Deuterated tryptamine derivatives and methods of use

Abstract

This invention provides compounds and the use of such compounds in the treatment of diseases related to the serotonin 5-HT2 receptor. [Solution] A solid oral administration form comprising the compound described in formula (III-d) (R2, R6 and R7 are hydrogen, and R8 and R9 are fully deuterated methyl) or a pharmaceutically acceptable salt or solvate thereof. JPEG2026048628000132.jpg6463

Description

Technical Field

[0001] The present disclosure generally relates to compounds and, in some embodiments, to serotonin 5-HT2 receptor agonists and their use in the treatment of diseases associated with the 5-HT2 receptors.

Background Art

[0002] The serotonin 5-HT2 receptors (5-HT2Rs) have three closely related subtypes, 5-HT 2C , 2B , 5-HT 2B , and 5-HT 2C , which are the main targets of classical serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin, and 2,5-dimethoxy-4-bromoamphetamine (DOB). They share approximately 60% transmembrane amino acid homology, which poses challenges in designing molecules with selectivity for one subtype over the others. Each subtype is expressed in a distinct pattern in mammals (both peripheral tissues and the central nervous system) and, when stimulated, produces distinct biochemical, physiological, and behavioral effects. For example, activation of 5-HT 2A Rs mainly mediates hallucinogenic effects and causes anti-inflammatory effects, whereas activation of 5-HT 2C Rs decreases feeding behavior. However, chronic activation of 5-HT 2B Rs is associated with valvular heart disease (VHD), a life-threatening adverse event (AE). Furthermore, there is also concern that patients who may benefit from 5-HT 2A R drug therapy may be resistant to experiencing hallucinogenic effects.

[0003] Tryptamines are a class of serotonergic hallucinogens and have very high potency at serotonin 5-HT2Rs (in some cases, subnanomolar affinity). One tryptamine has a higher affinity for 5-HT 2B Rs and 5-HT 2C Rs than for 5-HT 2AIt is distinguished from typical hallucinogens and other serotonergic hallucinogens by its selectivity for Rs—up to 100 times in some cases.

[0004] AEs caused by tryptamine and other serotonergic hallucinogens are associated with relatively high dose intake. This is likely due to 5-HT 2A Rs and 5HT 2C Due to its extremely high potency at Rs, the active oral dose of tryptamine is extremely low. For example, 2C-C-NBOMe(2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethane-1-amine) is orally active at a low dose of 25 μg, while very potent hallucinogenic doses are in the range of 500-700 μg. Therefore, misuse or abuse at or above these doses can cause visual and auditory hallucinations, agitation, aggression, and psychosis, and intoxication is associated with toxicity (e.g., rhabdomyolysis) and death. Furthermore, tryptamine can undergo extensive first-pass metabolism and become inactive orally.

[0005] 5-HT 2B Serotonin 5-HT overcomes R-related problems and hallucinogenic effects. 2A There is a need for R agonists, as well as a need to improve their bioavailability and enhance their oral activity. There is a further need for efficient, more convenient, and controllable tryptamine formulations that do not result in neurologically toxic (e.g., psychotropic toxicity) plasma concentrations. [Overview of the project]

[0006] This disclosure is at least in part based on the identification of compounds that modulate serotonin 5-HT2 receptors and methods of using them to treat serotonin 5-HT2 receptor-related diseases. More specifically, this disclosure relates, for example, to once-daily administration of compounds that modulate 5-HT2 receptors without causing hallucinogenic effects. 2A This invention provides novel compounds that enable selective engagement with Rs and treatment of other neuropsychiatric and inflammation-related disorders.

[0007] While not bound by any particular theory, novel compounds described herein that exhibit selective deuteration, such as in the extracyclic component, are thought to enable significant delay in enzymatic degradation and an increase in the blood / brain ratio through improved exposure (i.e., prevention of acutely observed high drug concentrations (spikes) after administration), resulting in improved oral bioavailability. Some compounds described herein provide similar benefits through selective deuteration of the phenyl ring.

[0008] This specification discloses the compound of formula (III) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0009] In some embodiments, X1 and X2 are deuterium.

[0010] In some embodiments, Y1 and Y2 are hydrogen or deuterium.

[0011] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0012] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0013] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0014] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0015] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0016] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0017] In some embodiments, R4 is hydroxyl, and R2, R5, R6, and R7 If all are hydrogen atoms, then neither R8 nor R9 are -CD3. If R2, R4, R5, R6, and R7 are all hydrogen atoms, then neither R8 nor R9 are unsubstituted methyl groups.

[0018] In some embodiments, if R4 is hydroxyl, then R9 is hydrogen.

[0019] In some embodiments, if R4 is hydroxyl, then R9 is deuterium.

[0020] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0021] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0022] In some embodiments, the compound of formula (III) is as follows: formulas (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), (III-k), (III-l), (III-m), (III-n), (III-o), (III-p), (III-q), (III-r), (III-s), (III-t), (III-u), and (III-v).

[0023] This specification discloses the compound of formula (III-a) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0024] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0025] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0026] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0027] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0028] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0029] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0030] In some embodiments, if R4 is hydroxyl and R2, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both -CD3, and if R2, R4, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both unsubstituted methyl groups.

[0031] In some embodiments, if R4 is hydroxyl, then R9 is hydrogen or deuterium.

[0032] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0033] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0034] This specification discloses the compound of formula (III-b) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0035] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0036] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0037] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0038] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0039] In some embodiments, if R2, R6, and R7 are all hydrogen atoms, then R8 and R9 are both not unsubstituted methyl atoms.

[0040] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0041] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0042] This specification discloses the compound of formula (III-c) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0043] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0044] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0045] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0046] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0047] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0048] In some embodiments, both R8 and R9 are unsubstituted, partially, or completely overlapping. It is not hydrogenated ethyl.

[0049] This specification discloses the compounds of formula (III-d) or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0050] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0051] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0052] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0053] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0054] In some embodiments, if R2, R6, and R7 are all hydrogen, then R8 and R9 are both not -CD3.

[0055] In some embodiments, R9 is hydrogen.

[0056] In some embodiments, R9 is hydrogen or deuterium.

[0057] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0058] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0059] This specification discloses the compound of formula (III-e) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0060] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0061] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0062] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0063] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0064] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0065] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0066] This specification discloses compounds of formula (III-f) or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0067] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0068] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0069] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0070] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0071] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0072] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0073] This specification discloses the compound of formula (III-g) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0074] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0075] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0076] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0077] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0078] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0079] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0080] This specification discloses the compound of formula (III-h) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0081] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0082] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0083] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0084] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0085] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0086] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0087] This specification discloses the compound of formula (III-i) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0088] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0089] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0090] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0091] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0092] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0093] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0094] This specification discloses the compound of formula (III-j) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0095] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0096] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0097] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0098] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0099] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0100] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0101] This specification discloses the compound of formula (III-k) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0102] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0103] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0104] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0105] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0106] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0107] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0108] In some embodiments, if R4 is hydroxyl and R2, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both -CD3, and if R2, R4, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both unsubstituted methyl groups.

[0109] In some embodiments, if R4 is hydroxyl, then R9 is hydrogen or deuterium.

[0110] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0111] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0112] This specification discloses the compound of formula (III-l) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0113] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0114] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0115] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0116] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0117] In some embodiments, if R2, R6, and R7 are all hydrogen atoms, then R8 and R9 are both not unsubstituted methyl atoms.

[0118] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0119] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0120] This specification discloses the compound of formula (III-m) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0121] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0122] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0123] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0124] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0125] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0126] This specification discloses the compound of formula (III-n) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0127] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0128] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0129] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0130] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0131] In some embodiments, if R2, R6, and R7 are all hydrogen, then R8 and R9 are both not -CD3.

[0132] In some embodiments, R9 is hydrogen.

[0133] In some embodiments, R9 is deuterium.

[0134] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0135] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0136] This specification discloses the compound of formula (III-o) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0137] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0138] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0139] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0140] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0141] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0142] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0143] This specification discloses the compound of formula (III-p) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0144] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0145] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0146] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0147] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0148] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0149] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0150] This specification discloses the compound of formula (III-q) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0151] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0152] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogen.

[0153] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0154] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted or partially or fully deuterated methyl or ethyl.

[0155] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0156] In some embodiments, neither R8 nor R9 is unsubstituted or partially or fully deuterated ethyl.

[0157] Disclosed herein are the compounds described by formula (III-r) or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs.

Chemical formula

[0159] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogen.

[0160] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0161] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0162] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0163] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0164] This specification discloses the compound of formula (III-s) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0165] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0166] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0167] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0168] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0169] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0170] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0171] This specification discloses the compound of formula (III-t) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0172] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0173] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0174] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0175] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0176] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0177] In some embodiments, neither R8 nor R9 is unsubstituted or partially or fully deuterated ethyl.

[0178] Disclosed herein are compounds of formula (III-u) or optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

Chemical formula

[0179] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0180] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogen.

[0181] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0182] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted or partially or fully deuterated methyl or ethyl.

[0183] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0184] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0185] This specification discloses compounds of formula (III-v) or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0186] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0187] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0188] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0189] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0190] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0191] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0192] In some embodiments, the compound is as follows: [ka] [ka] [ka] [ka]

[0193] In some embodiments, the compound has the following structure. [ka]

[0194] In some embodiments, the compound is an agonist of the serotonin 5-HT2 receptor.

[0195] In some embodiments, the compound is serotonin 5-HT 2A It could be a receptor agonist.

[0196] Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable vehicles disclosed herein are also included. This will be disclosed in the specification.

[0197] Furthermore, methods for treating subjects with a disease or disorder are disclosed herein, including administering a therapeutically effective dose of the compounds disclosed herein to the target subject.

[0198] Furthermore, methods for treating subjects with a disease or disorder are disclosed herein, including administering a therapeutically effective dose of the compounds disclosed herein to the target subject.

[0199] Furthermore, a method for treating a subject having a serotonin 5-HT2 receptor-related disease or disorder is disclosed herein, which includes administering a therapeutically effective dose of the compounds disclosed herein to the subject. In some embodiments, the compounds have the following structure. [ka]

[0200] In some embodiments, the disease or disorder may include, for example, 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, non-suicidal self-injury disorder (NSSID), bipolar and related disorders (including, but not limited to, bipolar I disorder, bipolar II disorder, and cyclothymic disorder), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders (including, but not limited to, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder), anorexia nervosa, bulimia nervosa, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency, significant neurocognitive impairment, mild neurocognitive impairment, sexual dysfunction, and central nervous system (CNS) disorders such as obesity. In some embodiments, the disease or disorder is alcohol use disorder. In some embodiments, the disease or disorder may include autonomic nervous system (ANS) conditions. In some embodiments, the disease or disorder may include lung disorders (e.g., asthma and chronic obstructive pulmonary disease (COPD)). In some embodiments, the disease or disorder may include cardiovascular disorders (e.g., atherosclerosis).

[0201] Furthermore, a method for treating a subject with alcohol use disorder related to serotonin 5-HT2 receptors is disclosed, comprising administering a therapeutically effective amount of a compound having the following structure to the subject. [ka]

[0202] This specification also discloses monolayer oral tablet compositions comprising tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or pharmaceutically acceptable salts thereof, and polymers. In some embodiments, the compounds have the following structures. [ka]

[0203] In some embodiments, the composition is adapted to achieve maximum sustained release.

[0204] In some embodiments, the tablet composition comprises a combination of (i) a water-insoluble neutral charged nonionic matrix, (ii) a polymer supporting one or more negatively charged groups, and (iii) a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the nonionic matrix is ​​selected from cellulosic polymers alone or cellulosic polymers enhanced by mixing with components such as starch, wax, neutral rubber, polymethacrylate, PVA, PVA / PVP blends, or mixtures thereof.

[0206] In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC).

[0207] In some embodiments, the polymer supporting one or more load groups is polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resin, clay, zeolite, hyaluronic acid, anionic rubber, salts thereof, or mixtures thereof.

[0208] In some embodiments, the anionic rubber is a natural material, a semi-synthetic material, or a combination thereof.

[0209] In some embodiments, the natural materials are alginic acid, pectin, xanthan gum, carrageenan, locust bean gum, acacia gum, karaya gum, guar gum, tragacanth gum, or a combination thereof.

[0210] In some embodiments, the semi-synthetic material is carboxymethyl chitin, cellulose gum, or a combination thereof.

[0211] In some embodiments, the tablet composition contains a therapeutically effective amount of a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, for the treatment of pain.

[0212] In some embodiments, the tablet composition comprises a therapeutically effective amount of a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, for the treatment of brain injury.

[0213] In some embodiments, the tablet composition comprises a therapeutically effective amount of a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, for the treatment of depression.

[0214] In some embodiments, the tablet composition comprises a therapeutically effective amount of a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder related to the serotonin 5-HT2 receptor.

[0215] In some embodiments, the disease or disorder is major depressive disorder (MDD), major depressive disorder with suicidal ideation or suicidal behavior (MDD), suicidal ideation, suicidal behavior, non-suicidal self-injury disorder (NSSID), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar I disorder, bipolar II disorder, bipolar and related disorders including cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, alcohol use disorder, opioid use disorder The group consists of central nervous system (CNS) disorders, including harm, substance use disorders including amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive impairment, mild neurocognitive impairment, sexual dysfunction, chronic fatigue syndrome, Lyme disease, obesity, or combinations thereof. In some embodiments, the disease or disorder is alcohol use disorder.

[0216] In some embodiments, the disease or disorder includes a state of the autonomic nervous system (ANS).

[0217] In some embodiments, the disease or disorder includes lung disorders, including asthma and chronic obstructive pulmonary disease (COPD).

[0218] In some embodiments, the disease or disorder includes cardiovascular disorders, including atherosclerosis.

[0219] In some embodiments, the composition contains a complex concentration of DMT, 5-MeO-DMT, tryptamine derivatives such as psilocybin, psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in plasma concentrations of 10 to 500 (e.g., about 10, 20, 3) Achieve a concentration of 0, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 ng / ml or higher (or any range of approximately 10 to approximately 500 ng / ml, such as approximately 100 to approximately 300 ng / ml, approximately 250 to approximately 450 ng / ml, or approximately 50 to approximately 400 ng / ml), and maintain this concentration for the duration of the release period.

[0220] In some embodiments, the polymer includes one or more negatively charged groups.

[0221] Also disclosed herein are tablet compositions formulated for oral administration, comprising tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or pharmaceutically acceptable salts thereof, and polymers. In some embodiments, the compounds have the following structures. [ka]

[0222] In some embodiments, the polymer includes one or more negatively charged groups.

[0223] In some embodiments, the polymer contains one or more acidic groups.

[0224] In some embodiments, the polymer comprises a water-insoluble, neutrally charged, nonionic matrix.

[0225] In some embodiments, the nonionic matrix is ​​selected from cellulosic polymers alone or cellulosic polymers enhanced by mixing with components such as starch, wax, neutral rubber, polymethacrylate, PVA, PVA / PVP blends, or mixtures thereof.

[0226] In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC).

[0227] Also described herein is a kit for the treatment of a target, comprising 1) a monolayer oral tablet composition disclosed herein, and 2) instructions for use in the treatment of pain.

[0228] Furthermore, this specification describes a kit for the treatment of a subject, comprising 1) a monolayer oral tablet composition disclosed herein, and 2) instructions for use in the treatment of brain injury.

[0229] Also described herein is a kit for the treatment of a target, comprising 1) a monolayer oral tablet composition disclosed herein, and 2) instructions for use in the treatment of depression.

[0230] Also described herein is a kit for the treatment of a target, comprising 1) a monolayer oral tablet composition disclosed herein, and 2) instructions for use in the treatment of a disease or disorder related to the serotonin 5-HT2 receptor. [Modes for carrying out the invention]

[0231] The following detailed description of embodiments of the Disclosure includes numerous specific details to provide a complete understanding of the embodiments of the Disclosure. However, it will be apparent to those skilled in the art that embodiments of the Disclosure can be carried out without these specific details. In other examples, well-known methods, procedures, components, and circuits are not described in detail so as not to unnecessarily obscure aspects of the embodiments of the Disclosure.

