Novel benzyltryptamine compounds

Abstract

Disclosed is a compound of formula (I): and any pharma- ceutically acceptable salt or zwitterion thereof; wherein: R is hydrogen, methyl, or ethyl; R 1 is hydrogen or C1-C2 alkoxy; R 2 is methyl or a C2-C4 group which may be saturated or unsaturated, branched or straight chain; and R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl, halogen, methyl optionally substituted with hydroxy, methoxy, ethoxy, and saturated or unsaturated C2-C3 optionally substituted with hydroxyl, with the proviso that: (i) R 4 , R 5 , R 6 and R 7 must be hydrogen; and (ii) R 3 , R 4 , R 5 and R 6 may be selected such that the adjacent pairs together form a ring having at least 5 members. The compounds of formula (I) are believed to be useful in treating a disease or disorder in a subject that can be alleviated by a 5HT2A agonist (e.g., a CNS disorder and one or more symptoms of any one of depression, alcoholism, tobacco addiction, cocaine addiction, inflammation, cluster headache, and PTSD in a subject). [Formula 1] TIFF2024539368000034.tif4066

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of Provisional Patent Application No. 63 / 273,720 (filed October 29, 2021) and Provisional Patent Application No. 63 / 334,443 (filed April 25, 2022), the contents of each of which are incorporated herein by reference.

[0002] 2. Background of the Invention FIELD OF THEINVENTION In one of its aspects, the present disclosure relates to novel benzyl-tryptamine compounds, preferably novel N-methoxybenzyl-tryptamine compounds.In another of its aspects, the present disclosure relates to a method for producing benzyl-tryptamine compounds, preferably N-methoxybenzyl-tryptamine compounds.In yet another of its aspects, the present disclosure relates to novel pharmaceutical compositions.In yet another of its aspects, the present disclosure relates to the treatment of CNS disorders. [Background technology]

[0003] Description of the Prior Art Psilocybin is a naturally occurring hallucinogenic prodrug compound produced by more than 200 species of mushrooms collectively known as psilocybin mushrooms. As a prodrug, psilocybin is rapidly metabolized by the body to produce the bioactive compound psilocin, which has psychoactive effects similar to those produced by lysergic acid diethylamide (LSD), mescaline, and N,N-dimethyltryptamine (DMT). These effects include: especially Symptoms may include euphoria, visual and psychological hallucinations, altered perception, a distorted sense of time, and supernatural experiences, and may also include possible adverse reactions such as nausea and panic attacks.

[0004] Although psilocybin and its therapeutic potential, along with that of other hallucinogenic drugs such as LSD in psychiatry, was recognized over 50 years ago and studied in Sandoz by Hofmann and coworkers (e.g., U.S. Patent Nos. 5,393,633 and 5,431,641), subsequent investigations into the recreational use of psilocybin and related hallucinogens (e.g., LSD) were curtailed in the early 1970s. Since then, psilocybin has remained classified as a scheduled drug of abuse in most countries by the drug laws of many countries.

[0005] However, in recent years, clinical investigations have led to increased recognition of the potential of hallucinogens and psilocybin as breakthrough therapies, particularly for treating CNS disorders that represent an unmet medical need. These disorders that may be addressed include both difficult-to-treat mental health disorders associated with significant morbidity, such as treatment-resistant depression (TRD) (Non-Patent Document 1), as well as neurological disorders such as cluster headaches, which also have significant associated morbidity.

[0006] As a phosphate phenolic prodrug, psilocybin is rapidly metabolized when ingested to the bioactive component psilocin, which then acts on serotonin receptors in the brain. [ka]

[0007] 5-hydroxytryptamine receptors (5-HT) receptors, or serotonin receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in both the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. 5-HT receptors are activated by their natural ligand, the neurotransmitter 5-hydroxytryptamine, more commonly known as serotonin.

[0008] Other prodrug linkages are taught in the literature, such as in the literature (2) and (3).

[0009] A small clinical trial involving cancer patients treated with psilocybin as a novel antidepressant found that high-dose psilocybin produced significant reductions in clinician-rated and self-rated measures of depressed mood and anxiety, as well as reduced fear of death, along with increases in quality of life, meaning in life, and optimism. At 6-month follow-up, these changes were sustained, with approximately 80% of participants continuing to show clinically significant reductions in depressed mood and anxiety.

