Combination of nitrous oxide and 5-HT2A receptor agonists

Abstract

5-HT 2A Combination medications including a receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist (e.g., nitrous oxide, xenon, argon, ketamine, etc.) are provided. Pharmaceutical compositions and methods of treating central nervous system (CNS) disorders or psychiatric illnesses using the combination medications, e.g., via aerosol inhalation, are also described.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 362,258, filed March 31, 2022, 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 discussion that may not have been admitted as prior art at the time of filing, are not expressly or implicitly 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, mediated by the effects of hallucinogenic compounds such as psilocybin, psilocin, N,N-dimethyltryptamine (DMT), phenethylamine, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), and ketamine. 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 the receptors is believed to increase the risk of a bad trip experience, which may lead to therapy interruption, therapy cessation, or even an adverse treatment event.

[0007] In clinical settings, during supervised hallucinogenic experiences, medical professionals, treatment monitors, or other session participants may attempt to reduce acute hallucinogenic crisis events by shifting the patient's perspective, providing reassurance, or reducing anxiety through other specialized psychological means. If the acute hallucinogenic crisis rises to a significant level, the medical professional supervising the hallucinogenic experience may administer benzodiazepines or other anti-anxiety medications. 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 pose an increased risk of acute hallucinogenic 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 adverse psychiatric symptoms, including dissociative effects such as 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 this 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 disease or condition, such as a central nervous system (CNS) disorder or a psychiatric disorder, 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 produces unexpected beneficial therapeutic results by modulating the uptake of both serotonin and glutamate, while improving the patient experience, for example, by 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 provides a therapeutic benefit greater than the sum of each component administered individually, for example, in the form of increased neuroplasticity, while the combination of a 5-HT receptor agonist and an NMDA receptor antagonist provides a therapeutic benefit greater than the sum of each component administered individually, for example, in the form of increased neuroplasticity. 2A The present invention enhances the patient's experience by reducing or eliminating adverse psychoactive effects such as acute hallucinatory crises and dissociative effects that can be caused by taking only receptor agonists or NMDA receptor antagonists.

[0014] Thus, the present disclosure provides: (1) Combination drug therapy, nitrous oxide, an N-methyl-D-aspartate (NMDA) receptor antagonist; 5-HT 2-hydroxybenzoates, which are compounds of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: 2A a receptor agonist; [ka] During the ceremony, X1 and X2 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; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 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; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, and unsubstituted or substituted alkoxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; R9 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.

[0015] (2) X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R 10 The combination drug therapy according to (1), wherein at least one of the following contains deuterium.

[0016] (3) X1, X2, R9, and R 10 The combination drug therapy according to (1) or (2), wherein the compound contains deuterium.

[0017] (4) X1, X2, Y1, Y2, R9, and R 10 The combination drug therapy according to any one of (1) to (3), wherein the compound contains deuterium.

[0018] (5) The combination drug therapy according to any one of (1) to (4), wherein X1, X2, and R5 contain deuterium.

[0019] (6) X1, X2, Y1, Y2, R5, R9, and R 10 The combination drug therapy according to any one of (1) to (5), wherein the compound contains deuterium.

[0020] (7) The compound of formula (I) is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(5-methoxy-d 3) 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0021] (8)5-HT 2A Receptor agonists include 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, and 2-(5-methoxy-d3 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4.

[0022] (9)5-HT 2AThe receptor agonist is an active agonist mixture of at least two compounds of formula (I), the active agonist mixture being selected from the group consisting of: (i) 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; (ii) one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and optionally, (iii) one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0023] (10) The active agonist mixture comprises: (i) 60% to 99% by weight of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the active agonist mixture; or (ii) 1% to 40% by weight, in total, of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the active agonist mixture. and (iii) 0% to less than 10% by weight, in total, of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, based on the total weight of the active agonist mixture.

[0024] (11) NMDA receptor antagonists and 5-HT 2A The combination drug therapy according to any one of (1) to (10), wherein the receptor agonist is provided as a separate pharmaceutical composition.

[0025] (12) A method for treating a subject having a central nervous system (CNS) disorder or a psychiatric disorder, the method comprising: The subject is administered a therapeutically effective amount of an N-methyl-D-aspartate (NMDA) receptor antagonist that is nitrous oxide and a therapeutically effective amount of a 5-HT 2 receptor antagonist that is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 2A and a receptor agonist, [ka] During the ceremony, X1 and X2 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; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 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; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, and unsubstituted or substituted alkoxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; R9 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.

[0026] (13) X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R 10 The method according to (12), wherein at least one of the following contains deuterium.

[0027] (14) X1, X2, R9, and R 10 The method according to (12) or (13), wherein the hydrogen atom contains deuterium.

[0028] (15) X1, X2, Y1, Y2, R9, and R 10 The method according to any one of (12) to (14), wherein the hydrogen atom contains deuterium.

[0029] (16) The method according to any one of (12) to (15), wherein X1, X2, and R5 contain deuterium.

[0030] (17) X1, X2, Y1, Y2, R5, R9, and R 10 The method according to any one of (12) to (16), wherein the hydrogen atom contains deuterium.

[0031] (18) The compound of formula (I) is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(5-methoxy- d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2, and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0032] (19)5-HT 2A Receptor agonists include 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(5-methoxy-d 3) The method according to any one of (12) to (18), wherein the compound is at least one fumarate, benzoate, salicylate, or succinate selected from the group consisting of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4.

[0033] (20)5-HT2A The receptor agonist is an active agonist mixture of at least two compounds of formula (I), the active agonist mixture being selected from the group consisting of: (i) 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; (ii) one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; 12. The method of claim 11, further comprising administering to said patient a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and optionally, (iii) one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0034] (21) The active agonist mixture comprises: (i) 60% to 99% by weight of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the active agonist mixture; or (ii) 1% to 40% by weight, in total, of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the active agonist mixture. and (iii) 0% to less than 10% by weight, in total, of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, based on the total weight of the active agonist mixture.

[0035] (22) 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, nicotine use disorder, cocaine use disorder, The method according to any one of (12) to (21), wherein the condition is at least one selected from the group consisting of 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.

[0036] (23) The method according to any one of (12) to (22), wherein the CNS disorder or psychiatric disease is major depressive disorder (MDD).

[0037] (24) The method according to any one of (12) to (22), wherein the CNS disorder or psychiatric disease is treatment-resistant depression (TRD).

[0038] (25) The method according to any one of (12) to (22), wherein the CNS disorder or psychiatric disease is generalized anxiety disorder (GAD).

[0039] (26) The method according to any one of (12) to (22), wherein the CNS disorder or psychiatric disease is generalized anxiety disorder (GAD) accompanied by depression.

[0040] (27) The method according to any one of (12) to (22), wherein the CNS disorder or psychiatric disorder is social anxiety disorder.

[0041] (28) The method according to any one of (12) to (22), wherein the CNS disorder or psychiatric disorder is alcohol use disorder.

[0042] (29)5-HT 2A The method according to any one of (12) to (28), wherein the receptor agonist is administered at a dose of about 0.01 mg / kg to about 3 mg / kg.

[0043] (30)5-HT 2A The method according to any one of (12) to (29), wherein the receptor agonist and the NMDA receptor antagonist are administered 1 to 8 times over the course of treatment.

[0044] (31)5-HT 2A The method according to any one of (12) to (30), wherein the receptor agonist and the NMDA receptor antagonist are administered simultaneously as a single pharmaceutical composition.

[0045] (32)5-HT 2A The method of (31), wherein the receptor agonist and the NMDA receptor antagonist are administered to the subject as an aerosol by inhalation.

[0046] (33)5-HT 2A The method according to any one of (12) to (30), wherein the receptor agonist and the NMDA receptor antagonist are administered as separate pharmaceutical compositions.

[0047] (34)5-HT 2A The method according to (33), wherein the receptor agonist and the NMDA receptor antagonist are administered sequentially.

[0048] (35)5-HT 2A The method according to (33), wherein the receptor agonist and the NMDA receptor antagonist are administered simultaneously.

[0049] (36)5-HT 2A The method according to any one of (33) to (35), wherein the receptor agonist is administered intravenously and the NMDA receptor antagonist is administered via inhalation.

[0050] (37)5-HT 2A 36. The method of claim 36, wherein the receptor agonist is administered intravenously to the subject as a single bolus.

[0051] (38)5-HT 2A The method according to (36) or (37), wherein the receptor agonist is administered at a dose of about 0.01 mg / kg to about 0.8 mg / kg.

[0052] (39)5-HT 2A The method of (36), wherein the receptor agonist is administered to the subject intravenously as an infusion.

[0053] (40)5-HT 2A The method according to (39), wherein the receptor agonist is administered at a dose of about 0.1 mg / kg to about 2.0 mg / kg.

[0054] (41) The method of (39) or (40), wherein the infusion is administered over a duration of about 5 minutes to about 2 hours.

[0055] (42)5-HT 2A The method of any one of (36) to (41), wherein the receptor agonist is administered intravenously to the subject as a bolus followed by an infusion.

[0056] (43)5-HT 2A The method according to any one of (33) to (35), wherein the receptor agonist is administered intramuscularly to the subject and the NMDA receptor antagonist is administered via inhalation.

[0057] (44)5-HT 2A The method according to any one of (33) to (35), wherein the receptor agonist is administered subcutaneously to the subject and the NMDA receptor antagonist is administered via inhalation.

[0058] (45) The method according to any one of (12) to (44), wherein the nitrous oxide is administered via inhalation as a therapeutic gas mixture containing nitrous oxide.

[0059] (46) The method of (45), 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 and O2-enriched medical air, or a mixture of N2O, He, and O2.

[0060] (47) The method according to (45) or (46), 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.

[0061] (48) The method 2A The method according to any one of (12) to (47), wherein the method synergistically increases C-FOS expression in the subject's frontal cortex as measured by mRNA levels relative to pre-treatment, compared to the sum of the C-FOS expression levels following separate administration of an NMDA receptor agonist and an NMDA receptor antagonist.

[0062] (49) The method 2A The method according to any one of (12) to (48), wherein the expression of EGR2 in the subject's frontal cortex is synergistically increased as measured by mRNA levels relative to before treatment, compared to the sum of the expression levels of EGR2 after administration of the receptor agonist and the NMDA receptor antagonist separately.

[0063] (50) The method 2A The method according to any one of (12) to (49), wherein the expression of IKBA in the subject's frontal cortex is synergistically increased as measured by mRNA levels relative to before treatment, compared to the sum of the expression levels of IKBA after administration of a receptor agonist and an NMDA receptor antagonist separately.

[0064] (51) The method 2A The method according to any one of (12) to (50), wherein the expression of SGK1 in the subject's frontal cortex is synergistically increased as measured by mRNA levels relative to before treatment, compared to the sum of the expression levels of SGK1 after administration of a receptor agonist and an NMDA receptor antagonist separately.

[0065] (52) The method 2A The method according to any one of (12) to (51), wherein the expression of FGF2 in the subject's frontal cortex, as measured by mRNA levels relative to before treatment, is synergistically increased compared to the sum of the expression levels of FGF2 after administration of a receptor agonist and an NMDA receptor antagonist separately.

[0066] (53)5-HT 2A The method according to any one of (12) to (52), wherein the receptor agonist and the NMDA receptor antagonist are administered in amounts effective to reduce or inhibit an acute hallucinatory crisis.

