate, natural and synthetic rubbers (e.g., polyisobutylene), ethylene vinyl acetate copolymers, polysiloxanes, polyurethanes, plasticized polyether block amide copolymers, plasticized styrene butadiene rubber block copolymers, and mixtures thereof. The pressure-sensitive adhesive layer used in the transdermal patches of the present disclosure may be formed from an acrylic polymer pressure-sensitive adhesive, preferably an acrylic copolymer pressure-sensitive adhesive. Acrylic copolymer pressure-sensitive adhesives may be obtained by copolymerization of one or more alkyl (meth)acrylates (e.g., 2-ethylhexyl acrylate), aryl (meth)acrylates, arylalkyl (meth)acrylates, and (meth)acrylates with functional groups such as hydroxyalkyl (meth)acrylates (e.g., hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl methacrylate, and 4-hydroxybutyl methacrylate), carboxylic acid-containing (meth)acrylates (e.g., acrylic acid), and alkoxy (meth)acrylates (e.g., methoxyethyl acrylate), optionally with one or more copolymerizable monomers (e.g., vinylpyrrolidone, vinyl acetate, etc.). Specific examples of acrylic pressure-sensitive adhesives include DURO-TAK 87-900A, DURO-TAK Examples of suitable DURO-TAK products include, but are not limited to, DURO-TAK products (Henkel) such as DURO-TAK 87-9301, DURO-TAK 87-4098, DURO-TAK 87-2074, DURO-TAK 87-235A, DURO-TAK 87-2510, DURO-TAK 87-2287, DURO-TAK 87-4287, DURO-TAK 87-2516, DURO-TAK 387-2052, and DURO-TAK 87-2677.

[0342] The backing used in the transdermal patch of the present disclosure may include flexible backings such as films, nonwoven fabrics, Japanese paper, woven cotton fabrics, knitted fabrics, woven fabrics, and laminated composites of nonwoven fabrics and films. Such backings are preferably made of soft materials that can closely contact the skin and conform to its movements, and that can prevent skin rashes and other discomfort after prolonged use of the patch. Examples of backing materials include, but are not limited to, polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polystyrene, nylon, cotton, rayon acetate, rayon, rayon / polyethylene terephthalate composites, polyacrylonitrile, polyvinyl alcohol, acrylic polyurethane, ester polyurethane, ether polyurethane, styrene-isoprene-styrene copolymer, styrene-butadiene-styrene copolymer, styrene-ethylene-propylene-styrene copolymer, styrene-butadiene rubber, ethylene-vinyl acetate copolymer, or cellophane. Preferred backings do not adsorb or release the active ingredient. In order to prevent the adsorption and release of the active ingredient, improve the percutaneous absorption of the active ingredient, and prevent skin rashes and other discomfort, the backing preferably comprises one or more layers made of the above-mentioned materials and having water vapor permeability.Specific examples of the backing include, but are not limited to, 3M COTRAN products such as 3M COTRAN ethylene vinyl acetate membrane film 9702, 3M COTRAN ethylene vinyl acetate membrane film 9716, 3M COTRAN polyethylene membrane film 9720, and 3M COTRAN ethylene vinyl acetate membrane film 9728.

[0343] The release liner used in the transdermal patch of the present disclosure may include, but is not limited to, polyester film with one or both sides treated with a release coating, polyethylene-laminated high-quality paper treated with a release coating, and glass paper treated with a release coating. The release coating may be a fluoropolymer, silicone, fluorosilicone, or any other release coating known to those skilled in the art. The release liner may have an uneven surface to facilitate easy removal of the transdermal patch from the package. Examples of release liners include, but are not limited to, SCOTCHPAK products from 3M Company, such as 3M SCOTCHPAK 9744, 3M SCOTCHPAK 9755, 3M SCOTCHPAK 9709, and 3M SCOTCHPAK 1022.

[0344] Other layers may also be used, such as an abuse-deterrent layer formulated with one or more irritants (eg, sodium lauryl sulfate, poloxamer, sorbitan monoester, glyceryl monooleate, spices, etc.).