[0232] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains.

[0233] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms. This term includes linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0234] The term "substituted alkyl" refers to an alkyl group as defined herein, in which one or more carbon atoms in the alkyl chain are optionally -O-, -N-, -S-, -S(O) n Substituted with heteroatoms such as -(n is 0-2), -NR-(R is hydrogen or alkyl), and alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, 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, -SO2-aryl 2- Heteroaryl and -NR a R b , where R ’ and R ’ ’ They may be the same or different, and hydrogen may be optionally substituted. It has 1 to 5 substituents selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic groups.

[0235] "Alkilen" is -O-, -NR 10 -, -NR 10 C(O)-, -C(O)NR 10 This term refers to a divalent aliphatic hydrocarbyl group having 1 to 6 carbon atoms surrounding 1 to 3 carbon atoms, either in a straight chain or branched, and optionally interrupted by one or more groups selected from the following. Examples of this term include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), etc.

[0236] "Substituted alkylenes" are those in which carbon is substituted, as described in the definition of "substitution" below. This refers to an alkylene group having 1 to 3 hydrogen atoms substituted with a specific group.

[0237] The term "alkane" refers to alkyl and alkylene groups as defined herein.

[0238] The terms "alkylaminoalkyl", "alkylaminoalkenyl", and "alkylaminoalkynyl" are R ’ NHR ” - refers to the base, R ’ R is an alkyl group as defined herein, ” is an alkylene, alkenylene, or alkynylene group as defined herein.

[0239] The terms "alkalyl" or "aralkyl" refer to alkylene, substituted alkylene, and aryl, as defined herein, -alkylene-aryl and -substituted alkylene-aryl groups.

[0240] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Examples of alkoxys include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and others. The term "alkoxy" also refers to alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O- groups, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0241] The term "substituted alkoxy" refers to the groups of 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.

[0242] The term "alkoxyamino" refers to an -NH-alkoxy group, where alkoxy is defined herein.

[0243] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group are substituted with a halo group, and includes groups such as trifluoromethoxy as an example.

[0244] The term "haloalkyl" refers to an alkyl group that has been substituted as described above, in which one or more hydrogen atoms on the alkyl group are substituted with a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as trifluoromethyl, difluoromethyl, and trifluoroethyl.

[0245] The term "alkylalkoxy" refers to the group of alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl, where alkyl, substituted alkyl, alkyl, alkylene, and substituted alkylene are as defined herein.

[0246] The term "alkylthioalkoxy" refers to alkylene-S-alkyl groups, alkylene-S-substituted alkyl groups, substituted alkylene-S-alkyl groups, and substituted alkylene-S-substituted alkyl groups, where alkyl, substituted alkyl, alkyl, alkylene, and substituted alkylene are as defined herein.

[0247] "Alkenyl" refers to a linear or branched hydrocarbyl group having 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, and at least one double bond unsaturated site, such as 1 to 2. Examples of this term include vivinyl, allyl, and buta-3-en-1-yl. This term also includes cis and trans isomers, or these isomers. It contains a mixture of [the following].

[0248] The term "substituted alkenyl" refers to an alkenyl group as defined herein having 1 to 5 substituents or 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, 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.

[0249] "Alkynyl" refers to a monovalent hydrocarbyl group having 2 to 6 carbon atoms, such as 2 to 3 carbon atoms, and at least one triple-bond unsaturated site, such as 1 to 2. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH).

[0250] The term "substituted alkynyl" refers to an alkynyl group as defined herein, having 1 to 5 substituents or 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, 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.

[0251] "Alkynyloxy" refers to an -O-alkynyl group, where alkynyl is as defined herein. Examples of alkynyloxy include ethynyloxy and propynyloxy.

[0252] "Acyl" refers to HC(O)-group, alkyl-C(O)-group, substituted alkyl-C(O)-group, alkenyl-C(O)-group, substituted alkenyl-C(O)-group, alkynyl-C(O)-group, substituted alkynyl-C(O)-group, cycloalkyl-C(O)-group, substituted cycloalkyl-C(O)-group, cycloalkenyl-C(O)-group, substituted cycloalkenyl-C(O)-group, aryl-C(O)-group, substituted aryl-C(O)-group, heteroaryl-C( The terms refer to the O)-group, substituted heteroaryl-C(O)-group, heterocyclyl-C(O)-group, and substituted heterocyclyl-C(O)-group, while 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 contains the "acetyl" group CH3C(O).

[0253] "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 group, -NR 20 C(O) heterocyclic group, and -NR 20 This refers to a C(O) substituted heterocyclic group, 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.

[0254] "Aminocarbonyl" or the term "aminoacyl" is -C(O)NR 21 R 22 It refers to the base, R 21 and R 22 R 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. 21 and R 22 The nitrogen atom is optional and can bond to the nitrogen atom bonded to it to form a heterocyclic or substituted heterocyclic group, 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.

[0255] "Aminocarbonylamino" is -NR 21 C(O)NR 22 R 23 It refers to the base of R 21 , R 22 , and R 23 The R groups are independently selected from hydrogen, alkyl, aryl, or cycloalkyl, and the two R groups are bonded together to form a heterocycline group.

[0256] The term "alkoxycarbonylamino" refers to the -NRC(O)OR group, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, and alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0257] The term "acyloxy" refers to alkyl-C(O)O-groups, substituted alkyl-C(O)O-groups, cycloalkyl-C(O)O-groups, substituted cycloalkyl-C(O)O-groups, aryl-C(O)O-groups, heteroaryl-C(O)O-groups, and heterocyclyl-C(O)O-groups, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0258] "Aminosulfonyl" is -SO2NR 21 R 22 It refers to the base, R 21 and R 22 R 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. 21 and R 22 The nitrogen atom is optional and can bond to it together with the nitrogen atom to form a heterocyclic or substituted heterocyclic group, 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.

[0259] "Sulfonylamino" is -NR 21 SO2R 22 It refers to the base, R 21 and R 22These are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cyclo Selected from the group consisting of alkenyls, substituted cycloalkenyls, heteroaryls, substituted heteroaryls, heterocyclic compounds, and substituted heterocyclic compounds, R 21 and R 22 The atom may optionally bond to the atom to which it is bonded, to form a heterocyclic or substituted heterocyclic group, 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.

[0260] "Aryl" or "ar" refers to a monovalent aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (e.g., present in a phenyl group) or a ring system having multiple fused rings, which may or may not be aromatic, provided that the bonding site is through an atom of an aromatic ring (examples of such aromatic ring systems include naphthyl, anthuryl, and indanyl). Examples of this term include phenyl and naphthyl. If not restricted by the definition of aryl substituents, 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, aryloxy, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamide, 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.

[0261] "Aryloxy" refers to an -O-aryl group, where aryl includes, as defined herein, for example, phenoxy, naphthoxy, and optionally substituted aryl groups, as also defined herein.

[0262] "Amino" refers to the NH2 group.

[0263] The term "substituted amino" refers to an -NRR group, where 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, provided that at least one R is not hydrogen.

[0264] The term "azid" refers to the -N3 group.

[0265] "Carboxyl," "carboxy," or "carboxylate" refers to -CO2H or a salt thereof.

[0266] The terms "carboxyl-ester" or "carboxy-ester," or "carboxyalkyl" or "carboxylalkyl," refer to -C(O)O-alkyl groups, -C(O)O-substituted alkyl groups, -C(O)O-alkenyl groups, -C(O)O-substituted alkenyl groups, -C(O)O-alkynyl groups, -C(O)O-substituted alkynyl groups, -C(O)O-aryl groups, -C(O)O-substituted aryl groups, -C(O)O-cycloalkyl groups, -C(O)O-substituted cycloalkyl groups, -C(O)O-cycloalkenyl groups, -C(O)O-substituted cycloalkenyl groups, -C(O)O-heteroaryl groups, and -C(O)O-substituted heteroaryl groups. This refers to an alkyl group, a -C(O)O-heterocyclic group, and a -C(O)O-substituted heterocyclic group, 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.

[0267] "(carboxyl-ester)oxy" or "carbonate" refers to -OC(O)O-alkyl groups, -O-C(O)O-substituted alkyl groups, -OC(O)O-alkenyl groups, -OC(O)O-substituted alkenyl groups, -OC(O)O-alkynyl groups, -O-C(O)O-substituted alkynyl groups, -OC(O)O-aryl groups, -OC(O)O-substituted aryl groups, -OC(O)O-cycloalkyl groups, -OC(O)O-substituted cycloalkyl groups, -OC(O)O-cycloalkenyl groups, -OC(O)O-substituted cy This refers to chloroalkenyl groups, -O-C(O)O-heteroaryl groups, -OC(O)O-substituted heteroaryl groups, -OC(O)O-heterocyclic groups, and -OC(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.

[0268] "Cyano" or "nitrile" refers to the -CN group.

[0269] "Cycloalkyl" refers to a cyclic alkyl group of 3 to 10 carbon atoms having one or more cyclic rings, including fusion, crosslinking, and spiro-ring systems. Examples of suitable cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Such cycloalkyl groups include, for example, single-ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl, or multi-ring structures such as adamantanyl.

[0270] The term "substituted cycloalkyl" includes alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, 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- This refers to a cycloalkyl group having 1 to 5 substituents selected from substituted alkyl groups, -SO2-aryl groups, and -SO2-heteroaryl groups, or 1 to 3 substituents.

[0271] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group consisting of 3 to 10 carbon atoms, having one or more rings and at least one double bond, such as one or two double bonds.

[0272] The term "substituted cycloalkenyl" includes alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocycline hydroxy, 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- This refers to a cycloalkenyl group having 1 to 5 substituents selected from substituted alkyl, -SO2-aryl, and -SO2-heteroaryl groups, or 1 to 3 substituents.

[0273] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group consisting of 5 to 10 carbon atoms, having a single ring or multiple rings and at least one triple bond.

[0274] "Cycloalkoxy" refers to -O-cycloalkyl.

[0275] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0276] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodine compounds.

[0277] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0278] A "heteroaryl" refers to an aromatic group comprising 1 to 10 heteroatoms selected from the group consisting of 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, and oxygen, nitrogen, and sulfur in the ring. Such a heteroaryl group may have a single ring in its ring system (e.g., pyridinyl, imidazolyl, or furyl) or multiple fused rings (e.g., in groups such as indolidinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), and at least one ring in the ring system is aromatic if the bonding site is through an atom of the aromatic ring. In some embodiments, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Examples of this term include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless restricted by the definition of heteroaryl substituents, such heteroaryl groups 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, azide, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamide, 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 selected from substituted alkyls, -SO2-aryls and -SO2-heteroaryls and trihalomethyls, or with 1 to 3 substituents.

[0279] The term "heteroaralkyl" refers to an alkylene-heteroaryl group, where alkylene and heteroaryl are defined herein. Examples of this term include pyridylmethyl, pyridylethyl, and indolylmethyl.

[0280] "Heteroaryloxy" refers to -O-heteroaryl.

[0281] "Heterocyclic," "heterocyclic formula," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings, including fusion bridges and spirocyclic systems, and containing 3 to 20 ring atoms, including 1 to 10 heteroatoms. The group is selected from the group consisting of nitrogen, sulfur, or oxygen, and in the fusion ring system, one or more of the rings may be cycloalkyl, aryl, or heteroaryl, provided that the bonding site is via a non-aromatic ring. In some embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0282] Examples of heterocyclic and heteroaryl compounds include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, dihydroindole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenanthridine, acridine, phenanthroline, isothiazole, and phen These include nadine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinil, thiomorpholinil (also called thiamorpholinil), 1,1-dioxothiomorpholinil, piperidinil, pyrrolidine, tetrahydrofuranil, and others.

[0283] Unless restricted by the definition of heterocyclic substituents, such heterocyclic groups include alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, 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 selected from substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fusion heterocycles, or with 1 to 3 substituents.

[0284] "Heterocyclyloxy" refers to the -O-heterocyclyl group.

[0285] The term "heterocyclilthio" refers to a heterocyclic -S- group.

[0286] The term "heterocyclene" refers to a diradical group formed from a heterocycle, as defined herein.

[0287] The term "hydroxyamino" refers to the -NHOH group.

[0288] "Nitro" refers to the NO2 group.

[0289] "Oxo" refers to an oxygen (O) atom.

[0290] "Sulfonyl" refers to SO2 alkyl groups, SO2-substituted alkyl groups, and SO2 alkyl groups. 2- Alkenyl group, SO2-substituted alkenyl group, SO2- Cycloalkyl group, SO2-substituted cycloalkyl group, SO 2- Cycloalkenyl group, SO2-substituted cycloalkenyl group, SO 2- Aryl group, SO2-substituted aryl group, SO 2- Heteroaryl group, SO2-substituted heteroaryl group, SO 2- Refers to a heterocyclic group and a SO2-substituted heterocyclic group, 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. Sulfonyl includes, by way of example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0291] "Sulfonyloxy" refers to an OSO2 alkyl group, an OSO2-substituted alkyl group, OSO 2- Alkenyl group, OSO2-substituted alkenyl group, OSO 2- Cycloalkyl group, OSO2-substituted cycloalkyl group, OSO 2- Cycloalkenyl group, OSO2-substituted cycloalkenyl group, OSO 2- Aryl group, OSO2-substituted aryl group, OSO 2- Heteroaryl group, OSO2-substituted heteroaryl group, OSO 2- Refers to a heterocyclic group and an OSO2-substituted heterocyclic group, 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.

[0292] The term "aminocarbonyloxy" refers to the -OC(O)NRR group, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, with alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic being as defined herein.

[0293] "Thiol" refers to the -SH group.

[0294] The term "thioxo" or "thioketo" refers to a (=S) atom.

[0295] "Alkylthio" or the term "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In some embodiments, sulfur may be oxidized to -S(O)-. The sulfoxide may exist as one or more stereoisomers.

[0296] The term "substituted thioalkoxy" refers to an -S-substituted alkyl group.

[0297] The term "thioaryloxy" refers to an aryl-S-group, and the aryl group includes any optionally substituted aryl groups as defined herein.

[0298] The term "thioheteroaryloxy" refers to an -S-heteroaryl group, and a heteroaryl group includes an optionally substituted aryl group as defined herein, as defined herein.

[0299] The term "thioheterocyclooxy" refers to an -S-heterocyclyl group, and a heterocyclyl group includes any substituted heterocyclyl groups as defined herein, as defined herein.

[0300] In addition to the disclosure of this specification, 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 replaced with the same or different substituents as defined below.

[0301] In addition to the groups disclosed for the individual terms of this specification, substituents (any two hydrogens on a single carbon can be replaced with =O, =NR 70 、=N-OR 70 、=N2 or =S) for replacing one or more hydrogens on saturated carbon atoms in a particular group or radical are, unless otherwise specified, -R 60 、halo, =O, -OR 70 、-SR 70 、-NR 80 R 80 、trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R 70 、-SO2O-M + 、-SO2OR 70 、-OSO2R 70 、-OSO2O-M + 、-OSO2OR 70 、-P(O)(O-)2(M + )2、-P(O)(OR 70 )O-M + 、-P(O)(OR 70 )2、-C(O)R 70 、-C(S)R 70 、-C(NR 70 )R 70 、-C(O)O-M + 、-C(O)OR 70 、-C(S)OR 70 、-C(O)NR 80 R 80 、-C(NR 70 )NR 80 R 80 、-OC(O)R 70 、-OC(S)R 70 、-OC(O)O-M<00OO122>、-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 The group consists of optionally substituted alkyl groups, cycloalkyl groups, heteroalkyl groups, heterocycloalkylalkyl groups, cycloalkylalkyl groups, aryl groups, arylalkyl groups, heteroaryl groups, and heteroarylalkyl groups, and each R 70 These are independently hydrogen or R 60 And each R 80 R is independent of R 70 Alternatively, two R atoms taken together with the nitrogen atom they bond to. 80’ The heterocycloalkyl groups consist of 5, 6, or 7 members, which optionally contain 1 to 4 additional heteroatoms, either the same or different, selected from the group consisting of O, N, and S, where N may have a -H or C1-C3 alkyl substitution, and each M + Each M is a counterion with a single net positive charge. + Independently, for example, K + kaNa + Li + Alkaline ions such as + N(R 60 ) Ammonium ions such as 4, or [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5These may include alkaline earth ions such as (the subscript 0.5 means that one of the counterions of such a divalent alkaline earth ion is the ionized form of the compound disclosed herein, and the other typical counterion, such as a chloride or one of the two ionized compounds disclosed herein, can serve as the counterion of such a divalent alkaline earth ion, or one of the biionized compounds disclosed herein can serve as the counterion of such a divalent alkaline earth ion). For example, -NR 80 R 80 It is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, and N-morpholinyl.

