Time-release tryptamine-related compositions and treatments

Abstract

Time-release pharmaceutical compositions, including those configured for sustained release, are disclosed herein. Also disclosed are methods of treating or managing a mental, a behavioural, or a neuropsychiatric condition, or the symptoms thereof, in a subject in need thereof, with such time-release pharmaceutical compositions, including those configured for sustained release.

Description

TIME-RELEASE TRYPTAMINE-RELATED COMPOSITIONS AND TREATMENTSFIELD OF THE INVENTION

[0001] The present invention relates to time-release compositions of tryptamine-related compounds and methods of treatment using such compounds.SUMMARY OF THE INVENTION

[0002] In some aspects of the disclosure, time-release compositions of tryptamine-related compounds are provided.

[0003] In some aspects of the disclosure, methods of treating or managing a mental, a behavioral, or a neuropsychiatric condition, or the symptoms thereof, in a subject in need thereof are provided comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a tryptamine-related compound, wherein the pharmaceutical composition is configured for time release.BRIEF DESCRIPTION OF THE DRAWINGS

[0004] FIG. 1 shows the results from Day 7 Total Immobility Time of male wistar rats in a Forced Swim Test.

[0005] FIG. 2 shows the results from Day 28 Total Immobility Time of male wistar rats in a Forced Swim Test.

[0006] FIG. 3 shows the effects of N,N-diisopropyltryptamine-4-glutarate and psilocin-4- glutarate administration on body weight as a function of dose and time.

[0007] FIG. 4 shows the effects of N,N-diisopropyltryptamine-4-glutarate and psilocin-4- glutarate administration on swimming time during the forced-swim test (FST).

[0008] FIG. 5 shows the effects of N,N-diisopropyltryptamine-4-glutarate and psilocin-4- glutarate administration on climbing time.DETAILED DESCRIPTIONDefinitions

[0009] As used herein, the term “about”, when used to describe a recited value, means within 5% of the recited value.

[0010] As used herein, the term “alkyl,” by itself or as part of another substituent, refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. The term “alkyl” includes cycloalkyl. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyls such as propan- 1-yl, propan-2-yl (isopropyl), cyclopropan-l-yl, etc.; butanyls such as butan-1- yl, butan-2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-l-yl, etc.; and the like. In some embodiments, an alkyl group comprises from 1 to 20 carbon atoms (C1-C20alkyl). In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms (C1-C10alkyl). In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms (C1-C6alkyl) or 1 to 4 carbon atoms (C1-C4). C1-C6alkyl is also known as “lower alkyl”.

[0011] As used herein, the term “arylalkyl” is a term of the art and refers to an alkyl group, for example a C1-6alkyl group, substituted with an aryl group, where the residue is linked to the main molecule through the alkyl group. An example of arylalkyl is the benzyl group, that is, the phenyl-methyl group.

[0012] As used herein, the term “substituted,” when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s). The term “substituted” specifically envisions and allows for one or more substitutions that are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as to not adversely affect the useful characteristics of the compound or adversely interfere with its function.

[0013] As used herein, the term “subject” means a human or a non-human mammal.

[0014] As used herein, “psychedelic state” refers to an altered state of consciousness experienced by a person, which may include intensified sensory perception, perceptual distortion or hallucinations, and / or feelings of euphoria or despair. Psychedelic states have been described as resulting from psychedelic drugs such as DMT (dimethyltryptamine), LSD, mescaline or psilocybin. Other known psychedelic drugs include the 4-hydroxy analogs of N- methyl-N-isopropyltryptamine (MiPT) and N,N-diisopropyltryptamine (DiPT).

[0015] As used herein, the term “mental disorder” includes those disorders which may be diagnosed by a mental health professional as a psychological or psychiatric disorder, includingthose which may be diagnosed by reference to Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

[0016] As used herein, the term “solvate” means that one or more solvent molecules is associated with a tryptamine-related compound as understood by those of ordinary skill in the art. A “hydrate” is a solvate when the solvent molecule is water.

[0017] As used herein, the term “tryptamine-related compound” refers to a compound based on tryptamine or having a tryptamine core such as those compounds based on or derived from psilocin; N,N-dimethyltryptamine; or psilocybin. Examples of tryptamine-related compounds include compounds within the scope of Formulae I, II, III, IV, V, VI, and VII (including all compounds set forth or exemplified herein) and their pharmaceutically acceptable salts, solvates, and zwitterions. In many embodiments, the tryptamine-related compound is a prodrug.Chemical Entities of Formulas I, II, III, IV, V, VI, and VII

[0018] In one aspect, the present disclosure comprises a tryptamine-related compound such as the tryptamine or isotryptamine compounds of Formula I, II, III, IV, V, VI, VII or a pharmaceutically acceptable salt, solvate, or zwitterion thereof which are formulated to be configured for time release. Tryptamine-related compounds of Formula I, II, III, and IV are set forth below:wherein, R1, R2, and R6 are each independently selected from hydrogen, linear or branched alkyl, C1-5alkyl, or arylalkyl;R4 is— X — CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain (C1-5alkyl), optionally substituted with — OH or — CO2H, or an aromatic ring, optionally substituted with alkyl or CO2H; orwherein R9 is X — CO2H, where X is as defined above and RIO is hydrogen, linear or branched alkyl (C1-5alkyl) or arylalkyl, optionally substituted with — OH or — CO2H;R5 is hydrogen, linear or branched alkyl (C1-5alkyl), arylalkyl, or O — R5', where R5' is hydrogen, linear or branched alkyl (C1-5alkyl); andR7 and R8: are each independently selected from hydrogen, linear or branched alkyl (C1-5alkyl), or arylalkyl, or together form a non-aromatic N-containing heterocycle, optionally substituted with alkyl, where the entire heterocyclic structure does not contain more than 12 atoms, for example, pyrrolidine (NC4ring) piperidine (NC5ring), or morpholine (NC4O ring).

[0019] These compounds of Formula I, II, III, or IV, or pharmaceutically acceptable salts, solvates, or zwitterions thereof, are converted to an active hydroxy-indole 5HT2A agonist after hydrolysis or metabolization of the ester function R4-CO — .

[0020] In some non-limiting examples, the compounds comprise diacid esters of tryptamine structures such as 4-hydroxy-N,N-dimethyltryptamine (psilocin or 4-HO-DMT), 4-hydroxy-N,N-diethyltryptamine (4-HO-DET), 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT), 4- hydroxy-N-methyl-N-isopropyltryptamine (4-OH-MIPT), 5-hydroxy-N,N- dimethyltryptamine, 4-methyl-5-hydroxy-N,N-dimethyl)tryptamme and 4-hydroxy-5-methyl- N,N-dialkyltryptamine, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof.

[0021] In some embodiments, the compounds include the 4- and 5-substituted hemisuccinates, hemiglutarates and citrates of 4-hydroxy derivatives of N,N- dimethyltryptamine (psilocin), N,N-diisopropyltryptamine (4-HO-DiPT), or N-methyl-N- isopropyl-tryptamine (4-HO-MiPT), or any pharmaceutically acceptable salt, solvate, or zwitterion thereof.

[0022] In some embodiments, the compound comprises a compound of Formula I, II, III or IV, wherein R1, R2, R5, R6, are each hydrogen; X is a linear C1-4alkyl; and R7 and R8 are each methyl, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof. In some embodiments, the compound is a compound of Formula I or II and X is C2alkyl, thus forming a 4- or 5-hemisuccinate of psilocin, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof.

[0023] In some embodiments, the compound comprises a compound of Formula I, II, III or IV, wherein R1, R2, R5, R6, are each hydrogen; X is a linear C1-C4alkyl chain; and R7 and R8 are each isopropyl, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof. In some embodiments, the compound is a compound of Formula I or n, X is C2alkyl, thus forming a hemisuccinate of 4- or 5-hydroxy-diisopropyltryptamine, or a pharmaceutically acceptable salt, solvate, or zwitterion thereof. In some embodiments, the compound is a compound of Formula I or II, X is a C2alkene, thus forming a hemifumarate of 4- or 5-hydroxy- diisopropyltryptamine, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof.

[0024] In some embodiments, the compound is a compound of Formula I or II and X is a C3alkyl chain, thus forming a hemiglutarate of 4- or 5-hydroxy-diisopropyltryptamine, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof.

[0025] In some embodiments, R7 and R8 are each chosen on the basis of retaining or enhancing the compound's ability to induce a psychedelic state. It is known that psychedelic activity of a tryptamine is reduced if R7 or R8 become larger than C4. However, such compounds, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof, are still within the scope of the present disclosure if they are still 5HT2A agonists which can produce beneficial therapeutic effect without a psychedelic state.

[0026] In some embodiments, compounds of the present disclosure are diacid zwitterions. Thus, where X is a linear saturated alkyl, the diacid may comprise a common linear alkyl α,ω- diacid, including without limitation oxalic, malonic, succinic, glutaric (pentanedioic), adipic (hexanedioic), pimelic (heptanedioic) and suberic acid (octanedioic). In some embodiments, where X is a linear alkene, the diacid may comprise an acid such as maleic, fumaric, or glutaconic acid. In other embodiments, the diacid may comprise a branched acid such as citraconic, mesaconic, 2,2-dimethylsuccinic acid; a substituted acid such as tartronic, 2-(2- hydroxyethyl)-malonic acid, a-hydroxyglutaric; citric acid; or an aryl dioic acid such as phthalic acid, isophthalic and p-phthalic, optionally with organic substituents on the aromatic ring.

[0027] In some embodiments, the compound, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof, may be one of the following:

[0028] In some embodiments, the diacid-modified tryptamines or isotryptamines exhibit product stability (oxidation and hydrolysis) and can be readily synthesized and purified. The diacid-modified tryptamines or isotryptamines may exhibit solubility in biological matrices in excess of the drug absent the diacid modification, making them superior drug candidates. As well, the diacid-modified tryptamines exhibit relatively quick rates of hydrolysis in vivo, so as to convert the prodrug rapidly to the active form of the drug. This can result in improved and desirable pharmacokinetic properties with the prodrug, including more reproducible pharmacokinetic profiles. These properties can depend on the nature of the indole, the various substituents attached to the indole and the nature of the diacid ester. Stability and hydrolysis rates can be determined experimentally.

[0029] In some embodiments, the compound, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof, may comprise a carbamate ester of tryptamine, where R4 is (R9)(R10)N — where R9 and RIO define a carbamate residue and are defined as above. In some embodiments, the carbamate function comprises a zwitterionic amino-functional mono or dicarboxylic acid which is linked via the carbamate, including without limitation, zwitterionic compounds such as:(a) natural and unnatural neutral or anionic amino acids, such as glycine, alanine, leucine, isoleucine, serine, theonine, glutamic acid, aspartic acid;(b) linear alkyl α,ω-amino acids, such as 3-aminoproprionic acid, 4-amino-butyric acid;(c) other branched amino acids and aromatic amino acids, such as 4-amino-benzoic acid.

[0030] In some embodiments, the disclosure may comprise zwitterionic compounds where R4 comprises more than one non-ester carboxy function, such as the citrate derivative of a 4- hydroxytryptamine (Formula V) or a glutamic acid carbamate of a 4-hydroxytryptamine (Formula VI):

[0031] In some embodiments, the zwitterionic compound is stable at neutral or slightly acidic pH. Acylation of the hydroxy functions of an indole can prevent oxidative reactions typical of substituted phenolic compounds and indoles specifically (Manevski 2010 Drug Metabolism and Disposition and Napolitano 1989 Tetrahedron), while also allowing for solubility. In some embodiments, the zwitterion has sufficient solubility (>30 mg / ml) in therange of neutral and pharmaceutically-acceptable pH values (3-8) to achieve the required potency / efficacy. Conventionally, non-prodrug pharmacophore tryptamines must be placed and held in acidic medium to achieve good solubility and stability. Acidic medium can preclude use as an injectable composition and can cause irritation.

[0032] Embodiments of the zwitterion may also provide for convenient purification and isolation by recrystallization from common pharmaceutical solvents, such as water, methanol, ethanol, propanol or isopropanol or acetone, or mixtures thereof.

[0033] The diacid moiety is cleaved metabolically in vivo providing the active ingredient in doses and with kinetics sufficient to achieve the psychedelic state believed to be necessary for use in the treatment of depressive conditions, such as psychedelic-assisted psychotherapy. This is particularly advantageous in designing convenient medications that produce a psychedelic experience with a duration of less than 8 hours, less than 6 hours, and less than 4 hours. In this sense, the requirement of hydrolysis is an additional step and therefore can reduce the speed of onset of psychoactive properties when compared to injection of the free drug (with no acylation of the hydroxy function). A slightly slower speed of onset may be some in some cases, so as to avoid a sudden onset which can cause anxiety, particularly in the psychedelic- naTve patient. Thus, in some embodiments, the speed of onset may be controlled by the rate of metabolism which can be a function of the ester and the target enzyme required for hydrolysis.

[0034] In some embodiments, certain prodrug diacid moieties, for example a succinate, may reduce the potential for abuse by inhalation or snorting. As a zwitterion, it is not likely to be absorbed rapidly through tissue devoid of esterase activity. Furthermore, the zwitterion is likely not absorbed directly by a passive mechanism into the brain. The rate of cleavage in the gut may be slower and absorption slower versus the non-acylated version and thus delay peak rates and the “rush” feeling that may be sought by persons with the intent to abuse.Method of Preparation of Formulas I, II, III, IV, V, and VI

[0035] The tryptamine-related compounds of the disclosure can be synthesized using the methods described below, or similar methods, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Some methods may include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being affected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent withthe transformations proposed. This will sometimes require a judgment, well within the skill of a skilled artisan, to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the disclosure.

[0036] Protection and de-protection in the processes below may be carried out by procedures generally known in the art (see, for example, Greene, T. W. et al, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley (1999)). General methods of organic synthesis and functional group transformations are found in: Trost, B. M. et al, eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modem Organic Chemistry, 1' Edition, Pergamon Press, New York, N.Y. (1991); March, J., Advanced Organic Chemistry.

[0037] 4- and 5-hydroxy-tryptamines can be made by adapting methods described in the art by Baumann et al. (Beilstein 2011, 7, 442) Shulgin (The Vaults of Erowid: TiHKAL: The Chemical Story, by Alexander and Ann Shulgin) and Fricke (Eur Chem J 2019, 25, 897), as well as in U.S. Pat. No. 3,075,992 and Chen (JOC 1994, 3738).

[0038] For example, succinate prodrug compounds described herein may be prepared using the synthetic scheme as outlined in Scheme 1 starting from the corresponding hydroxy-indole and the diacid anhydride. The reaction conditions such as temperature, time, choice of solvent and workup procedures are selected which may be suitable for experimental conditions recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate or analogous methods must then be used.

[0039] Other diacid prodrugs may be prepared using other diacid anhydrides, as may be readily visualized by those skilled in the art.

[0040] A glutarate prodrug compound may be made using glutaric anhydride, using Scheme2 below:

[0041] One skilled in the art may readily select suitable conditions and solvents. The reaction with the diacid anhydride may take place in dichloromethane and triethylamine, or pyridine. In some embodiments, the solvent contains a base with pKa greater than 4 but less than 9. If pyridine is used, the product precipitates directly from the reaction mixture in pure form as the zwitterion.

[0042] The solid zwitterion may be converted to a suitable salt, for example, a hydrochloride salt, by addition of anhydrous HC1 (gas) in a suitable solvent or by triturating in anhydrous ether HC1 or dioxane HC1.

[0043] Synthesis of the diacid hemiester prodrugs may also be produced using a variety of other methods and techniques well known to those skilled in the art (Rautio, Nature Rev in Drug Discovery 2018, 17, 559), for example, using anhydride or doubly-activated forms of the diacids, such as dichloride, di-N-hydroxysuccinimide (using dicyclohexylcarbodiimide (DCC)or l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide and DMAP), di-imizadolide (using carbonyldimidizole), or other activated form of the diacid with the hydroxy form of the active heterocyclic species. When using the diactivated forms, one may use a 2-25-fold excess of the doubly activated diacid to avoid covalently binding 2 tryptamines to the diacid.

[0044] Similarly, one skilled in the art can apply these methods to 6- or 7-hydroxy isotryptamines.

[0045] Further description on the synthesis of Formulas I, II, III, IV, V, and VI are provided in the EXAMPLES.Chemical Entities of Formula VII

[0046] The present disclosure also provides tryptamine-related compounds of Formula VII and any pharmaceutically acceptable salt, solvate, or zwitterion thereof which are formulated and configured for time-release and method of treatment regarding same:wherein:R is hydrogen, methyl or ethyl;R1is hydrogen or C1-C2alkoxy;R2is methyl or a C2-C4group which may be saturated or unsaturated, branched or linear; andR3, R4, R5and R6each are independently selected from hydrogen, hydroxyl, halogen, methyl optionally substituted with hydroxy, methoxy, ethoxy, and a saturated or unsaturated C2-C3that may be optionally substituted with hydroxyl, with the provisos that: at least two of R4, R5, R6and R7must be hydrogen, andR3, R4, R5and R6may be selected such that an adjacent pair thereof join to form a ring having at least 5 members.