[0345] The methods disclosed herein using transdermal patch dosage forms provide systemic delivery of small amounts of active ingredient over a preferably extended period of time, for example, up to 168 hours, such as 2 to 96 hours, or 4 to 72 hours, or 8 to 24 hours, or 10 to 18 hours, or 12 to 14 hours. In particular, the 5-HT 2A In some embodiments, the 5-HT receptor agonist and / or NMDA receptor antagonist of the present disclosure can be delivered in small, stable, and consistent doses to avoid harmful or unwanted side effects. 2A Receptor agonists and / or NMDA receptor antagonists are administered transdermally at serotonergic but subpsychoactive concentrations.

[0346] Accordingly, a method for treating a disease or disorder associated with serotonin 5-HT2 receptors, such as a central nervous system (CNS) disorder, a psychological disorder, or a disease or disorder modulated by N-methyl-D-aspartate (NMDA) activity, including administering 5-HT via a transdermal patch. 2A Methods are provided herein that include administering a 5-HT receptor agonist and / or an NMDA receptor antagonist. 2A The receptor agonist and / or NMDA receptor antagonist can diffuse from the matrix of the transdermal patch (eg, from the pressure-sensitive adhesive layer), through the subject's skin, and into the subject's bloodstream.

[0347] An exemplary drug-in-adhesive (DIA) patch formulation contains 5-30% by weight of an NMDA receptor antagonist (e.g., ketamine), 5-30% by weight of 5-HT 2A Receptor agonists (e.g., DMT, DMT-d 10 and the like), 30-70 wt. % pressure-sensitive adhesive (e.g., DURO-TAK 387-2052, DURO-TAK 87-2677, and DURO-TAK 87-4098), 1-10 wt. % permeation / absorption enhancer (e.g., oleyl oleate, oleyl alcohol, levulinic acid, diethylene glycol monoethyl ether, and the like), and 5-25 wt. % crystallization inhibitor (e.g., polyvinylpyrrolidone acetate, polymethacrylate, and the like), each based on the total weight of the DIA patch formulation, although it should be understood that many variations are possible in light of the teachings herein.

[0348] The automatic injection device provides a method of delivering the compositions disclosed herein to a patient. The compositions disclosed herein may be administered to a patient using an automatic injection device via several known devices, a non-limiting list of which includes transdermal, subcutaneous, and intramuscular delivery.

[0349] In some transdermal, subcutaneous or intramuscular applications, the compositions disclosed herein are absorbed through the skin.Passive transdermal patch devices often include an absorption layer or membrane that is placed on the outer layer of the skin.The membrane typically contains a dose of a substance that is allowed to be absorbed through the skin to deliver the composition to the patient.Typically, only substances that are easily absorbed through the outer layer of the skin can be delivered by such transdermal patch devices.

[0350] Other automatic injection devices disclosed herein are configured to provide increased skin permeability to improve delivery of the disclosed compositions. Non-limiting examples of structures used to increase permeability to improve movement of the compositions into, across, or into the muscle include the use of one or more microneedles, which in some embodiments may be coated with the compositions disclosed herein. Alternatively, hollow microneedles may be used to provide a fluid channel for delivery of the disclosed compositions below the outer layer of the skin. Other devices disclosed herein include transdermal delivery via iontophoresis, sonophoresis, reverse iontophoresis, or a combination thereof, and other techniques known in the art for increasing skin permeability to facilitate drug delivery.

[0351] Pharmaceutical compositions can also be administered locally by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection, e.g., POWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, Oreg.).

[0352] The pharmaceutical compositions disclosed herein can be in the form of ointment, cream and gel.Suitable ointment excipients include, for example, oily or hydrocarbon solvents, including lard, benzoated lard, olive oil, cottonseed oil and other oils, white petrolatum; emulsifying or absorbing solvents, such as hydrophilic petrolatum, hydroxystearic sulfate and anhydrous lanolin; water-removing solvents, such as hydrophilic ointments; water-soluble ointment solvents, including polyethylene glycols of various molecular weights; emulsion solvents, including cetyl alcohol, glyceryl monostearate, lanolin, stearic acid, either water-in-oil (W / O) emulsion or oil-in-water (O / W) emulsion (see Remington: The Science and Practice of Pharmacy, supra).These solvents are emollients, but generally require the addition of antioxidants and preservatives.