[0302] In addition to the disclosures herein, the substituents of hydrogen on unsaturated carbon atoms in “substituted” alkenes, alkynes, aryl and heteroaryl groups are, unless otherwise specified, -R 60 Hello, -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 + , -CO2R70 , -C(S)OR 70 -C(O)NR 80 R 80 -C(NR 70 )NR 80 R 80 -OC(O)R 70 ,-OC(S)R 70 , -OCO2 - M + , -OCO2R 70 ,-OC(S)R 70 ,-NR 70 C(O)R 70 ,-NR 70 C(S)R 70 ,-NR 70 CO2 - M + ,-NR 70 CO2R 70 , -NR 70 C(S)OR 70 ,-NR 70 C(O)NR 80 R 80 ,-NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 And R 60 , R 70 , R 80 and M + This is as previously defined, except in the case of substituted alkenes or alkynes, where the substituent is -O - M + , -OR 70 ,-SR 70 , or -S - M + isn't it.

[0303] In addition to the groups disclosed with respect to individual terms herein, substituents on hydrogen atoms on nitrogen in "substituted" heteroalkyl and cycloheteralkyl groups are, unless otherwise specified, -R 60 ,-OM + , -OR 70 , -SR 70 -SM + , -NR80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 -S(O)2 OM + -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 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 And, R 60, R 70 , R 80 and M + This is as previously defined.

[0304] In addition to the disclosures herein, in some embodiments, the substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0305] It is understood that polymers achieved by defining substituents having further substituents on themselves in all substituents defined above (for example, a substituted aryl having a substituted aryl group as a substituent itself substituted with a substituted aryl group, which is then further substituted with a substituted aryl group) are not intended to be included herein. In such cases, the maximum number of such substitutions is three. For example, the sequential substitution of substituted aryl groups specifically intended herein is limited to substituted aryl-(substituted aryl)-substituted aryl.

[0306] Unless otherwise indicated, the naming of substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group, followed by the adjacent functional groups toward the bonding site. For example, the substituent "arylalkyloxycarbonyl" refers to the (aryl)-(alkyl)-OC(O)- group.

[0307] It is understood that, with respect to any of the groups disclosed herein that contain one or more substituents, such groups do not include any substitutions or substitution patterns that are sterically unrealizable and / or synthetically impractical. Furthermore, the compounds in question include all stereochemical isomers arising from the substitutions of these compounds.

[0308] The term “pharmaceutically acceptable salt” means a salt that is acceptable for administration to patients, such as mammals (a salt having a counterion that has an acceptable mammalian safety for a given administration regimen). Such salts can be obtained from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of a compound, which is derived from a variety of organic and inorganic counterions well known in the art, including, but only by example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and, if the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, and oxalate.

[0309] The term "salt" refers to a compound formed when a proton of an acid is substituted by a cation, such as a metal cation or an organic cation. Where applicable, the salt is pharmaceutically acceptable, although this is not required for salts of intermediate compounds not intended for administration to patients. For example, salts of this compound include those in which the compound is protonated by an inorganic or organic acid to form a cation, and the salt has a conjugate base of the inorganic or organic acid as its anionic component.

[0310] A "solvate" refers to a complex formed by a combination of solvent molecules and solute molecules or ions. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents, but not limited to, include methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the resulting solvate is a hydrate.

[0311] "Stereoisomers" and "stereoisomers (plural)" refer to compounds that have the same atomic bonding but different atomic arrangements in space. Stereoiomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.

[0312] A "tautomer" refers to an alternative molecular form that differs only in the electron bonding of atoms and / or in the position of protons, such as enol-keto and imine-enamine tautomers, or to a tautomer of a heteroaryl group containing an -N=C(H)-NH-ring atom configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Those skilled in the art will recognize that other tautomer ring atom configurations are possible.

[0313] It will be understood that the term "its salt, solvate, or stereoisomer" is intended to include all substitutions of salts, solvates, and stereoisomers, such as solvates of pharmaceutically acceptable salts of stereoisomers of the compound in question.

[0314] As used herein, the term “maximum sustained release” describes the release window of a particular formulation of this disclosure formulated to increase the release period to a maximum value, which is ultimately limited to the time when the gastrointestinal tract naturally eliminates all of the drug with food.

[0315] The term "tamper-resistant" is recognized in the art to describe a form of drug formulation that makes it more difficult to abuse the drug portion of the formulation, through extraction for intravenous use or grinding for free base use, and thus reduces the risk of drug abuse.

[0316] As used herein, the term “steady state” describes a stable or steady-state level of molecular concentration, such as the concentration of any compound described herein.

[0317] As used herein, the term “composition” is equivalent to the term “formulation.”

[0318] As used herein, the term “administration event” describes the administration of a given dose to a target in the form of one or more tablets within a short time frame, for example, less than 10 minutes.

[0319] As used herein, the term “release period” describes the time frame over which any compound described herein is released from the matrix to obtain the plasma concentration of the compound described herein. The start time of the release period is defined from the time of oral administration to the subject, which is considered to be approximately equivalent to entry into the stomach and initial dissolution by gastric enzymes and acids. The end time of the release period is defined as the time when the entire loaded drug has been released. In embodiments, the release period may be more than about 4 hours, more than 8 hours, more than 12 hours, more than 16 hours, or more than 20 hours, more than about 24 hours, more than 28 hours, more than 32 hours, more than 36 hours, or more than 48 hours, or less than about 48 hours, less than 36 hours, 4 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less.

[0320] As used herein, the terms “to treat” or “to cure” mean treating or curing a disease or medical condition of a patient, such as a mammal (especially a human), which means improving a disease or medical condition, such as causing the elimination or regression of the disease or medical condition of the patient, for example, the disease or This includes suppressing the onset of a medical condition by delaying or stopping it, or reducing the symptoms of a patient's disease or medical condition. In one embodiment, preventive treatment may prevent the onset of a disease or medical condition in a subject.

[0321] "Patient" refers to both human and non-human subjects, particularly mammals.

[0322] As used herein, unless otherwise specified, the terms “prevent,” “preventing,” and “prevention” refer to the prevention of the onset, recurrence, or spread of a disease, disorder, or condition, or one or more of its symptoms. The terms encompass the inhibition or reduction of symptoms of a particular disease, disorder, or condition. Subjects with a family history of a disease, disorder, or condition are, in particular, candidates for a preventive regimen in certain embodiments. Furthermore, 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 “preventive treatment.”

[0323] As used herein, and unless otherwise specified, the terms “to manage,” “managing,” and “control” refer to preventing or delaying the progression, spread, or worsening of a disease, disorder, or condition, or one or more of its symptoms. In many cases, the beneficial effects obtained by a subject from preventive and / or therapeutic treatment do not result in a cure for the disease, disorder, or condition. In this regard, the term “managing” encompasses treating a subject suffering from a particular disease, disorder, or condition in an attempt to prevent or minimize recurrence of the disease, disorder, or condition.

[0324] "Pharmacologically effective dose" and "therapeutic effective dose" refer to the amount of a compound sufficient to treat a particular disorder or disease, or one or more symptoms thereof, and / or to prevent the onset of the disease or disorder.

[0325] As used herein, and unless otherwise specified, the “prophylactic effective dose” of an active agent is an amount sufficient to prevent a disease, disorder, or condition, or to prevent its recurrence. The term “prophylactic effective dose” may include an amount that improves overall prevention or enhances the prophylactic effect of another prophylactic agent.

[0326] The term “neurologically toxic spike” is used herein to describe a spike in the concentration of any compound described herein that may produce adverse effects such as sedation or psychotropic effects such as hallucinations, dizziness, and nausea, which may have immediate effects as well as affect treatment compliance. In particular, adverse effects may be more pronounced at blood concentration levels above approximately 300 ng / L (e.g., approximately 300, 400, 500, 600 or more ng / L).

[0327] As used herein, and unless otherwise specified, “neuropsychiatric disorder or condition” is defined as a behavioral or psychological problem associated with a known neurological condition, typically as a group of co-occurring 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 manic-depressive illness, depression, or any combination thereof.

[0328] As used herein, “inflammatory condition” or “inflammatory disease” broadly refers to chronic or acute inflammatory diseases. Inflammatory conditions and inflammatory diseases include, but are not limited to, rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis), spondyloarthritis (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome), crystalline arthropathy (e.g., gout, pseudogout, calcium pyrophosphate deposition disease), multiple sclerosis, Lyme disease, polymyalgia rheumatica, and This includes polytissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjögren's syndrome), vasculitis (e.g., polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome), inflammatory conditions including those resulting from trauma or ischemia, sarcoidosis, atherosclerotic vascular disease, atherosclerosis, and occlusive vascular diseases (e.g., atherosclerosis, ischemic heart disease, myocardial infarction, stroke, peripheral vascular disease), and vascular diseases including vascular stent restenosis, as well as ocular diseases including uveitis, corneal diseases, iritis, iridocyclitis, and cataracts.

[0329] As used herein, the terms “and / or” include any and all combinations of one or more of the enumerated items relating to them. As used throughout this specification and the subsequent claims, unless the context otherwise clearly indicates, the meanings of “a,” “an,” and “the” include both plural and singular references. The term “about” relating to a number means that the value will fluctuate by 5% above or below. For example, for a value of about 100, it means 95 to 105 (or any value between 95 and 105).

[0330] compound

[0331] This specification discloses the compound of formula (I), or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof, where X1 and X2 are deuterium and Y1 and Y2 are deuterium. [ka]

[0332] In some embodiments, R is [ka] That is the case.

[0333] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0334] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0335] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0336] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens. In some embodiments, R8 is partially or completely an alkyl deuterated element. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated element.

[0337] In some embodiments, if R4 is hydroxyl, then if both R8 and R9 are not -CD3, then R9 and R 10 These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0338] In some embodiments, if R4 is hydroxyl, then if R9 is hydrogen or deuterium, then R9 and R 10 These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0339] In some embodiments, if R4 is hydroxyl, then if R9 is not unsubstituted or substituted alkyl, then R9 and R 10 These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0340] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0341] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0342] This specification discloses the compound of formula (Ia), or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug, where X1 and X2 are deuterium and Y1 and Y2 are deuterium. [ka]

[0343] In some embodiments, R is [ka] That is the case.

[0344] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0345] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0346] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0347] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens. In some embodiments, R8 is partially or completely an alkyl deuterated element. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated element.

[0348] In some embodiments, if R4 is hydroxyl, and neither R8 nor R9 is -CD3, then R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0349] In some embodiments, if R4 is hydroxyl, and R9 is hydrogen or deuterium, then R9 may be hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, The compounds are selected from unsubstituted or substituted heteroaryl compounds.

[0350] In some embodiments, if R4 is hydroxyl, and R9 is not an unsubstituted or substituted alkyl, then R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0351] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0352] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0353] This specification discloses the compound of formula (Ib), or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug, where X1 and X2 are deuterium and Y1 and Y2 are deuterium. [ka]

[0354] In some embodiments, R is [ka] That is the case.

[0355] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0356] In some embodiments, R4 can independently be hydrogen, deuterium, hydroxyl, unsubstituted, or substituted. Selected from substituted alkoxys, unsubstituted or substituted acetoxys, and phosphoryloxys.

[0357] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0358] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens. In some embodiments, R8 is partially or completely an alkyl deuterated element. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated element.

[0359] In some embodiments, if R4 is hydroxyl, then if both R8 and R9 are not -CD3, then R9 and R 10 These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0360] In some embodiments, if R4 is hydroxyl, then if R9 is hydrogen or deuterium, then R9 and R 10 These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0361] In some embodiments, if R4 is hydroxyl, then if R9 is not unsubstituted or substituted alkyl, then R9 and R 10 These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0362] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0363] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0364] This specification discloses the compound represented by formula (Ic) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0365] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0366] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0367] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0368] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0369] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0370] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0371] This specification discloses the compound represented by formula (Id) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0372] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0373] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0374] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0375] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0376] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0377] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0378] This specification discloses the compound represented by formula (Ie) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0379] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0380] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0381] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0382] In some embodiments, if both R8 and R9 are not -CD3, then R9 is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, or unsubstituted The following are selected from substituted heterocycloalkyls, unsubstituted or substituted aryls, and unsubstituted or substituted heteroaryls.

[0383] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0384] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0385] This specification discloses the compound represented by formula (If) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0386] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0387] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0388] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0389] In some embodiments, if both R8 and R9 are not -CD3, then R9 and R 10 These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0390] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0391] In some embodiments, "substituted" means partially or completely replaced with deuterium. This means, for example, that a substituted alkyl is a partially or completely deuterated alkyl.

[0392] This specification discloses the compound represented by formula (Ig) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0393] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0394] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0395] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0396] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0397] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0398] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0399] This specification discloses the compound represented by formula (Ih) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0400] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0401] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0402] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0403] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0404] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0405] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0406] This specification discloses the compound of formula (Ii) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0407] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0408] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0409] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0410] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0411] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0412] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0413] This specification discloses the compound represented by formula (Ij) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0414] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0415] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0416] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0417] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0418] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0419] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0420] This specification discloses the compound represented by formula (Ik) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0421] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0422] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0423] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0424] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0425] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0426] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0427] This specification discloses the compound of formula (II), or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof, where X1 and X2 are deuterium and Y1 and Y2 are hydrogen. [ka]

[0428] In some embodiments, R is [ka] That is the case.

[0429] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0430] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0431] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0432] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens. In some embodiments, R8 is partially or completely an alkyl deuterated element. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated element.

[0433] In some embodiments, R9 and R 10 These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0434] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0435] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0436] This specification discloses the compound described in formula (II-a), or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, where X1 and X2 are deuterium, Y1 and Y2 are hydrogen, and R is [ka] That is the case.

[0437] [ka]

[0438] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0439] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0440] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0441] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens. In some embodiments, R8 is partially or completely an alkyl deuterated element. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated element.

[0442] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0443] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0444] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0445] This specification discloses the compound of formula (II-b), or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, where X1 and X2 are deuterium, Y1 and Y2 are hydrogen, and R is [ka] That is the case.

[0446] [ka]

[0447] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0448] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0449] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0450] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens. In some embodiments, R8 is partially or completely an alkyl deuterated element. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated element.

[0451] In some embodiments, R9 and R 10 These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0452] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0453] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0454] This specification discloses the compound described in formula (II-c), or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, where X1 and X2 are deuterium, Y1 and Y2 are hydrogen, and R is [ka] That is the case.

[0455] [ka]

[0456] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0457] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0458] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0459] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogen. In some embodiments, R 10 R is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R 10 These are partially or completely deuterated methyl or ethyl compounds.