[0047] In some embodiments, R2is selected from the group consisting of methyl, ethyl, n- propyl, i-propyl, 2-propenyl, 2-methyl-2-propenyl, 2-butenyl (trans) and 2-butenyl (cis).

[0048] In some embodiments, R3, R4, R5and R6may be selected such that an adjacent pair thereof join to form a ring having at least 5 members, e.g., from 5 to 8 members, 5 or 6 members, or 5 members. In some embodiments, the ring contains at least 1 oxygen atom, e.g, 1 or 2 oxygen atom.

[0049] In some embodiments:R1and R3each are methoxy;R2is methyl; andR, R4, R5and R6each are hydrogen.

[0050] In some embodiments:R1and R3each are methoxy;R2is ethyl; andR, R4, R5and R6each are hydrogen.

[0051] In some embodiments:R1and R3each are methoxy;R2is i-propyl; andR, R4, R5 and R6each are hydrogen.

[0052] In some embodiments:R1and R3each are methoxy;R2is 2-propenyl; andR, R4, R5and R6each are hydrogen.

[0053] In some embodiments:R, R1, R3, R5and R6each are hydrogen;R2is methyl; andR4is methoxy.

[0054] In some embodiments:R, R1, R3, R4and R6each are hydrogen;R2is methyl; andR5is methoxy.

[0055] In some embodiments:R, R2, R5and R6each are hydrogen;R2is methyl; andR3and R4each are methoxy.

[0056] In some embodiments:R, R1, R5and R6each are hydrogen;R2is i-propyl; andR3and R4each are methoxy.

[0057] In some embodiments:R, R1, R3, R4, R5and R6each are hydrogen;R2is methyl.

[0058] In some embodiments:R, R1, R3, R5and R6each are hydrogen;R2is 2-butenyl (cis); andR4is methoxy.

[0059] In some embodiments:R, R1, R3, R5and R6each are hydrogen;R2is 2-butenyl (trans); andR4is methoxy.

[0060] In some embodiments:R, R1, R3, R5and R6each are hydrogen;R2is 2-methyl-2 -propenyl; andR4is methoxy.

[0061] In some embodiments:R, R1, R3, R5and R6each are hydrogen;R2is methyl; andR4is ethyl.

[0062] In some embodiments:R, R1, R3, R5and R6each are hydrogen;R2is methyl; andR4is hydroxyl.

[0063] In some embodiments:R, R1, R3, R5and R6each are hydrogen;R2is methyl; andR4is bromine.

[0064] In some embodiments:R, R1, R3, R5and R6each are hydrogen;R2is methyl; andR4is hydroxyethyl.

[0065] In some embodiments:R, R1, R3, R5and R6each are hydrogen;R2is methyl; andR4is 2-propynyl.

[0066] In some embodiments:R, R1, R5and R6each are hydrogen;R2is methyl; andR3is methoxy, R4is hydroxyl, and R3and R4join to form a 1,3-dioxolane group.

[0067] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement hydrogen, carbon, nitrogen, oxygen, chlorine, or fluorine with2H,3H,11C,13C,14C,13N,15N,17O,18O,36C1 or18F, respectively, are within the scope of this disclosure. Such compounds are usefill, for example, as analytical tools, as probes in biological assays, or as active pharmaceutical agents in accordance with the present disclosure. Additionally, incorporation of heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increase in vivo half-life, or reduced dosage requirements.

[0068] Unless otherwise stated, diastereomeric excess is expressed as % de, i.e., for diastereomers X and Y, the diastereomeric excess of X=((x-y) / (x+y))* 100, where x and y are the fractions of X and Y, respectively.

[0069] Unless otherwise stated, enantiomeric excess is expressed as % ee, i.e., for enantiomers X and Y, the enantiomeric excess of X=((x-y) / (x+y))*100, where x and y are the fractions of X and Y, respectively.

[0070] The disclosure also provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of tryptamine-related compounds, formulated together with one or more pharmaceutically acceptable excipients (additives) and / or diluents, and optionally, one or more additional active pharmaceutical agents. While it is possible for a compound described herein to be administered alone, the compound may be administered as a pharmaceutical composition.

[0071] The tryptamine-related compounds of the present disclosure may be formulated for time release, such as sustained release, and can be administered for any of the uses or methods described herein by any suitable means, for example, orally, such as tablets, capsules (each of which may include sustained release or timed release compositions), pills, powders, granules,elixirs, suspensions (including nano suspensions, micro suspensions, spray-dried dispersions), syrups, and emulsions; sublingually (e.g. as thin films, effervescent tablets or tablets that dissolve spontaneously under the tongue). The compounds of the present disclosure may be administered nasally, including administration to the nasal membranes, such as by inhalation spray; or rectally such as in the form of suppositories.

[0072] Regardless of the route of administration selected, the tryptamine-related compounds of the present disclosure are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0073] The dosage regimen for the time-release compositions, including sustained-release compositions, of the tryptamine-related compounds described herein will vary depending upon known factors, such as the pharmacokinetic and pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient; and, the effect desired. The selected dosage level may also depend on the additional factors including the activity of the particular compounds and pharmaceutical compositions described herein, whether an ester, salt or amide substituent is of the compound is used, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs that may be administered to the patient, compounds and / or materials used in combination with the particular compound employed and like factors well known in the medical arts.

[0074] An effective dosage can be administered in one or more administrations. For the purposes of this disclosure, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another therapy, drug, compound or pharmaceutical composition.Time-Release Compositions

[0075] The term “time release” as used herein means a composition or dosage form that is not an immediate-release composition or dosage form. In immediate-release dosage forms, the active ingredient is rapidly administered to the body. For example, in orally administered immediate release tablets, disintegrants are often used to cause the tablet to disintegrate quickly enabling the rapid release of the active pharmaceutical into the body. The corresponding excipients and dosage design are not configured to delay or otherwise materially influence the release kinetics of the active pharmaceutical ingredient. In time-release compositions or dosage forms, however, the compositions and dosage forms are designed to change the active pharmaceutical release characteristics so as to differentiate from immediate release forms and provide a timed release thereof.

[0076] There are multiple types of time-release dosage forms. For example, in delayed- release compositions there is a time lag after drug delivery before an active pharmaceutical ingredient is released in the subject. An example of such a composition is an oral enteric-coated tablet. In sustained-release compositions, an active pharmaceutical ingredient is released gradually over time to maintain a therapeutic effect for a period of time. The term “extended release composition” is often used to denote a once-daily sustained release composition. A controlled-release composition is designed to release an active pharmaceutical ingredient in a predetermined manner. The tryptamine-related compounds of the disclosure may be configured in a composition for time release characteristics. For example, embodiments of the disclosure include such time-release characteristics which are one or more of delayed release, sustained release, extended release, and controlled release. In many embodiments, sustained release compositions of the disclosure have characteristics of one or more of delayed release, extended release, and controlled release.

[0077] With respect to sustained-release compositions, because the composition does not release the full dose of the active ingredient immediately after administration, a reduction in dosage frequency may be achieved. Such gradual release of the active ingredient may further result in a steady concentration in the blood / plasma of the subject over a period of time which is at a lower concentration than the maximum concentration achieved from a corresponding immediate-release composition. Such lower concentration may be beneficial from a safety standpoint such as a side effect profile.

[0078] In some embodiments, a timed-release composition comprising a tryptamine-related compound is configured to release a tryptamine-related compound in vivo at substantially the same rates the tryptamine-related compound is eliminated.

[0079] In some embodiments, a timed-release composition comprising a tryptamine-related compound is configured to release a tryptamine-related compound in vivo at a rate less than the rate that the tryptamine-related compound is eliminated.

[0080] In some embodiments, a timed-release composition comprising a tryptamine-related compound is configured to release a tryptamine-related compound in vivo at a rate which is below the threshold for producing a psychedelic state but of sufficient concentration to treat a mental disorder.

[0081] Sustained-release compositions of the disclosure may be produced in several different ways. In some embodiments, sustained-release compositions of tryptamine-related compounds of the disclosure are embedded in a matrix of materials which may retard the release of the compound and then compressed into a tablet. In some embodiments, a material which may retard the release of a compound is layered in the composition between the tryptamine- related compounds of the disclosure and the elution medium such as with a coating. In some embodiments, osmotic pressure is used to design a sustained-release dosage form comprising a tryptamine-related compound of the disclosure.

[0082] For example, in some embodiments, a pharmaceutical composition comprising a tryptamine-related compound of the disclosure is formulated for sustained release using an osmotic-controlled release oral delivery system (OROS®) composition. In such controlled- release dosage forms, a tablet is constructed with a semi-permeable outer membrane with one or more small holes, often laser-drilled, in the membrane. After ingestion by a subject, fluid is absorbed into the tablet via the semipermeable membrane through osmosis which results in pressure building inside the tablet which, in turn, pushes the tryptamine-related compound through the one or small holes and into the gastrointestinal tract. Examples of such osmotic- controlled release oral delivery systems are described EP 0378404 published August 31, 1994, to Curatolo, and US 2008 / 0145427 published June 19, 2008, to Berchielli, et al, the entire contents of each are incorporated by reference.

[0083] In some embodiments, a tryptamine-related compound is formulated for transmucosal delivery such as for buccal delivery. For transmucosal routes including buccal routes, such tryptamine-related compounds of the disclosure may be prepared as a mucoadhesive strip configured for sustained release. In these and other embodiments, such compositions, such as with mucoadhesive strips, comprise a tryptamine-related compound of the disclosure and one or more water soluble polymers and water insoluble cross-linkedpolycarboxylic polymers. Such compositions may, in some embodiments, comprise between about 1% and about 75% by weight water soluble polymer and between about 0.5% and about 10% by weight water insoluble cross-inked polycarboxylic polymer. In some embodiments, such compositions further comprise between about 5% and about 50% cellulose and may also comprise between about 0.5% and about 25% by weight starch and between about 1 % and about 50% by weight lactose.

[0084] In some embodiments, the compositions comprise from about 0.01% up to about 2% by weight, including about 1% by weight silica; and / or up to about 2% by weight, including about 0.5% to about 2% by weight and up to about 0.5% by weight talc; and / or up to about 2.5% by weight, including about 0.5% to about 2% by weight magnesium stearate.

[0085] In some embodiments, said starch is present in about 14% to 24% by weight, said lactose is present in about 17% to about 27% by weight, said water soluble polymer is present in about 5% to about 20% by weight, and said tablet is adapted for delivering the tryptamine- related compound to the bloodstream of a patient via the patient's buccal cavity.

[0086] In yet further embodiments, the mucoadhesive strip comprises: an effective amount of a tryptamine-related compound of the disclosure, about 2% to about 30% by weight binder, about 5% to about 40% by weight lactose, about 1% to about 3% by weight water insoluble cross-linked polycarboxylic polymer, and about 5% to about 50% by weight water soluble polymer, and may further comprise from about 0.2% to about 2% by weight silica; and / or about 0.5% to about 2% by weight talc; and / or about 0.5% to about 2% by weight magnesium stearate.

[0087] Examples of compositions and methods of making and using such mucoadhesive strips are described in U.S. Patent No. 6,248,358, issued on June 19, 2001, to Bologna et al., the entire contents of which are incorporated herein by reference.

[0088] In some embodiments, a pharmaceutical composition comprising a tryptamine- related compound of the disclosure is formulated as a lozenge and configured for sustained release. Lozenges are designed to dissolve slowly over time and may be deployed for slower release than an immediate release composition. Further, lozenges of the disclosure may be prepared with sufficient uniform content uniformity so as to release the drug in a controlled and constant manner.

[0089] In some embodiments, the lozenge is made of a soluble sugar matrix, at least one buffer, at least one tryptamine-related compound of the disclosure and typically at least one excipient. A stick may be attached, as in a lollipop, to the lozenge, for the subject to hold. Examples of lozenges using fentanyl citrate as an active pharmaceutical agent and methods of making such lozenges are described in US20070104763A1 to Jobdevairakkam et al, published May 10, 2007, the contents of which are hereby incorporated by reference.

[0090] In some embodiments, a lozenge comprising a tryptamine-related compound is administered to a subject one or more times a day. In some embodiments, the lozenge is administered twice a day (BID), thrice a day (TID), four times a day (QID), five times a day, or more. In some embodiments, the lozenge is administered every two hours, three hours, four hours, five hours, six hours, seven hours, eight hours, nine hours, ten hours, eleven hours, twelve hours, or once every 24 hours.

[0091] In some embodiments, a lozenge comprising a tryptamine-related compound is administered in the morning, midday, evening, or night. In some embodiments, the lozenge is administered after a subject consumes a meal. In some embodiments, the lozenge can be administered during a fast.

[0092] In some embodiments, a tryptamine-related compound of the disclosure is formulated as a sustained release implant. The implant may be formed from a biodegradable polymer. In some embodiments, the biodegradable polymer is selected from one or more of Poly(D-lactic acid), Poly(L-lactic acid), Poly(racemic lactic acid), Poly(glycolic acid), Poly(lactic acid-co-glycolic acid) (PLGA), Poly(caprolactone), Methylcellulose, Ethylcellulose, Hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), poly(vinyl alcohol) (PVA), polyethylene oxide) (PEO), polyethylene glycol, starch, natural and synthetic gum and wax. In some embodiments, the pharmaceutical composition is formulated as a sustained release implant formed from a non- biodegradable polymer. The non-biodegradable polymer may be selected from one or more of silicone, urethane, acrylates and their copolymers, polyvinylidene fluoride copolymers, polyethylene vinyl acetate-ethylene vinyl acetate, and dimethylpolysiloxane. Methods for incorporating compounds into a biodegradable implant or a non-biodegradable implant are further described in International Publication No. WO2022 / 204771, published October 6, 2022, to Peracchi, the entire contents of which are incorporated by reference.

[0093] In some embodiments, the implant may be formed from a core polymer matrix encapsulated by a membrane polymer matrix. Additional description is provided in U.S. Patent Publication No. 2023 / 0277469, published September 7, 2023, to Schneider, the contents of which are incorporated by reference.

[0094] In some embodiments, a tryptamine-related compound is formulated for depot injection by encapsulation in a lipid or polymer. Lipids for such depot compositions are typically hydrophobic or amphiphilic small molecules. In these and other embodiments, the tryptamine-related compounds of the disclosure are dissolved in an oil, such as vegetable oil or other pharmaceutically acceptable oils (e.g., sesame oil) and are typically injected into subjects via a subcutaneous or intramuscular route. In other embodiments, such depot compositions may be made by incorporating the tryptamine-related compounds of the disclosure into liposomes or microparticles and injected into a subject to achieve sustained release.

[0095] In some embodiments, the tryptamine-related compounds may be configured for sustained release as an implant comprising an osmotic pump. The osmotic pump may include a hollow receptacle capable of receiving one or more compounds disclosed herein. The hollow receptacle may be formed in an osmotic polymer material except for an opening for inserting and releasing the one or more compounds disclosed herein. The osmotic polymer material is surrounded by a semi-permeable membrane capable of transferring water from an external environment to the osmotic polymer material. An example of an implantable osmotic pump is the commercially available ALZET Osmotic Pump (available by Durect Corporation).

[0096] In some embodiments, a tryptamine-related compound of the disclosure is formulated as an injectable sustained release delivery device. Such devices may, for example, comprise micronized particles comprising a core of tryptamine-related compound of the disclosure in a polymer matrix wherein the polymeric tube surrounds the core which is impermeable to it. The devices, which are shaped for injection through a needle, in some embodiments, are coated with a permeable or semipermeable polymeric layers. These and other embodiments are further described in US 2019 / 0201324 to Chou et al, published on July 4, 2019, the contents of which are hereby incorporated by reference.

[0097] In some embodiments, a tryptamine-related compound of the present disclosure is formulated as a transderm al delivery device, e.g., a transdermal delivery patch. Exemplary transdermal delivery devices include a drug-in adhesive transdermal delivery device, a reservoir transdermal delivery device, a matrix transdermal delivery device, and a micro-reservoir transdermal delivery device. (Wong, W.F.; Ang, K.P.; Sethi, G.; Looi, C.Y. Recent Advancement of Medical Patch for Transdermal Drug Delivery. Medicina 2023, 59, 778, the contents of which are incorporated herein by reference.)

[0098] Transdermal delivery devices typically contain at least a backing layer, a drug layer, an adhesive, and a liner layer. The backing layer is the outermost layer of the patch and serves to protect the other layers from the environment. The backing layer is usually made of a flexible, waterproof material (e.g., polyethylene or polypropylene). The adhesive layer serves to attach the patch to the skin and keep it in place. The adhesive comprises a pressure-sensitive, hypoallergenic adhesive that is gentle on the skin. The drug layer contains the tryptamine related compounds of the present disclosure that are delivered through the skin. The liner acts as a protector for the transdermal delivery device (in particular, the adhesive) and is removed prior to use, exposing the adhesive surface of the transdermal delivery device for application to the subject’s skin surface. Reservoir and matrix transdermal delivery devices contain a membrane layer made of semi-permeable materials that allow the tryptamine related compounds to pass through the membrane at a controlled rate. In some embodiments, the transdermal delivery device further comprises one or more solubilizing agents and / or permeation enhancers.