[0353] Suitable cream bases can be oil-in-water or water-in-oil. Cream vehicles are water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal" phase, is generally composed of petrolatum and fatty acid alcohols such as cetyl or stearyl alcohol. The aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation can be a nonionic, anionic, cationic, or amphoteric surfactant.

[0354] Gels are semi-solid suspensions. Single-phase gels contain organic polymers dispersed substantially uniformly throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers, such as carbomer, carboxypolyalkylene, Carbopol®; hydrophilic polymers, such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose-based polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate, and gelatin. To prepare a uniform gel, dispersants such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, and / or stirring.

[0355] The pharmaceutical compositions disclosed herein may be administered rectally, urethrally, vaginally, or perivaginally in the form of a suppository, pessary, bougie, poultice or cataplasm, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, emulsion, tampon, gel, foam, spray, or enema. These dosage forms can be prepared using conventional processes as described in Remington: The Science and Practice of Pharmacy (supra).

[0356] Rectal, urethral, ​​and vaginal suppositories are solids for insertion into bodily orifices; they are solid at normal temperatures but melt or soften at body temperature, releasing the active ingredient into the orifice. Pharmaceutically acceptable excipients utilized in rectal and vaginal suppositories include bases, such as stiffening agents, that produce melting points near body temperature when formulated into the pharmaceutical compositions disclosed herein. Antioxidants described herein include bisulfite and sodium metabisulfite. Suitable excipients include cocoa butter (theobroma oil), glycerinated gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids; hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid, and glycerinated gelatin. Combinations of various excipients may be used, but are not limited to these. Rectal and vaginal suppositories may be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0357] The pharmaceutical compositions disclosed herein may be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solution, gels, intraocular inserts, and implants.

[0358] The pharmaceutical compositions disclosed herein can be administered intranasally. They can be in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, or atomizer, such as a nebulizer that uses electrohydrodynamics to generate a fine mist, or a nebulizer, either alone or in combination with a suitable propellant, such as a hydrofluoroalkane, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, 1,1,1,2-tetrafluoroethane (HFA 134A) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), carbon dioxide, a perfluorinated hydrocarbon, such as perflubron, or other suitable gas. Pharmaceutical compositions can be disclosed as dry powders for inhalation, alone or in combination with an inert carrier, such as lactose or phospholipids; and as nasal drops. For intranasal use, the powder can contain a bioadhesive agent, including chitosan or cyclodextrin.

[0359] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers can be formulated to contain ethanol, aqueous ethanol, or a suitable substitute for dispersing, solubilizing, or sustaining the release of the active ingredients disclosed herein, a propellant as a solvent; and / or a surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0360] The pharmaceutical compositions disclosed herein can be micronized to a size suitable for delivery, such as about 50 micrometers or less, or about 10 micrometers or less, etc. Particles of such sizes can be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0361] Capsules, blisters, and cartridges for use in inhalants or insufflators can be formulated to contain a powder mix of the pharmaceutical compositions disclosed herein; a suitable powder base such as lactose or starch; and a performance modifier such as l-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions disclosed herein for inhalation / intranasal administration can further contain a suitable flavoring agent, such as menthol and levomenthol, or a sweetener, such as saccharin or saccharin sodium.

[0362] The pharmaceutical compositions disclosed herein for topical administration may be formulated to be immediate or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.

[0363] D. Modified-Release Dosage Forms The pharmaceutical compositions disclosed herein can be formulated as modified release dosage forms.As used herein, the term "modified release" refers to a dosage form in which the release rate or release location of active ingredient is different from that of an immediate dosage form when administered by the same route.The pharmaceutical compositions of modified release dosage forms can be prepared using various modified release devices and methods known to those skilled in the art, including but not limited to matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof.The release rate of active ingredient can also be modified by changing the particle size and polymorphism of active ingredient.

[0364] As used herein, immediate release refers to the release of an active ingredient substantially upon administration. In some embodiments, immediate release occurs when there is dissolution of the active ingredient within 1 to 20 minutes after administration. Dissolution can be all or less than all (e.g., about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, 99.9%, or 99.99%) of the active ingredient. In some embodiments, immediate release results in complete or less than complete dissolution within about 1 hour after administration. Dissolution can occur in the stomach and / or intestines of a subject. In some embodiments, immediate release results in dissolution of the active ingredient within 1 to 20 minutes after entry into the stomach. For example, 100% dissolution of the active ingredient can occur within a given time period. In some embodiments, immediate release occurs upon inhalation, with dissolution occurring in the subject's lungs.