[0460] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0461] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0462] This specification discloses the compound of formula (II-d) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0463] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0464] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0465] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0466] In some embodiments, R9 is hydrogen, an unsubstituted or substituted alkyl group, or an unsubstituted or substituted alkyl group. The following are selected: substituted allyls, unsubstituted or substituted alkenyls, unsubstituted or substituted alkynyls, unsubstituted or substituted cycloalkyls, unsubstituted or substituted heterocycloalkyls, unsubstituted or substituted aryls, and unsubstituted or substituted heteroaryls.

[0467] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0468] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0469] This specification discloses the compound of formula (II-e) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs.

[0470] [ka]

[0471] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0472] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0473] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0474] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0475] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0476] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0477] This specification discloses the compound of formula (II-f) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0478] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0479] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0480] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0481] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0482] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0483] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0484] This specification discloses the compound of formula (II-g) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0485] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0486] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0487] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0488] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0489] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0490] This specification discloses the compound of formula (II-h) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0491] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0492] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0493] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0494] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0495] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0496] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0497] This specification discloses the compound of formula (II-i) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0498] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0499] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0500] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0501] In some embodiments, R9 is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0502] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0503] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0504] This specification discloses the compound of formula (II-j) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0505] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0506] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0507] In some embodiments, R8 is partially or completely an alkyl deuterated. In some embodiments, R8 is partially or completely a methyl or ethyl deuterated.

[0508] In some embodiments, R9 is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted. The selection is made from substitutional aryls and unsubstituted or substituted heteroaryls.

[0509] In some embodiments, the unsubstituted or substituted alkyl group is unsubstituted or partially or completely deuterated methyl or ethyl group.

[0510] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0511] This specification discloses the compound of formula (III) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0512] In some embodiments, X1 and X2 are deuterium.

[0513] In some embodiments, Y1 and Y2 are hydrogen or deuterium.

[0514] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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. In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0515] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0516] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0517] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0518] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0519] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially substituted, or completely substituted. It is deuterated methyl or ethyl.

[0520] In some embodiments, if R4 is hydroxyl and R2, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both -CD3, and if R2, R4, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both unsubstituted methyl groups.

[0521] In some embodiments, if R4 is hydroxyl, then R9 is hydrogen.

[0522] In some embodiments, if R4 is hydroxyl, then R9 is deuterium.

[0523] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0524] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0525] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0526] In some embodiments, the compound of formula (III) is as follows: formulas (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), (III-k), (III-l), (III-m), (III-n), (III-o), (III-p), (III-q), (III-r), (III-s), (III-t), (III-u), and (III-v).

[0527] This specification discloses the compound of formula (III-a) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0528] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0529] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0530] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0531] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0532] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0533] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0534] In some embodiments, if R4 is hydroxyl and R2, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both -CD3, and if R2, R4, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both unsubstituted methyl groups.

[0535] In some embodiments, if R4 is hydroxyl, then R9 is hydrogen or deuterium.

[0536] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0537] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0538] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0539] This specification discloses the compound of formula (III-b) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0540] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0541] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0542] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0543] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0544] In some embodiments, if R2, R6, and R7 are all hydrogen atoms, then R8 and R9 are both not unsubstituted methyl atoms.

[0545] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0546] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0547] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0548] This specification discloses the compound of formula (III-c) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0549] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0550] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogen. ru.

[0551] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0552] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0553] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0554] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0555] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0556] This specification discloses the compounds of formula (III-d) or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0557] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0558] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0559] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0560] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0561] In some embodiments, if R2, R6, and R7 are all hydrogen, then R8 and R9 are both not -CD3.

[0562] In some embodiments, R9 is hydrogen.

[0563] In some embodiments, R9 is deuterium.

[0564] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0565] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0566] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0567] This specification discloses the compound of formula (III-e) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0568] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0569] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0570] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0571] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0572] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0573] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0574] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0575] This specification discloses compounds of formula (III-f) or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0576] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0577] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0578] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0579] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0580] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0581] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0582] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0583] This specification discloses the compound of formula (III-g) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0584] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0585] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0586] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0587] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0588] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0589] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0590] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0591] This specification discloses the compound of formula (III-h) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0592] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0593] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0594] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0595] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0596] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0597] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0598] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0599] This specification discloses the compound of formula (III-i) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0600] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0601] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0602] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0603] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0604] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0605] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0606] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0607] This specification discloses the compound of formula (III-j) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0608] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0609] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0610] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0611] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0612] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0613] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0614] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0615] This specification discloses the compound of formula (III-k) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0616] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0617] In some embodiments, R4 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy.

[0618] In some embodiments, R5 is independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy.

[0619] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0620] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0621] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0622] In some embodiments, if R4 is hydroxyl and R2, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both -CD3, and if R2, R4, R5, R6, and R7 are all hydrogen, then R8 and R9 are not both unsubstituted methyl groups.

[0623] In some embodiments, if R4 is hydroxyl, then R9 is hydrogen or deuterium.

[0624] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0625] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0626] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl. In some embodiments, an alkoxy is a methoxy or ethoxy.

[0627] This specification discloses the compound of formula (III-l) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0628] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0629] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0630] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0631] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0632] In some embodiments, if R2, R6, and R7 are all hydrogen atoms, then R8 and R9 are both not unsubstituted methyl atoms.

[0633] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0634] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0635] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0636] This specification discloses the compound of formula (III-m) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0637] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0638] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0639] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0640] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0641] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0642] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0643] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0644] This specification discloses the compound of formula (III-n) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0645] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0646] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0647] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0648] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0649] In some embodiments, if R2, R6, and R7 are all hydrogen, then R8 and R9 are both not -CD3.

[0650] In some embodiments, R9 is hydrogen.

[0651] In some embodiments, R9 is deuterium.

[0652] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0653] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0654] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0655] This specification discloses the compound of formula (III-o) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0656] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0657] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0658] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0659] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0660] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0661] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0662] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0663] This specification discloses the compound of formula (III-p) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0664] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0665] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0666] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0667] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0668] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0669] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0670] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0671] This specification discloses the compound of formula (III-q) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0672] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0673] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0674] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0675] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0676] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0677] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0678] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0679] This specification discloses the compound of formula (III-r) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0680] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0681] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogen.

[0682] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0683] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0684] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0685] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0686] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0687] This specification discloses the compound of formula (III-s) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0688] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0689] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0690] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0691] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0692] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0693] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0694] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0695] This specification discloses the compound of formula (III-t) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0696] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0697] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0698] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0699] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0700] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0701] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0702] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0703] This specification discloses the compound of formula (III-u) or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0704] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0705] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0706] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0707] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0708] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0709] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0710] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0711] This specification discloses compounds of formula (III-v) or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs. [ka]

[0712] In some embodiments, R2 is independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, 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.

[0713] In some embodiments, R6 and R7 are selected from hydrogen, deuterium, and halogens.

[0714] In some embodiments, R8 is unsubstituted or partially or fully deuterated methyl or ethyl.

[0715] In some embodiments, R9 is hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

[0716] In some embodiments, R2 is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or fully deuterated methyl or ethyl.

[0717] In some embodiments, both R8 and R9 are not unsubstituted or partially or completely deuterated ethyl acetate.

[0718] In some embodiments, "substituted" means partially or completely substituted with deuterium; for example, a substituted alkyl is a partially or completely deuterated alkyl.

[0719] In some embodiments, the compound is selected from the following: [ka] [ka] [ka] [ka]

[0720] In some embodiments, the compound has the following structure. [ka]

[0721] In some embodiments, the compounds described herein are deuterium or deuterium-substituted R2, R4, R5, R6, R7, R9, and R 10 It has at least one of the following.

[0722] In some embodiments, the compounds described herein have at least one of R2, R4, R5, R6, and R7 being deuterium or substituted with deuterium.

[0723] In some embodiments, R2 of the compounds described herein is deuterium or is substituted with deuterium.

[0724] In some embodiments, R4 of the compounds described herein is deuterium or is substituted with deuterium.

[0725] In some embodiments, R5 of the compounds described herein is deuterium or is substituted with deuterium.

[0726] In some embodiments, R6 of the compounds described herein is deuterium or is substituted with deuterium.

[0727] In some embodiments, R7 of the compounds described herein is deuterium or is substituted with deuterium.

[0728] In some embodiments, R9 of the compounds described herein is deuterium or is substituted with deuterium.

[0729] In some embodiments, the R of the compound described herein 10 It is either deuterium or substituted with deuterium.

[0730] In some embodiments, R6 and / or R7 of the compounds described herein are halogens.

[0731] In some embodiments, R4 and / or R5 of the compounds described herein are deuterium or are substituted with deuterium.

[0732] In some embodiments, the compound is an agonist of the serotonin 5-HT2 receptor.

[0733] In some embodiments, the compound is serotonin 5-HT 2A It could be a receptor agonist.

[0734] While not bound by any particular theory, novel compounds described herein that exhibit selective deuteration, such as in the extracyclic component, are thought to enable significant delay in enzymatic degradation and an increase in the blood / brain ratio through improved exposure (i.e., prevention of acutely observed high drug concentrations (spikes) after administration), resulting in improved oral bioavailability. Some compounds described herein provide similar benefits through selective deuteration of the phenyl ring.

[0735] Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable vehicles disclosed herein are also disclosed herein.

[0736] A “pharmaceutically acceptable vehicle” may be a vehicle approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally accepted pharmacopoeia for use in mammals such as humans. The term “vehicle” refers to a diluent, adjuvant, excipient, or carrier into which the compounds of this disclosure are formulated for administration to mammals. Such a pharmaceutically acceptable vehicle may be a liquid, such as water or oil, including petroleum, animal, plant, or synthetic origins such as peanut oil, soybean oil, mineral oil, or sesame oil. A pharmaceutically acceptable vehicle may be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, or urea. In addition, auxiliaries, stabilizers, thickeners, lubricants, and colorants may be used.

[0737] When administered to mammals, the compounds and compositions of this disclosure, as well as pharmaceutically acceptable vehicles, excipients, or diluents, may be sterile. In some cases, when the compounds of interest are administered intravenously, they may be sterilized with water, saline, and aqueous dextrose and glycerides. Aqueous media such as roll solutions are used as the vehicle.

[0738] Pharmaceutical compositions can take the form of capsules, tablets, pills, pellets, throat 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 examples, pharmaceutical compositions are formulated for administration according to routine procedures as pharmaceutical compositions adapted for oral or intravenous administration to humans. Examples of suitable pharmaceutical vehicles and their formulation methods are described in Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack This is described in Publishing Co. Easton, Pa., 19th ed., 1995, Chapters 86, 87, 88, 91, and 92, which are incorporated herein by reference. The selection of excipients will be determined in part by the specific compounds and by the specific method used to administer the composition. Thus, there are a wide variety of suitable formulations of the pharmaceutical composition in question.

[0739] The administration of the target compound may be systemic or topical. In some embodiments, administration to a mammal results in systemic release (e.g., into the bloodstream) of the compound of the Disclosure. Methods of administration may include oral, oral, sublingual, and enteral routes such as the rectum; topical administration such as transdermal and intradermal; administration by inhalation via a nebulizer or inhaler; and parenteral administration.

[0740] In some embodiments, the composition comprises the compound disclosed herein in a purity of at least 50% by weight of the total amount of isotopologs of the present formula. In some embodiments, any position in the compound containing deuterium has a minimum deuterium incorporation of at least 45% deuterium. In some embodiments, the composition is substantially free of other isotopologs of the compound.

[0741] In some embodiments, the pharmaceutical composition comprises (i) a water-insoluble neutral charged nonionic matrix and (ii) a polymer supporting one or more load groups.

[0742] In some embodiments, the nonionic matrix is ​​selected from cellulosic polymers such as HPMC alone, or cellulosic polymers such as HPMC that are enhanced by mixing with components such as starch, wax, neutral rubber, polymethacrylate, PVA, PVA / PVP blend, or mixtures thereof. In some embodiments, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC).

[0743] In some embodiments, the polymer supporting one or more load groups is polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resin, clay, zeolite, hyaluronic acid, anionic rubber, salts thereof, or mixtures thereof.

[0744] In some embodiments, the anionic rubber is a natural or semi-synthetic material. In some embodiments, the natural material is arginine, pectin, xanthan gum, carrageenan, locust bean gum, acacia gum, karaya gum, guar gum, tragacanth gum, or a mixture thereof. In some embodiments, the semi-synthetic material is carboxymethyl chitin, cellulose gum, or a mixture thereof.

[0745] In some embodiments, a controlled-release oral formulation is provided. In some embodiments, the oral formulation may be constructed using either deuterated tryptamine or non-deuterated tryptamine and is intended for low-dose maintenance therapy, taking advantage of tryptamine's ability to bind to anionic polymers.

[0746] Pharmaceutical compositions may be prepared and administered in a wide variety of dosage forms. The compounds described may be administered orally, rectally, by inhalation, or by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally).

[0747] For preparing pharmaceutical compositions from the compounds described herein, pharmaceutically acceptable carriers may be either solid or liquid. Preparations in solid form include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may also be one or more substances that function as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials.

[0748] In the case of a powder, the carrier may be a finely divided solid in a mixture with the finely divided active ingredient. In the case of a tablet, the active ingredient may be mixed with a carrier having the required binding properties in an appropriate proportion and compressed into the desired shape and size.

[0749] Powders and tablets may contain approximately 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter. The term “preparation” is intended to include, and therefore associated with, formulations of the active compound having an encapsulating material as a carrier, which provides a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier. Similarly, cachets and throat lozenges are included. Tablets, powders, capsules, pills, cachets, and throat lozenges can be used as solid dosage forms suitable for oral administration.

[0750] To prepare the suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first dissolved, and the active ingredient is uniformly dispersed therein by stirring. The molten, homogeneous mixture is then poured into a mold of a suitable size and cooled, thereby solidifying.

[0751] Liquid preparations include solutions, suspensions, and emulsions, such as water or a water / propylene glycol solution. For parenteral injection, liquid preparations can be formulated as a solution in an aqueous polyethylene glycol solution.

[0752] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding appropriate colorants, flavorings, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing finely divided active ingredients in water using viscous materials such as natural or synthetic rubber, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0753] The preparations also include solid forms intended to be converted into liquid preparations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0754] Pharmaceutical preparations can be in the form of unit dosage forms. In such forms, the preparation is divided into unit doses containing an appropriate amount of the active ingredient. A unit dosage form may be a package containing individual amounts of the preparation, such as individually packaged tablets, capsules, and powders in vials or ampoules. Alternatively, a unit dosage form may be the capsule, tablet, cachet, or throat lozenge itself, or any appropriate number of these in packaging form.

[0755] The amount of the active ingredient in a unit dose preparation may be varied or adjusted according to the specific use and the potency of the active ingredient, ranging from about 0.001 mg to about 10 mg (e.g., about 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 mg or more), or any range from about 0.001 to about 10.0 mg (e.g., about 0.0001 to about 0.1, about 0.1 to 1.0, about 0.0005 to 0.5, or about 0.01 to about 2.0 mg). The composition may also contain other suitable therapeutic agents, if desired.

[0756] Some compounds have limited solubility in water and therefore may require a surfactant or other suitable co-solvent in the composition. Such co-solvents include polysorbate 20, 60, and 80, Pluronic F-68, F-84, and P-103, cyclodextrin, and polyoxyl 35 castor oil. Such co-solvents are typically used at levels of about 0.01% to about 2% by weight. Viscosity greater than that of a simple aqueous solution may be desirable to reduce variability when dispensing the formulation, reduce the physical separation of components in the suspension or emulsion of the formulation, and / or otherwise improve the formulation. Such viscosity builders include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations thereof. Such agents are typically used at levels of about 0.01% to about 2% by weight.

[0757] The pharmaceutical composition may additionally include components for providing sustained release and / or sustained comfort. Such components include high molecular weight, anionic mucus-mimicking polymers, gelling polysaccharides, and finely separated drug carrier substrates. These components are discussed in detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

[0758] Pharmaceutical compositions may be intended for intravenous use. Pharmaceutically acceptable excipients may include buffers to adjust the pH to a desirable range for intravenous use. Many buffers are known, including salts of inorganic acids such as phosphates, borates, and sulfates.