[0067] (54)5-HT 2A The method according to any one of (12) to (53), wherein the receptor agonist and the NMDA receptor antagonist are administered in amounts effective to reduce or inhibit the dissociation effect.

[0068] (55) Use of a combination drug therapy of any one of (1) to (11) for treating patients with central nervous system (CNS) disorders and / or psychological disorders.

[0069] (56) The combination drug therapy according to any one of (1) to (11) for use in a therapy. [Brief explanation of the drawings]

[0070] 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.

[0071] [Figure 1A] 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 are shown (Figure 1B). [Figure 1B] Same as above. [Figure 2] 1 shows DMT and DMT-d10 plasma concentration-time profiles after IV administration (1 mg / kg) in rats. [Figure 3] Figure 1 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. 1 shows DMT and DMT-d10 plasma concentration-time profiles after PO (oral gavage, OG) administration (10 mg / kg) in rats. [Figure 5] DMT plasma concentration-time profiles after IV, inhaled, and PO (OG) administration are shown, dose normalized to 1 mg / kg. [Figure 6] DMT-d10 plasma concentration-time profiles after IV, inhaled, and PO (OG) administration, dose normalized to 1 mg / kg. [Figure 7] A transparent, airtight plexiglass anesthesia induction chamber setup for preclinical rodent studies is shown. [Figure 8A] Figure 8A shows the head twitch response (HTR) in mice from experimental groups A, B, C, and D over the period from 0 to 15 min (Figure 8A) and 15 to 30 min (Figure 8B). Asterisks indicate significant multiple comparisons (Dunn's test), *P<0.05, ****P<0.0001. [Figure 8B] Same as above. [Figure 9A] Figure 9A shows the total distance traveled (cm) from 0 to 15 minutes (Figure 9A) and from 15 to 30 minutes (Figure 9B) from experimental groups A, B, C, and D. Asterisks indicate significant multiple comparisons (Dunn's test) **P<0.01. [Figure 9B] Same as above. [Figure 10] A general experimental design for a human study probing the synergistic interaction between DMT and nitrous oxide (NO) is presented. DETAILED DESCRIPTION OF THE INVENTION

[0072] 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.

[0073] 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.

[0074] "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 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, 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-).

[0075] 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, has 1 to 10 substituents selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic.

[0076] "Alkylene" is -O-, -NR 10 -, -NR 10 C(O), -C(O)NR 10 - refers to a divalent aliphatic hydrocarbyl group having 1 to 6 carbon atoms, including 1 to 3 carbon atoms, either straight or branched, optionally interrupted with 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.

[0077] "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.

[0078] The term "alkane" refers to alkyl and alkylene groups as defined herein.

[0079] 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.

[0080] The terms "alkaryl" or "aralkyl" refer to the groups -alkylene-aryl and -substituted alkylene-aryl, where alkylene, substituted alkylene, and aryl are defined herein.

[0081] "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.

[0082] 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.

[0083] The term "alkoxyamino" refers to the group --NH-alkoxy, where alkoxy is as defined herein.

[0084] 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.

[0085] The term "haloalkyl" refers to an alkyl group substituted as described above, in which one or more hydrogen atoms on the alkyl group are replaced with a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0086] The term "alkylalkoxy" refers to -alkylene-O-alkyl groups, alkylene-O-substituted alkyl groups, substituted alkylene-O-alkyl groups, and substituted alkylene-O-substituted alkyl groups, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0087] The term "alkylthioalkoxy" refers to the groups -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl, and substituted alkylene-S-substituted alkyl, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0088] "Alkenyl" refers to a straight or branched chain hydrocarbyl group having from 2 to 6 carbon atoms, e.g., from 2 to 4 carbon atoms, and having at least one site of double bond unsaturation, e.g., from 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.

[0089] 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.

[0090] "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 or 2. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CHC≡CH).

[0091] 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.

[0092] "Alkynyloxy" refers to the group -O-alkynyl, where alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0093] "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).

[0094] "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.

[0095] "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.

[0096] "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.

[0097] 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.

[0098] 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.

[0099] "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 are 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.

[0100] "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 are optionally joined together with the atoms to which they are bound 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.

[0101] "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.

[0102] "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.

[0103] "Amino" refers to the group NH2.

[0104] 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.

[0105] The term "azido" refers to the group -N3.

[0106] "Carboxyl", "carboxy" or "carboxylate" refers to -CO2H or a salt thereof.

[0107] "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 ...substituted cycloalkyl group, a -C(O)O-cycloalkenyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-cycloalkenyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O) "C(O)O" refers to alkyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-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.

[0108] "(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-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.

[0109] "Cyano" or "nitrile" refers to the group --CN.

[0110] "Cycloalkyl" refers to cyclic alkyl groups of from 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.

[0111] 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.

[0112] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond, eg, 1 to 2 double bonds.

[0113] 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, or 1 to 3 substituents, selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0114] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group of 5 to 10 carbon atoms having single or multiple rings and at least one triple bond.

[0115] "Cycloalkoxy" refers to -O-cycloalkyl.

[0116] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0117] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0118] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0119] "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 that at least one ring within the ring system is aromatic if the point of attachment is through an atom in the aromatic ring. 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 can include 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.

[0120] 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.

[0121] "Heteroaryloxy" refers to -O-heteroaryl.

[0122] "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 the N-oxide, -S(O)-, or -SO2- moieties.

[0123] 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, ...

[0124] Unless constrained by the definition of a heterocyclic substituent, such heterocyclic groups can be substituted with 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.

[0125] "Heterocyclyloxy" refers to the group --O-heterocyclyl.

[0126] The term "heterocyclylthio" refers to the group heterocyclic -S-.

[0127] The term "heterocyclene" refers to a diradical group formed from a heterocycle, as defined herein.

[0128] The term "hydroxyamino" refers to the group --NHOH.

[0129] "Nitro" refers to the -NO2 group.

[0130] "Oxo" refers to the (=O) atom.

[0131] "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-.

[0132] "Sulfonyloxy" refers to an -OSO2-alkyl group, an OSO2-substituted alkyl group, an OSO2-alkenyl group, an OSO2-substituted alkenyl group, an OSO2-cycloalkyl group, an OSO2-substituted cycloalkyl group, an OSO2-cycloalkenyl group, an OSO2-substituted cycloalkenyl group, an OSO2- 2- Aryl group, OSO2-substituted aryl group, OSO 2- refers to heteroaryl groups, OSO2-substituted heteroaryl groups, OSO2-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.

[0133] 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.

[0134] "Thiol" refers to the group --SH.

[0135] The term "thioxo" or "thioketo" refers to the atom (=S).

[0136] The term "alkylthio" or "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In certain embodiments, the sulfur may be oxidized to -S(O)-. Sulfoxides can exist as one or more stereoisomers.

[0137] The term "substituted thioalkoxy" refers to an --S-substituted alkyl group.

[0138] The term "thioaryloxy" refers to an aryl-S- group, where aryl is as defined herein, including an optionally substituted aryl group, as defined herein.

[0139] The term "thioheteroaryloxy" refers to the group --S-heteroaryl, where heteroaryl is as defined herein, including an optionally substituted aryl group, as defined herein.

[0140] The term "thioheterocyclooxy" refers to the group -S-heterocyclyl, where heterocyclyl is as defined herein, including optionally substituted heterocyclyl groups, as defined herein.

[0141] 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.

[0142] 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)R70 , -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)OM + , -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’and 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 independently, 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.

[0143] Further to the disclosure herein, the substituents of hydrogen on unsaturated carbon atoms in "substituted" alkene, alkyne, aryl, and heteroaryl groups can be deuterium, -R, unless otherwise specified. 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 + 0, -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 8, -OCO2 - M + , -OCO2R 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 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.

[0144] 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 , -NR 70C(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.

[0145] 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.

[0146] Unless otherwise specified, it is understood that for all substituents defined above, polymers 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.) are not intended to be encompassed herein. 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.

[0147] 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)-.

[0148] For any group disclosed herein that contains one or more substituents, it is of course understood that such group does 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.

[0149] When a substituent or group is described 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, if the substituent "-R" is defined as "containing deuterium," it is to be understood that -R can be -D (-deuterium), or a group such as -CD3 consistent with the other requirements set forth for -R.

[0150] As used herein, the term "fat" refers to a compound having a long-chain (linear) hydrophobic moiety composed of hydrogen and 4 to 26 carbon atoms, and can be fully saturated or partially unsaturated.

[0151] 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 tissues 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.

[0152] The term "salt thereof" refers to a compound formed when a 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, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. As an 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.

[0153] "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.

[0154] "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 are contemplated herein, including racemates and optically pure stereoisomers. 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, for example, R- and / or S-stereoisomers, and each permutation of those diastereomers as long as such diastereomers are geometrically feasible.

[0155] A "crystalline" solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules forming a crystal lattice with long-range order, and therefore exhibits sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern. In some cases, a crystalline solid can exist in different crystalline forms known as "polymorphs," which have the same chemical composition but differ in crystalline solid-state packing, geometric arrangement, and other descriptive properties. Thus, polymorphs can have different solid-state physical properties that affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility of the compound, as well as the safety and efficacy of pharmaceuticals based on the compound. In the process of preparing polymorphs, further refinement can also be achieved in terms of overall physical or optical purity. As used herein, the term "non-crystalline" refers to a solid material that does not have substantial long-range order in its molecular positions; the molecules are arranged randomly, such that there is effectively no well-defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., they exhibit similar properties in all directions and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have substantially sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in the XRPD pattern. Broad peaks are characteristic of amorphous solids. Thus, a "non-crystalline" subject compound / material is a compound / material characterized as having substantially no crystallinity, with a crystallinity of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, or 0%, i.e., at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined by XRPD, for example. For example, in some embodiments, the % crystallinity may be determined by measuring the intensity of one or more peaks in an XRPD diffractogram compared to a reference peak, which may be a known standard or an internal standard.For example, other characterization techniques such as differential scanning calorimetry (DSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods, including quantitative methods that provide the above percentages in terms of weight percent, may be used to determine the percent amorphous or crystalline of the subject compound / substance.

[0156] When referring to X-ray powder diffraction (XRPD) patterns of materials of the present disclosure, the phrase "characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from" should be understood to include those materials characterized as having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more (inclusive) of the recited characteristic XRPD diffraction peaks. Furthermore, this phrase is intended to be open to the inclusion of other XRPD diffraction peaks not recited. Unless otherwise stated, XRPD analysis was performed on an X-ray powder diffractometer using a CuKα radiation source (wavelength=1.54060 Å).

[0157] "Tautomer" refers to alternative forms of molecules that differ only in the electronic bonding of atoms and / or in the position of protons, such as enol-keto, imine-enamine, and neutral / zwitterionic tautomers, or tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Other tautomeric ring atom configurations are possible. For example, compounds containing acid and base groups in the same molecule shown in the neutral form may exist in zwitterionic form, as in amino acid / ammonium carboxylate tautomers. Thus, compounds of the present disclosure shown containing both amino phosphate and dihydrogen phosphate functionality in the neutral form may exist in zwitterionic form as ammonium monohydrogen phosphate zwitterions.