[0365] In some embodiments, the pharmaceutical composition has an onset of therapeutic action of 60, 50, 40, 30, 20, 10, or 5 minutes or less. In some embodiments, the pharmaceutical composition has a duration of acute effect of 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, or 5 minutes or less.

[0366] In some embodiments, the pharmaceutical compositions described herein are controlled-release compositions. In some embodiments, controlled-release results in dissolution of the active ingredient within 20 to 180 minutes after entry into the stomach. In some embodiments, controlled-release occurs when dissolution of the active ingredient occurs within 20 to 180 minutes after swallowing. In some embodiments, controlled-release occurs when dissolution of the active ingredient occurs within 20 to 180 minutes after entry into the intestine. In some embodiments, controlled-release results in substantially complete dissolution after 1 hour or more after administration; for example, the release period can be greater than about 4 hours, 8 hours, 12 hours, 16 hours, or 20 hours. In some embodiments, controlled-release results in substantially complete dissolution after 1 hour or more after oral administration.

[0367] 1. Matrix release control devices The pharmaceutical compositions disclosed herein in modified release dosage forms may be prepared using matrix release control devices known to those skilled in the art (see Takada et al. in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz ed., Wiley, 1999).

[0368] In some embodiments, the pharmaceutical compositions disclosed herein in modified release dosage forms are formulated using dissolving matrix devices that are water-swellable, erodible, or soluble polymers, including synthetic polymers, natural polymers and derivatives, e.g., polysaccharides and proteins.

[0369] Materials useful for forming a dissolving matrix include chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phospholipids, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose. Acetate trimellitate (HPMCAT), and ethylhydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamic acid; degradable lactic acid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0370] In some embodiments, the pharmaceutical composition is formulated as a non-eluting matrix device. The active ingredient is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. Materials suitable for use as a non-eluting matrix device include insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber. These include, but are not limited to, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer; and hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, cross-linked partially hydrolyzed polyvinyl acetate, aliphatic compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0371] In matrix controlled-release systems, the desired release kinetics can be controlled, for example, through the type of polymer used, the polymer viscosity, the particle size of the polymer and / or the active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0372] The pharmaceutical compositions disclosed herein in modified-release dosage form may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[0373] 2. Osmotic Controlled Release Devices The pharmaceutical compositions disclosed herein in modified-release dosage forms can be manufactured using osmotic controlled release devices, including one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient, and (b) a semipermeable membrane with at least one delivery port that encapsulates the core. The semipermeable membrane controls the influx of water from an aqueous environment into the core during use, causing drug release by extrusion through the delivery port.

[0374] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that generates a driving force for water transport from the environment of use into the core of the device. One type of osmotic agent is a water-swellable hydrophilic polymer, also called an "osmopolymer" and "hydrogel," which includes, but is not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0375] Another type of osmotic agent is an osmogen, which can absorb water and affect the osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as glucose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0376] Osmotic agents with different dissolution rates can be used to affect the rate at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as Mannogeme EZ (SPI Pharma, Lewes, Del.) can be used to provide rapid delivery in the first few hours to immediately produce the desired therapeutic effect, with the remaining amount gradually and continuously released to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient is released at a rate that replaces the amount of active ingredient that is metabolized and excreted.

[0377] The core may also include a variety of other excipients and carriers described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0378] Materials useful for forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pH, or susceptible to being rendered water-insoluble by chemical changes such as crosslinking. Examples of suitable polymers useful for forming coatings include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethylcarbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethylcarbonate, CA chloroacetate, CA ethyloxalate, CA methylsulfonate, CA butylsulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG. copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters, poly(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0379] The semipermeable membrane may also be a hydrophobic microporous membrane whose pores are substantially gas-filled and not wetted by aqueous media but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor-permeable membranes are typically made of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0380] Delivery ports on the semipermeable membrane can be formed after coating by mechanical or laser drilling. Delivery ports can be formed in situ by erosion of a plug of water-soluble material or by rupture of a thin section of the membrane over a core cavity. Additionally, delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0381] The total amount and rate of release of the active ingredient can be substantially controlled via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0382] The osmotic controlled-release dosage form of the pharmaceutical composition may further comprise additional conventional excipients or carriers as described herein to facilitate performance or processing of the composition in the formulation.