[0759] A pharmaceutical composition may contain a composition in which the active ingredient is present in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application depends, in particular, on the condition being treated.

[0760] The dose and frequency (single or multiple doses) of the compound administered may vary depending on various factors, including the route of administration, the recipient's size, age, sex, health, weight, body mass index, and diet, the nature and severity of the symptoms of the disease being treated, the presence of other diseases or other health problems, the type of concomitant therapy, and complications from any disease or treatment regimen. Other treatment regimens or agents may be used in conjunction with the methods and compounds disclosed herein.

[0761] The therapeutically effective dose for use in humans may be determined from animal models. For example, the dose for humans may be formulated to achieve a concentration that has been found to be effective in animals. The dose for humans may be adjusted, as described above, by monitoring the response to the treatment of constipation or dry eye and adjusting the dose upward or downward.

[0762] The dosage may vary depending on the requirements of the subject and the compound used. In relation to the pharmaceutical composition, the dose administered to the subject should be sufficient to produce a beneficial therapeutic response over time. The size of the dose will also be determined by the presence, nature, and degree of adverse side effects. Generally, treatment is initiated with a dose lower than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect under the given circumstances is achieved.

[0763] Dosage and intervals can be individually adjusted to provide levels of the administered compound effective for the specific clinical signs being treated. This will provide a treatment regimen that is appropriate to the severity of the individual's disease state.

[0764] By utilizing the teachings provided herein, it is possible to plan effective prophylactic or therapeutic treatment regimens that do not cause substantial toxicity and are fully effective in treating the clinical symptoms exhibited by specific patients. This plan should involve careful selection of active compounds by considering factors such as the potency of the compound, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected drug.

[0765] Furthermore, a method for treating a subject with a disease or disorder is disclosed, comprising administering a therapeutically effective dose of one of the compounds disclosed herein to the subject.

[0766] Furthermore, a method for treating a subject with a disease or disorder is disclosed, comprising administering a therapeutically effective dose of one of the compounds disclosed herein to the subject.

[0767] Furthermore, a method for treating a subject having a disease or disorder related to the serotonin 5-HT2 receptor is disclosed, comprising administering a therapeutically effective dose of the compounds disclosed herein to the subject. In some embodiments, the compounds have the following structure. [ka]

[0768] In some embodiments, administration of the disclosed method is by an oral, sublingual, oral, parenteral, topical, nasal, inhalation, or injection route.

[0769] In some embodiments, the disease or disorder is major depressive disorder (MDD), major depressive disorder with suicidal ideation or suicidal behavior (MDD), suicidal ideation, suicidal behavior, non-suicidal self-injury disorder (NSSID), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar I disorder, bipolar II disorder, bipolar and related disorders including cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders including alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood onset The group consists of central nervous system (CNS) disorders, including fluency disorder, severe neurocognitive impairment, mild neurocognitive impairment, sexual dysfunction, chronic fatigue syndrome, Lyme disease, obesity, or a combination thereof. In some embodiments, the disorder or condition is alcohol use disorder.

[0770] In some embodiments, the disease or disorder includes a state of the autonomic nervous system (ANS).

[0771] In some embodiments, the disease or disorder includes lung disorders, including asthma and chronic obstructive pulmonary disease (COPD).

[0772] In some embodiments, the disease or disorder includes cardiovascular disorders, including atherosclerosis.

[0773] Furthermore, a method for treating a subject with alcohol use disorder related to serotonin 5-HT2 receptors is disclosed, comprising administering a therapeutically effective amount of a compound having the following structure to the subject. [ka]

[0774] formulation Furthermore, this specification discloses pharmaceutical compositions formulated for oral administration, such as pills (e.g., tablets, capsules, caplets, lozenges, throat lozenges, cache, gel caps, caps, pellets, boluses, pastilles, orally disintegrating tablets, sublingual tablets, and oral tablets), which have reduced neurological adverse effects compared to existing oral formulations, and monolayer tablet compositions formulated for oral administration, such as tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, psilocin, or any of the compounds described herein, or pharmaceutically acceptable salts thereof. The pharmaceutical compositions are formulated to ensure steady-state release of therapeutically effective concentrations of the tryptamine derivatives described herein from the oral pharmaceutical composition without analgesic or psychotropic toxicity spikes at plasma concentrations of any of the compounds described herein (tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or pharmaceutically acceptable salts thereof). Such spikes in plasma concentrations have been well documented to have serious psychotropic side effects, including but not limited to hallucinations, dizziness, and nausea, which not only have immediate effects but also negatively impact treatment compliance. In this regard, this disclosure provides novel and original formulations for oral administration, comprising an optimal matrix discovered for long-term steady-state release of any of the compounds described herein, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or pharmaceutically acceptable salts thereof, with reduced analgesic and psychotropic side effects.

[0775] In some embodiments, the pharmaceutical composition (for example, a single-layer tablet composition, formulated for oral administration) is used. The tablet composition comprises one of the compounds described herein (tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the following structure. [ka]

[0776] In some embodiments of this disclosure, the tablet composition is a controlled-release tablet adapted for sustained release, for example, maximum sustained release.

[0777] In some embodiments of this disclosure, the tablet composition is adapted for tamper resistance. In some embodiments, the tablet composition comprises polyethylene oxide (PEO) in a MW of about 2,000 to about 7,000 kDa, for example, in combination with HPMC. In some embodiments, the tablet composition may further comprise polyethylene glycol (PEG), for example, PEG8K. In some embodiments, the tablet composition may further comprise a polymer supporting one or more negatively charged groups, for example, polyacrylic acid. In certain embodiments, the tablet composition comprising PEO is further subjected to heating / annealing, for example, under extrusion molding conditions.

[0778] In some embodiments of this disclosure, the pharmaceutical composition comprises a combination of (i) a water-insoluble neutral charged nonionic matrix, (ii) a polymer supporting one or more negatively charged groups, and (iii) a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof.

[0779] In some embodiments of this disclosure, the polymer supporting one or more load groups is polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resin, clay, zeolite, hyaluronic acid, anionic rubber, salts thereof, or mixtures thereof. In some embodiments, the anionic rubber is a natural material, a semi-synthetic material, or a combination thereof. In some embodiments, the natural material is arginine, pectin, xanthan gum, carrageenan, locust bean gum, acacia gum, karaya gum, guar gum, tragacanth gum, or a combination thereof. In other embodiments, the semi-synthetic material is carboxymethyl chitin, cellulose gum, or a combination thereof.

[0780] Furthermore, although not intended to be theoretically bound, in some embodiments, the role of a polymer carrying one or more load groups, which possesses an acidic moiety such as the acidic polymers described herein, surprisingly results in significant retention in the matrix of tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or pharmaceutically acceptable salts thereof. In some embodiments, this negative charge is based, for example, on the release of protons by pKa. Furthermore, these can be generated in situ under specific pH conditions or via electrostatic interactions / negative charge generation. It should also be noted that the acidic polymer may be a salt of the corresponding weak acid that becomes the relevant protonating acid in the stomach, and although not intended to be bound by theory, this may neutralize the charge and reduce the interaction with the matrix of tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or their pharmaceutically acceptable salts. In addition, the release matrix may be further complemented by other inert pharmaceutical components to assist in the preparation of suitable solid dosage forms such as fillers, disintegrants, flow improvers, lubricants, colorants, and taste masks.

[0781] In some embodiments of this disclosure, the tablet composition is adapted for tamper resistance. In some embodiments, the tablet composition contains polyethylene oxide (PEO) in a MW of approximately 2,000 to approximately 7,000 kDa, for example. In certain embodiments, the tablet composition containing PEO is further subjected to heating / annealing, such as extrusion.

[0782] In some embodiments of the present disclosure, the nonionic matrix is ​​selected from cellulosic polymers such as HPMC alone, or from cellulosic polymers such as HPMC that are reinforced by mixing with components such as starch, wax, neutral rubber, polymethacrylate, PVA, PVA / PVP blend, or mixtures thereof.

[0783] In some embodiments of this disclosure, the cellulosic polymer is hydroxypropyl methylcellulose (HPMC). In some embodiments, the tablet composition comprises about 20 to 60% by weight of hydroxypropyl methylcellulose, about 10 to 30% by weight of starch, or any combination thereof.

[0784] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for the treatment of pain. In some embodiments, the pain to be treated is cancer pain, e.g., refractory cancer pain. In some embodiments, the pain to be treated is postoperative pain. In some embodiments, the pain to be treated is orthopedic pain. In some embodiments, the pain to be treated is back pain. In some embodiments, the pain to be treated is neuropathic pain. In some embodiments, the pain to be treated is toothache. In some embodiments, the pain to be treated is chronic pain in opioid-resistant patients.

[0785] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for the treatment of depression.

[0786] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for the treatment of brain injury.

[0787] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for the treatment of stroke.

[0788] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use, for example, in migraine with aura.

[0789] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in refractory asthma.

[0790] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of alcohol dependence.

[0791] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for the treatment of post-traumatic stress disorder (PTSD).

[0792] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of depression (e.g., treatment-resistant depression (TRD) or bipolar disorder).

[0793] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of major depressive disorder (MDD).

[0794] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of anxiety (e.g., generalized anxiety disorder).

[0795] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of schizophrenia.

[0796] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of bipolar disorder.

[0797] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of suicidal tendencies or suicidal ideation.

[0798] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of autism.

[0799] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of diabetic neuropathy.

[0800] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of neuropathic pain.

[0801] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of acute pain (e.g., acute traumatic pain).

[0802] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of chronic pain.

[0803] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of levodopa-induced dyskinesia.

[0804] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment and regulation of pseudobulb effect or ocular function.

[0805] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of Alzheimer's disease or conditions associated with Alzheimer's disease (e.g., dementia or agitation in Alzheimer's disease).

[0806] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of tinnitus.

[0807] In some embodiments, the tablet composition contains a therapeutically effective amount of any compound described herein for use in the treatment of a disease or disorder related to the serotonin 5-HT2 receptor.

[0808] In some embodiments, the disease or disorder is major depressive disorder (MDD), major depressive disorder with suicidal ideation or suicidal behavior (MDD), suicidal ideation, suicidal behavior, non-suicidal self-injury disorder (NSSID), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar I disorder, bipolar II disorder, bipolar and related disorders including cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, alcohol use disorder, opioid use disorder The group consists of central nervous system (CNS) disorders, including harm, substance use disorders including amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive impairment, mild neurocognitive impairment, sexual dysfunction, chronic fatigue syndrome, Lyme disease, obesity, or combinations thereof. In some embodiments, the disease or disorder is alcohol use disorder.

[0809] In some embodiments, the disease or disorder includes a state of the autonomic nervous system (ANS).

[0810] In some embodiments, the disease or disorder includes lung disorders, including asthma and chronic obstructive pulmonary disease (COPD).

[0811] In some embodiments, the disease or disorder includes cardiovascular disorders, including atherosclerosis.

[0812] Depression, anxiety, or stress may be common in patients with chronic and / or life-threatening illnesses such as Alzheimer's disease, autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, and psoriasis), cancer, coronary heart disease, diabetes, epilepsy, HIV / AIDS, hypothyroidism, multiple sclerosis, Parkinson's disease, and stroke. Symptoms of depression, anxiety, or stress may occur after a diagnosis of a disease or illness. Patients with depression, anxiety, or stress concurrently with other medical conditions or illnesses may have more severe symptoms of both, and the illness and depression, anxiety, or stress may persist even as the patient's physical health improves. The compounds and formulations described herein may be used to treat depression associated with chronic or life-threatening diseases or illnesses.

[0813] In some embodiments, the tablet composition contains an amount of any of the compounds described herein that are released from the matrix at a rate of 0.05 to 2 mg / kg / h over 12 to 24 hours, for example, over 24 hours.

[0814] In some embodiments of this disclosure, the composition contains a composite concentration of DMT, 5-MeO-DMT, tryptamine derivatives such as psilocybin, psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in plasma at concentrations of approximately 10 to 500 ng / ml (e.g., approximately 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 ng / ml or greater (e.g., approximately 100 to approximately 300 ng / ml, approximately 250 to approximately 450 ng / ml, or approximately 50 to approximately 400 ng / ml) The concentration is achieved in any range of approximately 10 to approximately 500 ng / ml (e.g., ml) and maintained during the release period. In some embodiments, the composition achieves a composite concentration of DMT, 5-MeO-DMT, psilocybin, psilocybin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in plasma in the range of approximately 10 to 300 ng / ml and maintains this concentration during the release period. In some embodiments, the composition achieves a composite concentration in plasma in the range of approximately 10 to 100 ng / ml, or approximately 50 to 100 ng / ml A composite concentration of tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, is achieved and maintained for the duration of the release period. In some embodiments, the composition achieves a composite concentration of tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in plasma in the range of about 10 to 20 ng / ml, and maintains this concentration for the duration of the release period.

[0815] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is 4 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less.

[0816] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives, such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is greater than 4 hours.

[0817] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives, such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is more than approximately 8 hours.

[0818] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives, such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is greater than approximately 12 hours.

[0819] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives, such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is greater than approximately 16 hours.

[0820] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives, such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is greater than approximately 20 hours.

[0821] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is approximately 24 hours or longer.

[0822] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives, such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is approximately 28 hours or longer.

[0823] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is approximately 32 hours or longer.

[0824] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives, such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is approximately 36 hours or longer.

[0825] In some embodiments of this disclosure, the formulations of this disclosure include tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or compounds described herein. The release period for either of these, or their pharmaceutically acceptable salts, is less than approximately 48 hours.

[0826] In some embodiments of the present disclosure, the release period of any of the tryptamine derivatives, such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, in the formulations of the present disclosure is less than approximately 36 hours.

[0827] In some embodiments of this disclosure, the tablet compositions of this disclosure are used as applications for twice-daily (BID), three times-daily (TID), or four times-daily (QID).

[0828] In some embodiments of this disclosure, the tablet compositions of this disclosure are used for once-daily (QD) use.

[0829] In some embodiments of this disclosure, the tablet compositions of this disclosure are used for nighttime (QHS) use.

[0830] In some embodiments of this disclosure, the tablet compositions of this disclosure are used as appropriate (PRN) applications.

[0831] In some embodiments of this disclosure, the oral pharmaceutical composition is enhanced. In some embodiments, to achieve the same effect as comparative oral tablets not described herein by improving administration efficiency, the formulation may utilize smaller amounts of tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin for therapeutic purposes.

[0832] In some embodiments of this disclosure, an oral administration event providing an appropriate single unit dose may include one single tablet or multiple tablets.

[0833] Furthermore, in some embodiments, various types of enteric coatings may be used to protect the tablets from the acidic environment in the stomach and maintain long-term release.

[0834] In some embodiments of this disclosure, a single-layer tablet or caplet is coated with a protective layer of an inactive pharmaceutical component to form a controlled-release formulation, for example, to ensure steady-state release of the drug from the matrix and to avoid a concentration burst at an early release point.

[0835] Some embodiments of this disclosure provide a controlled-release formulation of a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, which ensures a steady-state release of a therapeutically effective concentration of any of the compounds described herein (such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof) without a toxic spike in analgesic or psychotropic effects at plasma concentrations of the compound. The formulations comprise a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and are formulated in an osmotically controlled-release pharmaceutical composition, such as a tablet, caplet, or granule. In these formulations, a single core layer comprising a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof (as defined, for example, by other tablet formulations described herein) is surrounded by a semipermeable membrane having or not having a drug delivery orifice. While not intended to be bound by theory, these systems are intended for the controlled delivery of the active material. Because water osmosis is used, the delivery rate is expected to be independent of the gastrointestinal state. In combination with novel and original embodiments of this disclosure, permeable asymmetric membrane technology or AMT (e.g., technology targeting monolayer tablets, caplets, or granules coated with an insoluble, asymmetric microporous membrane produced by controlled phase separation) can be used to produce formulations useful for therapeutic methods and kits described herein.