[0010] In a proof-of-concept study of psilocybin for use in the treatment of alcohol dependence, which involved 10 patients diagnosed with alcohol dependence according to DSM-IV, a significant reduction in alcohol use was observed among the patients following psilocybin administration (Non-Patent Document 4).

[0011] In a study on the treatment of tobacco addiction with psilocybin, researchers found that 80 percent of participants demonstrated biologically-proven 7-day abstinence rates at 6-month follow-up. A 12-month follow-up showed that 67% of participants were biologically-proven to have abstinence. A 2.5-year follow-up after the subject cessation date showed that 75% had abstinence (Non-Patent Document 5).

[0012] Pharmacologically, the bioactive component psilocin has the following properties as summarized in Table 1: In vitro Receptor binding and functional assays have demonstrated that it acts at multiple serotonin receptor subtypes, consistent with its structural similarity to serotonin (Non-Patent Document 6).

[0013] [Table 1]

[0014] Psilocin (unlike LSD) shows no significant effects on dopamine receptors and appears to act only on the noradrenergic system at very high doses. A variety of pharmacological effects, with particular relevance for therapeutic utility and limitations, can be explained by psilocin's activation of 5-HT2A, 5-HT2B, and 5-HT2C receptors specifically as a functional agonist.

[0015] Receptor binding assays are used to characterize the interaction between receptor molecules and any potential ligands. Such assays can also determine the intrinsic affinity of the ligand to the receptor, the binding / dissociation rates, and the density of the receptor in tissues or cells. Receptor binding assays are typically cell-free methods suitable for screening many GPCRs (5HT receptors are G-Protein Coupled Receptors) that do not involve downstream signaling from the receptor. This type of assay cannot distinguish whether a candidate compound is an agonist, antagonist, or inverse agonist, but only whether it binds to the receptor or not. Analysis of the biological response after compound binding requires a functional assay. Upon ligand binding, GPCRs change their conformation and activate coupled G proteins, which in turn promote second messenger production via downstream effectors. Functional assays measure either G protein activation or G protein-mediated events, including second messenger production and reporter activity, and are therefore defined as G protein-dependent functional assays. (Non-Patent Document 7).

[0016] A known limitation to the therapeutic potential of psilocybin is the serious toxicological safety disadvantage, namely valvular heart disease, which can be expected from the strong agonist activity of psilocin at the 5-HT2B receptor. Thus, previous drugs with 5-HT2B receptor agonist activity have been found to have life-threatening side effects, such as valvular heart disease (Non-Patent Document 8; Non-Patent Document 9) and pulmonary hypertension (Non-Patent Document 10). Furthermore, individuals with underlying cardiovascular problems may be excluded from accessing the extremely effective potential of hallucinogenic compounds and drugs, since they are more susceptible to undesirable cardiovascular changes that may occur even with the infrequent use of hallucinogenic molecules that activate the 5-HT2B receptor.

[0017] The development of 5-HT2C receptor agonists acting in the brain has focused on treating obesity (Non-Patent Document 11; Non-Patent Document 12). Locaserin, a selective agonist of 5-HT2C versus 5-HT2B, has been shown to have no increased risk of valvular heart disease in patients and has been approved by the FDA for the treatment of obesity (Non-Patent Document 13).

[0018] Sard et al. described the synthesis and characterization of 5-HT2 receptor activity of psilocin analogs (Non-Patent Document 14; Patent Document 3; Patent Document 4). The goal of these studies was to identify 5-HT2C selective agonists, and psilocin analogs were identified that have potent 5-HT2C agonist functional activity that lacks 5-HT2B agonist functional activity.

[0019] Selected analogs with this profile were also tested in an obsessive-compulsive disorder (OCD) mouse behavior model, against psilocybin and psilocin as active reference compounds (Non-Patent Document 15). In this report, compound 1, a 1-methyl analog compound of psilocin, was found to have high functional agonist selectivity for activating phosphoinisitol hydrolysis at the human 5-HT2C receptor versus the 5-HT2A and 5-HT2B receptors. Compound 1 was reported to have a potency of 12 nM at the human 5-HT2C receptor, with a functional efficacy response of about 45% versus serotonin (set at 100%). At the human 5-HT2A receptor, compound A was reported to have a potency of 633 nM, with a functional efficacy response of about 30% versus serotonin. Compound 1 was reported to be inactive as an agonist at the 5-HT2B receptor, but a potent antagonist (38 nM). Finally, the efficacy demonstrated for compound 1 in mouse OCD model was attributed to 5-HT2C receptor agonist activity. Compound 1 was later found to be effective in mouse head twitch assay model for 5-HT2A activity, but significantly less effective than psilocin (Non-Patent Document 16). Compound 6, the 1-butyl analog of psilocin, was reported to be selective for 5-HT2C agonists, but was significantly less effective (about 600 nM), showing a dramatic loss of efficacy as the size of the group substitution at the indole 1-nitrogen increases.