[0099] In some embodiments, tryptamine-related compounds of the present disclosure are formulated in a composition resistant to abuse.

[0100] In some embodiments, the present disclosure provides abuse deterrent compositions comprising a tryptamine-related compound of the present disclosure. In some embodiments, an abuse deterrent composition comprises a tryptamine-related compound of the present disclosure and an antagonist agent, wherein the antagonist agent is “sequestered” in a form that prevents it from being released when the composition is administered normally. This approach is described for opioid agonists in US 3,966,940; US 3,773,955; CA 2,400,578, CA 2,400,567; and US 8,236,351, the contents of which are incorporated by reference.

[0101] In some embodiments, an abuse deterrent composition comprises solid multiparticulates with an extremely thick coating layer which assures the modified release of the drug and simultaneously imparts crushing resistance to the coated microparticles so as to avoid misuse. These and other embodiments are further described in US 20100092553 andUS 2007224129 (Endo Pharmaceuticals), the contents of which are incorporated by reference.

[0102] In some embodiments, an abuse deterrent composition comprises a tamper resistant oral extended-release dosage form comprising a tryptamine-related compound of the present disclosure and an extended release matrix, e.g., as described in CA 2,707,204; CA 2,661,573; and WO200823261, the contents of which are incorporated by reference.

[0103] In some embodiments, an abuse deterrent composition comprises a tryptamine-related compound of the present disclosure and a gelling agent. The gelling agent makes it more difficult for an abuser to tamper with the dosage form and subsequently inhale, inject, and / or swallow a tryptamine-related compound recovered from the tampered dosage form. Essentially, a gelling agent works when a dosage form is being dissolved for extraction of the drug by forming a gel when placed in a solvent. Once formed, the gel prevents the misuse of the drug because of the gel formation which, in turn, cannot be abused intranasal, orally, or intravenously.Therapeutic Methods and Uses

[0104] Treatment with time-release compositions of tryptamine-related compounds of the disclosure, such as sustained release compositions, may substantially alleviate clinical or subclinical depression and may avoid relapse, particularly if used in combination with psychotherapy for the treatment of depression. It is known that administration of an effective dose of psilocybin produced rapid and large reductions in depressive symptoms, and many subjects achieve remission through a four-week follow up. Without restriction to a theory, it is believed that the psychedelic state is associated with the beneficial effects, however, some compounds which are 5HT2A agonists may provide the desired therapeutic effect without the psychedelic state. One aspect of the present disclosure comprises prodrugs of those 5HT2A agonists which do provide a beneficial therapeutic state.

[0105] In general, the present disclosure includes the use of a tryptamine-related compound of the disclosure herein in a time-release composition such as a sustained-release composition, to treat any disease or disorder which may be alleviated by a 5HT2A agonist, or the use of the tryptamine-related compound, of the disclosure herein to manufacture a medicament to treat any disease or disorder which may be alleviated by a 5HT2A agonist, or a method of treating any disease or disorder which may be alleviated by a 5HT2A agonist.

[0106] In some embodiments, a method of treating or managing a mental, a behavioral, or a neuropsychiatric condition, or the symptoms thereof, in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of one or more tryptamine-related compounds wherein the dosage form is configured for timed release such as sustained release. In many embodiments, the treatment with a therapeutically effective amount of one or more tryptamine-related compounds does not trigger a hallucinogenic response and / or the hallucinogenic response is limited. In some embodiments, a method of treating or managing a mental, a behavioral, or a neuropsychiatric condition, or the symptoms thereof is an attentiondeficit condition or a cognitive condition. In some embodiments, a method of treating or managing a mental, a behavioral, or a neuropsychiatric condition, or the symptoms thereof is selected from the group consisting of addiction, anxiety, apathy, and depression. In some embodiments, the symptoms are physical symptoms, behavioral symptoms, emotional symptoms, mental symptoms, or a combination thereof.

[0107] In some embodiments, the tryptamine-related compound is delivered for greater than or equal to four hours. In some embodiments, the tryptamine-related compound is delivered for greater than or equal to six hours. In some embodiments, the tryptamine-related compound is delivered for greater than or equal to eight hours. In some embodiments, the tryptamine-related compound is delivered for greater than or equal to twelve hours. In some embodiments, the tryptamine-related compound is delivered for greater than or equal to eighteen hours. In some embodiments, the tryptamine-related compound is delivered for greater than or equal to twenty- four hours.

[0108] In some embodiments, the disclosure may comprise the use of the tryptamine-related compounds of the disclosure in a time-release composition to treat mental disorders or other conditions wherein the composition is configured for time release such as sustained release. In some embodiments, the disclosure may comprise the use of the tryptamine-related compounds of the disclosure to treat depression such as drug resistant depression. In some embodiments, the disclosure may comprise the use of the tryptamine-related compounds of the disclosure to treat depression such as treatment-resistant depression. Other conditions that may be treated include: anxiety disorders, including anxiety in advanced stage illness (e.g. cancer) as well as generalized anxiety disorder, depression including major depressive disorder, postpartum depression, cluster headaches, obsessive compulsive disorder, personality disorders including conduct disorder, drug disorders including: alcohol dependence, nicotine dependence, opioid dependence, cocaine dependence and other addictions including gambling disorder, eating disorder and body dysmorphic disorder, chronic pain, or chronic fatigue.

[0109] In some embodiments, the disclosure may comprise the use of the tryptamine-related compounds in a time-release composition of the disclosure, such as sustained release, to treat metabolic syndrome and insulin resistance.

[0110] In some embodiments, the disclosure may comprise a method of treating mental disorders comprising administering to a subject in need thereof a therapeutically effective amount of a tryptamine-related compound of the disclosure in a time-release composition, such as a sustained-release composition. In one embodiment, there is provided a method of treating depression comprising administering to a subject in need thereof therapeutically effective amount of a tryptamine-related compound of the disclosure in a time-release composition. Examples of depression include drug-resistant depression or major depressive disorder. Other examples of depression include treatment-resistant depression or major depressive disorder.

[0111] In some embodiments, treatment with a tryptamine-related compound of the disclosure in a time-release composition, such as a sustained-release composition, may be combined with concomitant treatment with another anti-depressant drugs, either concurrently or consecutively. In some embodiments, treatment with a tryptamine-related compound of the disclosure is combined with psychotherapy, which may be applied prior to or after treatment. If prior to, the session may focus the patient on the intent of treatment. If after, psychotherapy is performed within 48 hours of the dosing session to help the patient integrate any feelings, emotions, visions or thoughts that may have occurred during the session, as well as to allow the psychotherapist may offer advice on how best to change thinking or behavior patterns so as to improve antidepression outcomes. Psychotherapy may continue as needed after the dosing session, for example, up to an additional 3 months, to help the patient integrate any experiences or learnings that occurred to the patient during the dosing session.

[0112] In many embodiments of the disclosure, the dosing of the subject undergoing the treatments herein are dosed once or multiple times. In some embodiments, patients are dosed at time intervals until the desired effect is achieved. For example, in some embodiments, subjects are dosed about every 12 hours. In some of the embodiments, patients are dosed twice.

[0113] In Example 49, an in vivo study describing the effect of treatments of wistar rats with N,N-diisopropyltryptamine-4-glutarate and negative and positive controls is described. In the study, one cohort of rats received a single bolus whereas the other cohort received a continuous infusion for 24 hours by way of a mini osmotic pump this providing for sustained release delivery. A standard “Forced-Swim Test” (FST) was used as described in Example 49 as ameasurement for behavioral despair. Safety aspects were also observed with the rats between cohorts. The rats were also observed for side effect profiles. The vehicle (negative control) produced no side effect profile at either a bolus or a continuous dose. By comparison, for both the positive control and the bolus dose of N,N-diisopropyltryptamine-4-glutarate, head and body twitches were observed whereas for continuous infusion, there were no such head or body twitches for the sustained release delivery, indicating a superior safety profile. In addition to diminished head and body twitch, sustained release delivery of N,N-diisopropyltryptamine-4- glutarate led to improved immobility times (decreased immobility) in the FST. Decreased immobility time in an FST is a model for depression amelioration.EXAMPLES

[0114] Aspects of the present disclosure may be described with reference to the following Examples. These Examples are provided for the purpose of illustration only and should not be used to construe or limit the scope of the disclosure. All terms, names, abbreviations or acronyms are those commonly understood by those skilled in the art. Compounds shown in their zwitterionic form may readily be visualized in their neutral form by one skilled in the art, and vice versa.

[0115] EXAMPLE 1 - Synthesis of 4-Hemisuccinate of Psilocin

[0116] 4-Hydroxyindoles were prepared using methods or modestly adapted from methods described in the literature, such as in Kargbo 2020 ACS Omega): Accordingly, 4-acetoxyindole was reacted with oxalyl chloride in methyl-t-butyl ether (MTBE) and the resulting intermediate was quenched with dimethylamine. The indole-oxalyl-dimethylamide was reduced with Lithium Aluminum Hydride (LAH) in tetrahydrofuran (THF) to give the 4-acetoxy-3-(N,N- dimethylaminoethyl)indole, which was deprotected using aqueous base to give 4-hydroxy- dimethyltryptamine (psilocin).

[0117] The 4-hydroxytryptamine was reacted with an excess of succinic anhydride in dichloromethane (DCM) containing triethylamine, and catalyzed by N,N- dimethylaminopyridine, to give psilocin-4-succinate. A precipitate was formed which was recovered after decantation and trituration with DCM. The solid was acidified in aqueous HC1, purified by chromatography and recovered after evaporation of solvents. The structure was confirmed by NMR. Purity was determined by HPLC.

[0118] EXAMPLE 2 - Synthesis of 4-hemisuccinate of 4-hydroxy-diisopropyltryptamine (4- OH-DiPT)

[0119] 4-Acetoxyindole was reacted with oxalyl chloride in MTBE and the resulting intermediate was quenched with diisopropylamine. The resulting oxalyl-amide was reduced with Lithium Aluminum Hydride (LAH) in THF to give the 4-acetoxy-3-(N,N- diisopropylaminoethyl)indole, which was in turn deprotected with aqueous base to give 4- hydroxy-3-(N,N-diisopropylaminoethyl)indole. In a 250 mL round-bottom flask containing a stir bar was added 4-OH-DiPT (5.8 g, 22.3 mmol, 1 eq.), dissolved in dichloromethane (28 mL, 5xV) and stirred at room temperature. Then succinic anhydride (1.3 eq.) was added slowly to the stirring solution, and the resulting suspension was stirred overnight at room temperature. The precipitate formed in the reaction was recovered by decantation and trituration with DCM. The solid was acidified in aqueous HC1, purified by chromatography and recovered after evaporation of solvents. The structure was confirmed by NMR. Purity was determined by HPLC.

[0120] EXAMPLE 3 - Synthesis of 4-hemifumarate of 4-OH-DiPT

[0121] 4-Benzyloxyindole is reacted with oxalyl chloride in diethylether in the presence of a Friedel-Kraft catalyst and the resulting intermediate is quenched with di-isopropylamine. The resulting oxalyl-amide is reduced with Lithium Aluminum Hydride (LAH) in THF to give the 4-benzyloxy-3-(N,N-diisopropylaminoethyl)indole, which is in turn deprotected using a H2 and Pd / C to give 4-hydroxy-3-(N,N-diisopropylaminoethyl)indole. This substance is reacted with an excess of a diactivated fumaric acid (N-hydroxysuccinimide) in dichloromethane, followed by quenching any unreacted N-hydroxysuccinimide ester with aqueous acid, leaving 4- fumaroyl-3-(N,N-diisopropylaminoethyl)indole.

[0122] EXAMPLE 4 Synthesis of 5-hemi succinate of 5-hydroxy-4-methyl- dimethyltryptamine

[0123] 4-methyl-5-hydroxyindole (1) is reacted with benzyl chloride in the presence of K2CO3in ACN to give 5-benzyloxy-4-methyl-indole, which is then reacted with oxalyl chloride in diethylether in the presence of a Friedel-Kraft catalyst and the resulting intermediate is quenched with di-methylamine. The resulting oxalyl-amide is reduced with Lithium Aluminum Hydride (LAH) in THF to give the 4-methyl-5-benzyloxy-3-(N,N-dimethylaminoethyl)indole, which is in turn deprotected using a H2 and Pd / C to give 4-methyl-5-hydroxy-3-(N,N- dimethylaminoethyl)indole. This substance is reacted with succinic anhydride in dichloromethane, catalyzed by N,N-dimethylamino-pyridine to give 4-methyl-5-succinoyl-3- (N,N-dimethylaminoethyl)indole .

[0124] EXAMPLE 5 - Synthesis of N,N dimethylisotryptamine-6-succinate

[0125] Following methods outlined in Glennon (JMedChem 1984), 6-O-Benzyl- dim ethylisotryptamine is prepared by N-alkylation of 5-BzO-indole using NaH. The benzyl group is removed by catalytic hydrogenation using Pd / C / H2 to give the HO — junction which is succinylated in a subsequent step using succinic anhydride, resulting in the named species.

[0126] EXAMPLE 6 - Synthesis of N,N diisopropyltryptamine-4-glutarate

[0127] In an oven-dried 50 mL round bottom flask containing 1.2 mL of anhydrous DCM was added glutaric anhydride (0.205 g, 1.8 mmol, 1.8 eq.) and the suspension was stirred under Ar. A solution of 4-OH-DiPT (0.26 g, 1 mmol, 1 eq.) in 1.5 mL anhydrous DCM was added, followed by addition of 4-dimethylaminopyridine (DMAP) (37 mg, 0.3 mmol, 0.3 eq.) and trimethylamine (0.18 mL, 1.3 eq.) and the resulting suspension was stirred overnight at r.t. under Ar.

[0128] The mixture was decanted, and the solid was triturated with anhydrous DCM (3 mL) with a few drops of anhydrous MeCN. The suspension was acidified with IM HC1 (~1.1 eq.) and concentrated to dryness. The crude product was purified by Cl 8 reverse-phase column chromatography (40 g, A: 0.05% HC1 in H2O, B: 0.05% HC1 in MeCN).

[0129] The structure was confirmed by NMR. Purity was determined by HPLC (>97%). The solid was resuspended in IM HCl-dioxane to form the HC1 salt which was filtered, washed with ether and dried. Yield (>95%, purity >95%; DSC endotherm 174C). The solid could be dissolved in water up to 50 mg / ml and lyophilized to form a white “cake”.

[0130] EXAMPLE 7 - Synthesis of hemiester of 3,3-dimethylglutaric acid and 4- hydroxydiisopropyltryptamine

[0131] 4-Hydroxy-3-(N,N-diisopropylaminoethyl)indole was reacted with 3,3-dimethyl glutaric anhydride in pyridine to give 4-succinoyl-3-(N,N-diisopropylaminoethyl)indole with stoichiometries and parameters mentioned in example 6. A precipitate formed in the reaction was recovered by decantation and trituration in THF. The solid was washed with DCM and dried. The structure was confirmed by NMR.

[0132] EXAMPLE 8 - Synthesis of psilocin-4-glutarate

[0133] 4-Hydroxydimethyltryptamine (psilocin) was reacted with an excess of glutaric anhydride in dichloromethane (DCM) containing triethylamine to give psilocin-4-glutarate. In another example, the reaction occurred in pyridine. In either case, a precipitate was formedwhich was recovered after decantation and trituration with THF. The solid was washed withDCM and then dried. The structure was confirmed by NMR.

[0134] The reaction product was suspended in IM HCl-ether to yield the corresponding HC1 salt form of the product which was recovered by filtration in high yield and purity.

[0135] EXAMPLE 9 - Synthesis of HC1 salt of N,N diisopropyltryptamine-4-glutarate

[0136] In a 3-neck 1 L round bottom flask under argon was added 4-OH-DiPT (31.8 g, 0.122 mol, 1 eq.), dissolved in 160 mL of anhydrous pyridine (160 mL). After stirring for 15 mins, glutaric anhydride (18.1 g, 0.158 mol, 1.3 eq.) was added in portions. The resulting suspension was stirred at r.t. overnight.

[0137] Anhydrous DCM (160 mL) was added to the suspension and it was cooled to 0° C. with for 2 h. The solid was filtered and washed with 60 mL of cold anhydrous DCM and dried overnight.

[0138] The dried solid was triturated with 160 mL of anhydrous DCM, followed by 160 mL of anhydrous THF, and then 160 mL of anhydrous DCM at 0° C. After drying, 33.0 g was obtained with 72% yield and 98.1% purity by HPLC. The structure of the zwitterion was confirmed by 1H-NMR (DMSO-d6) and MS [M+H]+=375.2.

[0139] In a 100 mL round bottom flask was charged 18 mL of anhydrous diethyl ether HC1 solution (4M in dioxane, 2.4 mL, 9.6 mmol, 1.2 eq.) was added slowly and stirred at r.t. for 10 mins. The zwitterion from above (3.0 g, 8.0 mmol) was added in portions and the resulting suspension was stirred for 2 h. The solid was filtered off and washed with 6 mL of Et2O. The solid was dried yielding 3.16 g of the corresponding hemiester tryptamine HC1 salt (96% yield, 99.0% purity by HPLC, [M+H]+=375.1).