[0836] In some embodiments of this disclosure, the counterion does not significantly affect the formulation of any of the tryptamine derivatives described herein, such as DMT, 5-MeO-DMT, psilocybin, psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, or has the desired therapeutic effect described herein, i.e., a similar steady release (e.g., based on symptoms) of a therapeutically effective concentration from an oral pharmaceutical composition such as a tablet, caplet, capsule, gel cap, cap, or granule, and the counterion does not significantly affect the formulation of any of the tryptamine derivatives described herein, such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein. To achieve the absence of analgesic or psychotropic toxicity spikes at concentrations of any of the compounds or their pharmaceutically acceptable salts, tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, psilocine, or any of the compounds described herein, or their pharmaceutically acceptable salts, the tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, psilocine, or any of the compounds described herein, or their pharmaceutically acceptable salts, may be formulated as pharmaceutically acceptable salts such as hydrochloride, aspartate, or succinate, so as not to significantly affect the ability of the compound or its pharmaceutically acceptable salt to achieve the absence of an analgesic or psychotropic toxicity spike at concentrations of any of the compounds or their pharmaceutically acceptable salts. Examples of salts within this range include, but are not limited to, salts having inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid; acids having organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid, tartaric acid, and other mineral acids and carboxylic acids well known to those skilled in the art. Additional examples include salts having inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminum, and zinc, and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, and procaine. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0837] Some embodiments of this disclosure provide kits for treating a subject with a pharmaceutical composition such as a pill, which includes a pharmaceutical composition such as an orally administered pharmaceutical composition, which includes one of the formulations described herein, which includes a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and instructions for use for the treatment, prevention, or management of a disease, disorder, or condition such as pain as described herein.

[0838] In some embodiments of this disclosure, the pain to be treated is cancer pain, for example, refractory cancer pain.

[0839] In some embodiments of this disclosure, the pain to be treated is postoperative pain.

[0840] In some embodiments of this disclosure, the pain to be treated is orthopedic pain.

[0841] In some embodiments of this disclosure, the pain to be treated is back pain.

[0842] In some embodiments of this disclosure, the pain to be treated is neuropathic pain.

[0843] In some embodiments of this disclosure, the pain to be treated is a toothache.

[0844] In some embodiments of this disclosure, the pain to be treated is chronic pain in opioid-resistant patients.

[0845] In some embodiments, the disease or disorder is a disease or disorder related to the serotonin 5-HT2 receptor.

[0846] In some embodiments, the disease or disorder is major depressive disorder (MDD), major depressive disorder with suicidal ideation or suicidal behavior (MDD), suicidal ideation, suicidal behavior, non-suicidal self-injury disorder (NSSID), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), bipolar I disorder, bipolar II disorder, bipolar and related disorders including cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, alcohol use disorder, opioid use disorder The group consists of central nervous system (CNS) disorders, including harm, substance use disorders including amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, severe neurocognitive impairment, mild neurocognitive impairment, sexual dysfunction, chronic fatigue syndrome, Lyme disease, obesity, or combinations thereof. In some embodiments, the disease or disorder is alcohol use disorder.

[0847] In some embodiments, the disease or disorder includes a state of the autonomic nervous system (ANS).

[0848] In some embodiments, the disease or disorder includes lung disorders, including asthma and chronic obstructive pulmonary disease (COPD).

[0849] In some embodiments, the disease or disorder includes cardiovascular disorders, including atherosclerosis.

[0850] Some embodiments of this disclosure provide kits for treating a subject with DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein

[0851] Some embodiments of this disclosure provide kits for treating a subject with DMT, 5-MeO-DMT, tryptamine derivatives such as formula psilocybin and psilocine, or any of the compounds described herein

[0852] Some embodiments of this disclosure include pharmaceutical compositions such as pill-like orally administered tablets, comprising one of the formulations herein containing a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof. The present invention provides a kit for treating a subject using either or a pharmaceutically acceptable salt thereof, and instructions for use in, for example, the treatment of migraine with aura.

[0853] Some embodiments of this disclosure provide kits for treating a subject with DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein

[0854] Some embodiments of this disclosure provide a kit for treating a subject with a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein

[0855] Some embodiments of this disclosure provide a kit for treating a subject with a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein

[0856] In some embodiments, instructions for use form an integrated component of the packaging for the tablet composition.

[0857] In embodiments, the present disclosure features an oral, controlled-release pharmaceutical composition for oral administration to a subject for treating a subject diagnosed with, suffering from, or susceptible to, a disease, disorder, or condition for which tryptamine therapy may be suggested, considered, or recommended, wherein the subject requires treatment with the oral, controlled-release pharmaceutical composition, and the oral, controlled-release pharmaceutical composition is (a) an effective amount for treating, preventing and / or managing a disease, disorder, or condition in a subject, comprising a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient, comprising When a release-controlled pharmaceutical composition is orally administered to a subject, steady-state release of the drug from the release-controlled pharmaceutical composition is maintained so that no neurological toxicity spikes occur in the subject's plasma during the drug release period from the pharmaceutical composition.

[0858] General tablet formulations The formulations of this disclosure include orally administered pharmaceutical compositions such as tablets, capsules, caplets, gel caps, and cap compositions, which may include uncoated or coated tablets, caplets, and caps (including film-coated tablets, sugar-coated tablets, and gastric-resistant / enteric-coated tablets). Oral pharmaceutical compositions for oral use may include diluents, disintegrants, binders, and palladium. The active ingredients may include tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, mixed with pharmaceutically acceptable inert excipients such as lubricants, powder flow improvers, wetting agents, sweeteners, flavoring agents, colorants, and preservatives. Furthermore, the oral pharmaceutical compositions of this disclosure are solid dosage forms intended for oral administration, obtained, for example, by dry granulation by single or multiple compressions of powder or granules. In some embodiments, the oral pharmaceutical compositions may be obtained using wet granulation techniques. In some embodiments, the oral pharmaceutical compositions may be obtained by molding, heating / annealing, or extrusion techniques.

[0859] In some embodiments, the oral tablets are cylindrical, with flat or convex end faces, and the ends may be angled. In some embodiments, the surface is convex. Furthermore, they may have lines or break marks (scores), symbols, or other marks.

[0860] In some embodiments, break marks are intended to allow for precise subdivision of tablets to provide doses less than one tablet. In some embodiments of this disclosure, the tablet composition includes one or more excipients, such as diluents, binders, disintegrants, lubricants, substances that can modify the dosage form and the action of the active ingredient in the gastrointestinal tract, colorants approved by the appropriate national or regional authorities, and flavoring agents. When such excipients are used, it is necessary to ensure that they do not adversely affect the stability, dissolution rate, bioavailability, safety, or efficacy of the active ingredient, and there should be no incompatibility between the components of the dosage form.

[0861] Coated tablets are tablets covered with one or more layers of a mixture of substances such as natural or synthetic resins, polymers, rubber, fillers, sugars, plasticizers, polyols, waxes, colorants approved by the appropriate national or regional authorities, and flavorings. Such coating materials do not contain any active ingredients such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or their pharmaceutically acceptable salts. Tablets may be coated for a variety of reasons, such as protection of the active ingredient from burst emission from the matrix, air, moisture, or light, masking of unpleasant tastes and odors, or improvement of appearance. The substances used for coating may be applied as solutions or suspensions.

[0862] In some embodiments, the manufacturing process of an oral pharmaceutical composition, such as a tablet, meets the requirements of Good Manufacturing Practices (GMP). In some embodiments, in the manufacture of an oral pharmaceutical composition, one or more measures selected from the following are taken: ensuring that mixing with excipients is carried out in a manner that ensures homogeneity; ensuring that the oral pharmaceutical composition has sufficient mechanical strength to avoid crushing or destruction in subsequent processing such as coating, storage, and distribution; minimizing degradation of the active ingredient; minimizing the risk of microbial contamination; and minimizing the risk of secondary contamination. Furthermore, in the manufacture of split tablets (tablets with split marks or multiple marks) intended to be divided to provide doses less than one tablet, measures are taken as necessary to ensure the effectiveness of the split marks on the uniformity of the mass or content of the divided parts so that the patient receives the intended dose.

[0863] Generally, appropriate doses range from approximately 0.01 to approximately 10 mg per kilogram of body weight per day for the recipient, for example, in the range of approximately 0.1 to approximately 5 mg per kilogram of body weight per day. Additional details regarding formulation and administration techniques are described in detail in scientific literature and patent documents. See, for example, the latest issue of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. ("Remington's"). After the pharmaceutical composition has been formulated into an acceptable carrier, it should be placed in an appropriate container for processing under the indicated conditions. (They may be labeled.) For the administration of a preparation containing any of the compounds described herein (tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein), or a preparation containing a pharmaceutically acceptable salt thereof, such labeling may include, for example, instructions regarding the amount, frequency, method of administration, treatment regimen, and symptoms.

[0864] Monograph adherence

[0865] In some embodiments, the formulations of the Disclosure conform to a certain industry-recognized monograph to result in compliance with the Federal Food, Drug, and Cosmetic Act. In particular, the formulations of the Disclosure are deemed compliant and acceptable under visual inspection, mass uniformity analysis, content uniformity analysis, and / or dissolution / disintegration analysis, all of which are established by the relevant monograph.

[0866] In some embodiments, certain procedures are verified and monitored throughout the entire manufacturing process by implementing appropriate in-process controls. These are designed to ensure the effectiveness of each stage of the manufacturing process. In-process controls during tablet manufacturing may include the moisture content of the final lubrication mixture, granule size, flow of the final mixture, and, where applicable, the uniformity of mass of the tablet core before coating. In-process controls during tablet manufacturing may also include the dimensions (thickness, diameter), mass uniformity, hardness and / or pulverability, abrasion, disintegration, or dissolution rate (e.g., for controlled-release tablets) of the final dosage form. Appropriate test methods that can be used to demonstrate these properties are known in the art.

[0867] In some embodiments, the packaging may be required to be adequate for protecting the pharmaceutical composition, including the tablets, from light, moisture, and damage during transport.

[0868] In additional embodiments, a commercially available formulation (e.g., a kit) complies with the labeling requirements specified in Good Manufacturing Practices (GMP). Such labeling includes: (1) Name of the drug (2) The name of the active ingredient, the International Common Name (INN), should be used whenever possible. (3) Amount of active ingredient in each tablet and the number of tablets in the container (4) Batch (lot) number assigned by the manufacturer (5) Expiration date, and manufacturing date if applicable. (6) Special storage conditions or any necessary handling precautions. (7) Instructions regarding use, warnings, and precautions that may be necessary (8) Name and address of the manufacturer or person responsible for bringing the product to market (9) In the case of split tablets, where the instructions for use include splits that provide doses less than one tablet, the label must also include the storage conditions and shelf life of those split pieces that are not to be taken or administered immediately.

[0869] In some embodiments, pharmaceutical compositions such as tablets can withstand handling, including packaging and transportation, without losing their integrity.

[0870] The formulations of this disclosure may be used in the methods of this disclosure, such as the therapeutic methods of this disclosure. Accordingly, this disclosure relates to the use of the formulations or compositions (e.g., pharmaceutical compositions) of this disclosure, which include, for example, DMT, 5-MeO-DMT, psilocybin, and psilocin, tryptamine derivatives, or any of the compounds described herein, or pharmaceutically acceptable salts thereof, for example, for the treatment of pain. Accordingly, in some embodiments, this disclosure provides the management of different types of pain, including, as described herein, refractory cancer pain, neuralgia, postoperative pain, complex regional pain syndrome (CRPS), such as migraine with aura, and depression. This includes, but is not limited to, other conditions including alcoholism, refractory asthma, epilepsy, acute brain injury and stroke, Alzheimer's disease, and other disorders including oral administration of the formulations of this disclosure. In some embodiments, the use of the formulations of this disclosure may be used as a monotherapy. In some embodiments, the use of the formulations of this disclosure may be used as an adjuvant / combination therapy.

[0871] In some embodiments, this disclosure provides management of different types of pain, including, for example, cancer pain such as refractory cancer pain, neuropathic pain, opioid-induced hyperalgesia and opioid-related tolerance, neuralgia, postoperative / post-surgical pain, complex regional pain syndrome (CRPS), shock, limb amputation, severe chemical burns or burns, sprains, ligament ruptures, fractures, wounds, and other tissue injuries, dental surgery, procedures, and diseases. This disclosure includes, but is not limited to, other conditions including work and delivery pain, pain during physical therapy, radiation poisoning, acquired immunodeficiency syndrome (AIDS), epidural (or epidural) fibrosis, orthopedic pain, back pain, failure of back surgery and failure of laminectomy, sciatica, painful sickle cell crisis, arthritis, autoimmune diseases, refractory bladder pain, pain associated with certain viruses such as herpes zoster pain or herpes pain, acute nausea, such as pain that can cause nausea, or abdominal pain that is often accompanied by severe nausea, such as migraine with aura, and depression (e.g., acute or chronic depression), painful depression, alcohol dependence, acute agitation, refractory asthma, acute asthma (e.g., unrelated pain conditions can trigger asthma), epilepsy, acute brain injury and stroke, Alzheimer's disease and other disorders. Furthermore, this disclosure includes the treatment / management of any combination of these types of pain or conditions.

[0872] In some embodiments, the pain to be treated / managed is wind-up-related pain that may occur in acute breakthrough pain or chronic pain conditions.

[0873] In some embodiments of this disclosure, the pain to be treated / managed is, for example, cancer pain such as refractory cancer pain.

[0874] In some embodiments of this disclosure, the pain to be treated / managed is postoperative pain.

[0875] In some embodiments of this disclosure, the pain being treated / managed is orthopedic pain.

[0876] In some embodiments of this disclosure, the pain to be treated / managed is back pain.

[0877] In some embodiments of this disclosure, the pain being treated / managed is neuropathic pain.

[0878] In some embodiments of this disclosure, the pain to be treated / managed is toothache.

[0879] In some embodiments of this disclosure, the condition being treated / managed is depression.

[0880] In some embodiments of this disclosure, the pain to be treated / managed is chronic pain in opioid-tolerant patients.

[0881] In embodiments, this disclosure relates to a method for treating a disease or condition by modulating NMDA activity, the method comprising administering an effective amount of any of the compounds described herein (e.g., tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein) to a subject in need. In embodiments, the disease or condition is levodopa-induced dyskinesia, dementia (e.g., Alzheimer's disease), tinnitus, treatment-resistant depression (TRD), major depressive disorder, neuropathic pain, agitation caused by or associated with Alzheimer's disease, pseudoglobulin effect, autism, ocular function The following are selected from generalized anxiety disorder, Alzheimer's disease, schizophrenia, diabetic neuropathy, acute pain, depression, bipolar depression, suicidal ideation, neuropathic pain, or post-traumatic stress disorder (PTSD). In embodiments, the disease or condition is a mental disorder or psychiatric disorder (e.g., schizophrenia, mood disorder, substance-induced psychosis, major depressive disorder (MDD), bipolar disorder, bipolar depression (BDep), post-traumatic stress disorder (PTSD), suicidal ideation, anxiety, obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD). In other embodiments, the disease or condition is a neurological disorder (e.g., Huntington's disease (HD), Alzheimer's disease (AD), or systemic lupus erythematosus (SLE)).

[0882] For example, in some embodiments, the Disclosure provides a method for treating a subject with a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, which includes the step of administering to a patient an orally administered tablet composition, such as a matrix composition, comprising a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, so that the subject is treated.

[0883] The administering physician may provide a prophylactic or therapeutic treatment by adjusting the amount and timing of a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, based on observation of one or more symptoms of the disorder or condition being treated.