[0020] [ka]

[0021] Although psilocybin has recognized therapeutic efficacy for treating a variety of CNS diseases and disorders, including treatment-resistant depression (TRD), alcohol dependence, smoking, and cluster headache, there is an unmet need for safer drugs and analogs of psilocin that maintain 5-HT2A receptor agonist activity but lack the cardiotoxic 5-HT2B agonist activity. [Prior art documents] [Patent documents]

[0022] [Patent Document 1] Hofmann, A., Troxler, F. U.S. Patent No. 3,075,992 [Patent Document 2] U.S. Patent No. 3,078,214 [Patent Document 3] Sard et al., Indole Compounds Useful as Serotonin Selective Agents; International Publication No. WO 2006 / 047302A1 [Patent Document 4] Sard et al., Indole Compounds and Methods of Use Thereof, U.S. Patent Application Publication No. US2009 / 033822 [Non-patent literature]

[0023] [Non-Patent Document 1] Daniel J, Haberman M. Clinical potential of psilocybin as a treatment for mental health conditions. Ment. Health Clin. 2017, 7(1), 24-8 [Non-Patent Document 2] Wiemer et al. Top Curr Chem. 2015; 360:115-160 [Non-Patent Document 3] Mahato et al. Adv Drug Deliv Rev. 2011 Jul 18; 63(8):659-670 [Non-Patent Document 4] Bogenschutz MP et al., Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J. Psychopharmacol. 2015, 29(3), 289-99 [Non-Patent Document 5] Johnson, MW, and Griffiths, RR (2017) Potential Therapeutic Effects of Psilocybin. Neurotherapeutics. 14、734

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[0024] Compounds with this selectivity profile for 5-HT2A versus 5-HT2B are described as having broad efficacy for treating various CNS diseases.However, psilocybin does not fit this specific profile, so its potential application as a drug treatment remains limited.It would be desirable to create a tryptamine 5HT2A agonist that has some of the same pharmacological properties as psilocin, but lacks its 5-HT2B agonist activity associated with undesirable side effects such as valvular heart disease. [Means for solving the problem]

[0025] Summary of the Invention It is an object of the present disclosure to obviate or mitigate at least one of the above-mentioned disadvantages of the prior art.

[0026] It is another object of the present disclosure to provide novel benzyl-tryptamine compounds, preferably novel N-methoxybenzyl-tryptamine compounds.

[0027] It is another object of the present disclosure to provide novel methods for producing the benzyl-tryptamine compounds of the present disclosure, preferably the N-methoxybenzyl-tryptamine compounds of the present disclosure.

[0028] Thus, in one of its aspects, the present disclosure provides a compound of formula (I): [ka] and any pharma- ceutically acceptable salt or zwitterion thereof; During the ceremony: R is hydrogen, methyl or ethyl; R 1 is hydrogen or C1-C2 alkoxy; R 2 is methyl or a C2-C4 group which may be saturated or unsaturated, branched or straight chain; and R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl, halogen, methyl optionally substituted with hydroxy, methoxy, ethoxy, and saturated or unsaturated C2-C3 optionally substituted with hydroxyl, with the proviso that: (i) R 4 , R 5 , R 6 and R 7 must be hydrogen; and (ii) R 3 , R 4 , R 5 and R6 may be selected such that adjacent pairs thereof together form a ring having at least 5 members.

[0029] In another of its aspects, the present disclosure provides a compound of formula (I): [ka] [In formula: R is hydrogen, methyl or ethyl; R 1 is hydrogen or C1-C2 alkoxy; R 2 is methyl or a C2-C4 group which may be saturated or unsaturated, branched or straight chain; and R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl, halogen, methyl optionally substituted with hydroxy, methoxy, ethoxy, and saturated or unsaturated C2-C3 optionally substituted with hydroxyl, with the proviso that: (i) R 4 , R 5 , R 6 and R 7 must be hydrogen; and (ii) R 3 , R 4 , R 5 and R 6 may be selected such that adjacent pairs thereof together form a ring having at least five members; and any pharma- ceutically acceptable salts or zwitterions thereof. The present invention provides a pharmaceutical composition comprising:

[0030] The present inventors have unexpectedly discovered that the compounds of formula (I) bind to but do not activate 5HT2B receptors, and they are shown to be antagonists associated with serotonin at 5-HT2B receptors, and therefore are potentially safe for valvopathies, and furthermore, the compounds maintain agonist activity at 5-HT2A receptors, and therefore are expected to have broad utility as therapeutic agents.Therefore, the compounds of formula (I) appear to have a selectivity profile for 5-HT2A versus 5-HT2B, and are believed to have broad potential for treating various CNS diseases while overcoming the above-mentioned shortcomings of psilocybin.The present inventors believe that the important advantage of the compounds of formula (I) is that they will not act as agonists of 5-HT2B.

[0031] In currently preferred embodiments, the compounds of formula (I) have a 5-HT2A binding constant (Ki) determined according to the Cheng-Prusoff equation of less than about 500 nM, or less than about 300 nM, or in the range of about 0.1 nM to about 100 nM, or in the range of about 0.1 nM to about 30 nM, or in the range of about 0.1 nM to about 5 nM. Additionally, the compounds of the present invention exhibit selectivity in activating 5-HT2A over 5-HT2B by 10-fold or more, 20-fold or more, 50-fold or more, or 100-fold or more. In some embodiments, these molecules are potent activators of 5-HT2A but do not activate 5-HT2B, and are antagonists or inactive, yet bind to the 5-HT2B receptor.

[0032] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the present invention will now be described with reference to the accompanying drawings, in which like reference numbers indicate like parts: [Brief description of the drawings]

[0033] [Figure 1] FIG. 1 shows the plasma profiles related to the results observed in Example 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As used herein, the term "about," when used to describe a stated value, means within 5% of the stated value.

[0035] As used herein, the term "carrier" refers to a diluent, adjuvant, or excipient with which the psilocybin analogues described herein may be administered. Such pharmaceutical carriers may be liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Carriers may be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants, and colorants may be used. Pharmaceutically acceptable carriers are sterile.

[0036] As used herein, the term "chemical entity" refers to a compound having the indicated structure, whether in its "free" form (e.g., "free compound" or "free base" or "free acid" form, as applicable), or in a salt form, particularly a pharma- ceutically acceptable salt form, and further whether in solid state form. In some embodiments, the solid state form is an amorphous (i.e., amorphous) form; in some embodiments, the solid state form is a crystalline form. In some embodiments, a crystalline form (e.g., a polymorph, pseudohydrate, or hydrate). Similarly, the term encompasses the compound whether provided in solid form or in any other form. Unless otherwise specified, all statements made herein with respect to a "compound" apply to the relevant chemical entity as defined.

[0037] As used herein, the terms "comprising," "having," "including," and "containing," and grammatical variations thereof, are inclusive or open ended and do not exclude additional, unrecited elements and / or method steps. The term "consisting essentially of" when used herein in relation to a composition, use, or method indicates that additional elements, method steps, or both additional elements and method steps may be present, but that these additions do not materially affect the manner in which the described composition, method, or use functions. The term "consisting of" when used herein in relation to a composition, use, or method excludes the presence of additional elements and / or method steps.

[0038] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases.

[0039] Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharma-ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N-type salts such as 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0040] As used herein, the term "subject" includes mammals (e.g., humans, including in some embodiments prenatal human forms). In some embodiments, the subject is afflicted with the relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to the disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject is one who has one or more characteristics of susceptibility to or risk for a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual for whom and / or for whom a diagnosis and / or treatment is being and / or has been performed. In some embodiments, the subject is a fetus, an infant, a child, a teenager, an adult, or an elderly person (i.e., the subject is elderly, such as over 50 years of age). In some embodiments, a child refers to a human between 2 and 18 years of age. In some embodiments, an adult refers to a human 18 years of age or older.

[0041] Chemical entities of formula (I) The present disclosure provides a compound of formula (I): [ka] and any pharma- ceutically acceptable salt or zwitterion thereof; During the ceremony: R is hydrogen, methyl or ethyl; R 1 is hydrogen or C1-C2 alkoxy; R 2 is methyl or a C2-C4 group which may be saturated or unsaturated, branched or straight chain; and R 3 , R 4 , R 5 and R 6are each independently selected from hydrogen, hydroxyl, halogen, methyl optionally substituted with hydroxy, methoxy, ethoxy, and saturated or unsaturated C2-C3 optionally substituted with hydroxyl, with the proviso that: (i) R 4 , R 5 , R 6 and R 7 must be hydrogen; and (ii) R 3 , R 4 , R 5 and R 6 may be selected such that adjacent pairs of them together form a ring having at least 5 members.