[0158] "Prodrug" is meant to refer to a compound that can be converted into a biologically active compound described herein under physiological conditions or by solvation. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. For example, prodrugs such as esters, phosphate esters, etc. may be inactive when administered to a subject, but are converted into active compounds in vivo, for example, by hydrolysis to a free carboxylic acid or a free hydroxyl group. Prodrug compounds often offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. As used herein, prodrugs of active compounds can be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to form a free hydroxyl, amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is bonded to any group that cleaves to form a free hydroxyl, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject.Examples of prodrugs include, but are not limited to, derivatives of amine functional groups in active compounds, such as esters (e.g., acetates, formates, benzoates, etc.), carbonates, carbamates, and dihydrogen phosphate derivatives of alcohols or amides (e.g., acetamides, formamides, benzamides, etc.), carbamates, etc.

[0159] 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.

[0160] 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.

[0161] 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, xenon, argon, 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 liquid 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 air, oxygen, helium, or other gases, such as nitrous oxide and / or noble gases, including 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.

[0162] 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, e.g., 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., 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 drug load has been released. In some embodiments, the release period can be about 0.5 hours or more, 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, 8 hours or more, 12 hours or more, 16 hours or more, 20 hours or more, 24 hours or more, 28 hours or more, 32 hours or more, 36 hours or more, or 48 hours or more, and 48 hours or less, 36 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less, or any range therebetween.

[0163] The term "tamper-resistant" is recognized in the art to describe an aspect of a drug formulation that makes it more difficult to use the formulation to abuse the drug portion of the formulation, for example, via extraction for intravenous use or crushing for free base use, thereby reducing the risk of drug abuse.

[0164] 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 isolated form or in the form of 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 isolated solid form or in the form of a solid formulation provided in admixture with, for example, a pharmaceutically acceptable carrier, diluent, or adjuvant described herein, with little or no solid-state change (e.g., hydration, dehydration, solvation, desolvation, crystallization, recrystallization, or solid-state phase transition).

[0165] As used herein, the term "composition" is equivalent to the term "formulation."

[0166] 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 site of biological action. Routes or modes of administration are as described herein.

[0167] As used herein, "simultaneous" administration or administration performed "concurrently" 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 period within the administration period of the first active ingredient), or that are non-overlapping but approximately adjacent, i.e., separated by 30 seconds or less, i.e., the start of administration of a first active ingredient is separated by the end of administration of a second active ingredient, or vice versa. For example, the administration of two injections, one following within 30 seconds of the other, is considered simultaneous administration herein. "Sequential" administration or administration performed "sequentially" refers to the administration of two or more active ingredients with a time interval of more than 30 seconds between their non-overlapping endpoints (i.e., the start of administration of a first active ingredient is separated from the end of administration of a second active ingredient, or vice versa, by more than 30 seconds).

[0168] As used herein, the term " inhalation session " describes the administration event that 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 10mg of drug twice a day will carry out two inhalation sessions, and each inhalation session will provide 10mg 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 dosage form, and the breathing pattern of subject.

[0169] 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, such as causing elimination or 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 one or more symptoms of the disease or medical condition in a patient. Treatment may provide a therapeutic benefit, such as eradicating or ameliorating one or more physiological or psychological symptoms associated with an underlying condition, disease, or disorder, such that an improvement is observed in the patient, regardless of 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.

[0170] 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.

[0171] 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."

[0172] 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, or one or more symptoms thereof.

[0173] A "therapeutically effective amount" refers to an amount of a compound sufficient to treat a particular disorder or disease, or one or more of its symptoms, and / or prevent the occurrence of the disease or disorder (a prophylactically effective amount). 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.

[0174] 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.

[0175] The term "toxic spike" is used herein to describe a spike in the concentration of any compound described herein that would result in sedative or psychotomimetic side 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 ng / L or higher).

[0176] As used herein, and unless otherwise specified, a "neuropsychiatric disease or disorder" is a behavioral or psychological problem associated with a known neurological condition, typically defined as a constellation 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.

[0177] As used herein, "inflammatory condition" or "inflammatory disease" broadly refers 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); blood disorders (e.g., pulmonary tuberculosis, pulmonary tuberculosis, pulmonary arthritis, pulmonary tuberculosis ... vascular diseases, including atherosclerosis, vascular occlusive diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular stent restenosis; and ophthalmic diseases, including uveitis, corneal disease, iritis, iridocyclitis, glaucoma, and cataracts.

[0178] All diseases and disorders listed herein may be defined as set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association or the International Classification of Diseases (ICD) published by the World Health Organization.

[0179] 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).

[0180] Combination drug therapy In some embodiments, 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 reducing 5-HT 2A It offers many benefits, including enhancing the patient's experience by reducing or eliminating the adverse psychiatric effects, such as acute hallucinogenic crises (bad trips), that are commonly seen when taking receptor agonists or NMDA receptor antagonists alone, and the dissociative effects (out-of-body experiences) of hallucinogens.

[0181] 5-HT 2A Receptor agonists As used herein, "5-HT 2A "Receptor agonists" are 5-HT 2AIt refers to compounds that increase the activity of the 5-HT2 receptor, a subtype of 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 agonists used in combination drug therapy 2A The 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.

[0182] 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 dihydrogen phosphate, and 4-hydroxyTMT salt (salt of 4-hydroxy-N,N,N-trimethyltryptamine), N,N-dimethyltryptamine (DMT, also referred to herein as 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine), 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lyserilic 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., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8), 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-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5), 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d13 ), 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol, etc.), and pharmaceutically acceptable salts, stereoisomers, tautomers or solvates thereof.

[0183] 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 described and exemplified below, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a combination thereof.

[0184] In some embodiments, 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.

[0185] 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 -benzodioxolyl-N-methylbutanamine (MBDB); trimethoxyamphetamines such as 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); Cyanphetamine (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-iodoamines, including (R)-DOI. doamphetamine (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.

[0186] 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.

[0187] In some embodiments, 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.

[0188] As used herein, 5-HT 2A The receptor agonist may be a compound substituted with 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), (II-d), or a combination thereof, containing at least one deuterium atom. 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.

[0189] 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 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; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 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; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, and unsubstituted or substituted alkoxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; R9 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.

[0190] 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.

[0191] 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.

[0192] 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 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, R2 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0193] 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 can be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc. may also be used.

[0194] 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.

[0195] 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.

[0196] R9 and R 10 can be the same or different. In some embodiments, R and R 10 are the same. 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.

[0197] In some embodiments, R and / or R 10 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R9 and / or 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 / or R 10 is a substituted or unsubstituted C3-C 10 In some embodiments, R and / or R are cycloalkyl. 10 is 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 / or R 10 is 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.

[0198] 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, wherein X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R 10 In some embodiments, any one or more of X, X, Y, Y, R, R, R, R, R, and R 10 In some embodiments, at least one of X, X, Y, Y, R, R, and R 10 In some embodiments, at least one of X, X, Y, Y, R, and R 10 In some embodiments, at least one of X, X, R, and R comprises deuterium. 10 In some embodiments, X, X, Y, Y, R, and R 10 In some embodiments, X1, X2, and R5 comprise deuterium. In some embodiments, X1, X2, Y1, Y2, R5, R9, and R 10 contains deuterium.

[0199] 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 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; R4 and R5 are independently selected from the group consisting of 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; R9, R 10 , and R 11 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.

[0200] 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.

[0201] 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 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, R2 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0202] 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 C alkoxy group (i.e., a methoxy group), the substituted C alkoxy group can be -OCDH, -OCD, H, -OCD, -OCFH, -OCF, H, -OCF, etc. In some embodiments, R is an unsubstituted phosphoryloxy group (i.e., -OP(O)(OH) or its deprotonated form). In some embodiments, R is a substituted phosphoryloxy group in which one or more of the hydrogen atoms in -OP(O)(OH) 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) are replaced with substituents, the substituents can be the same or different from each other.

[0203] 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 from each other.

[0204] 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.

[0205] In some embodiments, R is [ka] R9 and R10 can be the same or different. In some embodiments, R and R 10 are the same. 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.

[0206] In some embodiments, R and / or R 10 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R9 and / or 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 / or R 10 is a substituted or unsubstituted C3-C 10 In some embodiments, R and / or R are cycloalkyl. 10 is 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 / or R 10 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, R and / or R 10 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0207] 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 In some embodiments, two of R 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, for example, unsubstituted or substituted allyl. In some embodiments, R is a quaternary ammonium cation (where R, R 10 , and R 11 and each is not hydrogen. In some embodiments, R is a protonated ammonium cation, where R, R 10 , and R 11where one, two, or three of are hydrogen. When R represents either a quaternary ammonium cation or a protonated ammonium cation, R is accompanied by a suitable conjugate base pair, examples of which 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-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-oxoglucan lutaric acid, glycolic 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., D These include, but are not limited to, conjugated bases of any of the following acids: L-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.).

[0208] In some embodiments, 5-HT2A The 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).

[0209] 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).

[0210] 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).

[0211] 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] During the ceremony, 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).

[0212] In some embodiments, 5-HT 2A Receptor agonists are [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0213] In some embodiments, 5-HT 2A Receptor agonists are [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0214] In some embodiments, 5-HT 2A The receptor agonist is a compound of formula (III) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, 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 is 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 5together 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; Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0215] 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 substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 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 Y2 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.

[0217] 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 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 may 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.

[0218] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 3is 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 may 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 is.

[0219] 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 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.

[0220] 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 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 aIn 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. 4 is -OCH3, -OCD3, -Br, -SCH3, -SCH2CH3, or -SCH2CH2CH3, and / or R 5 is hydrogen, -OMe, or -OCD3.

[0221] In some embodiments, R 4 and R 5 R is bonded together with the atoms to which it is attached to form 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.

[0222] R 6 and R 7 can be the same or different. R 6 and R 7can 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).

[0223] 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, two or more R a In such a case, each R a can 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 R a 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.

[0224] 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.

[0225] 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; X 1 , X 2 , Y 1 , Y 2 , R 3 , R 6 , R 7 , and R a is as defined for formula (III).

[0226] 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 2is 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.

[0227] In some embodiments, Z 1 , Z 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 6 , and R 7 At least one of the atoms contains deuterium.

[0228] In some embodiments, R 6 and R 7 are independently hydrogen, —CH3, or —OCD3.

[0229] In some embodiments, 5-HT 2A Receptor agonists are [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0230] In some embodiments, 5-HT 2A The receptor agonists are N-substituted phenethylamines (NSPs).

[0231] 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] During the ceremony, 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 4 is hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR 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 7are 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; Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0232] 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. 2When R is substituted C1-C6, preferred substituents may 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.

[0233] In some embodiments, R 3 is deuterium. In some embodiments, R 3 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 may 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.

[0234] 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.

[0235] 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.

[0236] 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, 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, R5 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.

[0237] 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 6 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. 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 6is -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.

[0238] 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.

[0239] 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.

[0240] 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 substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 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.

[0241] 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.

[0242] 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, Y1 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 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.

[0243] 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).

[0244] 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 R10 Two of them are the same.

[0245] 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, 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 ais a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0246] 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, 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 ais a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0247] 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, 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 ais a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0248] 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 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, -ORa , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0249] 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 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, -ORa , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0250] 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.

[0251] 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, two or more R a In such a case, each R a can 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 R a 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.

[0252] 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.