[0383] Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

[0384] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as AMT controlled-release dosage forms, which comprise an asymmetric osmotic membrane coating a core containing an active ingredient and other pharmaceutically acceptable excipients or carriers. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip-coating.

[0385] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as ESC controlled-release dosage forms comprising an osmotic membrane coating a core comprising the active ingredient(s), hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

[0386] 3. Multiparticulate controlled release devices The pharmaceutical compositions disclosed herein in modified-release dosage forms can be manufactured as multiparticulate controlled-release devices containing multiple particles, granules, or pellets ranging in diameter from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to about 1 mm. Such multiparticulates can be manufactured by processes known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing, and by spray-coating seed cores. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[0387] Other excipients described herein may be blended with the pharmaceutical composition to aid in the processing and formation of the multiparticulates. The resulting particles themselves constitute the multiparticulate device, or they may be coated with various film-forming materials, such as enteric polymers, water-swellable polymers, and water-soluble polymers. The multiparticulates can be further processed as capsules or tablets.

[0388] 4. Targeted delivery The pharmaceutical compositions disclosed herein can also be formulated to target specific tissues, receptors, or other areas of the body of the subject being treated, including using liposomes, resealed red blood cells, and antibody-based delivery systems.

[0389] E. Inhalation Administration The pharmaceutical compositions disclosed herein can be formulated for inhalation administration, for example, for pulmonary absorption.Suitable preparations can include the above-mentioned liquid form preparations, such as solutions and emulsions, which can be delivered as aerosols, preferably mist, with or without carrier gases, such as air, oxygen, a mixture of helium and oxygen, or other gases and gas mixtures, including therapeutic gas mixtures, and optionally contain buffers, for example, solutions and emulsions in water, water / water-miscible vehicles such as water / propylene glycol solutions, or organic solvents.The pharmaceutical compositions can be formulated as dry powders for inhalation, alone or in combination with inert carriers such as lactose or phospholipids.

[0390] The pharmaceutical composition may be in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as a nebulizer that uses electrohydrodynamics to generate a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane (HFA 134A) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), carbon dioxide, perfluorinated hydrocarbons such as perflubron, and other suitable gases. Such propellants may be used alone or in addition to nitrous oxide (which, when used, may serve dual roles as both active ingredient and propellant / drive gas). The 5-HT relative to the propellant present in the aerosol. 2A The weight ratio of receptor agonist typically ranges from 0.01:100 to 0.1:100, 0.025:75 to 0.1:75, or for example, 0.05:75, although other ratios may also be used.

[0391] Aqueous solutions suitable for inhalation can be prepared by dissolving the active ingredient in water, optionally with other aqueous compatible excipients / cosolvents. Suitable stabilizers and thickeners can also be added. Emulsions suitable for inhalation can be prepared by solubilizing the active ingredient in an aqueous medium and dispersing the solubilized form in a hydrophobic medium, optionally using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents.

[0392] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers may be formulated to contain a surfactant or other suitable cosolvent, or a suitable substitute for dispersing, solubilizing, or sustaining the release of the active ingredients disclosed herein, and optionally a propellant. Such surfactants or cosolvents may include, but are not limited to, polysorbates 20, 60, and 80; Pluronic® F-68, F-84, and P-103; cyclodextrin; polyoxyl 35 castor oil; sorbitan trioleate, oleic acid, or oligolactic acid. Surfactants and cosolvents are typically used at concentrations of about 0.01% to about 2% by weight of the pharmaceutical composition. A viscosity greater than that of a simple aqueous solution may, in some cases, be desirable to reduce variability in dispensing the formulation, reduce physical separation of emulsion components of the formulation, and / or otherwise improve formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the above. Such agents, if desired, are typically used at a concentration of about 0.01% to about 2% by weight of the pharmaceutical composition.

[0393] The active ingredient can also be dissolved in an organic solvent or an aqueous mixture of organic solvents.The organic solvent can be, for example, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloromethane, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, ethanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethylene, or xylene, and combinations thereof.The organic solvent can belong to functional groups such as ester solvents, ketone solvents, alcohol solvents, amide solvents, ether solvents, and hydrocarbon solvents, and each can be used.