[0042] In a preferred embodiment, R 2 is 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).

[0043] In a preferred embodiment, R 3 , R 4 , R 5 and R 6 may be selected such that adjacent pairs thereof together form a ring having at least 5 members, preferably 5 to 8 members, preferably 5 or 6 members, preferably 5 members. In a preferred embodiment, the ring preferably contains at least 1, preferably 1 or 2 oxygen atoms.

[0044] In a preferred embodiment: R 1 and R 3 are each methoxy; R 2 is methyl; and R, R 4 , R 5 and R 6 Each is hydrogen.

[0045] In a preferred embodiment: R 1 and R 3are each methoxy; R 2 is ethyl; and R, R 4 , R 5 and R 6 are hydrogen.

[0046] In a preferred embodiment: R 1 and R 3 are each methoxy; R 2 is i-propyl; and R, R 4 , R 5 and R 6 are hydrogen.

[0047] In a preferred embodiment: R 1 and R 3 are each methoxy; R 2 is 2-propenyl; and R, R 4 , R 5 and R 6 are hydrogen.

[0048] In a preferred embodiment: R, R 1 , R 3 , R 5 and R 6 are hydrogen; R 2 is methyl; and R 4 is methoxy.

[0049] In a preferred embodiment: R, R 1 , R 3 , R 4 and R 6 are hydrogen; R 2 is methyl; and R 5 is methoxy.

[0050] In a preferred embodiment: R, R 1 , R 5 and R 6 are hydrogen; R 2 is methyl; and R 3 and R 4 are each methoxy.

[0051] In a preferred embodiment: R, R 1 , R 5 and R 6 are hydrogen; R 2 is i-propyl; and R 3 and R 4 are each methoxy.

[0052] In a preferred embodiment: R, R 1 , R 3 , R 4 , R 5 and R 6 are hydrogen; R 2 is methyl.

[0053] In a preferred embodiment: R, R 1 , R 3 , R 5 and R 6 are hydrogen; R 2 is 2-butenyl (cis); and R 4 is methoxy.

[0054] In a preferred embodiment: R, R 1 , R 3 , R 5 and R 6 are hydrogen; R 2is 2-butenyl (trans); and R 4 is methoxy.

[0055] In a preferred embodiment: R, R 1 , R 3 , R 5 and R 6 are hydrogen; R 2 is 2-methyl-2-propenyl; and R 4 is methoxy.

[0056] In a preferred embodiment: R, R 1 , R 3 , R 5 and R 6 are hydrogen; R 2 is methyl; and R 4 is ethyl.

[0057] In a preferred embodiment: R, R 1 , R 3 , R 5 and R 6 are hydrogen; R 2 is methyl; and R 4 is hydroxyl.

[0058] In a preferred embodiment: R, R 1 , R 3 , R 5 and R 6 are hydrogen; R 2 is methyl; and R 4 is bromine.

[0059] In a preferred embodiment: R, R 1 , R3 , R 5 and R 6 are hydrogen; R 2 is methyl; and R 4 is hydroxyethyl.

[0060] In a preferred embodiment: R, R 1 , R 3 , R 5 and R 6 is hydrogen; R 2 is methyl; and R 4 is 2-propynyl.

[0061] In a preferred embodiment: R, R 1 , R 5 and R 6 are hydrogen; R 2 is methyl; and R 3 is methoxy and R 4 is hydroxyl, and R 3 and R 4 together form a 1,3-dioxolane group.

[0062] Unless otherwise stated, a structure depicted herein is also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present disclosure are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. Additionally, unless otherwise stated, a structure depicted herein is also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms; for example, hydrogen, carbon, nitrogen, oxygen, chlorine, or fluorine, respectively.2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 17 O. 18 O. 36 Cl or 18 Compounds having this structure including the replacement with F are within the scope of this invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents in accordance with the present disclosure. Additionally, deuterium ( 2 The incorporation of heavier isotopes such as H) offers certain therapeutic advantages resulting from higher metabolic stability, e.g. In vivo Increased half-lives or reduced dosage requirements can be provided.