[0140] EXAMPLE 10 - Synthesis of hemiglutarate of psilocin

[0141] Psilocin is reacted with 1.2 equivalents glutaric anhydride in warm THF to give psilocin- 4-glutarate which precipitates from the reaction mixture according to methods above. The precipitate is recovered by filtration, is washed with cold 1:1 DCM / THF and dried.

[0142] EXAMPLE 11 - Synthesis of 4-hemimalonate of 4-OH-DiPT

[0143] 4-OH-DiPT was dissolved in pyridine and coupled with an excess of malonic acid and 1.2 equivalents of DCC at room temperature for 18 h. The reaction mixture was passed through a flash column (5 parts diatomaceous earth), and the first fractions containing the prodrugcompound were isolated by precipitation and washing. Yield approx. 50%. Purity >95% by HPLC.

[0144] EXAMPLE 12 - Comparative Rates of Prodrug Hydrolysis in Serum

[0145] Pooled mixed gender human plasma (2 ml), mouse plasma, rat plasma and dog plasma were equilibrated at 37° C. The compound of example 9 was added so as to achieve a concentration of 1.0 μg / mL. Aliquots (50 μL) of the mixture were withdrawn at timed intervals (0, 0.004, 0.5, 1, 2 and 4 hours) and quenched with 200 μL of methanol / acetonitrile (1:1). The samples were vortexed and stored at -80° C. until analysis. Assays were done in triplicate. Control samples were done in phosphate buffered saline (PBS, pH 7.4) and simulated gastric fluid (SGF, pH 2). Analysis of samples as performed by HPLC-MS to determine the amounts of prodrug and drug in each sample tested. Table 1 provides the mean concentrations of prodrug remaining at different time points of the experiment. The experiment demonstrates the rapid enzymatic cleavage of the prodrug in plasma versus slow non-enzymatic hydrolysis in relevant biological media.TABLE 1. Percentage of remaining prodrug, N,N diisopropyltryptamine-4-glutarate

[0146] EXAMPLE 13 - Pharmacokinetics in Rats

[0147] The compound from Example 9 was administered to rats by injection (intravenous and subcutaneous) with a sterile solution (2 mg / ml) at a rate of 1.4-2 mg / kg. Blood samples were taken at 15, 30, 45, 60, 120, 240 min and 360 min and analyzed by LCMS for drug and prodrug. PK profile for the prodrug and active species were obtained and relative bioavailability was determined for each of the routes of administration.

[0148] In rodent, prodrug was not observed, as it was rapidly converted to the active form. Relevant PK parameters for i.v. and s.c administrations 4-HO-DiPT were determined and are shown in Table 2:TABLE 2: PK parameters (% coefficient of variation in parentheses) for 4-HO-DiPT after subcutaneous administration of N,N diisopropyltiyptamine-4-glutarate (2 mg / kg).

[0149] The above table is based on PK parameters from the i.v. administration of 4-HO-DiPT.

[0150] In some cases, Head Twitch Response (HTR) or Wet Dog Shakes (WDS) were recorded by visual observation and counting of the relevant muscle twitches. In general, the intensity of the HTR was proportional to the plasma concentration of 4-HO-DIPT with the highest intensity of head twitch occurring at the Tmax of the PK profile.

[0151] Pharmacokinetics of 1.34 mg / ml 4-HO-DiPT HC1 administered by intravenous or subcutaneous injection were performed in parallel under identical conditions as above. PK parameters are shown in Table 3.TABLE 3: PK parameters (% coefficient variation in parentheses) for 4-HO-DiPT after subcutaneous administration of N,N diisopropyltryptamine-4-glutarate (2 mg / kg).

[0152] EXAMPLE 14 - Pharmacokinetics in Human Volunteers

[0153] The compound from example 6 (N,N diisopropyltryptamine-4-glutarate) is administered to human volunteers by subcutaneous injection of a sterile solution (1 mg / ml) at a dosage of 0.1-0.6 mg / kg. Blood samples are taken at 5, 15, 30, 45, 60, 120, 240 and 480 min and 24 h. Samples are analyzed by LCMS for drug and prodrug. Subjective effects are measured using standardized questionnaires. The PK analysis shows a maximal plasma concentration (CMax) at approx. 45 min after the injection. Subjective effects show an intensity of psychoactivity that correlates with blood levels.

[0154] The compound from example 2 (4-hemisuccinate of 4-OH-DiPT) is administered to human volunteers by oral ingestion of a tablet containing 50 mg of the prodrug. Blood samples are taken at 5, 15, 30, 45, 60, 120, 240 and 480 min and 24 h. Samples are analyzed by LCMS for drug and prodrug. Subjective effects are measured using standardized questionnaires. The PK analysis shows a CMax at approx. 90 min for the injection. Subjective effects show an intensity of psychoactivity that correlates with blood levels.EXAMPLE 15 - Use in Treatment

[0155] The compound of Example 6 (N,N diisopropyltryptamine-4-glutarate) is administered by i.m. or s.c. injection (ca. 25 mg; 0.4-0.5 mg / kg) to a human patient suffering depression, or by oral administration (ca. 50-200 mg; 0.8-3.2 mg / kg) with tablets. In another example of use, the compound of Example 6 (4-hemiglutarate of 4-OH-DiPT) is similarly administered. Prior to the dosing session, the patient is qualified for the experience by measurement of depression scores, screened for exclusions (e.g. history of psychoses, unfavorable heart condition, pregnancy) and finally, the patient is encouraged to formulate an intent for the dosing session. Dosing is performed in a quiet clinic setting with the patient resting comfortably in an inclined, but unrestrained, position to avoid falls. The patients' eyes are covered, and music is applied. The drug is administered. After 4 h, the patient reports no longer feeling the effects of the drug and is asked to sit up while under supervision. Feeling normal, the patient is allowed to stand (supervised) and feeling in control, is allowed to move around. One hour later, the patient is discharged. Later by 24 h, the patient returns to the clinic to meet with a psychotherapist to recount the session. The patient records a depression score via questionnaire and is again discharged. At regular intervals the patient is consulted for recurrence of depressive symptoms.EXAMPLE 16 - Injectable Composition Kit

[0156] A vial is prepared with 25 mg of compound in Example 6 as a hydrochloride salt (sterilized powder or lyophilizate). In a separate vial is placed 1 ml of a sterile filtered solution containing 70 mM Na2HPO4. The final pH of the solution is 4.0-5.0. These 2 components constitute a kit for reconstitution of a drug product for subcutaneous injection at point of care.EXAMPLE 17 — Synthesis of 2-(N-(2-methoxybenzyl)-N-Methyl)aminoethyl)-5-Methoxy- IH-indole

[0157] Step 1. To a 150 mL RBF with stir bar was added 5-methoxyindole-3-acetic (1.0 equiv), followed by anhydrous ACN (25 mL) under N2. To this solution was then slowly added 2- methoxy-N-methylbenzylamine (2.0 equiv), then triethylamine (4.0 equiv). To the reactionmixture was then added n-propyl phosphonic acid cyclic anhydride (TP3) (8.68 g, 50% w / w in EtOAc). The reaction mixture was allowed to stir at room temperature overnight and monitored by TLC. The solvent was removed under vacuum. The residue was diluted with DCM (40 mL) and washed with brine (30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness to give an orange oil (6.73 g of crude orange oil). Flash Chromoatography (Biotage SNAP KP-SIL 340 g cartridge) using MeOH in EtOAc 0-5% gradient yielded 2.3 g of pure product as a yellow sticky solid (99% yield).

[0158] Step 2. To LiAlH4(5.0 equiv) in THF (100 ml) was added dropwise a solution containing 3.38 g product from step 1 in THF (60 mL) at 0° C. (ice bath). The reaction mixture was allowed to stir for 2 days as it slowly warmed to room temperature. The reaction was monitored by UPLC for disappearance of the starting material. After cooling the mixture to 0° C., the reaction was quenched by slow addition of MTBE (60 mL) followed by careful slow addition of 0.5 M NaOH (60 mL). MgSO4was added and the mixture was left stirring until a white precipitate was formed. The precipitate was filtered through a pad of Celite and washed with DCM. The filtrate was concentrated to dryness to give a greenish oil. Flash chromatography (Biotage SNAP KP-SIL 340 g cartridge) MeOH in EtOAc 0-5% in gradient yielded 3.78 g of crude orange oil (yield near quantitative). Purity UPLC=96%, QNMR (1,4- Dinitrobenzene; using peak at 6.7 (1H)) from compound in example)=96% (determined in two separate analyses). Exact mass by LCMS (MH+) 325.16. 1H NMR: 2.3 ppm (s, 3H, NMe), 2.6 ppm (m, 2H, — CH2N), 2.8 ppm (m, 2H, Indole-CH2-) , 3.5 ppm (s, 2H, NCH2Ph), 3.7 ppm (s, 3H, OMe), 3.75 ppm (s, 3H, OMe), 6.7 ppm (m, 1H, aromCH), 6.9 ppm (m, 2H, aromCH), 6.95 ppm (d, 1H, aromCH), 7.1 ppm (s, 1H, aromCH), 7.2 ppm (m, 2H, aromCH), 7.4 ppm (m, 1H, aromCH), 10.7 ppm (m, 1H, NH).

[0159] Inhibition in functional GCPR assays for Adrenergic Alpha 1A and Alpha 2A were determined: IC50 (A1A): 1800 nM; IC50(A2A): 1700 nM.EXAMPLE 18 — 5HT1A Competitive Binding Assay

[0160] Competitive binding assay (Eurofins Cerep) was performed using human recombinant 5-HT1 A transfected to HEK-293 cells, [3H]8-OHDPAT (0.5 nM) and the test compound from Example 20 was tested at 8 concentrations ranging from 0.01 mM to 30 mM (Choi DS et al. FEBS Letters 1994, 352, 393). The analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc). The binding constant (Ki 540nM) were calculated using the Cheng Prusoff equation. The compound is a modest agonist at the 5HT1A receptor, but prefers the 5HT2A receptor (Ki 110 nM) by about 5-fold selectivity.EXAMPLE 19 — 5HT2A Competitive Binding Assay

[0161] Competitive binding assay (Eurofins Cerep) was performed using human recombinant 5-HT2A transfected to HEK-293 cells, 1251-D0.1 (0.1 nM) and the test compound from Example 17 was tested at 8 concentrations ranging from 0.01 mM to 30 mM (Choi DS et al. FEBS Letters 1994, 352, 393). The analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc). The binding constant (Ki 110 nM) were calculated using the Cheng Prusoff equation. The compound is approximately equipotent to psilocybin based on data from the http: / PDSP.unc.edu / databases / pdsp.php.EXAMPLE 20 — 5HT2A Functional Assay

[0162] Competitive binding assay (Eurofins Cerep) was performed using human recombinant 5-HT2A transfected to HEK-293 cells, serotonin (30 nM) and the test compound from Example 17 was tested at 8 concentrations ranging from 0.01 mM to 30 mM (Choi D S et al. FEBS Letters 1994, 352, 393). The analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc). The results show agonism at 5HT2A with EC50 of 520 nM reaching 80% maximum efficacy at the highest concentrations.EXAMPLE 21 — 5HT2B Competitive Binding Assay

[0163] Competitive binding assay was performed (Eurofins Cerep) using human recombinant 5-HT1A transfected to CHO cells, 125I-DOI (0.2 nM) and the test compound from Example 17 was tested at 8 concentrations ranging from 0.01 mM to 30 mM, (Choi D S et al. FEBS Letters 1994, 352, 393). The analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc). No binding constant could be determined (Ki 180 nM) using the Cheng Prusoff equation. The compound will bind to the 5HT2B receptor with similar strength to the 5HT2A receptor (Ki 1 lOnM).EXAMPLE 22 — 5HT2B (isotol phosphate, IP1) Functional Assay

[0164] A functional assay was performed (Eurofins Cerep) using human recombinant 5-HT2B transfected to CHO cells and the test compound from Example 17 was tested at 8 concentrations ranging from 0.01 mM to 30 mM, (see Porter, RHP et al. Brit. J. Pharmacol. 1999, 128, 13. Serotonin (1 uM) was used as a control. Quantification of myo-Inositol 1 phosphate was performed using HTRF. The analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc). EC50 could not be determined for lack of activity of the compound at the receptor. Combined with the results of Example 21, this suggests that the compound will bind to the 5HT2B receptor, but does not generate any functional activity of the receptor and is thus acting as a neutral agonist or antagonist at therapeutic levels.EXAMPLE 23 — 5HT2B Functional Antagonist Assay

[0165] A antagonist functional assay was performed (Eurofins Cerep) using human recombinant 5-HT2B transfected to CHO cells, with background serotonin (10 uM) and the test compound from Example 17 was tested at 8 concentrations ranging from 0.01 mM to 30 mM (see Porter, R H P et al. Brit. J. Pharmacol. 1999, 128, 13). Quantification of myo-Inositol-1- phosphate was performed using HTRF. The analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc). The results show that the Compound from Example 20 is a full antagonist with IC50 <10 uM, when determined using the Cheng Prusoff equation.EXAMPLE 24 — 5HT2C Competitive Binding Assay

[0166] Competitive binding assay was performed (Eurofins Cerep) using human recombinant 5-HT1A transfected to CHO cells, 125I-DOI (0.2 nM) and the test compound from Example 17 was tested at 8 concentrations ranging from 0.01 mM to 30 mM, (Choi D S et al. FEBS Letters 1994, 352, 393). The analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc). No binding constant could be determined (Ki 680 nM) using the Cheng Prusoff equation. The compound is a modest agonist at the 5HT2C receptor but prefers the 5HT2A receptor (Ki 110 nM) by about 6-fold selectivity.EXAMPLE 25 — Pharmacokinetics After i.v. Administration in Rats

[0167] The compound of Example 17 was dispersed in water containing phosphate buffered saline at a rate of 1 mg / ml and then acidified to pH 4 to create a solution. The solution was administered to each of 3 rats (ca. 300 g each) at a rate of 1.0 mg / kg (ca. dose 0.33 ml, dose volume 0.33 mg) via a catheter placed in the jugular vein. Animals were observed over a period of 12 h with counting the cumulative number head-twitch actions over each 10 min up to 2 hours and then for 10 min each at 3, 3.5 and 4 hours. Blood samples (0.25 ml) were collected via the catheter using 1 ml syringes into 0.8 ml K2EDTA tubes at 0.0833, 0.25, 0.5, 0.75, 1, 2, 4, 6 hours after the dose and placed on wet ice until processing. Psyciological saline (0.25 ml) was reinjected after each blood draw via the catheter to the animal to flush the catheter and replenish blood volumes. The blood samples collected were centrifuged (3200 g, 5 min, 4 C) within 5 min of collection and the plasma recovered and placed in a cryovial and frozen in liquid nitrogen and stored at -80 C thereafter until analysis. A bioanalytical method was developed to quantify the compound in plasma using a Sciex 6500 Q-trap MSMS equipped with a standard LC system and after calibration with the compound of the example.

[0168] The mean plasma half-life was 66 minutes. There was no significant head twitch activity during the duration of the rat i.v. PK experiment indicating reduced hallucinogenic potential of the compound, despite showing 5HT2A receptor binding and functional assays (Examples 20 and 21 above). A non-hallucinogenic 5HT2A agonist could have significant potential utility in treating mood disorders and overcome the requirement for monitoring requirements typical of similar 5HT2A agonsits in the same class, which produce a hallucinogenic state.EXAMPLE 26 — Synthesis of 2-(N-(3-methoxybenzyl)-N-Methyl)aminoethyl)-1H-indole

[0169] The 2-step synthesis process, amide coupling, followed by reduction, in example 20 was performed using 3-methoxy-N-methylbenzylamine (2.0 equiv) instead of the 2-methoxy- modified amine described in Example 17. Yield of step 1: 85%; Yield of step 2: 20%. Purity UPLC: 98%, QNMR (1,4-Dinitrobenzene; using peak at 6.7 (1H)) from compound in example):96%. Exact mass by MS (MH+): 295.0. 1H NMR (dmso-d6): 2.3 ppm (s, 3H, NMe), 2.6 ppm (m, 2H, — CH2N), 2.8 ppm (m, 2H, Indole-CH2-), 3.5 ppm (s, 2H, NCH2Ph), 3.7 ppm (s, 3H, OMe), 3.75 ppm (s, 3H, OMe), 6.8 ppm (m, 1H, aromCH), 6.9 ppm (m, 2H, aromCH), 6.95 ppm (m, 1H, aromCH), 7.05 ppm (s, 1H, aromCH), 7.13 ppm (m, 2H, aromCH), 7.2 (d, 1H, aromCH), 7.4 ppm (m, 1H, aromCH), 10.7 ppm (m, 1H, NH). 5HT1A Binding Ki 510 nM. 5HT2A Ki 14 nM. 5HT2B Binding Ki 380 nM. 5HT2B functional agonist mode IC50 1050 nM (Efficacy <20% up to 30 uM). 5HT2C Binding Ki 42 nM.EXAMPLES 27 - 45

[0170] Below is provided details on the synthesis and testing of the following compounds.TABLE 4:EXAMPLE 27 Synthesis of N-ethyl-2-(5-methoxy-1H-indol-3-yl)-N-(2- methoxybenzyl)ethan- 1 -amine

[0171] The following reaction scheme was used:

[0172] To a stirred solution of 2-methoxybenzaldehyde (3.0 g, 1.0 equiv) in EtOH (20 mL) was added Ethyl amine (0.99 g, 1.0 equiv) at room temperature. The reaction mixture was cooled to 0° C., stirred for 5 min., NaBH4 (1.63 g, 2.0 equiv) was added portion wise. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (50 mL), extracted with EtOAc (2x100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford N-(2 -methoxybenzyl) ethanamine (2, 2.7 g, 74%) as colorless thick syrup.