[0253] 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, 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).

[0254] 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.

[0255] 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, 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).

[0256] In some embodiments, X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R8 , R 9 , R 10 , R 11 , R 12 At least one of the atoms contains deuterium.

[0257] 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 -SR 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 12are 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; Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0258] 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.

[0259] 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.

[0260] 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 substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 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.

[0261] 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 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, 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.

[0262] 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).

[0263] 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 Two of them are the same.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] R 11 and R 12 can be the same or different. In some embodiments, R 11 is deuterium. In some embodiments, R11 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.

[0268] In some embodiments, R 12 is deuterium. In some embodiments, R12 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.

[0269] In some embodiments, R 11 and R 12together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0270] 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, two or more R a In such a case, each R a can 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 R a 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.

[0271] In some embodiments, W1 , 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.

[0272] 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 is selected from the group consisting of 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).

[0273] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R3 , 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.

[0274] 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; 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).

[0275] 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.

[0276] In some embodiments, 5-HT 2A The 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 -SR 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 -SRa 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; Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0277] 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.

[0278] 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.

[0279] X 1 and X 2may 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 substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 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.

[0280] 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 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, 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.

[0281] 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).

[0282] 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 Two of them are the same.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] R 11 and R 12 can be the same or different. In some embodiments, R 11 is deuterium. In some embodiments, R11 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.

[0287] In some embodiments, R 12 is deuterium. In some embodiments, R12 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.

[0288] In some embodiments, R 11 and R 12together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0289] 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, two or more R a In such a case, each R a can 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 R a 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、 -SEt, -Sn-Pr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -OMe, These may include, but are not limited to, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2CFH2.

[0290] 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.

[0291] 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 is selected from the group consisting of 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).

[0292] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y2 , 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.

[0293] 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; 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).

[0294] 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.

[0295] In some embodiments, 5-HT 2A The receptor agonist is at least one N-substituted phenethylamine (NSP) having at least one deuterium atom, which is [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0296] 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, naphthyl 2-sulfonic acid, benzophenone-1,2-dione ... 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, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glutamic acid, Licholic 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., 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.).

[0297] 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), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8), 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-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5), or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 13 ) is formed.

[0298] In some embodiments, 5-HT 2A Receptor agonists are [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, of at least one compound selected from the group consisting of:

[0299] 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, including, for example, 5-HT, including fumarate, benzoate, and salicylate. 2A It is a receptor agonist.

[0300] 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-d 10 ) is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt. In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8). In some embodiments, the pharmaceutically acceptable salt is a 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 (5-MeO-DMT-d 10) fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5). In some embodiments, the pharmaceutically acceptable salt is the fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 13 ) fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate.

[0301] In some embodiments, 5-HT 2A The receptor agonist is a pharmaceutically acceptable salt of DMT or deuterated DMT, a crystalline solid disclosed in PCT / EP2023 / 050702, which is incorporated herein by reference in its entirety.

[0302] In some embodiments, the pharmaceutically acceptable salt is a fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (DMT, described below). In some embodiments, the fumarate salt of DMT is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 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. [ka]

[0303] In some embodiments, the pharmaceutically acceptable salt is a benzoate salt of DMT, which is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 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.

[0304] In some embodiments, the pharmaceutically acceptable salt is a salicylate salt of DMT, which is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 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.

[0305] In some embodiments, the pharmaceutically acceptable salt is a succinate salt of DMT, which 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 9.8°, 11.7°, 14.3°, 14.7°, 17.0°, 17.4°, 19.6°, 20.6°, 22.3°, 22.6°, 22.9°, 23.1°, 23.4°, 24.9°, 25.2°, 26.3°, 26.8°, 27.3°, 27.7°, 28.8°, 29.1°, 30.9°, 31.5°, 33.8°, 34.5°, 36.5°, and 39.2°, as determined by XRPD using a CuKα radiation source.

[0306] In some embodiments, the pharmaceutically acceptable salt is the oxalate salt of DMT, which is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 11.3°, 12.3°, 15.6°, 17.7°, 19.5°, 20.0°, 20.8°, 21.4°, 22.3°, 22.7°, 24.8°, 25.7°, 26.7°, 27.9°, 28.7°, 29.5°, 31.4°, 33.0°, 35.4°, 36.5°, and 38.6°, as determined by XRPD using a CuKα radiation source.

[0307] In some embodiments, the pharmaceutically acceptable salt is a glycolate salt of DMT, which is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 8.2°, 12.2°, 12.9°, 15.8°, 16.3°, 17.8°, 19.2°, 20.1°, 21.7°, 23.6°, 24.4°, 24.6°, 24.9°, 26.0°, 26.6°, 27.8°, 29.6°, 30.2°, 32.0°, 32.3°, 33.0°, 33.9°, and 34.6°, as determined by XRPD using a CuKα radiation source.

[0308] In some embodiments, the pharmaceutically acceptable salt is the hemi-oxalate salt of DMT, which has a molecular weight of 8.7°, 11.5°, 13.6°, 14.2°, 15.2°, 17.4°, 17.6°, 18.0°, 19.3°, 19.6°, 20.1°, 20.6°, 21.9°, 22.1°, 22.9°, 23.2°, 23.5°, 24.5°, 25.5°, 26.5°, 27.5°, 28.5°, 29.5°, 30.5°, 31.5°, 32.5°, 33.5°, 34.5°, 35.5°, 36.5°, 37.5°, 38.5°, 39.5°, 40.5°, 41.5°, 42.5°, 43.5°, 44.5°, 45.5°, 46.5°, 47.5°, 48.5°, 49.5°, 50.5°, 51.5°, 52.5°, 53.5°, 54.5°, 55.5°, 56.5°, 57.5°, 58.5°, 59.5°, 60.5°, 61.5°, 62.5°, 63.5°, 64.5°, 65.5°, 66.5°, 67.5°, 68.5°, 69.5°, 70.5°, 71.5°, 72.5°, 73.5°, 74.5°, 75.5°, and 33.9°, 25.0°, 25.5°, 26.1°, 26.4°, 27.1°, 28.4°, 28.7°, 29.8°, 30.4°, 30.7°, 31.4°, 31.8°, 33.4°, and 33.9° (2θ±0.2°).

[0309] In some embodiments, the pharmaceutically acceptable salt is a hemifumarate salt of DMT, which has a molecular weight of 8.1°, 11.3°, 12.2°, 13.3°, 14.2°, 16.2°, 17.6°, 18.3°, 18.6°, 19.5°, 19.8°, 20.0°, 20.2°, 20.9°, 21.4°, 21.9°, 22.3°, 22.7°, 23.7°, 24.7°, 25.7°, 26.7°, 27.7°, 28.7°, 29.7°, 30.7°, 31.7°, 32.7°, 33.7°, 34.7°, 35.7°, 36.7°, 37.7°, 38.7°, 39.7°, 40.7°, 41.7°, 42.7°, 43.7°, 44.7°, 45.7°, 46.7°, 47.7°, 48.7°, 49.7°, 50.7°, 51.7°, 52.7°, 53.7°, 54.7°, 55.7°, 56.7°, 57.7°, 58.7°, 59.7°, 60.7°, 61.7°, 62.7°, 63.7°, 64.7°, 65.7°, 66.7°, 67.7°, 68.7°, 69.7°, 70.7°, 71.7°, 72.7°, 73.7°, 7 and 32.7°, 22.9°, 23.8°, 24.5°, 25.0°, 25.2°, 26.1°, 26.4°, 26.9°, 28.4°, 28.8°, 29.5°, 29.8°, 30.9°, and 32.7° (2θ±0.2°).

[0310] 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, DMT-d is a fumarate salt of DMT-d 10of fumarate salt as determined by XRPD using a CuKα radiation source were 7.8°, 10.3°, 10.9°, 12.5°, 13.6°, 14.6°, 15.2°, 15.5°, 15.8°, 16.1°, 16.6°, 17.0°, 18.4°, 19.0°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.3°, 23.8°, 24.1°, 25.1°, 26.2°, 26.8°, 27. In some embodiments, DMT-d 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: 27.9°, 28.3°, 28.9°, 29.3°, 29.6°, 29.9°, 30.6°, 31.0°, 31.3°, 32.4°, 32.9°, 33.3°, 33.6°, 34.3°, 34.9°, 35.7°, 36.1°, 37.4°, 38.0°, and 38.5°. 10 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 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.8°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuKα radiation source. In some embodiments, DMT-d 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 23.8°, 24.1°, and 25.1°, as determined by XRPD using a CuKα radiation source. [ka]

[0311] In some embodiments, the pharmaceutically acceptable salt is DMT-d 10In some embodiments, DMT-d 10 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 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.3°, 24.6°, 25.1°, 25.3°, 25.5°, 26.9°, 28.3°, 28.9°, 29.3°, 31.4°, 31.6°, 32.0°, 32.3°, 32.8°, 35.1°, and 36.1° as determined by XRPD using a CuKα radiation source. 10 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 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.6°, 26.9°, 29.3°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source. 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 23.8°, 24.6°, 26.9°, 29.3°, and 35.1°, as determined by XRPD using a CuKα radiation source.

[0312] In some embodiments, the pharmaceutically acceptable salt is DMT-d 10 In some embodiments, DMT-d 10of salicylate are determined by XRPD using a CuKα radiation source at 9.6°, 10.5°, 11.4°, 12.3°, 13.4°, 14.2°, 14.9°, 15.6°, 16.1°, 17.1°, 18.1°, 18.7°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 22.2°, 22.6°, 23.7°, 24.6°, 25.2°, 25.6°, 26. In some embodiments, DMT-d 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: 26.1°, 26.4°, 27.4°, 27.5°, 27.8°, 28.5°, 28.8°, 29.4°, 29.7°, 30.3°, 31.0°, 31.3°, 32.1°, 32.7°, 33.1°, 33.5°, 34.4°, and 35.0°. 10 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 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.1°, 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. 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.3°, 24.6°, 25.6°, 28.5°, and 32.1°, as determined by XRPD using a CuKα radiation source.

[0313] Also, 5-HT 2A Also disclosed herein are methods for preparing pharmaceutically acceptable salts of receptor agonists. Various methods and procedures for addition salt formation are known to those skilled in the art, any of which may be utilized in the present disclosure. In some embodiments, the method comprises: (a) 5-HT in a solvent or mixture of solvents 2A suspending the free base of a receptor agonist; (b) Acid to 5-HT 2A contacting the compound with a receptor agonist to provide a mixture; (c) optionally heating the mixture; (d) optionally cooling the mixture; (e) isolating the salt.

[0314] The disclosed methods can use a variety of solvents, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent used in the method of preparing the salt is a protic solvent. In some embodiments, the solvent used in the method of preparing the salt is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxane (1,4-dioxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), ether solvents (e.g., t-butyl methyl ether (TBME)), hexane, heptane, and octane, and combinations thereof. In some embodiments, the solvent is ethanol.

[0315] Acids suitable for use in preparing pharmaceutically acceptable acid addition salts may include those previously described. The acid may be an inorganic acid or an organic acid, with organic acids being preferred. In some embodiments, the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, and glycolic acid. In some embodiments, the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, and succinic acid, with fumaric acid, benzoic acid, and salicylic acid being preferred.