[0063] Unless otherwise stated, diastereomeric excess is expressed as %de, i.e., for diastereomers X and Y, diastereomeric excess of X=((xy) / (x+y))*100, where x and y are the proportions of X and Y, respectively.

[0064] Unless otherwise stated, enantiomeric excess is expressed as % ee, i.e., for enantiomers X and Y, the enantiomeric excess of X=((xy) / (x+y))*100, where x and y are the proportions of X and Y, respectively.

[0065] Formulations and Compositions The present disclosure also provides pharma- ceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described herein, formulated together with one or more pharma- ceutically acceptable carriers (additives) and / or diluents, and, optionally, one or more additional therapeutic agents. While it is possible for the compounds described herein to be administered alone, it is preferred to administer the compounds as a pharmaceutical composition.

[0066] The term "pharmaceutical composition" refers to a composition that contains a compound of the present disclosure in combination with at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a vehicle generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, i.e., depending on the mode of administration and the nature of the dosage form, includes vehicles such as adjuvants, excipients or diluents, osmotic complements, preservatives, bulking agents, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, polymers, solubilizers, stabilizers, antioxidants and dispersants. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient.

[0067] As used herein, "oral" administration includes swallowing for ingestion in the stomach or intestine, and further includes lingual, sublingual, buccal and oropharyngeal administration. The compounds of the present disclosure 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 or extended release formulations), pills, powders, granules, elixirs, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually (e.g., thin films, effervescent tablets, or tablets that dissolve naturally under the tongue); parenterally, such as by subcutaneous, intravenous, intramuscular injection, or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, such as by inhalation spray, including administration to the nasal mucosa; or rectally, such as in the form of a suppository.

[0068] Dosage regimens for the compounds described herein will of course vary depending on 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 symptoms; type of concurrent treatment; frequency of treatment; route of administration, renal and hepatic function of the patient; and the desired effect. The selected dosage level may also depend on additional factors including the activity of the particular compounds and pharmaceutical compositions described herein, whether an ester, salt, or amide substituent of the compound is used, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, duration of treatment, other drugs that may be administered to the patient, compounds and / or materials used in combination with the particular compound used, and similar factors are well known in the medical arts.

[0069] Generally, when used for the indicated effects, dosages of prodrugs for a treatment session range from between about 0.001 to about 500 mg per dose, such as 10, 20, 30, 40, 50, 100 or 200 mg, preferably between about 0.01 to about 200 mg per dose, and most preferably between about 1 to about 50 mg per dose. Intravenously, the most preferred doses range from about 0.01 to about 10 mg / kg / min during a constant rate infusion.

[0070] The compounds of the present disclosure may be administered in a single daily dose, or the total daily dose may be administered in multiple divided doses, such as two, three, or four times a day. Alternatively, doses may be provided weekly, biweekly, or monthly. In preferred embodiments, only one or two doses are required for antidepressant effect, which may extend for one, two, three, or six months, or longer.

[0071] For tablet dosage forms, depending on the dose, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant comprises 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0072] Binders are generally used to impart cohesion to tablet formulations.Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and calcium hydrogen phosphate dihydrate.

[0073] Tablets may optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, surfactants are typically in an amount of 0.2% to 5% by weight of the tablet, and glidants are typically in an amount of 0.2% to 1% by weight of the tablet.

[0074] Tablets also generally contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants are generally present in an amount of 0.25% to 10%, preferably 0.5% to 3%, by weight of the tablet.

[0075] Other conventional ingredients include antioxidants, colouring agents, flavouring agents, preservatives and taste masking agents.

[0076] Exemplary tablets contain up to about 80% by weight of drug, about 10% to about 90% by weight of binder, about 0% to about 85% by weight of diluent, about 2% to about 10% by weight of disintegrant, and about 0.25% to about 10% by weight of lubricant.

[0077] Tablet blends may be compressed directly or by roller to form tablets. Alternatively, tablet blends or portions of blends may be wet-, dry-, or melt-granulated, melt congealed, or extrusion granulated before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; or may be encapsulated.

[0078] Tablet formulation is discussed in detail by H. Lieberman and L. Lachman in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", Marcel Dekker, NY, NY, 1980 (ISBN 0 8247 6918 X).

[0079] A typical capsule for oral administration contains at least one compound of the present disclosure (e.g., 25 mg), lactose (e.g., 75 mg), and magnesium stearate (e.g., 15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

[0080] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid, for example from a sachet.

[0081] The compounds of the present disclosure may be administered directly into bloodstream, into muscle, or into internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous.Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors and infusion techniques.