[0173] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.29 (dd, J=7.25, 0.88 Hz, 1H, aromCH), 7.15- 7.23 (m, 1H, aromCH), 6.95 (d, J=8.13 Hz, 1H, aromCH), 6.89 (t, J=7.38 Hz, 1H, aromCH), 3.77 (s, 3H, OMe), 3.66 (s, 2H, — CH2N), 2.53 (q, J=7.21 Hz, 2H, — CH2N), 1.02 (t, J=7.13 Hz, 3H, — CH2Me).

[0174] To a stirred solution of 2-(5-methoxy-1H-indol-3-yl)acetic acid (0.62 g, 1.0 equiv) and N-(2-methoxybenzyl) ethanamine (0.5 g, 1.0 equiv) in CH3CN (10 mL) was added TEA (1.8 mL, 12.12 mmol) at room temperature. The reaction mixture was cooled to 0 ° C., stirred for 5 min and 50%T3P solution in EtOAc (3.9 mL, 2.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), extracted with EtOAc (2x50 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography (20 to 30% EtOAc in heptane) to afford N-ethyl-2-(5-methoxy-1H-indol-3- yl)-N-(2-methoxybenzyl)acetamide (0.7 g, 65%) as colorless thick syrup. LCMS: Not done.

[0175] To a stirred solution of N-ethyl-2-(5-methoxy-1H-indol-3-yl)-N-(2-methoxybenzyl)- acetamide (0.7 g, 1.0 equiv) in THF (8 mL) was added a solution of 2M LiA1H4 (2.0 equiv) in THF (2 mL) at 0° C. dropwise. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0° C. and quenched with a saturated Na2SO4 solution (10 mL), white precipitate was filtered through pad of Celite and washed with EtOAc (100 mL). Filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was triturated with heptane (10 mL) to afford N-ethyl-2-(5-methoxy-1H-indol-3-yl)-N-(2- methoxybenzyl) ethan-1 -amine (0.45 g, 67%) as an off white solid.

[0176] MS (ESI) m / e [M+H]+: 339; HPLC purity: 99.84% (RT=5.9 min), 1HNMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1H, indole-NH) 7.40 (dd, J=7.38, 1.38 Hz, 1H, AromCH) 7.15-7.21 (m, 2H, AromCH), 7.05 (d, J=2.13 Hz, 1H, AromCH), 6.81-6.98 (m, 3H, AromCH), 6.68 (dd, J=8.76, 2.38 Hz, 1H, AromCH), 3.77 (s, 3H, OMe), 3.70 (s, 3H, OMe), 3.63 (s, 2H, CH2), 2.77- 2.84 (m, 2H, CH2), 2.65-2.71 (m, 2H, CH2), 2.59 (q, J=7.05 Hz, 2H, CH2), 1.04 (t, J=7.07 Hz, 3H, — CH2Me).EXAMPLE 29 Synthesis of N-(2-(5-methoxy-1H-indol-3-ypethyl)-N-(2- methoxybenzyl)propan-2-amine

[0177] The following reaction scheme was used:

[0178] To aa ssttiirrrreedd ssoolluuttiioonn ooff N-isopropyl-2-(5-methoxy-1H-indol-3-yl)-N-(2- methoxybenzyl) acetamide (1.0 g, 1.0 equiv) in THF (40 mL) was added dropwise a solution of 2M LiAlH4in THF (6.8 mL, 5.03 equiv) at 0° C. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0° C. and quenched with a solution of saturated Na2SO4in water (10 mL) white precipitation was filtered through pad of Celite, washed with EtOAc (100 mL). Filtrate was washed with water (50 mL), separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography (1 to 5% MeOH in EtOAc) to afford N-(2-(5-methoxy-1H-indol-3-yl)ethyl)- N-(2-methoxybenzyl)propan-2-amine (0.34 g, 35%) as an colorless sticky oil.

[0179] MS (ESI) m / e [M+H]+: 353; HPLC purity: 97.03% (RT=1.8 min);1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1H, indoleNH), 7.49 (dd, J=7.50, 1.50 Hz, 1H, aromCH), 7.14-7.22 (m, 2H, aromCH), 7.03 (d, J=2.25 Hz, 1H, aromCH), 6.87-6.96 (m, 2H, aromCH), 6.81 (d, J=2.38 Hz, 1H, aromCH), 6.67 (dd, J=8.69, 2.44 Hz, 1H, aromCH), 3.77 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.61 (s, 2H, CH2), 2.97-3.05 (m, 1H, CH), 2.62-2.76 (m, 4H, CH2), 1.01 (d, J=6.63 Hz, 6H, CH(CH3)2).EXAMPLE 29 Synthesis of N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-(2- methoxybenzyl)prop-2-en- 1 -amine

[0180] The following reaction scheme was used:

[0181] To a stirred solution of 2-methoxybenzaldehyde (1.0 g, 1.0 equiv) in EtOH (6 mL) was added prop-2-en-1-amine (0.46 g, 1.1 equiv) and stirred for at room temperature for 12h. The reaction mixture was cooled to 0° C., stirred for 5 min., NaBH4(0.45 g, 1.6 equiv) was added portion wise. The reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (10 mL) and the organic layer was concentrated in vacuo, diluted with water (50 mL) andextracted with EtOAc (2x100 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to N-(2-methoxybenzyl) prop-2-en-1-amine (0.7 g, 54%) as colorless thick syrup.

[0182] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.28-7.33 (m, 1H, aromCH) 7.18-7.27 (m, 1H, aromCH) 6.88-6.99 (m, 2H, aromCH) 5.87 (ddt, J=16.93, 11.07, 5.32, 5.32 Hz, 1H, alkeneCH) 5.11-5.25 (m, 1H, alkeneCH) 5.07 (d, J=10.27 Hz, 1H, alkeneCH) 3.79 (s, 3H, OMe) 3.66 (s, 2H, NCH2) 3.17 (d, J=4.89 Hz, 2H, NCH2)

[0183] To a stirred solution of N-(2-methoxybenzyl) prop-2-en-1-amine (0.7 g, 1.0 equiv) and 2-(5-methoxy-1H-indol-3-yl)acetic acid (0.81 g, 1.0 equiv) in ACN (10 mL) was added TEA (2.1 mL, 4.0 equiv) at room temperature. The reaction mixture was cooled to 0° C., stirred for 5 min and 50% T3P solution in EtOAc (5.0 mL, 2.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo to afford crude, diluted with water (30 mL), extracted with EtOAc (2x50 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography (20 to 30% EtOAc in heptane) to afford N-allyl-2-(5-methoxy- 1H-indol-3-yl)-N-(2-methoxybenzyl) acetamide (0.8 g, 55%) as colorless thick syrup. MS (ESI) m / e [M+H]: 365.

[0184] To a stirred solution of LAH (2M in THF, 7.7 mL, 3.9 equiv) in THF (50 mL) was added A1C13 (2.04 g, 4.0 equiv) portion wise at 0° C. The solution was stirred for 30 min at 0° C. N- allyl-2-(5-methoxy-1H-indol-3-yl)-N-(2-methoxybenzyl) acetamide (1.4 g, 1 equiv) in THF (25 mL) was added. The reaction mixture was stirred for 1 h at 0° C., then at room temperature for 12 h. Progress of the reaction was monitored by TLC. After was completion, the reaction mixture was cooled to 0° C. and quenched with 20% NaOH solution (10 mL) precipitate was filtered through pad of Celite, washed with EtOAc (100 mL). Filtrate was washed with water (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash (50 to 100% EtOAc in heptane) to afford N-ethyl-2-(5-methoxy- 1H-indol-3-yl)-N-(2-methoxybenzyl) ethan-l-amine (0.8 g, 59%) as an off white solid.

[0185] MS (ESI) m / e [M+H]+: 351; HPLC purity: 99.43% (RT=6.06 min) 1H NMR (400 MHz, DMSO-d6) δ ppm 10.55 (s, 1H, indoleNH), 7.40 (d, J=7.38 Hz, 1H, aromCH), 7.19 (d, J=8.76 Hz, 2H, aromCH), 7.00- 7.06 (m, 1H, aromCH), 6.96 (d, J=8.13 Hz, 1H, aromCH), 6.90 (t, J=7.38 Hz, 1H, aromCH), 6.85 (d, J=2.13 Hz, 1H, aromCH), 6.67 (dd, J=8.69, 2.31 Hz, 1H,aromCH), 5.86-5.97 (m, 1H, alkeneCH), 5.24 (s, 1H, alkeneCH), 5.14 (d, J=10.26 Hz, 1H, alkeneCH), 3.77 (s, 3H, OMe), 3.70 (s, 3H, OMe) 3.65 (s, 2H, CH2), 3.19 (d, J=6.13 Hz, 2H, CH2), 2.78-2.87 (m, 2H, CH2), 2.63-2.73 (m, 2H, CH2).EXAMPLE 30- Synthesis of 2-(1H-indol-3-yl)-N-(4-methoxybenzyl)-N-methylethan-l-amine

[0186] The following reaction scheme was used:

[0187] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (0.85 g, 1.0 equiv) and l-(4- methoxyphenyl)-N-methylmethanamine (0.88 g, 1.2 equiv) in CH3CN (40 mL) was added TEA (2.58 mL, 4.04 equiv) at room temperature. The reaction mixture was cooled to 0° C., stirred for 5 min., 50% T3P solution in EtOAc (6.1 mL, 2.02 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), extracted with EtOAc (2x50 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flashchromatography (20 to 30% EtOAc in heptane) to afford 2-(1H-indol-3-yl)-N-(4- methoxybenzyl)-N-methylacetamide (3, 1.1 g, 73%) as colorless oil.

[0188] MS (ESI) m / e [M+H]+: 308.9; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.24 (s, 1H, indoleNH), 7.58-7.67 (m, 1H, aromCH), 7.35 (d, J=8.00 Hz, 1H, aromCH), 7.05-7.22 (m, 5H, aromCH), 6.82 (d, J=8.25 Hz, 2H, aromCH), 4.33-4.62 (m, 2H, CH2), 3.89 (s, 2H, CH2), 3.79 (s, 3H, OMe), 2.93 (s, 3H, NMe).

[0189] To a stirred solution of 2-(1H-indol-3-yl)-N-(4-methoxybenzyl)-N-methylacetamide (1.1 g, 1.0 equiv) in THF (40 mL) was added a solution of 2M LiAlH4 in THF (4.46 mL, 2.5 equiv) at 0° C. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0° C. and quenched with saturated Na2SO4 solution (10 mL) white precipitate was filtered through pad of Celite, washed with EtOAc (100 mL). Filtrate was washed with water (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was triturated with n-heptane (10 mL) to afford 2-(1H-indol-3-yl)-N-(4-methoxybenzyl)-N-methylethan-l-amine (FT 165, 0.47 g, 44%) as an off white solid.

[0190] MS (ESI) m / e [M+H]+: 295; HPLC purity: 98.04% (RT=5.2 min); 1HNMR (400 MHz, DMSO-d6) δ ppm 10.73 (s, 1H, indoleNH), 7.42 (d, J=7.8 Hz, 1H, aromCH), 7.31 (d, J=8 Hz, 1H, aromCH), 7.28-7.17 (m, 2H, aromCH), 7.11 (s, 1H), 7.04 (t, J=7.6 Hz, 1H, aromCH), 6.93 (t, J=7.6 Hz, 1H, aromCH), 6.86 (d, J=7.8 Hz, 2H, aromCH), 3.73 (s, 3H, OMe), 3.48 (s, 2H, CH2), 2.94-2.77 (m, 2H, CH2), 2.67-2.55 (m, 2H, CH2), 2.21 (s, 3H, NMe).EXAMPLE 31 - Synthesis of N-(2,3-dimethoxybenzyl)-2-(1H-indol-3-yl)-N-methylethan-l- amine

[0191] The following reaction scheme was used:

[0192] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (0.87 g, 1.0 equiv) and Comp-2 (0.9 g, 4.97 mmol) in CH3CN (10 mL) was added TEA (2.9 mL, 4.0 equiv) at room temperature. The reaction mixture was cooled to 0° C., stirred for 5 min and 50% T3P solution in EtOAc (3.16 mL, 2.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo and diluted with water (50 mL), extracted with EtOAc (2×100 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude. The crude obtained was purified by combi flash chromatography (20 to 30% EtOAc in heptane) to afford N-(2,3-dimethoxybenzyl)-2-(1H-indol-3-yl)-N-methylacetamide (3, 1.0 g, 59%) as colorless oil.

[0193] MS (ESI) m / e [M+H]+: 339;1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (d, J=9.78 Hz, 1H, indoleNH), 7.53-7.61 (m, 1H, aromCH), 7.49 (d, J=7.34 Hz, 1H, aromCH), 7.27-7.40(m, 1H, aromCH), 7.19 (d, J=13.20 Hz, 1H, aromCH), 6.87-7.10 (m, 3H, aromCH), 6.54-6.67 (m, 1H, aromCH), 4.45-4.65 (m, 2H, CH2), 3.76-3.85 (m, 6H, OMe), 3.70 (d, J=15.16 Hz, 3H, NMe), 2.96 (s, 2H, CH2).

[0194] To aa ssttiirrrreedd solution of N-(2,3 -dimethoxybenzyl)-2-(1H-indol-3 -yl)-N- methylacetamide (1.5 g, 1.0 equiv) in THF (50 mL) was added a solution of 2M LiA1H4 in THF (4.88 mL, 2.02 equiv) at 0° C. dropwise. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0° C. and quenched with saturated Na2SO4 solution (10 mL) white precipitate was filtered through pad of Celite, washed with EtOAc (70 mL). Filtrate was washed with water (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography (40 to 60% EtOAc in heptane) to afford N-(2,3-dimethoxybenzyl)-2-(1H-indol-3-yl)-N-methylethan-l-amine (0.37 g, 38%) colorless sticky oil.

[0195] MS (ESI) m / e [M+H]+: 325; HPLC purity: 97.62% (RT=5.9 min); 1HNMR (400 MHz, DMSO-d6) δ ppm 10.73 (s, 1H, indoleNH), 7.43 (d, J=7.88 Hz, 1H, aromCH), 7.31 (d, J=8.13 Hz, 1H, aromCH), 7.09-7.13 (m, 1H, aromCH), 6.97-7.06 (m, 2H, aromCH), 6.90-6.97 (m, 3H, aromCH), 3.78 (s, 3H, OMe), 3.68 (s, 3H, OMe), 3.53 (s, 2H, CH2), 2.81-2.93 (m, 2H, CH2), 2.59-2.70 (m, 2H, CH2), 2.24 (s, 3H, NMe).EXAMPLE 32 - Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(2,3-dimethoxybenzyl)prop-2-an- 1 -amine

[0196] The following reaction scheme was used:

[0197] To a stirred solution of 2,3-dimethoxybenzaldehyde (3.0 g, 1.0 equiv) in EtOH (90 mL) was added Isopropyl ethyl amine (1.5 g, 1.5 equiv). The reaction mixture was stirred for 12 h at room temperature, cooled to 0° C. and NaBH4 (1.33 g, 2.0 equiv) was added portion wise. The reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (10 mL), the organic layer was concentrated in vacuo, diluted with water (50 mL), extracted with EtOAc (2x100 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford N-(2,3-dimethoxybenzyl)propan-2-amine (2.4 g, 63%) as colorless oil.

[0198] To a stirred solution ofN-(2,3-dimethoxybenzyl)propan-2-amine (2.4 g, 1.0 equiv) and Comp-3 (2.0 g, 1.0 equiv) in CH3CN (30 mL) was added TEA (6.1 mL, 4.0 equiv) at room temperature. The reaction mixture was cooled to 0 ° C., stirred for 5 min and 50% T3P solution in EtOAc (14.6 mL, 2.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo to afford crude, diluted with water (50 mL), extracted with EtOAc (2x100 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude. The crude obtained was purified by combi flash chromatography (20 to 30% EtOAc in heptane) to N-(2,3-dimethoxybenzyl)-2-(1H-indol- 3-yl)-N-isopropylacetamide (2.5 g, 59%) as colorless sticky oil.