[0316] In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is added to 5-HT 2A In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with the 5-HT receptor agonist. 2AContact with a receptor agonist. For example, if the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt, it may be desirable to use a substoichiometric amount of the acid.

[0317] In some embodiments, the mixture is heated, for example, to reflux, before cooling.

[0318] In some embodiments, the mixture is cooled and the salt precipitates from solution. In some embodiments, the salt precipitates from solution in a crystalline form. In some embodiments, the salt precipitates from solution in an amorphous form.

[0319] Isolation of the salt can be accomplished by a variety of well-known isolation techniques, such as filtration, decantation, etc. In some embodiments, the isolation step comprises filtering the mixture.

[0320] After isolation, additional crystallization and / or recrystallization steps may also be optionally performed, if desired, to, for example, increase purity, crystallinity, etc.

[0321] 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, 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, 5-HT is present as a hydrate. 2A The 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 2APharmaceutically 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 a solution, such as in the form of an aqueous solution, organic solvent solution, or mixed organic solvent-aqueous solution, 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.

[0322] 5-HT 2A Receptor 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 may 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 may be carried out by any suitable method known in the art.

[0323] In some embodiments, the compounds described herein, e.g., 5-HT 2AIn 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 may include equal mixtures or mixtures enriched in a particular diastereomer (where one diastereomer is present in a higher percentage than another).

[0324] In some embodiments, 5-HT 2A The receptor agonist is chemically pure, e.g., has a chemical purity of greater than 90%, 92%, 94%, 96%, 97%, 98%, or 99% by UPLC or HPLC. 2A The receptor agonist has no single impurity greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by UPLC or HPLC. In some embodiments, the 5-HT 2A The receptor agonist has a chemical purity of greater than 97 area %, greater than 98 area %, or greater than 99 area % by UPLC or HPLC. 2A The receptor agonist does not have more than 1 area%, more than 0.5 area%, more than 0.4 area%, more than 0.3 area%, or more than 0.2 area% of a single impurity as measured by UPLC or HPLC.

[0325] 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), acetonitrile, noble gases with NMDA receptor activity, such as xenon (Xe) and argon (Ar), or combinations thereof, including pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof. 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, dextromethorphan, xenon, argon, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0326] In some embodiments, the NMDA receptor antagonist is ketamine, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof (e.g., (S)-ketamine).

[0327] Pharmaceutically acceptable salts of NMDA receptor antagonists are contemplated herein. Suitable acids used to form pharmaceutically acceptable salts are those described herein.

[0328] 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, such as 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.

[0329] 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 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 may 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 may be carried out by any suitable method known in the art.

[0330] 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).

[0331] In some embodiments, the NMDA receptor antagonist is nitrous oxide and / or memantine, preferably nitrous oxide. In some embodiments, the NMDA receptor antagonist is nitrous oxide.

[0332] 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 thresholds, 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. In some embodiments, noble gases such as xenon and / or argon are used as NMDA receptor antagonists. In some embodiments, noble gases (e.g., xenon and / or argon) are used together with nitrous oxide or as a substitute for nitrous oxide. Thus, any embodiment described herein using nitrous oxide can be replaced with noble gases such as xenon, argon, or both.

[0333] In some embodiments, the combination medication is 5-HT 2AThis involves providing the 5-HT receptor agonist and 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, when the NMDA receptor antagonist is nitrous oxide, xenon, and / or argon, the 5-HT 2A The receptor agonist may be present in the liquid phase of the aerosol, while nitrous oxide, xenon, and / or argon may be present in the gas phase of the aerosol. Nitrous oxide, xenon, and / or argon (or a therapeutic gas mixture containing nitrous oxide) may be used to generate the aerosol or may be used as a carrier gas to deliver the generated aerosol to a 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. Alternatively, nitrous oxide, xenon, and / or argon may be used to generate aerosols, such as 5-HT 2A 5-HT is released by aerosolizing an aqueous solution containing both the receptor agonist and nitrous oxide, xenon, and / or argon (as dissolved gases). 2A In some embodiments, the combination drug therapy may be provided as a dissolved gas in the liquid phase of the aerosol along with the 5-HT receptor agonist as a separate dosage form. 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 injectables (e.g., intravenous, subcutaneous, intramuscular, etc.) for delivery as a bolus, infusion / perfusion, etc., while NMDA receptor antagonists are provided for inhalation delivery, such as in a therapeutic gas mixture.

[0334] 5-HT 2AThe co-action of receptor agonists with NMDA receptor antagonists (e.g., nitrous oxide, xenon, argon, ketamine, etc.) can provide multiple benefits. For example, NMDA receptor antagonists can control and / or reduce the effects of 5-HT2R activation, thereby reducing the risk of overstimulation and the occurrence of adverse psychotic effects such as acute hallucinatory crises. Furthermore, administration of NMDA receptor antagonists can reduce the effects of 5-HT 2A This may allow for the use of reduced therapeutic doses of the 5-HT receptor agonist, thereby reducing the likelihood of negative patient experiences or dose-dependent side effects. 2A Administration of a receptor agonist may reduce the amount of NMDA receptor antagonist required for therapeutic effect, which, in the case of NMDA receptor antagonists such as nitrous oxide, may reduce certain side effects such as induced involuntary laughter and the associated general feeling of anxiety. 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, xenon, argon, ketamine, etc.) to function more efficiently. Similarly, such co-administration reduces the time or amount of NMDA receptor antagonist (e.g., nitrous oxide, xenon, argon, ketamine, etc.) required for therapeutic effect. In particular, xenon is an expensive gas, and reducing the amount of xenon required to achieve a therapeutic effect results in significant cost savings.

[0335] NMDA receptor antagonists (e.g., nitrous oxide, xenon, and / or argon) 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 2AIt can be regulated by receptor activation and NMDA antagonism. Without being bound by theory, this regulation of mTOR pathway may 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 sub-hallucinogenic doses allows enhanced therapeutic efficacy with no or minimal psychosomatic adverse effects, such as acute hallucinogenic crisis.

[0336] Furthermore, neuronal atrophy in the prefrontal cortex (PFC) has been found to play an important role in the pathophysiology of other diseases or disorders disclosed herein that involve neuroplastic changes, such as depression and related disorders, neurological and neurodegenerative disorders, and those associated with suppressed neurogenesis or maladaptive neuroplasticity. The ability to promote both structural and functional plasticity in the PFC is hypothesized to underlie not only the rapid-acting antidepressant properties of the dissociative anesthetic ketamine, but also its long-lasting effects after a single administration. The combination drug therapies disclosed herein may function by synergistically increasing neuritogenesis and spinogenesis, including increased dendritic spine density, thereby providing or contributing to long-term therapeutic benefits. Indeed, NMDA receptor antagonism (e.g., as produced by nitrous oxide administration) and 5-HT 2A Both receptor agonist administration and drug administration were not associated with NMDA receptor antagonists or 5-HT 2A It activates neuroplasticity to a greater extent than can be achieved by administration of either receptor agonist alone, which may translate into significant therapeutic enhancement.

[0337] Thus, the combination drug therapies disclosed herein may induce transcriptional changes, for example, in the frontal cortex, that underlie beneficial clinical effects. 2ACombination therapy with a 5-HT receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist results in a synergistic increase in the expression of one or more genes (as measured by mRNA levels using reverse transcription quantitative polymerase chain reaction (RTqPCR)) in the brain, e.g., frontal cortex, of a subject, including the Fos proto-oncogene, AP-1 transcription factor subunit (c-FOS), early growth response protein 2 (EGR2), nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IKBA), serum / glucocorticoid-regulated kinase 1 (SGK1), and fibroblast growth factor 2 (FGF2), and the synergistic effect is greater than that of 5-HT administered individually (without the other). 2A It is defined as an expression level after combined drug therapy that is greater than the sum of the expression levels from a 5-HT receptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist, and is expressed in terms of change from baseline (pre-treatment). 2A If administration of a receptor agonist results in a 10% increase in expression of gene X compared to pre-treatment, and administration of an NMDA receptor antagonist results in a 10% increase in expression of gene X compared to pre-treatment, then a synergistic increase in expression of gene X from the combined drug therapy will be provided after a greater than 20% increase in expression of gene X compared to pre-treatment. Furthermore, the degree of synergy can be determined by the 5-HT 2A The increase in gene expression can be described as a percentage increase relative to the sum of the individual gene expression changes provided by administration of the NMDA receptor agonist and the NMDA receptor antagonist. In the above example, a combination drug therapy that achieves a 23% increase in expression of gene X compared to pre-treatment (defined herein as synergistic) increases the expression of 5-HT 2A This provides a 15% increase in the expression level of gene X (23% vs. 20%) relative to the sum of the % change in gene expression from pre-treatment provided by the separate administration of the receptor agonist and the NMDA receptor antagonist.

[0338] In some embodiments, the combination drug therapy disclosed herein synergistically increases the expression of c-FOS in the subject's brain, e.g., the frontal cortex. C-FOS is an immediate early gene associated with neuronal activity and neurogenesis (Velazquez FN, et al. c-Fos importance for brain development. Aging (Albany NY). 2015 Dec;7(12):1028-9). Thus, in some embodiments, the therapeutic methods of the present disclosure increase the levels of c-FOS, resulting in increased neuronal firing, learning, memory, and cognitive processes. In some embodiments, the combination drug therapy increases the expression of c-FOS (as measured by mRNA levels using RTqPCR) in the subject's frontal cortex by synergistically increasing the expression of 5-HT 2A The combined percent change in c-FOS expression from pre-treatment provided by the separate administration of the receptor agonist and the NMDA receptor antagonist increases by at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, and up to 100%, up to 95%, up to 90%, up to 85%, and up to 80%.

[0339] In some embodiments, the combination drug therapies disclosed herein synergistically increase the expression of EGR2 in the subject's brain, e.g., the frontal cortex. EGR2 is a growth factor that has been shown to mediate long-term potentiation associated with neuronal plasticity and the stabilization and maintenance of cognitive function (Mengozzi M, et al. Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9617-22), and is associated with the upregulation of 5-HT 2AIt has been proposed that 5-HT2A is a marker of hallucinogenic activation of the receptor (Gonzalez-Maeso et al., Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci. 2003;23(26),8836-43), and therefore, in some embodiments, the therapeutic methods of the present disclosure increase the levels of EGR2, resulting in neuroplastic and neuroprotective outcomes. In some embodiments, the combination drug therapy increases the expression of EGR2 (as measured by mRNA levels using RTqPCR) in the subject's frontal cortex, resulting in 5-HT2A activation. 2A The combined percent change in EGR2 expression from pre-treatment provided by the separate administration of the receptor agonist and the NMDA receptor antagonist increases by at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, and up to 60%, up to 50%, up to 40%, up to 30%, and up to 25%.

[0340] In some embodiments, the combination drug therapy disclosed herein synergistically increases the expression of IKBA in the subject's brain, for example, in the frontal cortex. IKBA is known to be an inflammatory response mediator and a transcriptional regulator of synaptic plasticity, and therefore, in some embodiments, the treatment method disclosed herein increases the level of IKBA, resulting in neuroplasticity and neuroinflammatory regulation. In some embodiments, the combination drug therapy increases the expression of IKBA (measured by mRNA levels using RTqPCR) in the subject's frontal cortex, by synergistically increasing the expression of 5-HT 2A The combined percent change in IKBA expression from pre-treatment provided by the separate administration of the receptor agonist and NMDA receptor antagonist increases by at least 1%, at least 1.5%, at least 2%, and up to 20%, up to 15%, up to 10%, up to 5%, or up to 3%.