[0082] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and pH adjusting or buffering agents (preferably to a pH of 3.0-7.0, preferably 4.0-6.0, and more preferably 4.5-5.5), although for some applications they may be more suitably formulated as sterile non-aqueous solutions or as a dry form for use in conjunction with a suitable vehicle such as sterile, pyrogen-free water or a preformed, premixed aqueous buffer. Osmotic agents may be included to control osmotic pressure.

[0083] The preparation of parenteral kits for reconstitution at the point-of-care under sterile conditions, eg, by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0084] A typical injectable formulation may be produced by aseptically placing at least one compound of the present disclosure (e.g., 25 mg) as a sterile-filtered solution into a vial, aseptically lyophilizing, and sealing. For use, the contents of the vial are mixed with, e.g., 2 mL of injectable saline, optionally with an appropriate amount of osmolality supplement and pH adjuster to achieve a slightly acidic to neutral pH (e.g., pH 4-7), to produce an injectable formulation that is mild but retains the solubility and / or stability of the prodrug.

[0085] The compounds of the present disclosure may be combined with soluble polymeric entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the above-mentioned modes of administration.

[0086] For example, drug cyclodextrin complexes have been found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with drugs, cyclodextrins can be used as auxiliary additives, i.e., carriers, diluents or solubilizers. Alpha, beta and gamma cyclodextrins are most commonly used for these purposes, and examples of these can be found in International Publications WO91 / 11172, WO94 / 02518 and WO98 / 55148.

[0087] Regardless of the route of administration selected, the compounds of the present disclosure, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure, are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those skilled in the art. Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0088] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start dosing the compounds of the present disclosure used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0089] Generally, a daily dose of a compound of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0090] As used herein, "therapeutically effective amount" refers to the amount of compound administered that relieves to some extent one or more of the symptoms of the disorder being treated.For the treatment of depression, a therapeutically effective amount refers to an amount that has the effect of reducing the severity of depression.The severity of depression can be assessed using well-known structured assessment tools such as the Structured Clinical Interview for DSM-5 (SCID-5) and the GRID-Hamilton Depression Rating Scale (GRID-HAMD).A therapeutically effective amount can be an amount less than that required for hallucinatory state.

[0091] An effective dosage may be administered in one or more administrations. For purposes of this disclosure, an effective dosage of a drug, compound or pharmaceutical composition is an amount sufficient to achieve prophylactic or therapeutic treatment, directly or indirectly. As understood in the clinical context, an effective dosage of a drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another treatment, drug, compound or pharmaceutical composition.

[0092] Treatment Methods and Uses Treatment with the novel compounds of the present disclosure can substantially alleviate clinical or subclinical depression and avoid relapse, especially when used in combination with psychotherapy for the treatment of depression.It is known that administration of an effective dose of psilocybin can rapidly reduce depressive symptoms, and many subjects achieve remission through a four-week follow-up (Davis et al.).Without being limited by theory, it is believed that the hallucinogenic state is associated with beneficial effects, but some compounds that are 5HT2A agonists can produce desirable therapeutic effects without hallucinogenic states.One embodiment of the present disclosure includes prodrugs of 5HT2A agonists that provide beneficial therapeutic states.

[0093] In general, the disclosure includes the use of the compounds disclosed herein for treating any disease or disorder that can be alleviated by a 5HT2A agonist, or the use of the compounds disclosed herein for the manufacture of a medicament for treating any disease or disorder that can be alleviated by a 5HT2A agonist, or a method for treating any disease or disorder that can be alleviated by a 5HT2A agonist.

[0094] In some embodiments, the present invention may include the use of the compounds of the present disclosure to treat psychiatric disorders.In some embodiments, the present invention may include the use of the compounds of the present disclosure to treat depression, and in particular drug-resistant depression.Other conditions that may be treated include: anxiety disorders, including generalized anxiety disorder, depression, including postpartum depression, cluster headaches, obsessive-compulsive disorder, personality disorders, including conduct disorder, drug disorders, including alcoholism, nicotineism, opioidism, cocaineism, and other addictions, including gambling disorders, eating disorders, and body dysmorphic disorder, chronic pain, or chronic fatigue.

[0095] In some embodiments, the present invention may include the use of the disclosed compounds for treating metabolic syndrome and insulin resistance.

[0096] In some embodiments, the present invention may include a method for treating a psychiatric disorder, comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof. In one embodiment, a method for treating depression is provided, comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof. The depression may be drug-resistant depression or depression.