[0884] In some embodiments, the Disclosure relates to the production of tablet compositions such as monolayer tablet compositions, and the steady release of a therapeutically effective concentration of a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, from an oral tablet over the full release period, such as an analgesic or psychotropic toxicity spike in plasma concentrations of DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof. The present invention provides a method for continuous oral administration of a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, into tablets such as monolayer tablets, without having a neurologically toxic spike, and provides a method for oral administration of a tablet composition to a target so that a continuous therapeutically effective concentration of DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, is provided to the target.

[0885] In some embodiments of this disclosure, the subject is a mammal.

[0886] In some embodiments of this disclosure, the mammal is a human.

[0887] In some embodiments, the Disclosure provides a method for formulating tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, from an oral formulation to ensure steady-state release of therapeutically effective concentrations of tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, without having neurologically toxic spikes such as analgesic or psychotic toxic spikes at plasma concentrations of the tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, from an oral formulation. In some embodiments, the method involves (i) a water-insoluble solution The method includes the step of combining (i) a charged nonionic matrix, (ii) a polymer supporting one or more negatively charged groups, and (iii) any tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, for example, to produce a monolayer orally administered tablet composition. In some embodiments, the method includes the step of combining (i) polyethylene oxide (PEO), such as MW with a strength of about 2,000 to about 7,000 kDa, including HPMC, and (ii) any tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, for example, to produce an orally administered monolayer tablet composition. In some embodiments, the method comprises the step of combining polyethylene oxide (PEO) containing HPMC with a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, wherein the tablet composition further comprises a polymer supporting one or more load groups, such as polyethylene glycol (PEG) such as PEG8K, or polyacrylic acid, and / or may further undergo heating / annealing, such as under extrusion conditions. In some embodiments, the formulations of the Disclosure may be administered in combination with other active therapeutic agents, such as opioids, to reduce pain. In some embodiments, the formulations of the Disclosure may help reduce the amount of opioid required to treat a patient.

[0888] In some embodiments, the formulations of this disclosure are not administered in combination with other active therapeutic agents.

[0889] In some embodiments, the formulations of the present disclosure may be administered in combination with another formulation of tryptamine or a derivative thereof, for example, an immediate-release formulation of tryptamine or a derivative thereof.

[0890] In some embodiments, the Disclosure provides a method for formulating tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, from an oral formulation to ensure steady-state release of therapeutically effective concentrations of tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, without having a toxic spike of analgesic or psychotic development at plasma concentrations of the tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof. The method comprises formulating tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocin, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, into osmotic controlled-release tablets. In these formulations, a single core layer containing a tryptamine derivative such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof, is surrounded by a semipermeable membrane having or not having a drug delivery orifice. In some embodiments, formulations useful for the methods and kits described herein can be prepared using novel and original pharmaceutical compositions of this disclosure (tryptamine derivatives such as DMT, 5-MeO-DMT, psilocybin, and psilocine, or any of the compounds described herein, or a pharmaceutically acceptable salt thereof) and permeable asymmetric membrane technology or AMT (e.g., technology targeting monolayer tablets coated with an insoluble, asymmetric microporous membrane produced by controlled phase separation). [Examples]

[0891] Example 1. Synthesis of PI-α,α-d2 The synthesis of PI-α,α-d2 involved iminoformylation with formaldehyde / dimethylamine, followed by conversion to a 3-acetic acid derivative using potassium cyanide under acidic conditions. The process was initiated with 4-oxybenzylindole. Subsequent treatment with thionyl chloride and dimethylamine produced the associated amide, which is reduced by LiAlD4, inserting a deuterated methylene group at the α-position. In the final step, the -OBz ​​protecting group was removed by hydrogen gas over a palladium catalyst to produce the final compound. The structure of the product is: 1 This was confirmed by 1H NMR and LC-MS. [ka]

[0892] Example 2. DMT-d 10 synthesis DMT-d 10 The synthesis was initiated with indole, which is first acylated with oxalyl chloride and then converted to the associated amide by treatment with dimethylamine-d6. Subsequent reduction with LiAlD4 leads to the final product. The structure of the material is, 1 This was confirmed by 1H NMR and LC-MS.

[0893] Example 3. Synthesis of 5-CD3O-DMP-α,α,5,5,5-d5

[0894] The synthesis of 5-CD3O-DMP-α,α,5,5,5-d5 was carried out similarly to DMT-α,α-d2 described in Example 2, which began with 5-deuterium methoxyindole prepared by methylation of 5-hydroxyindole using methyl deuterium iodide. The structure of the product is: 1 This was confirmed by 1H NMR and LC-MS.

[0895] Example 4. Synthesis of Aer-α,α,-d2

[0896] Aer-α,α-d2 was synthesized using the -OBz ​​bis-deuterated tryptamine intermediate obtained as described in Example 1. This material was alkylated with methylamine and then reduced with hydrogen on palladium to obtain the final product as an iodide salt (Scheme 2). The structure of the product is as follows: 1 This was confirmed by 1H NMR and LC-MS. [ka]

[0897] Example 5.5 - HT Receptor Pharmacology Binding affinity of PI and PI-α-d2 (K i ) and functional capabilities (EC 50 The values ​​are summarized in Table 1. Deuteration was found to have little effect on affinity and function at key receptor targets.

[0898] Receptor affinity assay: 5-HT 1A , 5-HT 2(A、B、C) Receptor affinity was determined by competitive binding of radioactive ligands. Membranes were collected from CHO-K1 cells or HEK293 cells expressing serotonergic receptors, and the K1 receptor was determined by competitive binding of the radioactive ligand. d The compounds were cultured in assay buffer at a specific concentration, and competing compounds for the receptor binding site were tested. After equilibration, the reaction was terminated by collecting the ligand-receptor-membrane complex (Microbeta, PerkinElmer), and radioactivity was measured using a scintillation counter (Microbeta2, PerkinElmer). The data were fitted to a nonlinear curve, and K i The values ​​were calculated according to the Cheng-Prusoff equation.

[0899] Receptor function assay: 5-HT 1A Receptor-mediated Gi stimulation (decrease in cyclic adenosine monophosphate (cAMP) levels) and 5-HT 2(A、B、C)Receptor-mediated Gq stimulation (phosphoinositide hydrolysis leading to the production of inositol phosphate 1 (IP1)) – a standard signaling pathway – was measured as described above using fluorescence resonance energy transfer (FRET) techniques (e.g., LANCE Ultra cAMP TR-FRET (PerkinElmer) and IP-One HTRF (Cisbio) kits) along with homogeneous time-resolved fluorescence (HTRF) compatible microplate readers (e.g., Mithras LB 940, Berthold) (Canal et al., 2013). Briefly, CHO-K1 cells or HEK293 cells expressing serotonergic receptors were cultured with the test compound in stimulation buffer. After equilibration, the reaction was terminated with donor and acceptor fluorescence conjugates in lysis buffer, and FRET was measured. Data were compared to a positive control (e.g., serotonin) to measure efficacy (e.g., EC). 50 ) and effectiveness (e.g., E MAX A nonlinear curve was fitted to calculate the result. [Table 1]

[0900] Example 6. In vitro hepatic metabolism and kinetic deuterium isotope effects 5-MeO-DMT and 5-MeO-DMT-α,α-d2 (10 μl of 2 μM solution) were cultured in 200 μl of medium consisting of 100 mg rat liver microsomes, an NADPH regeneration system (1 mM NADP, 1 unit / ml isocitrate dehydrogenase, 5 mM isocitrate, 5 mM magnesium chloride), and 25 mM phosphate buffer (pH 7.4). The reaction was terminated at different time points (0–60 minutes) by adding 300 μl of acetonitrile. For product analysis, the precipitated salts and proteins were spun out by centrifugation, the residual solution was diluted in 300 μl of water, and injected into an LC / MS (Agilent 1200 system coupled with an ABS Sciex 4000 QTRAP LC / MS / MS mass spectrometer). Metabolic stability was estimated by evaluating the rate of disappearance of the major parent peak. The observed overall dynamic deuterium isotope effect (decrease in reaction rate between deuterated and non-deuterated molecules) was substantial, at 150–200%. Similar effects were observed in this assay for DMT, DMT-α,α-d2, and DMT-α,α,β,β-d4. 10 Further enhancement of metabolic stability has been detected, demonstrating superiority in MAO-A enzyme assays and highlighting the further deuteration effect of the -N(CD3)2 substituent. [Table 2] [Table 3] [Table 4] [Table 5]

[0901] Example 7. PK test in rats and mice Table 3 shows the main PK parameters (expressed as the rate of change relative to the non-deuterated material), and the half-life (T 1 / 2This includes pharmacokinetics (AUC), area under the curve (F), bioavailability (F), and blood-plasma ratio (BPR). The pharmacokinetics of deuterated tryptamine were studied in rats. In a typical experiment, five rats with surgically inserted jugular vein catheters (Charles River, Andover, Massachusetts) were administered via cassette. Two groups of female rats (200–250 g) were fasted for 12 hours, and then 5 mg / kg of a deuterated analogue and 5 mg / kg of the related undeuterated analogue were administered to each group by forced oral administration or via catheter. Plasma samples obtained at 0, 15, 30, 60 minutes, and 2, 4, 8, and 24 hours were analyzed for the parent molecule using LC / MS spectroscopy. Two separate groups of five animals were used to determine the blood-to-plasma ratio (BPR). Each group was sacrificed at 15 and 30 minutes, and the concentration of the parent drug in the brain and plasma was determined by LC / MS spectroscopy. [Table 6]

[0902] Example 8. In vitro enzyme assay The metabolic outcomes of selective deuteration of tryptamine compounds were confirmed in two in vitro assays: monoamine oxidase A (MAO-A) and rat liver microsomes (RLM). The rat liver microsome assay is considered a good proxy for in vivo hepatic metabolism that controls the metabolic fate of tryptamines. Similar deuteration results were detected in in vitro assays of different animal species, including human liver microsomes.

[0903] While not bound by any particular theory, it is assumed that the major metabolic degradation pathways involving tryptamine, particularly the outer ring side chains of tryptamine, are regulated by MAO-A enzymes. Therefore, for certain molecules, specific deuteration of the outer ring portion of tryptamine (e.g., the N-CH2 fragment) can have a significant impact on the overall metabolic kinetics, i.e., a significant delay in the enzymatic degradation of tryptamine derivatives discussed herein. In these examples, increased metabolic stability was observed in both MAO-A and RLM assays compared to non-deuterated base compounds. In the absence of MAO-A metabolism, deuteration of the N-CH2 group did not affect RLM digestion kinetics. Metabolism of tryptamine by MAO-B enzymes was not observed.

[0904] The test results are summarized in Table 7, which establishes a set of exemplary compounds suitable for the selective deuteration of the N-CH2 fragment, and also provides additional information regarding the selective deuteration of other parts of the molecule. Comparisons between compounds were performed using best-fit curves to calculate the half-life, i.e., the point at which 50% of the compound is digested in the assay.

[0905] hrMAO-A (lot number 8213001) and hrMAO control (lot number 1067001) were purchased from XenoTech. The reaction mixture was prepared as described below. Co-administered TA was added to the reaction mixture at a final concentration of 1 microM each. The positive control, quinulamine (25 microM), was carried out simultaneously with TA in a separate reaction. The reaction mixture (without TA or quinulamine) was equilibrated in a shaking water bath at 37°C for 5 minutes. The reaction was initiated by the addition of TA or quinulamine, and the mixture was cultured in a shaking water bath at 37°C. Aliquots (100 microL) of the TA reaction mixture were collected at 0, 5, 10, 20, 30, 60, and 120 minutes. Aliquots (100 microL) of the positive control reaction mixture were collected at 0 and 30 minutes. The TA and quinulamine samples were subjected to 0.1% The reaction was terminated by immediately combining the samples with 100 microliters of ice-cold 100% MeCN containing formic acid and IS. The samples were then mixed and centrifuged to precipitate the proteins. All TA samples were assayed by LC-HRAMS. The PARR (sample relative to IS) at each time point was compared to the PARR at time 0 to determine the remaining percentage at each time point. Reaction composition: hrMAO 0.02 mg / mL, potassium phosphate, pH 7.4 100 mM magnesium chloride, 5 mM test substance (each) 1 microM.

[0906] The substrate was cultured in 200 μl of medium consisting of 100 mg rat liver microsomes, an NADPH regeneration system (1 mM NADP, 1 unit / ml isocitrate dehydrogenase, 5 mM isocitrate, 5 mM magnesium chloride), and 25 mM phosphate buffer (pH 7.4). The reaction was terminated at different time points (0, 5, 10, 20, 30, 60, and 120 minutes) by adding 300 μl of acetonitrile. For product analysis, the precipitated salts and proteins were spun out by centrifugation, the residual solution was diluted with 300 μl of water, and injected into an LC / MS (Agilent 1200 system coupled with an ABS Sciex 4000 QTRAP LC / MS / MS mass spectrometer). Metabolic stability was estimated by evaluating the rate of disappearance of the major parent peak. [Table 7] [Table 8]

[0907] As shown in Table 7, MAO-A metabolic activity was observed for tryptamine substrates with N-Me and N-Et substituents, as well as for asymmetrically substituted substrates such as N,N-Me,Et substituents. However, no MAO-A metabolic activity was observed for tryptamine substrates with an N,N-Et moiety. Consequently, for example, i-Pr and allyl, -NC Tryptamine substrates with N, N-Et or greater alkyl chains, such as deuterium in the H2-CH2 and N-R8,R9 fragments, showed no metabolic effect in either the MAO-A or RLM assay. Tetradeuteration via ethylene bridging or selective bisdeuteration at the alpha carbon stabilized the substrate for MAO-A activity compared to the metabolic activity, i.e., enzymatic degradation, of the base-nondeuterated substrate. Deuteration at the N-R8,R9 fragment further stabilized the substrate for MAO-A activity, as shown in Table 7. Deuterated DMT-d 15 Further deuteration at the phenyl ring 、 DMT-d, which is selectively deuterated in the extraring, as observed by RLM assay. 10 In comparison, it did not result in an improvement in half-life. However, deuteration of the phenyl ring is observed to play a role in slowing down the RLM metabolism of tryptamines that do not have MAO-A metabolism. Although not bound by any particular theory, it is thought that there is a contribution to the metabolism of tryptamine substrates from enzymes other than MAO, such as CYP isoforms, which generate cyclic hydroxylation metabolites. The involvement of CYP enzymes is also thought to be involved in the delay of RLM metabolism of 5-OMe deuterated tryptamines versus non-deuterated 5-OMe substituted tryptamines.

[0908] All patents, patent applications, and other scientific or technical literature referenced anywhere in this Spec. are incorporated herein by reference in their entirety. The embodiments described herein descriptively can be adequately implemented in the absence of any element or combination of elements, limitations, or combinations disclosed herein, specifically or non-specifically. Thus, for example, in each example herein, any of the terms “including,” “essentially consisting of,” and “consisting of” may be replaced with any of the other two terms, while retaining their ordinary meaning. The terms and expressions used are used as descriptive terms, not limitations, and in the use of such terms and expressions, there is no intention to exclude any equivalent of the features or parts thereof shown and described, and it is recognized that various modifications are possible within the claims. Thus, while the methods and compositions are specifically disclosed by the embodiments and any features, modifications and variations of the concepts of this disclosure can be left to those skilled in the art, and such modifications and variations should be understood to be within the scope of the compositions and methods defined by the described and appended claims.

[0909] Any single term, element, phrase, group of terms, group of phrases, or group of elements described herein may be specifically excluded from the claims.

[0910] For example, where a range such as a temperature range, time range, composition, or concentration range is given herein, all intermediate and partial ranges, as well as all individual values ​​within the given range, are intended to be included in this disclosure. Any partial range or individual value within a range or partial range included in the description herein may be excluded from the embodiments herein. Naturally, any element or step included in the description herein may be excluded from the claimed composition or method.

[0911] Furthermore, if the characteristics or aspects of a composition and method are described in terms of the Markush group or any other alternative grouping, a person skilled in the art will recognize that the composition and method are also described in terms of any individual member or subgroup of a member of the Markush group or any other group.