[0341] In some embodiments, the combination drug therapy disclosed herein synergistically increases the expression of SGK1 in the subject's brain, e.g., the frontal cortex. SGK1 is a neuronal stress response mediator, and increased expression of SGK1 in neurons of the CNS is associated with its role in activity-dependent promotion of learning and memory formation, long-term memory consolidation, promoting the expression of long-term potentiation in hippocampal neurons, and regulating synaptic plasticity (Arteaga, M. et al. A brain-specific SGK1 splice isoform regulates expression of ASIC1 in neurons, 2008, Proceedings of the National Academy of Sciences of the United States of America, 105, 4459-64). In some embodiments, the combination drug therapy synergistically increases the expression of SGK1 (measured by mRNA levels using RTqPCR) in the subject's frontal cortex, e.g., the frontal cortex, in response to 5-HT. 2A The combined percent change in SGK1 expression from pre-treatment provided by the separate administration of the receptor agonist and the NMDA receptor antagonist increases by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, and up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%.

[0342] In some embodiments, the combination drug therapy disclosed herein synergistically increases FGF2 expression in the subject's brain, e.g., the frontal cortex. FGF2 is a trophic factor expressed in both neuronal and glial cells and plays a major role in the response of adult brain to injury and neuroplastic events such as postnatal neurogenesis, dendritic plasticity, and long-term potentiation. More recently, FGF2 has also been implicated in anxiety and depressive behaviors in both rodent models and human studies. In humans, FGF2 and FGF receptor levels are downregulated in postmortem tissues from individuals with a history of mood disorders. In some embodiments, the combination drug therapy increases the expression of FGF2 (measured by mRNA levels using RTqPCR) in the subject's frontal cortex in a manner similar to that of 5-HT. 2AThe combined percent change in FGF2 expression from pre-treatment provided by the separate administration of the receptor agonist and the NMDA receptor antagonist increases by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, and up to 30%, up to 25%, up to 20%, up to 15%.

[0343] 5-HT administered in combination drug therapy 2A The ratio of 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 particular compounds used for the receptor agonists and NMDA receptor antagonists will depend on a variety of factors, including the age, sex, and general health of the patient, the time of administration, the rate of excretion, and the severity of the particular disease or condition being treated. 2A The weight ratio of receptor agonist to NMDA receptor antagonist can be in the range of 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, and up to about 2:1. In certain circumstances, ratios outside this range may be used.

[0344] Concomitant medications include 5-HT 2AIt is intended to encompass sequential administration of a 5-HT receptor agonist and an NMDA receptor antagonist (e.g., nitrous oxide, xenon, and / or argon), 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 having a fixed ratio of each active ingredient, or multiple single dosage forms for each of the active ingredients. 2A The administration of the 5-HT receptor agonist and the NMDA receptor antagonist (e.g., nitrous oxide, xenon, and / or argon), whether in a single dosage form or separate dosage forms, can be carried out independently 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 The 5-HT receptor agonist is administered intravenously (IV) as a bolus followed by an infusion / perfusion, and the NMDA receptor antagonist is administered via inhalation. 2A The 5-HT receptor agonist is administered subcutaneously and the NMDA receptor antagonist is administered via inhalation. 2A The 5-HT receptor agonist is administered intramuscularly and the NMDA receptor antagonist is administered via inhalation. 2A The 5-HT receptor agonist is administered intranasally and the NMDA receptor antagonist is administered via inhalation. 2A The 5-HT receptor agonist is administered orally and the NMDA receptor antagonist is administered via inhalation. 2A Both the receptor agonist and the NMDA receptor antagonist are administered transdermally, subcutaneously, intramuscularly, or intravenously. Compositions for inhalation, including pharmaceutically acceptable excipients for single or separate dosage forms, are described herein.

[0345] The present disclosure provides a method for treating rheumatoid arthritis using the 5-HT agonist disclosed herein in combination with any one or more of the NMDA receptor antagonists disclosed herein. 2A The 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) and nitrous oxide, 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. Any of the combinations described may additionally include xenon, or any of the combinations described may replace nitrous oxide with xenon.

[0346] 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 10 ) and nitrous oxide, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8) 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, 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5) and nitrous oxide, 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 13 ) and nitrous oxide, 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol 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, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8) and ketamine, 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, 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5) and ketamine, 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 13 ) and ketamine, 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol and ketamine, including pharmaceutically acceptable salts, stereoisomers, or solvates of any compound in the combination. Any of the combinations described may additionally include xenon, or any of the combinations described may replace nitrous oxide with xenon.

[0347] In the combination drug therapy disclosed herein, 5-HT 2A The 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 and provide therapy.

[0348] 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, e.g., hydrolyzed or oxidized, in the host to form the combination drug therapy of the present disclosure. Typical examples of prodrugs include compounds that are metabolized, e.g., hydrolyzed or oxidized, in the host to form the active compound (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 an 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.

[0349] Pharmaceutical Composition Also disclosed herein are pharmaceutical compositions. The pharmaceutical compositions can be used in combination drug therapy. The pharmaceutical compositions can be used to treat 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 pharmaceutically acceptable excipients.

[0350] 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.

[0351] 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 per se or as a pharmaceutical composition containing the active ingredient in combination with a pharmaceutically acceptable excipient. The pharmaceutical composition comprises at least 0.0001%, at least 0.001%, at least 0.01%, at least 0.05%, at least 0.1%, at least 0.5%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% by weight of the 5-HT disclosed herein, based on the total weight of the pharmaceutical composition. 2A In some embodiments, the pharmaceutical composition comprises up to 99%, up to 98%, up to 97%, up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, or up to 5% by weight of the 5-HT disclosed herein, based on the total weight of the pharmaceutical composition. 2A These include receptor agonists and / or NMDA receptor antagonists.

[0352] For fixed doses, 5-HT in unit dose preparations 2AThe amount of receptor agonist and / or NMDA receptor antagonist may be, for example, (on an activity basis) 0.001 mg to 1000 mg, or 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 500 mg, up to 400 mg, up to 300 mg, up to 200 mg, up to 100 mg, up to 95 mg, up to 90 mg, up to 85 mg, up to 80 mg, up to 75 mg, up to 70 mg, up to 65 mg, up to 60 mg, up to 55 mg, up to 50 mg, up to 45 mg, up to 40 mg, up to 35 mg, up to 30 mg of 5-HT. 2A Receptor agonists and / or NMDA receptor antagonists, or any range therebetween, or as otherwise deemed appropriate using sound medical judgment according to the particular use, route of administration, dosage form, potency of the active ingredient, etc. The compositions can also include other compatible active ingredients, if desired.

[0353] 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), 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) may be present in the pharmaceutical composition with a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, or at least 99 wt%, based on the total weight of the isotopologues of the 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), or formula (VI-b). For example, when DMT-d is used as the compound of interest, 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 compound 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 compound.

[0354] In some embodiments, any position designated as having deuterium in a compound has a minimum deuterium incorporation greater than the percentage naturally occurring in hydrogen (a natural abundance of deuterium of about 0.016 atomic %), hi some embodiments, any position designated as having deuterium in a compound 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.

[0355] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and at least two 5-HT 2A and a receptor agonist (referred to herein as an "active agonist mixture"). Such pharmaceutical compositions may optionally further include one or more NMDA receptor antagonists when it is desirable to administer combination drug therapies in the same dosage form.

[0356] In some embodiments, the pharmaceutical composition comprises: (i) a DMT-d 10(ii) DMT-d9, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 or a pharmaceutically acceptable salt, solvate, or prodrug thereof; (iii) DMT-d9, i.e., one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; or a prodrug thereof, and optionally (iii) an active agonist mixture comprising DMT-d8, i.e., one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. In some embodiments, the active agonist mixture comprises 60% to 99%, 60% to 98%, 65% to 97%, 70% to 96%, 75% to 95%, 80% to 94%, 85% to 93%, 90% to 92% by weight, or any range therebetween, of (i) DMT-d 10, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the active agonist mixture comprises a total of 1% to 40%, 2% to 40%, 3% to 35%, 4% to 30%, 5% to 25%, 6% to 20%, 7% to 15%, 8% to 10%, or any range therebetween, of (ii) DMT-d9, i.e., one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, based on the total weight of the active agonist mixture. In some embodiments, the active agonist mixture comprises, in total, 0% to less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.25% by weight, or any range therebetween, of (iii) DMT-d, i.e., one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,1-d, 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-2,2-d, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,2-d, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, based on the total weight of the active agonist mixture. 10, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and (ii) DMT-d9, i.e., one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0357] In some embodiments, the pharmaceutical composition comprises: (i) 5-MeO-DMT-d 10(ii) 5-MeO-DMT-d9, i.e., 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, solvate, or prodrug thereof; (iii) 5-MeO-DMT-d9, i.e., one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof; or a prodrug thereof, and optionally (iii) an active agonist mixture comprising 5-MeO-DMT-d8, i.e., one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. In some embodiments, the active agonist mixture comprises 60% to 99%, 60% to 98%, 65% to 97%, 70% to 96%, 75% to 95%, 80% to 94%, 85% to 93%, 90% to 92%, or any range therebetween, by weight of (i) 5-MeO-DMT-d 10, i.e., 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, solvate or prodrug thereof. In some embodiments, the active agonist mixture comprises, in total, between 1% and 40%, 2% and 40%, 3% and 35%, 4% and 30%, 5% and 25%, 6% and 20%, 7% and 15%, 8% and 10%, or any range therebetween, of (ii) 5-MeO-DMT-d9, i.e., one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the active agonist mixture. In some embodiments, the active agonist mixture comprises, in total, 0% to less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.25% by weight, or any range therebetween, of (iii) 5-MeO-DMT-d8, i.e., one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, based on the total weight of the active agonist mixture. In some embodiments, the active agonist mixture comprises: (i) 5-MeO-DMT-d 10or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and (ii) 5-MeO-DMT-d9, i.e., 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d3 and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0358] In some embodiments, the pharmaceutical composition comprises: (i) 5-MeO-DMT-d 13 , i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; (ii) 5-MeO-DMT-d 12 , i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and optionally, (iii) 5-MeO-DMT-d 11or active agonist mixtures comprising one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof. In some embodiments, the active agonist mixture comprises 60% to 99%, 60% to 98%, 65% to 97%, 70% to 96%, 75% to 95%, 80% to 94%, 85% to 93%, 90% to 92%, or any range therebetween, by weight of (i) 5-MeO-DMT-d 13 , i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the active agonist mixture comprises (ii) 5-MeO-DMT-d4 in a total amount of 1% to 40%, 2% to 40%, 3% to 35%, 4% to 30%, 5% to 25%, 6% to 20%, 7% to 15%, 8% to 10%, or any range therebetween, based on the total weight of the active agonist mixture. 12 In some embodiments, the active agonist mixture comprises one or more of (iii) 5-MeO-DMT-d, i.e., 2-(5-(methoxy-d)-1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,2,2-d and 2-(5-(methoxy-d)-1H-indol-3-yl)-N,N-bis(methyl-d)ethan-1-amine-1,1,2-d, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the active agonist mixture comprises, in total, 0% to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, of (iii) 5-MeO-DMT-d11 In some embodiments, the active agonist mixture comprises one or more of: 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. In some embodiments, the active agonist mixture comprises one or more of: (i) 5-MeO-DMT-d 13 , i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and (ii) 5-MeO-DMT-d 12 or consisting essentially of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0359] In some embodiments, the pharmaceutical composition comprises one or more of: (i) 5-MeO-DMT-d5, i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; (ii) 5-MeO-DMT-d4, i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)- and (iii) an active agonist mixture comprising one or more of N,N-dimethylethan-1-amine-1-d and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and optionally, (iii) 5-MeO-DMT-d3, i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the active agonist mixture comprises, in total, 60% to 99%, 60% to 98%, 65% to 97%, 70% to 96%, 75% to 95%, 80% to 94%, 85% to 93%, 90% to 92%, or any range therebetween, of (i) 5-MeO-DMT-d5, i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the active agonist mixture.In some embodiments, the active agonist mixture comprises, in total, between 1% and 40%, 2% and 40%, 3% and 35%, 4% and 30%, 5% and 25%, 6% and 20%, 7% and 15%, 8% and 10%, or any range therebetween, of (ii) 5-MeO-DMT-d4, i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, based on the total weight of the active agonist mixture. In some embodiments, the active agonist mixture comprises 0% to less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.25% by weight, or any range therebetween, of (iii) 5-MeO-DMT-d3, i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the active agonist mixture. In some embodiments, the active agonist mixture comprises (i) 5-MeO-DMT-d5, i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and (ii) 5-MeO-DMT-d4, i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0360] In some embodiments, two or more 5-HT agonists comprising the active agonist mixture 2AEach of the receptor agonists is in the form of a pharmaceutically acceptable salt. In some embodiments, the two or more 5-HT receptor agonists that make up the active agonist mixture are in the form of a pharmaceutically acceptable salt. 2A Each of the 5-HT receptor agonists is in the form of a fumarate salt. In some embodiments, the two or more 5-HT receptor agonists that make up the active agonist mixture are 2A In some embodiments, the two or more 5-HT receptor agonists that make up the active agonist mixture are each in the form of a benzoate salt. 2A Each of the 5-HT receptor agonists is in the form of a salicylate. In some embodiments, the two or more 5-HT receptor agonists that make up the active agonist mixture are 2A Each of the receptor agonists is in the form of a succinate salt.