[0199] To a ssttiirrrreedd solution ooff N-(2,3-dimethoxybenzyl)-2-(1H-indol-3-yl)-N- isopropylacetamide (1.5 g, 1.0 equiv) in THF (50 mL) was added dropwise a solution of 2M LiAlH4 in THF (10.2 mL, 5.1 equiv) at 0° C. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0° C. and quenched with saturated Na2SO4 solution (10 mL) white precipitation was formed and filtered through pad of Celite, cake was washed with EtOAc (100 mL). Filtrate was washed with water (50 mL), separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude. The crude obtained was purified by Prep HPLC which was triturated with MeOH (5 mL) to afford N-(2-(1H-indol-3- yl)pethyl)-N-(2,3-dimethoxybenzyl)propan-2-amine (0.4 g, 28%) as off white solid.

[0200] MS (ESI) m / e [M+H]+: 353; HPLC purity: 98.36% (RT=8.23 min); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (s, 1H, indoleNH), 7.21-7.38 (m, 2H, aromCH), 6.93-7.11 (m, 4H, aromCH), 6.87-6.93 (m, 2H, aromCH), 3.77 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.61 (s, 2H, CH2), 2.90-3.04 (m, 1H, NCH), 2.68-2.77 (m, 2H, CH2), 2.60-2.67 (m, 2H, CH2), 0.99 (d, J=6.85 Hz, 6 H, NCHMe).EXAMPLE 33 - Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(benzyl)methan-l-amine

[0201] The following reaction scheme was used:

[0202] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (1 g, 1.0 equiv) in 10 ml of ACN were added N-methyl-l-phenylmethanamine (0.8 g, 1.2 equiv) followed by T3P (3.6 g, 2.0 equiv) and Et3N (1.7 g, 3.0 equiv) at room temperature. The reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), extracted with EtOAc (2x50 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to get the desired product as white colour solid (1.2 g, 75% yield).

[0203] To a stirred solution of N-benzyl-2-(1H-indol-3-yl)-N-methylacetamide (1.2 g, 1.0 equiv) in 3 ml of THF was added a solution of 2M LAH (0.3 g, 2.0 equiv) dropwise. The reaction mixture was stirred at 0° C. for 4 h under N2 atmosphere. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a saturatedNa2SO4 solution (10 mL), white precipitate was filtered through pad of Celite and washed with EtOAc (100 mL). Filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to afford N-benzyl-2-(1H-indol-3-yl)-N-methylethan-l-amine (FT232, 0.6 g, 52%) as a brown solid.

[0204] MS (ESI) m / e [M+H|+: 265; HPLC purity: 99.6% (RT=5.7 min), 1H NMR (400 MHz, DMSO-d6) δ=10.74 (s, 1H, indoleNH), 7.42 (d, J=7.75 Hz, 1H, aromCH), 7.39-7.26 (m, 5H, aromCH), 7.25 (s, 1H, aromCH), 7.12 (d, J=2.0 Hz, 1H, aromCH), 7.04 (dt, J=2.0 Hz, 8.0 Hz, 1H, aromCH), 6.93 (dt, J=2.0 Hz, 8.0 Hz, 1H, aromCH), 3.56 (s, 2H, CH2), 2.88 (t, J=4.0 Hz, 2H, CH2), 2.64 (s, 2H, CH2), 2.24 (s, 3H, NMe).EXAMPLE 34 - Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(3-ethylbenzyl)prop-2-en-l-amine

[0205] 3-(aminoethyl)-1H-indole (1 equiv) was reacted with 3-methyoxybenzoic anhydride (1,2 equiv) in ethanol at 65 C for 7 h to fomr an intermediate imine which was then cooled to room temperature and reacted directly by the addition of NaBH4 (2 equiv). After quenching, extraction and evaporation of solvents, yielded the desired 3-(3-methoxybenzylaminoethyl)- IH-indole (1.1 g, 62%). This (0.6 g, 1 equiv) was then reacted with trans- l-bromo-2-butene (1.1 equiv) in a minimal amount of DMF using K2CO3 (2 equiv) at RT over 2 h. The product was isolated after extraction followed by flash chromatography to yield a semisolid (0.48 g, 57%). Purity (UPLC): 97.4%. MS MH+335. 1H-NMR (dmso-d6): 1.7 (d, 3H), 2.7 (m, 2H), 2.84 (m, 2H), 3.2 (m, 2H), 3.6 (m, 2H), 3.73 (s, 3H), 5.6 (m-m, 2H), 6.8 (dd, 1H), 6.9 (m, 3H), 7.05 (t, 1H), 7.08 (m, 1H), 7.2 (t, 1H), 7.3 (d, 1H), 7.4 (d, 1H), 10.7 (br s, 1H).

[0206] Example 35 — Synthesis of (Z)-N-(2-(1H-indol-3-yl)ethyl)-N-(3-methoxybenzyl)but-2- en-1 -amine

[0207] The following reaction scheme was used:

[0208] To a stirred solution of 2-(1H-indol-3-yl)ethan-l-amine (1.5 g, 1.0 equiv) in 40 mL of ethanol was added 3-methoxybenzaldehyde (1.5 g, 1.2 equiv) at room temperature. The reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was cooled to 0° C. and NaBH4(0.7 g, 2.0 equiv) was added portion wise and stirred further for 4 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-water and extracted with ethyl acetate (50 m1x2). The organic layer was washed with brine solution and dried over anhydrous Na2SO4, and filtered, concentrated in vacuo. The crude was purified by Flash chromatography (Combi-Flash Column, 24 g redisep cartridge) using 100% DCM to 2% MeOH in DCM to get desired product as thick orange syrup (1.8 g, 69% yield).

[0209] To a solution of but-2-yn-l-ol (2.0 g, 1.0 equiv) in 50 mL of methanol was added Lindlar catalyst (0.2 g, 0.04 equiv) at room temperature under 50 psi of hydrogen atmosphere.The reaction mixture was stirred at room temperature for 3 h. The progress of reaction wasmonitored by TLC. After completion, the Reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo gave crude compound ((Z)-but-2-en-l-ol) (1.8 g, 67% yield). The crude compound was used as such for next step.

[0210] To a stirred solution of (Z)-but-2-en-l-ol (1.8 g, 1.0 equiv) in 40 ml of diethyl ether at 0° C. was added PBr3(0.9 ml, 0.4 equiv) dropwise. The RM was stirred at room temperature for 3 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-water and aqueous layer was extracted with diethyl ether (50 m1x2). Organic layer was washed with brine solution and dried over anhydrous Na2SO4, and filtered, concentrated in vacuo, to obtained yellow liquid, which was used as such for next step (0.6 g, 16% yield).

[0211] To a stirred solution of 2-(1H-indol-3-yl)-N-(3-methoxybenzyl)ethan-l-amine (1.0 g, 1.0 equiv) in 8 ml of DMF were added K2CO3and (Z)-l-bromobut-2-ene (0.5 g, 1.1 equiv) dropwise. The RM was stirred at rt for 3h. Completion of the reaction was checked by TLC. The RM was diluted with water (30 ml) and DCM (50 ml). The organic layer was separated and washed with water (30 m1x2). Then organic layer was dried over anhydrous Na2SO4, and filtered, concentrated in vacuo. The crude was purified by Flash chromatography (Combi- Flash Column, 24 g redisep cartridge) using 100% DCM to 2% MeOH in DCM to get desired product as thick orange syrup (0.5 g, 37% yield).

[0212] MS (ESI) m / e [M+H]+: 335; HPLC purity: 98% (RT=6.2 min),4NMR (400 MHz, DMSO-d6) δ=10.74 (s, 1H, indoleNH), 7.39-7.29 (m, 2H, aromCH), 7.23 (s, 1H, aromCH), 7.12-6.99 (m, 2H, aromCH), 6.93 (d, J=6.8 Hz, 3H, aromCH), 6.81 (s, 1H, aromCH), 5.82- 5.46 (m, 2H, alkeneCH), 3.72 (s, 3H, OMe), 3.62 (s, 2H, CH2), 3.11 (s, 2H, CH2), 2.86 (s, 2H, CH2), 2.70 (s, 2H, CH2), 1.73-1.55 (m, 3H, alkeneMe).

[0213] Example 36 — Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(3-methoxybenzyl)2- methylprop-2-en- 1 -amine

[0214] 3-(3-methoxybenzylaminoethyl)-1H-indole of Example 18 (0.61 equiv, 1 equiv) was alkylated with 3-Bromo-2-methylpropene (1.1 equivalent) in a manner identical to the method described in Example 18 to yield the desired compound (0.5g, 60%). Purity (UPLC) 99.8%. MS MH+335. 1H-NMR (dmso-d6): 1.7 (s, 1H), 2.6 (m, 2H), 2.88 (m, 2H), 3 (s, 2H), 3.6 (s, 2H), 3.7 (s, 3H), 4.85 (s, 1H), 4.95 (s, 1H), 6.8 (d, 1H), 6.9 (mm, 3H), 7.1 (mm, 2H), 7.2 (t, 1H), 7.3 (d, 1H), 7.35 (d, 1H), 10.7 (br s, 1H).

[0215] Example 37 — Synthesis of 2-(1H-indol-3-yl)-N-(3-ethylbenzyl)-N-methylethan-l- amine

[0216] 3-ethylbenzaldehyde (1 equiv.) was reacted with methylamine (1.2 equiv) at room temperature in ethanol overnight, followed by reductive amination using NaBH4(2.5 equiv) at room temperature for 2 h. After quenching excess hydride, the amine was recovered after extracting into aqueous acid, repeated washing with DCM, extraction back into DCM, washed with basic bicarbonate solution, before drying over K2CO3and drying evaporation of solvent to give an oil (1 g, 91%). Coupling of the amine (1,2 equiv) with 3-indole acetic acid (1 equiv) was performed using polyphosphonic anhydride (2 equiv) and triethylamine (4 equiv) in acetonitrile at OC, which was allowed to naturally come to room temperature overnight. The workup included evaporation of solvent, redissolution in DCM, washing with mild aqueous acid and base to remove starting materials, drying over K2CO3and evaporation of the solvent to yield a semisold (1.1g, 54%), which was then reduced with LIAIH4(2 equiv) in THF at OC over 4 h. After reduction of the solvent, the compound was separated by flash chromatography EtOAc / heptane gradient to yield the desired compound as a semisolid (0.26 g, 29%). Purity (UPLC: 95.9%). MS MH+ 293. 1H-NMR (dmso-d6): 1.17 (t, 3H), 2.23 (s, 3H), 2.6 (m-m, 4H), 2.87 (t, 2H), 3.52 (s, 2H), 6.9 (t, 1H), 7.0-7.17 (mm, 5H), 7.2 (t, 1H), 7.3 (t, 1H), 7.4 (t, 1H), 10.75 (br s, 1H).EXAMPLE 38 — 3-(((2-(1H-indol-3-yl)ethyl)(methyl)amino)methyl)phenol

[0217] The following reaction scheme was used:

[0218] To a stirred solution of 2-(1H-indol-3-yl)-N-methylethan-l-amine (0.7 g, 1.0 equiv) in 25 ml of DCE were added 3-methoxybenzaldehyde (0.6 g, 1.0 equiv) and NaBH(OAc)3(1.3 g, 1.5 equiv). The reaction mixture was stirred at room temperature for 16 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM and quenched with saturated NaHCO3solution. The organic layer was separated, and aqueous layer was extracted with DCM (30 ml×2). Then organic layer was washed with brine solution and dried over anhydrous Na2SO4, and filtered, concentrated in vacuo. The crude was purified by Flash chromatography (Combi-Flash Column, 24 g redisep cartridge) using 100% DCM to 2% MeOH in DCM to get desired product as thick orange syrup (0.5 g, 44% yield).

[0219] To a stirred solution of 2-(1H-indol-3-yl)-N-(3-methoxyb enzyl)-N-methylethan-l- amine (0.5 g, 1.0 equiv) in 25 ml of DCM was added BBr3(0.5 ml, 3.0 equiv) dropwise at 0° C. . The reaction mixture was stirred at room temperature for 16 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated NaHCO3solution and aqueous layer was extracted with DCM (50 m1x2). Then organic layer was washed with brine solution and dried over anhydrous Na2SO4, and filtered, concentrated in vacuo. The crude was purified by Flash chromatography (Combi-Flash Column, 24 g redisep cartridge) using 100% DCM to 5% MeOH in DCM and washed with n-heptane to get desired product as off white solid (0.1 g, 25% yield).

[0220] MS (ESI) m / e [M+H]+: 281; HPLC purity: 97.5% (RT=7.9 min),1H NMR (400 MHz, DMSO-d6) δ=10.76 (s, 1H, indoleNH), 9.28 (s, 1H, aromOH), 7.44 (d, J=7.9 Hz, 1H, aromCH), 7.32 (d, J=7.9 Hz, 1H, aromCH), 7.28-6.98 (m, 3H, aromCH), 6.97-6.90 (m, 1H, aromCH), 6.88-6.71 (m, 2H, aromCH), 6.65 (d, J=6.1 Hz, 1H, aromCH), 3.52 (s, 2H, CH2), 2.90 (s, 2H, CH2), 2.67 (s, 2H, CH2), 2.27 (s, 3H, NMe).EXAMPLE 39 — Synthesis of N-(3-bromobenzyl)-2-(1H-indol-3-yl)-N-methylethan-1-amine

[0221] The following reaction scheme was used:

[0222] To a stirred solution of 2-(1H-indol-3-yl)ethan-l-amine (5 g, 1.0 equiv) in 50 ml of DCM, were added Et3N (13 ml, 3.0 equiv) and methyl chloroformate (2.9 ml, 1.2 equiv) at 0° C. The reaction mixture was stirred at RT for 16 h. The progress of reaction was monitored by TLC. After completion, the reaction was quenched with ice-water and aqueous layer was extracted with DCM (50 m1x2). The organic layer was washed with brine solution, dried over anhydrous Na2SO4, and filtered, concentrated in vacuo. The crude was purified by Flash chromatography (Combi-Flash Column, 24 g redisep cartridge) using 30% of ethyl acetate in n-heptane to get desired product as off white solid (4.8 g,70% yield).

[0223] To a stirred solution ofN-(2-(1H-indol-3-yl)ethyl)propionamide (4.8 g, 1.0 equiv) in 100 ml of THF was added 2M solution of LAH (3.9 ml, 3.0 equiv) dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h. The progress of reaction wasmonitored by TLC. After completion, the reaction mixture was quenched with a saturated Na2SO4 solution (10 mL), white precipitate was filtered through pad of Celite and washed with EtOAc (100 mL). Filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to afford 2-(1H-indol-3-yl)-N-methylethan-l-amine (3.2 g, 82% yield) as thick orange syrup.

[0224] To a stirred solution of 2-(1H-indol-3-yl)-N-methylethan-1-amine (1.0 g, 1.0 equiv) in 25 ml of DCE were added 3-bromobenzaldehyde (1.3 g, 1.2 equiv) and NaBH(OAc)3(1.8 g, 1.5 equiv) at RT. The Reaction mixture was stirred at room temperature for 16 h. The progress of reaction was monitored by TLC. After completion, the RM was diluted with DCM and quenched with saturated NaHCO3 solution. The organic layer was separated and washed with water followed by brine solution and dried over anhydrous Na2SO4, and filtered, concentrated in vacuo. The crude was purified by Flash chromatography (Combi-Flash Column, 24 g redisep cartridge) using 10-40% of ethyl acetate in n-heptane to get desired product as thick orange syrup (0.6 g, 30% yield).

[0225] MS (ESI) m / e [M+H]+: 343; HPLC purity: 98.6% (RT=5.4 min),11HNMR(400 MHZ DMSO-d6) δ=10.75 (s, 1H, indoleNH), 7.51 (s, 1H, aromCH), 7.43 (d, J=7.9 Hz, 2H, aromCH), 7.37-7.17 (m, 3H, aromCH), 7.12 (s, 1H, aromCH), 7.04 (t, J=7.5 Hz, 1H, aromCH), 6.94 (t, J =8.0 Hz 1H, aromCH), 3.56 (s, 2H, CH2), 2.88 (t, J=8.0 Hz, 2H, CH2), 2.63 (t, J=8.0 Hz, 2H, CH2), 2.24 (s, 3H, NMe).EXAMPLE 40 — Synthesis ofN-(2-(1H-indol-3-yl)ethyl)-N-(3-hydroxymethylbenzyl)methan- 1 -amine

[0226] To a stirred solution of 2-(1H-indol-3-yl)-N-methylethan-1-amine (0.9 g, 1.2 equiv) and isophthalic acid monomethyl ester (1.0 equiv) and triethylamine (4 equiv) in 25 ml of ACN at 0 C was added polyphosphonic anhydride (2 equiv) and the reaction was allowed to come to RT gradually over 16h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), extracted with EtOAc (2x50 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to get the desired product as an off-white solid (1.3 g, 76%). In a second step, the solid was reduced with LiAlH4 (3 equiv) in 30 ml THF at reflux for 16 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with asaturated Na2SO4solution (10 mL), white precipitate was filtered through pad of Celite and washed with EtOAc (100 mL). Filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to afford 2-(1H-indol-3-yl)-N-(3-hydroxymethylbenzyl)-N-methylethan-l- amine as a semi-solid (0.35g, 30%).