[0394] Pharmaceutical compositions can also be formulated as dry powder for inhalation administration, for example, via dry powder inhaler (DPI).The active ingredient itself can form a powder, or the powder can be formed from a pharmaceutically acceptable excipient or carrier, and the active ingredient is releasably bound to the surface of the carrier powder, so that when inhaled, the moisture in the lungs releases the active ingredient from the surface, making the drug available for systemic absorption.Examples of carrier particles include, but are not limited to, those made of lactose or other sugars, and mention may be made of α-lactose monohydrate.

[0395] Further description of pharmaceutical compositions adapted for inhalation and methods for inhalation administration is provided below.

[0396] Therapeutic Uses and Methods The present disclosure is also directed to combination drug therapies and methods for treating a subject having a disease or disorder, comprising administering to the subject a therapeutically effective amount of 5-HT 2A The disease or disorder involves administering a 5-HT receptor agonist and an NMDA receptor antagonist. 2AReceptor, NMDA receptor, or both may be associated with, for example, neuropsychiatric disease or disorder, central nervous system (CNS) disorder, and / or psychological disorder.Combined drug therapy can show enhanced activity and improved patient experience when treating such disease or disorder, for example, by providing therapeutic effectiveness with slight euphoria, thereby reducing or eliminating adverse psychological effects such as acute hallucinogenic crisis (bad trip) and dissociative effect (out-of-body experience) from hallucinogens.

[0397] The subjects treated herein have a serotonin 5-HT2 receptor (e.g., 5-HT 2A receptor) and / or an NMDA receptor-related disease or disorder.

[0398] In some embodiments, the disease or disorder is a neuropsychiatric disease or disorder.

[0399] In some embodiments, the disease or disorder is an inflammatory disease or disorder.

[0400] In some embodiments, the disease or disorder is post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar disorder and related disorders (including but not limited to bipolar I disorder, bipolar II disorder, cyclothymic disorder), obsessive-compulsive disorder (OCD), obsessive-compulsive behavior and other related symptoms, generalized anxiety disorder (GAD), acute hallucinatory crisis, social anxiety disorder, substance use disorders (including but not limited to alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, cocaine use disorder, and other addictive disorders). and / or central nervous system (CNS) disorders and / or psychiatric / psychological disorders, including, but not limited to, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive impairment, mild neurocognitive impairment, chronic fatigue syndrome, Lyme disease, gambling disorder, eating disorders (including, but not limited to, anorexia nervosa, bulimia nervosa, binge eating disorder, etc.), paraphilic disorders (including, but not limited to, pedophilic disorder, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, and cross-dressing disorder, etc.), sexual dysfunction (e.g., decreased libido), peripheral neuropathy, and obesity.

[0401] In some embodiments, the disease or disorder is major depressive disorder (MDD).

[0402] In some embodiments, the disease or disorder is treatment-resistant depression (TRD), defined herein as MDD with an inadequate response to at least two different conventional antidepressants.

[0403] In some embodiments, the disease or disorder is an anxiety disorder, such as generalized anxiety disorder (GAD).

[0404] In some embodiments, the disease or disorder is social anxiety disorder.

[0405] In some embodiments, the disease or disorder is obsessive-compulsive disorder (OCD).

[0406] In some embodiments, the disease or disorder is cancer-related depression and anxiety.

[0407] In some embodiments, the disease or disorder is headache (e.g., cluster headache, migraine, etc.).

[0408] In some embodiments, the disease or disorder is an alcohol use disorder. In some embodiments, the disease or disorder is an opioid use disorder. In some embodiments, the disease or disorder is an amphetamine use disorder. In some embodiments, the disease or disorder is a cocaine use disorder. In some embodiments, the disease or disorder is a nicotine use (e.g., smoking) disorder, and the therapy is used to quit smoking.

[0409] In some embodiments, the disease or disorder is depression. Types of depression that can be treated with the combination medications of the present disclosure include, but are not limited to, major depressive disorder (MDD), melan...