[0361] 5-HT 2AReceptor agonists, and similarly NMDA receptor antagonists, may 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 single molar ratio 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 approximately equal molar ratios (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.

[0362] The pharmaceutical composition includes one or more crystalline polymorphs of 5-HT 2A The 5-HT receptor agonist may be formulated in one or more crystalline forms. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline polymorphs. In some embodiments, the pharmaceutical composition comprises a single crystalline polymorph. The pharmaceutical composition may comprise one or more amorphous polymorphs of 5-HT receptor agonists. 2AThe receptor agonist may be formulated in one or more amorphous forms. In some embodiments, the pharmaceutical composition comprises a mixture of amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a single amorphous polymorph. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline and amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a 5-HT 2A For example, the pharmaceutical composition may comprise a highly pure crystalline form of a 5-HT receptor agonist. 2A The 5-HT receptor agonist present in the pharmaceutical composition may be 2A At least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the receptor agonist is in crystalline form as determined by, for example, X-ray powder diffraction and / or DSC.

[0363] 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, xenon, and / or argon) 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 (e.g., nitrous oxide, xenon, and / or argon) are formulated in a solution, which is then aerosolized and administered. In one non-limiting example, 5-HT 2A The receptor agonist and nitrous oxide may be formulated in an aqueous solution, with nitrous oxide present as a dissolved gas. 2A An aerosol, preferably a mist, containing droplets of the receptor agonist and nitrous oxide may be generated, and the droplets are dispersed in a gas phase, such as oxygen or air. 2A An aerosol combining both a 5-HT receptor agonist and an NMDA receptor antagonist may be administered to a patient via inhalation. 2ABoth the receptor agonist and the NMDA receptor antagonist (eg, ketamine) are administered together in a single pharmaceutical composition adapted for transdermal or subcutaneous administration, for example, a transdermal patch.

[0364] In some embodiments, 5-HT 2A The 5-HT receptor agonist and the NMDA receptor antagonist are administered as separate pharmaceutical compositions. When in separate pharmaceutical compositions, the combination medications may be provided / packaged together in a kit. 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, xenon, and / or argon) is adapted for parenteral delivery, such as intravenous, intramuscular, or subcutaneous administration, and a second pharmaceutical composition containing an NMDA receptor antagonist (e.g., nitrous oxide, xenon, and / or argon) is adapted for inhalation administration, such as a therapeutic gas mixture.

[0365] 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. 2A The receptor agonist may be formulated as a solution, while the NMDA receptor antagonist (e.g., nitrous oxide, xenon, and / or argon) may be formulated in a therapeutic gas mixture. 5-HT dissolved in the solution is then added. 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. 2AAn aerosol combining both a 5-HT receptor agonist and an NMDA receptor antagonist may be administered to a patient via inhalation. 2A The receptor agonist may be formulated as a solution, while the NMDA receptor antagonist (e.g., nitrous oxide, xenon, and / or argon) may be formulated in a therapeutic gas mixture. 5-HT dissolved in the solution is then added. 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.

[0366] A "pharmaceutically acceptable excipient" can be an excipient approved by a federal or state 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 any excipient that is suitable for use in the preparation of 5-HT-A or 5-HT-B of the present disclosure. 2AThe term "medicament" 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 pharmaceutically acceptable 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. Pharmaceutically acceptable excipients may include water, saline, juice (e.g., fruit juice), gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Pharmaceutically acceptable excipients may also include one or more gases, for example, to serve 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 via intravenous, intramuscular, or subcutaneous administration. In some embodiments, the pharmaceutically acceptable excipient is useful for transdermal administration.

[0367] 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.

[0368] Pharmaceutical compositions can take 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 to humans in accordance with routine procedures as pharmaceutical compositions adapted for oral, intravenous, subcutaneous, intramuscular, intradermal, transdermal, or inhalation administration, or other routes of administration described herein. Examples of suitable pharmaceutically acceptable 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 choice of excipient will be determined in part by the specific active ingredient and the particular method used to administer the composition. Therefore, there are a wide variety of suitable formulations of pharmaceutical compositions. Liquid form preparations include solutions and emulsions, such as water, water / propylene glycol solutions, viscous aqueous solutions / suspensions, or organic solvents. When administered to mammals, the compounds and compositions of the present disclosure and pharmaceutically acceptable excipients may be sterilized. In some cases, for example, when the subject compounds are administered parenterally (e.g., intravenously) or via inhalation, aqueous media such as water, saline, viscous aqueous solutions / suspensions, and aqueous dextrose and glycerol solutions are used as vehicles.

[0369] As described below, pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid, semi-solid, or liquid form, including those adapted for: A. Oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, films, or capsules, such as those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue, etc.; B. Parenteral administration, such as subcutaneous, intradermal, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained release formulation, including viscous aqueous solutions / suspensions or others producing a depot effect; C. Topical / transdermal administration, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin, or to a mucosal surface such as an orifice and / or nasal cavity, e.g., as an aqueous or non-aqueous solution, suspension, liposomal dispersion, emulsion, microemulsion, or sol-gel, e.g., intravaginally or rectally as a pessary, cream, or foam; D. Modified-release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, and programmed-release, and gastroretentive dosage forms, which 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.

[0370] Tamper-resistant dosage forms / packaging of any of the disclosed pharmaceutical compositions are contemplated.

[0371] A. Oral Administration The pharmaceutical compositions disclosed herein can be provided in solid, semi-solid, or liquid dosage forms for oral administration, including both intestinal / 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. The oral dosage forms of the present disclosure minimize enzymatic degradation mediated by monoamine oxidase (MAO) enzymes, such as deamination / oxidation processes, thereby enhancing the efficacy of the compounds disclosed herein, e.g., 5-HT 2A To improve the oral bioavailability of the receptor agonist, it may optionally be formulated with an MAO inhibitor, including a reversible inhibitor of monoamine oxidase type A (RIMA). In addition to the active ingredient and any MAO inhibitor, the pharmaceutical composition may contain one or more pharmaceutically acceptable vehicles, 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.

[0372] Binders or granulating agents impart cohesive properties to the tablet and ensure that the tablet 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), bee gum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (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.

[0373] 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.

[0374] 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.

[0375] 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 Bee Gum 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.

[0376] 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.

[0377] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-free talc.

[0378] 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 to hydrous heavy metal oxides, resulting in an insoluble form of the dye.

[0379] Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.

[0380] Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweetening agents, such as saccharin and aspartame.

[0381] 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.

[0382] Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, beegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0383] Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol.

[0384] Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0385] 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.

[0386] It is understood that many excipients can serve multiple functions, even within the same formulation.

[0387] The pharmaceutical compositions disclosed herein may be formulated as compressed tablets, tablet triturates, chewable lozenges, fast-dissolving 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 more than one compression cycle and include layered tablets and press-coated or dry-coated tablets.

[0388] 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.

[0389] 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. 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.

[0390] In some embodiments, the pharmaceutical compositions of the present disclosure may be orodispersible dosage forms (ODx), including orally disintegrating 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.

[0391] In some embodiments, the orodispersible dosage form is a sublingual dosage form that disintegrates / dissolves under the tongue, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the mucous membrane under the tongue and enter the venous circulation there. In some embodiments, the sublingual dosage form disintegrates / dissolves under the tongue, whereby, when mixed with saliva, it is converted into a liquid or semi-solid dosage form such as a solution, syrup, or paste, which is then swallowed. In some embodiments, the orodispersible dosage form is an oral dosage form that disintegrates / dissolves in the oral cavity, whereby the contents (e.g., a compound of the present disclosure) are absorbed through the mucous membrane under the tongue and enter the venous circulation there. In some embodiments, the oral dosage form disintegrates / dissolves in the oral cavity, whereby, when mixed with saliva, it is converted into a liquid or semi-solid dosage form such as a solution, syrup, or paste, which is then swallowed.

[0392] Orally disintegrating tablets can be prepared by different 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.

[0393] 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 mention being made of 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.

[0394] In some embodiments, the pharmaceutical composition is in the form of a lyophilized orodispersible film (ODF) (or wafer). In some embodiments, the pharmaceutical composition is in the form of a lyophilized ODF protected for long-term storage by special packaging that excludes moisture, oxygen, and light. In some embodiments, the lyophilized 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 lyophilized ODF comprises a thin, water-soluble film matrix. In some embodiments, the ODF comprises a two-component framework of a lyophilized matrix system that work together 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.

[0395] 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 of the layers can be different, or two of the 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.

[0396] Pharmaceutically acceptable excipients that may be used in orodispersible dosage forms (ODx) include, but are not limited to, cryoprotectants, preservatives, antioxidants, stabilizers, solubilizers, flavoring agents, cyclodextrins, bioadhesives, permeation / absorption enhancers, or other pharmaceutically acceptable vehicles listed herein.

[0397] 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.

[0398] Examples of pharmaceutically acceptable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0399] 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.

[0400] 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 gel.