[0227] MS (ESI) m / e [MH+] 295. HPLC purity: 98% (RT=7.56 min),1H NMR (400 MHz, DMSO-d6) δ=2.2 (br, 2H), 2.4 (s, 3H), 2.85 (t, 2H), 3.08 (t, 2H), 3.7 (s, 2H), 4.7 (s, 2H), 7.05 (s, 1H), 7.13 (t, 1H), 7.22 (t, 1H), 7.29-7.4 (overlapping multiplets, 5H), 7.56 (d, 1H), 8.1 (br s, 1H).EXAMPLE 41 — Synthesis of 2-(l H-indol-3-yl)-N-(3-ethynylbenzyl)-N-methylethan- 1 -amine

[0228] To an ethanolic solution containing 2-(1H-indol-3-yl)-N-methylethan-l-amine (0.5 g, 1.2 equiv, as prepared in Example 41) and 3-ethynyl-benzaldehyde (1.1 equiv), which had been stirred at room temperature overnight was added NaBH4(2.5 equiv). The mixture was stirred an additional 2 h before workup. The reaction mixture was quenched with ice-water and extracted with ethyl acetate (50 m1x2). The organic layer was washed with brine solution and dried over anhydrous Na2SO4, and filtered, concentrated in vacuo. The crude was purified by Flash chromatography (Combi-Flash Column, 24 g redisep cartridge) using 100% DCM to 2% MeOH in DCM to get desired product as thick orange syrup (0.3 g, 22% yield). MS (ESI) m / e [MH+] 289.2. Purity HPLC 99.56%. 'NMR (400 MHz, DMSO-d6): structure conforms.

[0229] Example 42 — Synthesis of 2-(1H-indol-3-yl)-N-(2,3-methylenedioxybenzyl)-N- methylethan- 1 -amine

[0230] To a stirred solution of 2-(1H-indol-3-yl)-N-methylethan-l-amine (0.5 g, 1.2 equiv, prepared in Example 23) in 25 ml of acetonitrile was added 2, 3-methylenedioxy-benzoic acid (1.0 equiv), polyphosphonic anhydride (1.5 equiv) and triethylamine (3 equiv) at 0° C. and the reaction was allowed of come to room temperature with stirring overnight. The progress of reaction was monitored by TLC. After completion, the RM was diluted with DCM and quenched with saturated NaHCO3solution. The organic layer was separated and washed with water followed by brine solution and dried over anhydrous Na2SO4, and filtered, concentrated in vacuo. The crude was purified by Flash chromatography (Combi-Flash Column, 24 g redisep cartridge) using 10-40% of ethyl acetate in n-heptane to get desired product (0.7 g, 69% yield). The resultant semisolid was then reduced using 2 equiv of LiAlH4in THF at 0 Cover 16 h to yield the desired product which was again purified by flash chromatography (0.3g, 42%). Purity (HPLC): 98.7%. MS (ESI) m / e MH+309. 1H-NMR (dmso-d6): 2.25 (3H, Me), 2.65 (m, 2H), 2.87 (m, 2H), 3.55 (s, 2H), 6.0 (s, 2H), 6.8 (m-m, 3H), 6.95 (t, (1H), 7.05 (t, 1H), 7.13 (m, 1H), 7.3 (d, 1H), 7.45 (d, 1H), 10.75 (br s, 1H).EXAMPLE 43 — Synthesis of 2-(5 -methoxy- 1H-indol-3-yl)-N-(3-methoxyb enzyl)-N- methylethan- 1 -amine

[0231] The following reaction scheme was used:

[0232] To a stirred solution of 2-(5-methoxy-1H-indol-3-yl)acetic acid (0.5 g, 1.0 equiv) in ACN were added l-(3-methoxyphenyl)-N-methylmethanamine (0.4 g, 1.2 equiv) followed by T3P (1.6 g, 2.0 equiv) and Et3N (0.8 g, 3.3 equiv) at room temperature. The reaction mixture was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC.After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), extracted with EtOAc (2x50 mL). Separated organic layer was dried over anhydrous Na2SO4,filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography (Combi-Flash Column, 24 g redisep cartridge) using 5% of DCM:MeOH to get the product as brown colour solid (0.62 g, 75% yield).

[0233] To a stirred solution of 2-(5-methoxy-1H-indol-3-yl)-N-(3-methoxybenzyl)-N- methylacetamide (0.62 g, 1.0 equiv) in THF was added a solution of 2M LAH (0.14 g, 2.0 equiv) dropwise. The reaction mixture was stirred at 0° C. for 4 h under N2 atmosphere.Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a saturated Na2SO4solution (10 mL), white precipitate was filtered through pad of Celite and washed with EtOAc (100 mL). Filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to afford 2-(5 -methoxy-1H-indol-3 -yl)-N-(3- methoxybenzyl)-N-methylethan-1-amine (FT230, 0.35 g, 60%) as an off white solid.

[0234] MS (ESI) m / e [M+H]+: 325; HPLC purity: 96.44% (RT=4.0 min),1H NMR (400 MHz, DMSO-d6) δ=10.59 (s, 1H, indoleNH), 7.27-7.12 (m, 2H, aromCH), 7.08 (d, J=2.0 Hz, 1H, aromCH), 6.88 (d, J=5.4 Hz, 3H, aromCH), 6.80 (d, J=7.8 Hz , 1H, aromCH), 6.68 (dd, J =2.4, 8.8 Hz, 1H, aromCH), 3.70 (d, J=2.0 Hz, 6H, OMe), 3.53 (s, 2H, CH2), 2.84 (t, J=4.0 Hz 2H, CH2), 2.62 (s, 2H,CH2), 2.26 (s, 3H, NMe).EXAMPLE 44 — Synthesis of 2-( 1 H-indol-3-yl)-N-(2-methoxybenzyl)-N-methylethan- 1 - amine

[0235] The following reaction scheme was used:

[0236] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (1 g, 1.0 equiv) in ACN solvent were added l-(2-methoxyphenyl)-N-methylmethanamine (1.6 g, 2.0 equiv) followed by T3P (3.6 g, 2.0 equiv) and Et3N (1.7 g, 3.0 equiv) at room temperature. The reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), extracted with EtOAc (2x50 mL). Separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to get the desired product (1.2 g, 68% yield).

[0237] To a stirred solution of 2-(1H-indol-3-yl)-N-(2-methoxybenzyl)-N-methylacetamide(1.2 g, 1.0 equiv) in THF was added a solution of 2M LAH (0.3 g, 2.0 equiv) solutiondropwise. The reaction mixture was stirred at 0° C. for 4 h under N2 atmosphere. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a saturated Na2SO4 solution (10 mL), white precipitate was fdtered through pad of Celite and washed with EtOAc (100 mL). Filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to afford 2-(1H-indol-3-yl)-N-(2-methoxybenzyl)-N- methylethan-1 -amine (FT231, 0.31 g, 27%) as an off white solid.

[0238] MS (ESI) m / e [M+H]+: 295; HPLC purity: 98% (RT=5.9 min),1H NMR (400 MHz, DMSO-d6) δ=10.74 (s, 1H, indoleNH), 7.44 (d, J=8.0 Hz, 1H, aromCH), 7.36-7.29 (m, 2H, aromCH), 7.25-7.17 (m, 1H, aromCH), 7.12 (d, J =2.3 Hz, 1H, aromCH), 7.08-7.01 (m, 1H, aromCH), 6.99-6.86 (m, 3H, aromCH), 3.76 (s, 3H, OMe), 3.55 (s, 2H, CH2), 2.88 (s, J=4.0 Hz 2H, CH2), 2.65 (s, J=8.0 Hz, 2H, CH2), 2.26 (s, 3H, NMe).EXAMPLE 45 — Synthesis ofN-(2-(1H-indol-3-yl)ethyl)-N-(3-methoxybenzyl)prop-2-en-l- amine

[0239] The following reaction scheme was used:

[0240] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (0.6 g, 1.0 equiv) in 10 ml of ACN solvent were added N-(3-methoxybenzyl)prop-2-en-1-amine (0.7 g, 1.2 equiv) followed by T3P (2.2 g, 2.0 equiv) and Et3N (1.0 g, 3.0 equiv) at RT. The reaction mixture was stirred at RT for 16 h under N2 atmosphere. After completion, the reaction mixture was concentrated under reduced pressure and diluted with DCM and extracted with DCM and water (40 ml).The organic layer was dried over anhydrous Na2SO4and concentrated in vacuo. The crude was purified by combi flash chromatography to get the desired product as off white solid (1.1 g, 96% yield).

[0241] To a stirred solution of LAH (0.5 g, 4.0 equiv) in 10 ml of THF was added AlCl3(1.9 g, 4.0 equiv) portionwise. Then the reaction mixture was continuously stirred at 0° C. to RT for 1 hr. After 1 hr, N-allyl-2-(1H-indol-3-yl)-N-(3-methoxybenzyl)acetamide (1.1 g, 1.0 equiv) in THF was added dropwise and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was quenched with a saturated Na2SO4 solution (10 mL), white precipitate was filtered through pad of Celite and washed with EtOAc (100 mL). Filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to afford N-(2-(1H- indol-3-yl)ethyl)-N-(3-methoxybenzyl)prop-2-en-1-amine (FT233, 0.6 g, 59%) as a brown colour solid.

[0242] MS (ESI) rn / e [M+H]+: 321; HPLC purity: 99% (RT=5.8 min),1H NMR (400 MHz, DMSO-d6) δ=10.73 (s, 1H, indoleNH), 7.38 (d, J=7.75 Hz, 1H, aromCH), 7.3 (d, J=8.0 Hz, 1H, aromCH), 7.22 (t, J=7.88 Hz, 1H, aromCH), 7.11-6.98 (m, 2H, aromCH), 6.91 (s, 3H, aromCH), 6.8 (d, J =7.5 Hz, 1H, aromCH), 6.00-5.80 (m, 1H, alkeneCH), 5.24 (d, J=17.3 Hz, 1H, alkeneCH), 5.15 (d, J=10.26 Hz, 1H, alkeneCH), 3.71 (s, 3H, OMe), 3.63 (s, 2H, CH2), 3.17 (d, J=5.75 Hz, 2H, CH2), 2.86 (t, J=8.0 Hz, 2H, CH2), 2.69 (t, J=8.0 Hz, 2H, CH2).Comparative Examples 46-48

[0243] Using a methodology similar to that described above for the compounds of Examples 17 and 248, the following compounds were synthesized and tested:

[0244] The results are reported in Table 5.

[0245] Table 5 reports, in nM, the binding associated with various examples herein.TABLE 5:TABLE 5:

[0246] Thus, serotonin-2A agonist has been tested and is proposed to treat multiple mood disorders by a new mechanism of action and thus could rescue patients not treatable with current medical options. However, agonists of serotonin-2A are often agonists of the nearly homologous serotonin-2B receptor. As mentioned above, agonism of the serotonin-2B receptor can result in valve hardening by a fibrotic mechanism, and was exemplified by the compound fenfluramine which was withdrawn from the pharmaceutical weight-loss market due to this adverse reaction in overweight patients. The present disclosure provides for molecules, methods and uses of new molecules based on benzyl-functionalized tryptamine that demonstrate strong serotonin-2A receptor agonism, and are atypically serotonin-2B antagonists and thus do not present cardiotoxic adverse reaction potential. The present disclosure could find use in novel mood indications, neural restoration / repair (neuroplasticity) and potential as more frequently used or chronic daily medicines for patients. Further the disclosure may allow patients with pre-existing cardiovascular fragilities to use these molecules after appropriate demonstrations of efficacy and safety to treat these disorders of the brain and who would otherwise be excluded from the use of classical serotonin agonists that more traditionally activate serotonin-2B.EXAMPLE 49 - In Vivo Study of Sustained Release Tryptamine Prodrugs

[0247] 72 male wistar rats between the age of 8-9 weeks old were used for an in vivo study. The rats were weighed and randomized into 6 groups of 12. The mice were initially quarantined for 7 days, and then acclimatized for two days prior to conducting the experiments

[0248] The experimental design for the 6 groups of 12 rats each are set forth in Table 6. The compounds administered were in a 10% DMSO / 90% water solution (which acted on its own as a vehicle control). N,N-diisopropyltryptamine-4-glutarate was the active, and N,N- dimethyltryptamine-4-glutarate (psilocin-4-glutarate) was used as a positive control.

[0249] Both N,N-diisopropyltryptamine-4-glutarate and psilocin-4-glutarate were formulated as follows. For the single subcutaneous dose group, and taking into account purity and salt correction factors, each compound was dissolved in a 10% DMSO / 90%water for injection to get a final concentration of 0.2 mg / mL at a dose volume of 5 mL / kg. For the Alzet osmotic minipump, the solution concentration was 1.19 mg / mL for each compound, and the solution was then filled in the minipumps with a volume of 220 μL and implanted subcutaneously for the 24 hours.

[0250] On Day 1, all the animals were weighed and randomized in to 6 different groups. All the test compounds were formulated and administered to respective animals of each group as per the body weight. Animals of group G1, vehicle control group, were administered with vehicle, single bolus. Animals of group G2, vehicle control group, were administered with vehicle, continuous infusion over 24h using Alzet mini osmotic pump (model 2001D, Durect corporation). Animals of group G3 were administered with the single dose of N,N- diisopropyltryptamine-4-glutarate at 1 mg / kg, single bolus. Animals of group G4 were administered with the single dose of psilocin-4-glutarate at 1 mg / kg, single bolus. Animals of group G5 were administered with the single dose of N,N-diisopropyltryptamine-4-glutarate at 1 mg / kg, continuous infusion over 24h using Alzet mini osmotic pump. Animals of group G6 were administered with the single dose of psilocin-4-glutarate at 1 mg / kg, continuous infusion using an Alzet mini osmotic pump. All the animals were subjected to forced swim test, postdose administration as per the time points, mentioned in Table 6. The experimental design is summarized in Table 7.Table 6. Scheduled time points for Forced swim test for different groupsTable 7: Experimental Designs.c. = subcutaneous.

[0251] A pre-swim session was conducted on days 6 and 27. Each rat was placed in the water filled cylinder container for 15 min for initial exposure. On the day of experiment (Day 7 and Day 28), all animals were placed individually in a glass cylinder (20 cm in diameter X 45 cm in height) containing 35 cm of water, with water temperature being maintained at 25±1 °C for the forced swim test. A camera located directly in front of the cylinder, recorded the session for 5 minutes. Immobility time (Sec.), swimming time (Sec.) and climbing time (Sec.) was measured by a blinded observer from recorded videos using a stopwatch for the entire 5 min session.

[0252] The experiment used the forced swim test (FST) (sometimes called the Porsolt swim test) to evaluate and compare the effects of a single injection (bolus) versus a continuous infusion (i.e., sustained release) of the compounds on the animals’ stress response. The FST is a common test used to evaluate the efficacy of anti-depressant drugs and the effects of various behavioral and neurobiological manipulations in basic and preclinical research. It is based on the assumption that when placing an animal (such as a rat) in a container filled with water, the animal will first make efforts to escape but eventually will exhibit immobility that may be considered to reflect a measure of behavioral despair. Time spent climbing or swimming is not included in the immobility measurement. This test has been extensively used because it involves the exposure of the animals to stress, which was shown to have a role in the tendency for major depression. Additionally, the FST has been shown to share some of the factors thatare influenced or altered by depression in humans, including changes in food consumption, sleep abnormalities and drug-withdrawal-induced anhedonia.

[0253] The FST tests were performed at Day 7 and Day 28. On Day 7, the differences between the bolus and infusion doses are set forth in FIG. 1. Data is demonstrated as Mean ± S.E.M(n=l 1-12), One way ANOVA followed by Bonferroni’s Multiple Comparison Test. Those total immobility times show that the bolus yields slightly higher immobility times than the sustained release. However, by Day 28 (FIG. 2), the opposite is the case and the immobility times are substantially less for the N,N-diisopropyltryptamine-4-glutarate arm than the bolus arm. Data is demonstrated as Mean ± S.E.M (n=12), One way ANOVA followed by Bonferroni’s Multiple Comparison Test. **p<0.01 vs. vehicle control; s.c. single dose ##p<0.01 vs vehicle control; s.c. continuous infusion. The bolus and infusion arms for psilocin-4-glutarate arm were not substantially different at either Day 7 or Day 28. The Day 28 results are presented herein as those are the data most reflective of the comparison between bolus dosing and sustained release dosing. In earlier studies with different batches of rats, the N,N-diisopropyltryptamine-4- glutarate arms showed lower immobility values than those reported here, however, in those studies there was no comparator with a sustained infusion. However, one can reduce the inherent variability in FST by using the same set of rats when doing experiments as was done here with the bolus versus infusion experiments. Accordingly, in the same population, these data show that the rats at Day 28 exhibited less despair with an infusion dose of N,N- diisopropyltryptamine-4-glutarate over 24 hours than with a single bolus dose. Animals were observed for any clinical signs to treatment throughout the study. Cage-side observations was made to detect any changes and general activity of the animals. After dose administration, all the animals were observed carefully for treatment related clinical signs, including morbidity and mortality (signs of acute serotonin syndrome are expected reactions of systemic exposure, which typically resolve with elimination of the drug). These signs included following observations as set forth in Table 8. Body weight of each animal was also recorded at the time of randomization and once every 3 days during the study period.Table 8: Clinical Signs potentially observed after administration of the compounds.