Claims

1. 5-HT ２Ａ 1. A pharmaceutical composition for treating a central nervous system (CNS) disorder or a psychiatric illness comprising a receptor agonist, the pharmaceutical composition is administered in combination with an N-methyl-D-aspartate (NMDA) receptor antagonist; wherein the 5-HT 2A receptor agonist is a compound of formula (I): 【Chemistry 1】 During the ceremony, X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen and deuterium; R 2 is selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R 4 and R 5 are independently selected from the group consisting of hydrogen, deuterium, hydroxy, and unsubstituted or substituted alkoxy; R 6 and R 7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; and R 9 and R 10 are independently selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is at least one selected from the group consisting of N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d10), and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d10), or a pharma- ceutically acceptable salt or solvate thereof.

3. The pharmaceutical composition of claim 1, wherein the compound of formula (I) contains at least one deuterium atom.

4. 2. The pharmaceutical composition of claim 1, wherein the NMDA receptor antagonist is at least one selected from the group consisting of ketamine, nitrous oxide, memantine, and dextromethorphan, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

5. 2. The pharmaceutical composition of claim 1, wherein the NMDA receptor antagonist is nitrous oxide.

6. The 5-HT ２Ａ 2. The pharmaceutical composition of claim 1, wherein the receptor agonist is N,N-dimethyltryptamine (DMT) or a pharma- ceutically acceptable salt or solvate thereof and the NMDA receptor antagonist is nitrous oxide.

7. The 5-HT ２Ａ 2. The pharmaceutical composition of claim 1, wherein the receptor agonist is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt or solvate thereof and the NMDA receptor antagonist is nitrous oxide.

8. The 5-HT ２Ａ 2. The pharmaceutical composition of claim 1, wherein the receptor agonist is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d10) or a pharma- ceutically acceptable salt or solvate thereof and the NMDA receptor antagonist is nitrous oxide.

9. The 5-HT ２Ａ 2. The pharmaceutical composition of claim 1, wherein the receptor agonist is 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d10) or a pharma- ceutically acceptable salt or solvate thereof and the NMDA receptor antagonist is nitrous oxide.

10. 2. The pharmaceutical composition of claim 1, wherein the NMDA receptor antagonist is ketamine, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

11. The 5-HT ２Ａ The receptor agonist (i) N,N-dimethyltryptamine (DMT) or a pharma- ceutically acceptable salt or solvate thereof; (ii) 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt or solvate thereof; (iii) 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (DMT-d 10 ) or a pharma- ceutically acceptable salt or solvate thereof; (iv) The pharmaceutical composition according to claim 10, which is 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (5-MeO-DMT-d 10 ) or a pharma- ceutically acceptable salt or solvate thereof.

12. The 5-HT ２Ａ The pharmaceutical composition of any one of claims 1 to 11, wherein the receptor agonist is administered as an injection and the NMDA receptor antagonist is administered as a therapeutic gas mixture.

13. The CNS disorder or psychiatric illness is selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-harm disorder (NSSID), bipolar disorder and related disorders, obsessive-compulsive disorder (OCD), obsessive-compulsive behavior and other related symptoms, generalized anxiety disorder (GAD), acute hallucinatory crisis, social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, cocaine use disorder, schizophrenia ...

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the therapeutic effect is selected from the group consisting of: alcohol use disorder, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood onset fluency disorder, severe neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease, gambling disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, pedophilic disorder, exhibitionism disorder, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, cross-dressing disorder, sexual dysfunction, peripheral neuropathy, and obesity.

14. The pharmaceutical composition according to any one of claims 1 to 11, wherein the CNS disorder or psychiatric illness is major depressive disorder (MDD).

15. The pharmaceutical composition according to any one of claims 1 to 11, wherein the CNS disorder or psychiatric disease is treatment-resistant depression (TRD).

16. The pharmaceutical composition according to any one of claims 1 to 11, wherein the CNS disorder or psychiatric illness is generalized anxiety disorder (GAD).

17. The pharmaceutical composition according to any one of claims 1 to 11, wherein the CNS disorder or psychiatric illness is social anxiety disorder.

18. The pharmaceutical composition according to any one of claims 1 to 11, wherein the CNS disorder or psychiatric disease is obsessive-compulsive disorder (OCD).

19. The pharmaceutical composition according to any one of claims 1 to 11, wherein the CNS or psychiatric disorder is an alcohol use disorder.

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