[0401] Examples of pharmaceutically acceptable solubilizers (or dissolution aids) 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, hydroxyethyl methacrylate, methylcellulose ... Examples of suitable sucrose-soluble 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.

[0402] Flavoring agents include natural flavors extracted from plants such as fruits, 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.

[0403] 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.

[0404] Examples of suitable bioadhesives include, but are not limited to, cyclodextrins, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose, modified cellulose gums, and sodium carboxymethylcellulose (NaCMC); starch derivatives such as moderately crosslinked starch, modified starch, and sodium starch glycolate; acrylic polymers such as carbomer and its derivatives (e.g., polycarbophil, Carbopol®); polyvinylpyrrolidone (PVP); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, and pectin; scleroglucan; xanthan gum; guar gum; polyco-(methyl vinyl ether / maleic anhydride); and croscarmellose (e.g., croscarmellose sodium). Such polymers may be crosslinked. Combinations of two or more bioadhesives may also be used.

[0405] 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; menthol; 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.

[0406] Disclosed herein is a pharmaceutical composition in a modified release dosage form, comprising an active ingredient disclosed herein and one or more of the release-controlling excipients or carriers described herein.Suitable modified 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-release-controlling excipients or carriers.

[0407] Further disclosed herein are pharmaceutical compositions in enteric-coated dosage forms 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.

[0408] 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.

[0409] 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 consecutive pulses separated by about 0.1 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 substances.

[0410] Also disclosed herein are pharmaceutical compositions in dosage forms for oral administration to a subject, which contain the 5-HT 2AThe 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.

[0411] 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.

[0412] 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.

[0413] 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.

[0414] 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.

[0415] The pharmaceutical compositions disclosed herein may be formulated as liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.

[0416] In some embodiments, oral liquid dosage forms are prepared by reconstituting a solid dosage form (e.g., an effervescent dosage form) disclosed herein in a pharmaceutically acceptable liquid medium (e.g., an aqueous medium) such as water, juice, or other drinkable fluid prior to use. In some embodiments, oral liquid dosage forms contain crystalline forms of 5-HT. 2A In some embodiments, the oral liquid dosage form is prepared by reconstituting a solid dosage form containing a pharmaceutically acceptable salt of a receptor agonist in a pharmaceutically acceptable aqueous medium. In some embodiments, the oral liquid dosage form contains an amorphous form of 5-HT 2A A solid dosage form containing a pharmaceutically acceptable salt of a receptor agonist is prepared by reconstitution in a pharmaceutically acceptable aqueous medium.

[0417] Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid and may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and, optionally, a preservative. Aqueous alcoholic solutions may 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 having one or more hydroxyl groups, e.g., propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. 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.

[0418] 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.

[0419] 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. The pharmaceutical compositions disclosed herein for oral administration may also be disclosed in the form of liposomes, micelles, microspheres, or nanosystems.

[0420] The pharmaceutical compositions disclosed herein may be disclosed as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable excipients used in effervescent granules or powders may include organic acids and a carbon dioxide source.

[0421] Coloring and flavoring agents may be used in all of the above dosage forms.

[0422] 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 complement the desired action. One example is the co-formulation of the active ingredient (e.g., 5-HT 2+ ) by minimizing enzymatic degradation mediated by monoamine oxidase (MAO) enzymes, such as deamination / oxidation processes. 2A Certain dosage forms (e.g., oral dosage forms) are formulated with MAO inhibitors, including reversible inhibitors of monoamine oxidase type A (RIMA), to improve the oral bioavailability of MAO inhibitors (receptor agonists).

[0423] 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.

[0424] 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).

[0425] In some embodiments, the pharmaceutical composition is in the form of an injectable (liquid) dosage form (e.g., for administration intravenously, intramuscularly, subcutaneously, etc.). In some embodiments, the injectable (liquid) dosage form (e.g., for administration intravenously, intramuscularly, subcutaneously, etc.) is prepared by reconstituting a solid dosage form disclosed herein in a pharmaceutically acceptable liquid medium, such as water, saline, a viscous aqueous solution / suspension, a water-miscible vehicle (e.g., an organic solvent such as N-methyl-2-pyrrolidone), etc., prior to use. In some embodiments, the injectable (liquid) dosage form contains a crystalline form of 5-HT. 2A In some embodiments, the injectable (liquid) dosage form is prepared by reconstituting a solid dosage form containing a pharmaceutically acceptable salt of a receptor agonist and / or an NMDA receptor antagonist in a pharmaceutically acceptable liquid medium. In some embodiments, the injectable (liquid) dosage form contains an amorphous form of 5-HT. 2A The solid dosage form is prepared by reconstitution of a pharmaceutically acceptable salt of a receptor agonist and / or an NMDA receptor antagonist in a pharmaceutically acceptable liquid medium.

[0426] 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.

[0427] 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.

[0428] Suitable antimicrobial agents or preservatives 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 isoton...

Claims

1. A pharmaceutical composition for treating a subject having a central nervous system (CNS) disorder or mental illness, comprising a 5-HT2A receptor agonist, wherein the pharmaceutical composition comprises: It is administered in combination with the nitrous oxide N-methyl-D-aspartate (NMDA) receptor antagonist, and the 5-HT2A receptor agonist, 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4, 2-(1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1-d2, 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4, 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d2, and 2-(5-(methoxy-d3)-1H-indole-3-yl)-N,N-bis(methyl-d3)ethane-1-amine-1,1,2,2-d4 The pharmaceutical composition comprising at least one compound selected from the group consisting of, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

2. The above 5-HT ２Ａ The receptor agonist is 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-1,1,2,2-d ４ 、2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-1,1-d ２ [[ID=!0]]、2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-1,1,2,2-d ４ 、2-(5-(methoxy-d ３ )-1H-indol-3-yl)-N,N-dimethylethane-1-amine-1,1-d ２ 、及び2-(5-(methoxy-d ３ )-1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-1,1,2,2-d ４ The pharmaceutical composition according to claim 1, comprising a fumarate, benzoate, salicylate, or succinate of at least one compound selected from the group consisting of

3. The aforementioned 5-HT ２Ａ The receptor agonist is (i) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, (ii) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2,2-d ３ and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2-d ３ One or more of the above, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and optionally, (iii)2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1-d ２ , 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-2,2-d ２ , and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2-d ２ The pharmaceutical composition according to claim 1, which is an agonist mixture comprising one or more of the above, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

4. The activating agent mixture (i) contains 60% to 99% by weight of 2-(1H-indole-3-yl)-N,N-bis(methyl-d) based on the total weight of the activating agent mixture. ３ ) Ethane-1-amine-1,1,2,2-d ４ , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, (ii) based on the total weight of the agonist mixture, a total of 1% to 40% by weight of 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2,2-d ３ and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2-d ３ One or more of the above, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and (iii) based on the total weight of the agonist mixture, a total of 0% to less than 10% by weight of 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1-d ２ , 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-2,2-d ２ , and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2-d ２ The pharmaceutical composition according to claim 3, comprising one or more of the above, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

5. The aforementioned CNS disorder or mental illness may 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 suicidal 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, nicotine use disorder, etc. The pharmaceutical composition according to claim 1, which is at least one selected from the group consisting of caine 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, bulimia nervosa, pedophilia disorder, exhibitionism, voyeurism, fetishism disorder, sexual masochism or sadism disorder, cross-dressing disorder, sexual dysfunction, peripheral neuropathy, and obesity.

6. The pharmaceutical composition according to claim 1, wherein the CNS disorder or mental disorder is major depressive disorder (MDD).

7. The pharmaceutical composition according to claim 1, wherein the CNS disorder or mental disorder is treatment-resistant depression (TRD).

8. The pharmaceutical composition according to claim 1, wherein the CNS disorder or mental disorder is generalized anxiety disorder (GAD).

9. The pharmaceutical composition according to claim 1, wherein the CNS disorder or mental disorder is generalized anxiety disorder (GAD) accompanied by depression.

10. The pharmaceutical composition according to claim 1, wherein the CNS disorder or mental disorder is social anxiety disorder.

11. The pharmaceutical composition according to claim 1, wherein the CNS disorder or mental disorder is alcohol use disorder.

12. The aforementioned 5-HT ２Ａ The pharmaceutical composition according to any one of claims 1 to 11, wherein the receptor agonist and the NMDA receptor antagonist are administered to the subject as an aerosol by inhalation.

13. The aforementioned 5-HT ２Ａ The pharmaceutical composition according to any one of claims 1 to 11, wherein the receptor agonist and the NMDA receptor antagonist are administered in succession.

14. The aforementioned 5-HT ２Ａ The pharmaceutical composition according to any one of claims 1 to 11, wherein the receptor agonist is administered intravenously and the NMDA receptor antagonist is administered by inhalation.

15. The aforementioned 5-HT ２Ａ The pharmaceutical composition according to claim 14, wherein the receptor agonist is administered intravenously to the subject as a bolus, and subsequently by injection.

16. The aforementioned 5-HT ２Ａ The pharmaceutical composition according to any one of claims 1 to 11, wherein the receptor agonist is administered intramuscularly to the subject, and the NMDA receptor antagonist is administered by inhalation.

17. The aforementioned 5-HT ２Ａ The pharmaceutical composition according to any one of claims 1 to 11, wherein the receptor agonist is administered subcutaneously to the subject, and the NMDA receptor antagonist is administered by inhalation.

18. The pharmaceutical composition according to any one of claims 1 to 11, wherein the nitrous oxide is administered by inhalation as a therapeutic gas mixture containing the nitrous oxide.

19. The therapeutic gas mixture comprises nitrous oxide and O ２ A mixture of N ２ A mixture of O and air, N ２ O and a mixture of medical air, N ２ O, N ２ , and O ２ A mixture of N ２ O and O ２ A mixture of concentrated medical air, or N ２ O, He, and O ２ It is a mixture of, and The pharmaceutical composition according to claim 18, wherein the nitrous oxide is present in the therapeutic gas mixture at a concentration of 5 to 50% by volume relative to the total volume of the therapeutic gas mixture.

20. The method described above is (i) The 5-HT ２Ａ The expression of C-FOS in the target frontal cortex, as measured by mRNA levels relative to pre-treatment levels, compared to the sum of C-FOS expression levels after individual administration of receptor agonists and NMDA receptor antagonists; (ii) EGR2 expression in the frontal cortex of the subject, as measured by mRNA levels relative to pretreatment, compared to the sum of EGR2 expression levels after individual administration of the 5-HT2A receptor agonist and the NMDA receptor antagonist; (iii) IKBA expression in the frontal cortex of the subject, as measured by mRNA levels relative to pretreatment, compared to the sum of IKBA expression levels after individual administration of the 5-HT2A receptor agonist and the NMDA receptor antagonist; (iv) Expression of SGK1 in the frontal cortex of the subject, as measured by mRNA levels relative to pretreatment, compared to the sum of SGK1 expression levels after individual administration of the 5-HT2A receptor agonist and the NMDA receptor antagonist; and (v) The expression of FGF2 in the frontal cortex of the subject, as measured by mRNA levels relative to pretreatment, compared to the sum of the expression levels of FGF2 after individual administration of the 5-HT2A receptor agonist and the NMDA receptor antagonist. A pharmaceutical composition according to any one of claims 1 to 11, which synergistically increases [the specified value].

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