[0912] Therefore, the foregoing merely describes the principles of the methods and compositions. Those skilled in the art will understand that various arrangements embodying the principles of this disclosure and falling within its spirit and scope can be devised, although these are not expressly described or shown herein. Furthermore, all examples and conditional statements listed herein are primarily intended to assist the reader in understanding the principles of this disclosure and the concepts to which the inventors have contributed to the advancement of the art, and are construed as not being limited to such specifically listed examples and conditions. It should be. Furthermore, all descriptions herein listing the principles, aspects, and embodiments of the present disclosure and specific examples thereof are intended to encompass both their structural and functional equivalents. Moreover, such equivalents are intended to include both currently known equivalents and those to be developed in the future, i.e., any developed elements that perform the same function regardless of their structure. Accordingly, the scope of this disclosure is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of this disclosure are embodied by the following:

Claims

1. The compound described in formula (III), 【Chemistry 1】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, X １ and X ２ It is deuterium, Y １ and Y ２ is hydrogen or deuterium, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ４ These are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy. R ５ These are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy. R ６ and R ７ are selected from hydrogen, deuterium, and halogen, R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ is hydrogen, deuterium, or unsubstituted, partially or completely deuterated methyl or ethyl, However, R ４ R is hydroxyl, ２ , R ５ , R ６ , and R ７ If all of them are hydrogen, then R ８ and R ９ Both are -CD ３ Rather, and R ２ , R ４ , R ５ , R ６ , and R ７ If all are hydrogen, then R ８ and R ９ Both are not unsubstituted methyl compounds, or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs.

2. R ４ If R is hydroxyl, ９ The compound according to claim 1, wherein is hydrogen.

3. R ４ If R is hydroxyl, ９ The compound according to claim 1, wherein is deuterium.

4. R ２ The compound according to claim 1, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

5. R ８ and R ９ The compound according to claim 1, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

6. The compound described in formula (III-a), 【Chemistry 2】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ４ These are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy. R ５ These are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ is hydrogen, deuterium, or unsubstituted, partially or completely deuterated methyl or ethyl, However, R ４ R is hydroxyl, ２ , R ５ , R ６ , and R ７ If all of them are hydrogen, then R ８ and R ９ Both are -CD ３ Rather, and R ２ , R ４ , R ５ , R ６ , and R ７ If all are hydrogen, then R ８ and R ９ Both are not unsubstituted methyl compounds, or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs.

7. R ４ If R is hydroxyl, ９ The compound according to claim 6, wherein is hydrogen or deuterium.

8. R ２ The compound according to claim 6, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

9. R ８ and R ９ The compound according to claim 6, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

10. The compound described in formula (III-b), 【Transformation 3】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ is hydrogen, deuterium, or unsubstituted, partially or completely deuterated methyl or ethyl, However, R ２ , R ６ , and R ７ If all of them are hydrogen, then R ８ and R ９ Both are not unsubstituted methyl compounds, or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs.

11. R ２ The compound according to claim 10, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

12. R ８ and R ９ The compound according to claim 10, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

13. The compound described in formula (III-c), 【Chemistry 4】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

14. R ２ The compound according to claim 13, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

15. R ８ and R ９ The compound according to claim 13, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

16. The compound described in formula (III-d), 【Transformation 5】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ is hydrogen, deuterium, or unsubstituted, partially or completely deuterated methyl or ethyl, However, when R ２ , R ６ , and R ７ are all hydrogen, R ８ and R ９ are not both -CD ３ , a compound or its optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug.

17. R ９ The compound according to claim 16, wherein is hydrogen.

18. R ９ The compound according to claim 16, wherein the compound is deuterium.

19. R ２ The compound according to claim 16, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

20. R ８ and R ９ The compound according to claim 16, wherein neither R ８ nor R ９ is unsubstituted or partially or fully deuterated ethyl.

21. The compound described in formula (III-e), 【Transformation 6】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

22. R ２ The compound according to claim 21, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

23. R ８ and R ９ The compound according to claim 21, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

24. The compound described in formula (III-f), 【Transformation 7】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

25. R ２ The compound according to claim 24, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

26. R ８ and R ９ The compound according to claim 24, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

27. The compound described in formula (III-g), 【Transformation 8】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

28. R ２ The compound according to claim 27, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

29. R ８ and R ９ The compound according to claim 27, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

30. The compound described in formula (III-h), 【Chemistry 9】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

31. R ２ The compound according to claim 30, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

32. R ８ and R ９ The compound according to claim 30, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

33. The compound described in formula (III-i), 【Chemistry 10】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

34. R ２ The compound according to claim 33, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

35. R ８ and R ９ The compound according to claim 33, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

36. The compound described in formula (III-j), 【Chemistry 11】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

37. R ２ These independently consist of hydrogen, deuterium, halogens, and unsubstituted, partially or completely. The compound according to claim 36, selected from deuterated methyl or ethyl.

38. R ８ and R ９ The compound according to claim 36, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

39. The compound described in formula (III-k), 【Chemistry 12】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ４ These are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, unsubstituted or substituted acetoxy, and phosphoryloxy. R ５ These are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkoxy, and phosphoryloxy. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ is hydrogen, deuterium, or unsubstituted, partially or completely deuterated methyl or ethyl, However, R ４ R is hydroxyl, ２ , R ５ , R ６ , and R ７ If all of them are hydrogen, then R ８ and R ９ Both are -CD ３ Rather, and R ２ , R ４ , R ５ , R ６ , and R ７ If all are hydrogen, then R ８ and R ９ Both are not unsubstituted methyl compounds, or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs.

40. R ４ If R is hydroxyl, ９ The compound according to claim 39, wherein is hydrogen or deuterium.

41. R ２ The compound according to claim 39, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

42. R ８ and R ９ The compound according to claim 39, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

43. The compound described in formula (III-l), 【Chemistry 13】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ is hydrogen, deuterium, or unsubstituted, partially or completely deuterated methyl or ethyl, However, R ２ , R ６ , and R ７ If all of them are hydrogen, then R ８ and R ９ Both are not unsubstituted methyl compounds, or their optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs.

44. R ２ The compound according to claim 43, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

45. R ８ and R ９ The compound according to claim 43, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

46. The compound described in formula (III-m), 【Chemistry 14】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

47. R ２ The compound according to claim 46, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

48. R ８ and R ９ The compound according to claim 46, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

49. The compound described in formula (III-n), 【Chemistry 15】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ is hydrogen, deuterium, or unsubstituted, partially or completely deuterated methyl or ethyl, However, R ２ , R ６ , and R ７ If all of them are hydrogen, then R ８ and R ９ Both are -CD ３ Not a compound or its optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug.

50. R ９ The compound according to claim 49, wherein is hydrogen.

51. R ９ The compound according to claim 49, wherein the compound is deuterium.

52. R ２ The compound according to claim 49, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

53. R ８ and R ９ The compound according to claim 49, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

54. The compound described in formula (III-o), 【Chemistry 16】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

55. R ２ The compound according to claim 54, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

56. R ８ and R ９ The compound according to claim 54, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

57. The compound described in formula (III-p), 【Chemistry 17】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

58. R ２ The compound according to claim 57, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

59. R ８ and R ９ The compound according to claim 57, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

60. The compound described in formula (III-q), [Chemistry 18] or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

61. R ２ The compound according to claim 60, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

62. R ８ and R ９ The compound according to claim 60, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

63. The compound described in formula (III-r), 【Chemistry 19】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

64. R ２ The compound according to claim 63, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

65. R ８ and R ９ The compound according to claim 63, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

66. The compound described in formula (III-s), 【Chemistry 20】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

67. R ２ The compound according to claim 66, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

68. R ８ and R ９ The compound according to claim 66, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

69. The compound described in formula (III-t), 【Chemistry 21】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

70. R ２ The compound according to claim 69, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

71. R ８ and R ９ The compound according to claim 69, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

72. The compound described in formula (III-u), 【Chemistry 22】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

73. R ２ The compound according to claim 72, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

74. R ８ and R ９ The compound according to claim 72, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

75. The compound described in formula (III-v), 【Chemistry 23】 or an optically pure stereoisomer thereof, a pharmaceutically acceptable salt, solvate, or prodrug, wherein in the formula, R ２ These are independently selected from hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted allyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. R ６ and R ７ These are selected from hydrogen, deuterium, and halogens. R ８ is unsubstituted or partially or completely deuterated methyl or ethyl, and R ９ The compound or its optically pure stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which are hydrogen, deuterium, or unsubstituted, partially or fully deuterated methyl or ethyl.

76. R ２ The compound according to claim 75, wherein is independently selected from hydrogen, deuterium, halogen, and unsubstituted or partially or completely deuterated methyl or ethyl.

77. R ８ and R ９ The compound according to claim 75, wherein both are not unsubstituted or partially or completely deuterated ethyl compounds.

78. The following compounds: 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】

79. A compound with the following structure. 【Chemistry 28】

80. The aforementioned compound is serotonin 5-HT ２ A compound according to any one of claims 1 to 79, which is a receptor agonist.

81. The aforementioned compound is serotonin 5-HT ２Ａ A compound according to any one of claims 1 to 80, which is a receptor agonist.

82. A compound according to any one of claims 1 to 81 and a pharmaceutically acceptable excipient , pharmaceutical composition.

83. A method for treating a subject having a disease or disorder, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 81.

84. A method for treating a subject having a disease or disorder, comprising administering a therapeutically effective amount of a compound described in any one of claims 1 to 81 to the subject, thereby treating the subject.

85. Serotonin 5-HT ２ A method for treating a subject having a receptor-related disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 81 to the subject.

86. The method according to any one of claims 83 to 85, wherein the disease or disorder is a neuropsychiatric disorder or an inflammatory disease or disorder.

87. The method according to claims 83 to 85, wherein the disease or disorder is a central nervous system (CNS) disorder, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), bipolar I disorder, bipolar II disorder, bipolar and related disorders including cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders including alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, significant neurocognitive impairment, mild neurocognitive impairment, sexual dysfunction, obesity, or a combination thereof.

88. The method according to claims 83 to 85, wherein the disease or disorder includes a state of the autonomic nervous system (ANS).

89. The method according to claims 83 to 85, wherein the disease or disorder includes lung disorders including asthma and chronic obstructive pulmonary disease (COPD).

90. The method according to claims 83 to 85, wherein the disease or disorder includes a cardiovascular disorder including atherosclerosis.

91. The method according to claims 83 to 85 and 87, wherein the disease or disorder is alcohol use disorder.

92. A monolayer oral tablet composition comprising a tryptamine derivative or a compound according to any one of claims 1 to 81, and a polymer.

93. The monolayer oral tablet composition according to claim 92, wherein the composition is adapted to maximum sustained release.

94. The monolayer oral tablet composition according to claim 92, wherein the tablet composition comprises a combination of (i) a water-insoluble neutral charged nonionic matrix, (ii) a polymer supporting one or more negatively charged groups, and (iii) the tryptamine derivative or a compound according to any one of claims 1 to 81.

95. The nonionic matrix may consist of a cellulose polymer alone, or starch, wax, etc. The monolayer oral tablet composition according to claim 94, which is a cellulosic polymer reinforced by mixing with neutral rubber, polymethacrylate, PVA, PVA / PVP blend, or a mixture thereof.

96. The monolayer oral tablet composition according to claim 95, wherein the cellulose polymer is hydroxypropyl methylcellulose (HPMC).

97. The monolayer oral tablet composition according to claim 94, wherein the polymer supporting one or more load groups is polyacrylic acid, polylactic acid, polyglycolic acid, polymethacrylate carboxylate, cation exchange resin, clay, zeolite, hyaluronic acid, anionic rubber, salts thereof, or mixtures thereof.

98. The monolayer oral tablet composition according to claim 97, wherein the anionic rubber is a natural material, a semi-synthetic material, or a combination thereof.

99. The monolayer oral tablet composition according to claim 98, wherein the natural material is arginine, pectin, xanthan gum, carrageenan, locust bean gum, acacia gum, karaya gum, guar gum, tragacanth gum, or a combination thereof.

100. The monolayer oral tablet composition according to claim 98, wherein the semi-synthetic material is carboxymethyl chitin, cellulose gum, or a combination thereof.

101. A monolayer oral tablet composition according to claim 92, comprising a therapeutically effective amount of the tryptamine derivative or a compound according to any one of claims 1 to 81, for the treatment of pain.

102. A monolayer oral tablet composition according to claim 92, comprising a therapeutically effective amount of the tryptamine derivative or a compound according to any one of claims 1 to 81, for the treatment of brain injury.

103. A monolayer oral tablet composition according to claim 92, comprising a therapeutically effective amount of the tryptamine derivative or a compound according to any one of claims 1 to 81, for the treatment of depression.

104. Serotonin 5-HT ２ A monolayer oral tablet composition according to claim 92, comprising a therapeutically effective amount of the tryptamine derivative or a compound according to any one of claims 1 to 81, for use in the treatment of a receptor-related disease or disorder.

105. The monolayer oral tablet composition according to claim 104, wherein the disease or disorder is a central nervous system (CNS) disorder, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), bipolar I disorder, bipolar II disorder, bipolar and related disorders including cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, substance use disorders including alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, Alzheimer's disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, significant neurocognitive impairment, mild neurocognitive impairment, sexual dysfunction, obesity, or a combination thereof.

106. The monolayer oral tablet composition according to claim 104, wherein the disease or disorder includes a state of the autonomic nervous system (ANS).

107. The monolayer oral tablet composition according to claims 104 to 105, wherein the disease or disorder is alcohol use disorder.

108. The monolayer oral tablet composition according to claim 104, wherein the disease or disorder includes lung disorders including asthma and chronic obstructive pulmonary disease (COPD).

109. The monolayer oral tablet composition according to claim 104, wherein the disease or disorder includes cardiovascular disorders, including atherosclerosis.

110. The monolayer oral tablet composition according to claim 92, wherein the composition achieves a combined concentration of the tryptamine derivative or the compound described in any one of claims 1 to 81 in plasma in the range of 10 to 500 ng / ml, and maintains this concentration during the release period.

111. The monolayer oral tablet composition according to claim 92, wherein the polymer comprises one or more negatively charged groups.

112. A tablet composition formulated for oral administration, comprising a tryptamine derivative or a compound according to any one of claims 1 to 81, and a polymer.

113. The tablet composition according to claim 112, wherein the polymer comprises one or more negatively charged groups.

114. The tablet composition according to claim 112, wherein the polymer comprises one or more acidic groups.

115. The tablet composition according to claim 112, wherein the polymer comprises a water-insoluble, neutrally charged, nonionic matrix.

116. The tablet composition according to claim 115, wherein the nonionic matrix is ​​a cellulose polymer alone, or a cellulose polymer reinforced by mixing with starch, wax, neutral rubber, polymethacrylate, PVA, PVA / PVP blend, or a mixture thereof.

117. The tablet composition according to claim 116, wherein the cellulose polymer is hydroxypropyl methylcellulose (HPMC).

118. 1) A single-layer oral tablet composition according to claim 92, and 2) a kit for the treatment of a target, comprising instructions for use in the treatment of pain.

119. 1) A monolayer oral tablet composition according to claim 92, and 2) a kit for the treatment of a subject, comprising instructions for use in the treatment of brain injury.

120. 1) A single-layer oral tablet composition according to claim 92, and 2) a kit for the treatment of a target, comprising instructions for use in the treatment of depression.

121. 1) A monolayer oral tablet composition according to claim 92, and 2) Serotonin 5-HT ２ A kit for the treatment of a target disease or disorder, including instructions for use in the treatment of receptor-related diseases or disorders.

122. The kit according to claim 118, wherein the polymer comprises one or more negatively charged groups.

123. The kit according to claim 119, wherein the polymer comprises one or more negatively charged groups.

124. The kit according to claim 120, wherein the polymer comprises one or more negatively charged groups.

125. The kit according to claim 121, wherein the polymer comprises one or more negatively charged groups.

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