[0254] These signs were recorded and the observed intensity and duration were reported and considered exaggerated pharmacology. Briefly, no clinical signs were observed in rats receiving the vehicle as a single dose or continuous infusion. Head twitch and body twitches were observed in rats receiving a single dose of N,N-diisopropyltryptamine-4-glutarate after the first two hours (Table 9 and Tables 12-14), but none were observed in rats receiving the continuous infusion of N,N-diisopropyltryptamine-4-glutarate. Similarly, the rats receiving a single dose of psilocin-4-glutarate showed head twitch, hind limb extension, and body twitches within the first hour of administration, but none were observed in rats receiving the continuous infusion of psilocin-4-glutarate.ResultsTable 9: Effect of Test Compounds on Clinical SignsThe effect of the N,N-diisopropyltryptamine-4-glutarate & psilocin-4-glutarate on body weight is shown in Table 10, Fig. 3, and summarized below.• G5, N,N-diisopropyltryptamine-4-glutarate, 1mg / kg, s.c. continuous infusion over 24h group demonstrated significant increase in body weight vs. G2, Vehicle Control, s.c. continuous infusion over 24h at day 22 and day 28.• G6, psilocin-4-glutarate, 1mg / kg, s.c. continuous infusion over 24h group demonstrated significant increase in body weight vs. G2, Vehicle Control, s.c. continuous infusion over 24h at day 22 and day 28Forced Swim TestThe effect of the N,N-diisopropyltryptamine-4-glutarate and psilocin-4-glutarate on immobility time, swimming time and climbing time in forced swim test at day 7 and 28 is shown in Table 11 and Figure 2.Immobility Time - FIGs. 1 and 2• G4, psilocin-4-glutarate (1 mg / kg, single dose, s.c.) group demonstrated significant reduction in immobility time (sec.) vs. G1, vehicle control; 5ml / kg; single s.c. dose group at day 28.• G5, N,N-diisopropyltryptamine-4-glutarate, 1 mg / kg, s.c. continuous infusion over 24h group demonstrated significant reduction in immobility time (sec.) vs. G2, Vehicle Control, s.c. continuous infusion over 24h at day 28.• G6, psilocin-4-glutarate, 1 mg / kg, s.c. continuous infusion over 24h group demonstrated significant reduction in immobility time (sec.) vs. G2, Vehicle Control, s.c. continuous infusion over 24h at day 28.• No significant difference in immobility time was observed across the other groups.Swimming Time -FIG. 4• G5, N,N-diisopropyltryptamine-4-glutarate, 1 mg / kg, s.c. continuous infusion over 24h group demonstrated significant increase in swimming time (sec.) vs. G2, Vehicle Control, s.c. continuous infusion over 24h at day 28.• G6, psilocin-4-glutarate, 1 mg / kg, s.c. continuous infusion over 24h group demonstrated significant increase in swimming time (sec.) vs. G2, Vehicle Control, s.c. continuous infusion over 24h at day 28.• No significant difference in swimming time was observed across the other groups.Climbing Time -FIG. 5• G4, psilocin-4-glutarate (1 mg / kg, single dose, s.c.) group demonstrated significant increase in climbing time (sec.) vs. G1, vehicle control; 5ml / kg; single s.c. dose group at day 28.• No significant difference in climbing time was observed across the other groups.Data is shown in FIGs. 1, 2, 4, and 5 as Mean ± S.E.M (n=ll-12), Significant difference as compared to G1, Vehicle Control, single dose, s.c. Significant difference as compared to G2 vehicle control continuous infusion over 24h group. One way ANOVA followed by Bonferroni’s Multiple Comparison test. * / #P < 0.05, ** / ##P < 0.01, < 0.001, **** / ####p< 0.0001.EXAMPLE 50 - Treatment of a Human Patient Having Depression with a time-release composition

[0255] A human patient is identified as having depression. A pharmaceutical composition, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof, in the form of a time-release composition containing a therapeutically effective amount of one or more tryptamine prodrugs is administered to the patient. The patient is monitored until symptoms are alleviated or ameliorated, and the pharmaceutical composition may be administered one or more additional times if it is determined that such administration is necessary or helpful for treatment.EXAMPLE 51

[0256] Treatment of a Human Patient Diagnosed with Depression with a sustained-release composition.

[0257] A human patient diagnosed with cancer is identified as having depression. A pharmaceutical composition, or any pharmaceutically acceptable salt, solvate, or zwitterion thereof, in the form of a sustained release composition containing a therapeutically effective amount of one or more tryptamine prodrugs is administered to the patient. The patient is monitored until symptoms are alleviated or ameliorated, and the pharmaceutical composition may be administered one or more additional times if it is determined that such administration is necessary or helpful for treatment.EQUIVALENTS AND INCORPORATION BY REFERENCE

[0258] While aspects of the present disclosure have been particularly shown and described with reference to certain embodiments and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the present disclosure.

[0259] Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the disclosure and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the disclosure as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure.

[0260] In at least some of the previously described embodiments, one or more elements used in an embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims.

[0261] All references, issued patents, and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes. Particularly, US 11,292,765 B2, PCT / CA2021 / 050907, PCT / CA2022 / 051797, and PCT / CA2024 / 050007.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or managing a mental, a behavioral, or a neuropsychiatric condition, or the symptoms thereof, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a tryptamine-related compound in a pharmaceutical composition; wherein the pharmaceutical composition is configured for time release.

2. The method of claim 1, wherein tryptamine-related compound is a 5-HT2A agonist.

3. The method of claim 1 or 2, wherein the tryptamine-related compound is a hydroxyindole 5-HT2A agonist.

4. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is a compound of Formula (I):or a pharmaceutically acceptable salt, solvate, or zwitterion thereof, wherein:R1 , R2, and R6 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl;R4 is — X — CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with — OH or — CO2H; or an aromatic ring, optionally substituted with alkyl or CO2H; orwherein R9 is X — CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with — OH or — CO2H; or an aromatic ring, optionally substituted with alkyl or CO2H; and RIO is a linear or branched alkyl or arylalkyl, optionally substituted with — OH or — CO2H;R5 is hydrogen, linear or branched alkyl, arylalkyl, or O — R5', where R5' is hydrogen, linear or branched alkyl; andR7 and R8 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl, with the proviso that each of R7 and R8 is not hydrogen, or together form a non-aromatic N-containing heterocycle, optionally substituted with alkyl.

5. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is a compound of Formula (II):or a pharmaceutically acceptable salt, solvate, or zwitterion thereof, wherein: R1, R2, and R6 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl;R4 is — X — CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with — OH or — CO2H; or an aromatic ring, optionally substituted with alkyl or CO2H; orwherein R9 is X — CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with — OH or — CO2H; or an aromatic ring, optionally substituted with alkyl or CO2H; and RIO is a linear or branched alkyl or arylalkyl, optionally substituted with — OH or — CO2H;R5 is hydrogen, linear or branched alkyl, arylalkyl, or O — R5', where R5' is hydrogen, linear or branched alkyl; andR7 and R8 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl, with the proviso that each of R7 and R8 is not hydrogen, or together form a non-aromatic N -containing heterocycle, optionally substituted with alkyl.

6. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is a compound of Formula (III):or a pharmaceutically acceptable salt, solvate, or zwitterion thereof, wherein: R1, R2, and R6 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl;R4 is X — CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with — OH or — CO2H; or an aromatic ring, optionally substituted with alkyl or CO2H; orwherein R9 is X — CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with — OH or — CO2H; or an aromatic ring, optionally substituted with alkyl or CO2H; and RIO is a linear or branched alkyl or arylalkyl, optionally substituted with — OH or — CO2H;R5 is hydrogen, linear or branched alkyl, arylalkyl, or O — R5', where R5' is hydrogen, linear or branched alkyl; andR7 and R8 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl, with the proviso that each of R7 and R8 is not hydrogen, or together form a non-aromatic N-containing heterocycle, optionally substituted with alkyl.

7. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is a compound of Formula (IV):or a pharmaceutically acceptable salt, solvate, or zwitterion thereof, wherein: R1, R2, and R6 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl;R4 is — X — CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with — OH or — CO2H; or an aromatic ring, optionally substituted with alkyl or CO2H; orwherein R9 is X — CO2H, where X is a linear, cyclic or branched, saturated or unsaturated carbon chain, optionally substituted with — OH or — CO2H; or an aromatic ring, optionally substituted with alkyl or CO2H; and RIO is a linear or branched alkyl or arylalkyl, optionally substituted with — OH or — CO2H;R5 is hydrogen, linear or branched alkyl, arylalkyl, or O — R5', where R5' is hydrogen, linear or branched alkyl; andR7 and R8 are each independently selected from hydrogen, linear or branched alkyl, or arylalkyl, with the proviso that each of R7 and R8 is not hydrogen, or together form a non-aromatic N-containing heterocycle, optionally substituted with alkyl.

8. The method of any one of claims 1 to 7, wherein: R1, R2, and R6 are each independently selected from hydrogen or linear C1-5-alkyl;R4 is — X — CO2H, where X is a linear or branched C1-5carbon chain, optionally substituted with -OH or -CO2H;R5 is hydrogen, linear or branched C1-5-alkyl, arylalkyl, or O-R5', where R5' is hydrogen, linear or branched Ci-5-alkyl; and / orR7 and R8 are each independently selected from hydrogen or linear or branched C1-5- alkyl, with the proviso that each of R7 and R8 is not hydrogen.

9. The method of claim 8, wherein R7 and R8 are the same or different, and are linear or branched Ci-4-alkyl.

10. The method of claim 9, wherein R7 and R8 are each methyl, ethyl, or isopropyl.

11. The method of claim 8, wherein X is a linear C 1-3 chain, optionally substituted with OH or CO2H.

12. The method of claim 10, wherein X is a linear C3chain.

13. The method of claim 12, wherein R7 and R8 are both methyl, or R7 and R8 are both isopropyl, or one of R7 and R8 is methyl and the other of R7 and R8 is isopropyl.

14. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

15. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

16. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

17. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

18. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

19. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

20. The method of claim 19, wherein the tryptamine-related compound is the hydrochloride salt of the21. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

22. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

23. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

24. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

25. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is:or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

26. The method of any one of claims 1 to 3, wherein the tryptamine-related compound is a compound of Formula (V):or a pharmaceutically acceptable salt, solvate, or zwitterion thereof, wherein:R is hydrogen or methyl;R1is hydrogen or methoxy;R2is methyl, i-propyl, 2-propenyl, 2-butenyl (cis), 2-butenyl (trans), or 2-methyl-2- propenyl;R3is hydrogen or methoxy,R4is hydrogen, methoxy, ethyl, hydroxyl, bromo, hydroxyethyl, or 2 propynyl,R5is hydrogen or methoxy, R5being hydrogen if R2is 2-propenyl, andR6is hydrogen, or R3, R4, R5and R6may be selected such that an adjacent pair thereof join to form a ring having at least 5 members, with the other pair thereof being hydrogen, with the provisos that: (i) at least one of R4and R5must be hydrogen, (ii) if R2is methyl or 2-propenyl, at least one of R, R1, R3, R4, and R5is not hydrogen, and (iii) if R5is hydrogen, R2is not methyl.

27. The method of claim 26, wherein the one tryptamine-related compound has a 5-HT2A binding constant (Ki) of less than about 500 nM.

28. The method of claim 26, wherein the tryptamine-related compound has a 5-HT2A binding constant (Ki) of less than about 300 nM.

29. The method of claim 26, wherein the tryptamine-related compound has a 5-HT2A binding constant (Ki) in a range of from about 0.1 nM to about 100 nM.

30. The method of claim 26, wherein the tryptamine-related compound has a 5-HT2A binding constant (Ki) in a range of from about 0.1 nM to about 30 nM.

31. The method of claim 26, wherein the tryptamine-related compound has a 5-HT2A binding constant (Ki) in a range of from about 0.1 nM to about 5 nM.

32. The method of any one of claims 26 to 31 , wherein R1and R3each are methoxy; and R4and R5each are hydrogen.

33. The method of any one of claims 26 to 31 , whereinR1and R3each are methoxy;R2is i-propyl; andR4and R5each are hydrogen.

34. The method of any one of claims 26 to 31 , whereinR1and R3each are methoxy;R2is 2-propenyl; andR4and R5each are hydrogen.

35. The method of any one of claims 26 to 31 , wherein R1, R3, and R5each are hydrogen; and R4is methoxy.

36. The method of any one of claims 26 to 31 , whereinR1, R3, and R4each are hydrogen;R2is methyl;-andR5is methoxy.

37. The method of any one of claims 26 to 31 , wherein R1and R5each are hydrogen; andR3and R4each are methoxy.

38. The method of any one of claims 26 to 31 , wherein R1and R5each are hydrogen;R2is i-propyl; andR3and R4each are methoxy.

39. The method of any one of claims 26 to 31 , wherein R, R1, R3, and R5each are hydrogen;R2is 2-butenyl (cis); and R4is methoxy.

40. The method of any one of claims 26 to 31 , wherein R, R1, R3, and R5each are hydrogen;R2is 2-butenyl (trans); and R4is methoxy.

41. The method of any one of claims 26 to 31 , wherein R, R1, R3, and R5each are hydrogen;R2is 2-methyl-2-propenyl; and R4is methoxy.

42. The method of any one of claims 26 to 31 , wherein R, R1, R3, and R5each are hydrogen; andR4is ethyl.

43. The method of any one of claims 26 to 31 , whereinR, R1, R3, and R5each are hydrogen; and R4is hydroxyl.

44. The method of any one of claims 26 to 31 , whereinR, R1, R3, and R5each are hydrogen; and R4is bromine.

45. The method of any one of claims 26 to 31 , whereinR, R1, R3, and R5each are hydrogen; and R4is hydroxy ethyl.

46. The method of any one of claims 26 to 31 , whereinR, R1, R3, and R5each are hydrogen; and R4is 2-propynyl.

47. The method of any one of claims 26 to 31 , whereinR, R1, and R5each are hydrogen; andR3is methoxy, R4is hydroxyl, and R3and R4join to form a 1,3-dioxolane group.

48. The method of any one of claims 1 to 47, wherein the mental, the behavioral, or the neuropsychiatric condition is an attention-deficit condition or a cognitive condition.

49. The method of any one of claims 1 to 47, wherein the mental, the behavioral, or the neuropsychiatric condition is selected from the group consisting of addiction, anxiety, apathy, and depression.

50. The method of any one of claims 1 to 47, wherein the symptoms are physical symptoms, behavioral symptoms, emotional symptoms, mental symptoms, or a combination thereof.

51. The method of any one of claims 1 to 50, wherein the tryptamine-related compound is delivered for greater than or equal to four hours.

52. The method of any one of claims 1 to 50, wherein the tryptamine-related compound is delivered for greater than or equal to six hours.

53. The method of any one of claims 1 to 50, wherein the tryptamine-related compound is delivered for greater than or equal to eight hours.

54. The method of any one of claims 1 to 50, wherein the tryptamine-related compound is delivered for greater than or equal to twelve hours.

55. The method of any one of claims 1 to 50, wherein the tryptamine-related compound is delivered for greater than or equal to eighteen hours.

56. The method of any one of claims 1 to 50, wherein the tryptamine-related compound is delivered for greater than or equal to twenty-four hours.

57. The method of any one of claims 1-56, wherein the time-release pharmaceutical composition is configured for sustained release.

58. A time-release pharmaceutical composition comprising a tryptamine-related compound.

59. The time-release pharmaceutical composition of claim 58, wherein the tryptamine-related compound is selected from Formulae I, II, III, IV, V, VI, and VII or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

60. The time-release pharmaceutical composition of claim 59, wherein the tryptamine-related compound is N,N-diisopropyltryptamine-4-glutarate or a pharmaceutically acceptable salt, solvate, or zwitterion thereof.

61. The time-release composition of claim 60, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

62. The time-release pharmaceutical composition of any one of claims 58 to 61 configured for sustained release.

63. The method of any one of claims 1-57, wherein the mental, behavioral, or neuropsychiatric condition is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression, drug-resistant depression, treatment-resistant depression alcoholism, tobacco addiction, cocaine addiction, opioid dependence, inflammation, cluster headache, gambling disorder, an eating disorder, chronic pain, chronic fatigue, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

64. The method of claim 63, wherein the method further comprises administering an antidepressant drug to the subject.

65. The method of claim 63, wherein the subject is concomitantly receiving an antidepressant drug.

66. The method of claim 64 or 65, wherein the method further comprises administering psychotherapy to the subject.

Images