[0097] For example, a patient diagnosed with depression may be screened prior to treatment and then prepared for a dosing session by a trained psychotherapist. Within the dosing session, the compound of the present disclosure may be administered to the patient at a rate of 0.01-0.3 mg / kg by injection of a sterile solution. The patient is preferably blindfolded while seated for the duration of the session. For safety, a trained health care professional may monitor the patient during the dosing session, which may last up to 12 hours. In some cases, music may be played for the patient. When the health care professional is able to determine that the drug substance has been removed, the psychotherapist assists the patient with any questions related to the hallucinatory experience, after which the patient may be discharged.

[0098] To further alleviate any anxiety that may arise related to treatment, a physician may choose to divide the therapeutic dose, thereby reducing the initial onset of psychoactivity, before applying the full complement of dosages to achieve the full effect.

[0099] In some embodiments, treatment with the compound of the present disclosure can be combined with concomitant treatment with another antidepressant, either simultaneously or sequentially.In a preferred embodiment, treatment with the compound of the present disclosure is combined with psychotherapy, which can be applied before or after treatment. In the former case, the session can focus the patient on the intention of treatment. In the latter case, psychotherapy is preferably performed within 48 hours of the medication session to help the patient integrate any feelings, emotions, perspectives or thoughts that may have occurred during the session, and also to allow the psychotherapist to provide advice on how best to change thinking or behavior patterns to improve antidepressant outcome.Psychotherapy can be continued as needed after the medication session, for example up to another 3 months, to help the patient integrate any experiences or learning that have occurred to the patient during the medication session. EXAMPLES

[0100] Working Example Aspects of the present disclosure may be described with reference to the following examples. These examples are provided for illustrative purposes only and should not be used to interpret or limit the scope of the present invention. All terms, names, abbreviations or acronyms are those commonly understood by those of ordinary skill in the art. Compounds shown in their zwitterionic form can be readily envisioned in their neutral form by those of ordinary skill in the art, and vice versa.

[0101] Example 1 - Synthesis of 2-(N-(2-methoxybenzyl)-N-methyl)aminoethyl)-5-methoxy-1H-indole [ka]

[0102] Step 1. To a 150 mL RBF containing a stir bar was added 5-methoxyindole-3-acetic acid (1.0 eq) followed by anhydrous ACN (25 mL) under N2. To this solution was then slowly added 2-methoxy-N-methylbenzylamine (2.0 eq) followed by triethylamine (4.0 eq). To the reaction mixture was then added n-propylphosphonic acid cyclic anhydride (TP3) (8.68 g, 50% w / w in EtOAc). The reaction mixture was left stirring 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 (crude orange oil 6.73 g). Flash chromatography (Biotage SNAP KP-SIL 340 g cartridge) using a 0-5% gradient of MeOH in EtOAc afforded 2.3 g of pure product as a yellow sticky solid (99% yield).

[0103] Step 2. To LiAlH4 (5.0 equiv.) in THF (100 ml) was added dropwise at 0° C. (ice bath) a solution containing 3.38 g of the product from step 1 in THF (60 mL). The reaction mixture was left stirring for 2 days and slowly warmed to room temperature. The reaction was monitored by UPLC for disappearance of 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). MgSO4 was added and the mixture was stirred until a white precipitate formed. The precipitate was filtered through a pad of Celite and washed with DCM. The filtrate was evaporated to dryness to give a greenish oil. Flash chromatography (Biotage SNAP KP-SIL 340 g cartridge) 0-5% gradient of MeOH in EtOAc gave 3.78 g (near quantitative yield) of crude orange oil. Purity UPLC = 96%, QNMR (1,4-dinitrobenzene; using the 6.7 peak (1H) from the compound in the examples) = 96% (determined in two separate analyses). Exact mass by LCMS (MH+) 325.16.1H NMR: 2.3ppm(s, 3H, NMe), 2.6ppm(m, 2H, -CH2N), 2.8ppm(m, 2H, indole-CH2-), 3.5ppm(s, 2H, NCH2Ph), 3.7ppm(s, 3H, OMe), 3.75ppm(s, 3H, OMe), 6.7ppm (m, 1H, aromatic CH), 6.9ppm (m, 2H, aromatic CH), 6.95ppm (d, 1H, aromatic CH), 7.1ppm (s, 1H, aromatic CH), 7.2ppm (m, 2H, aromatic CH), 7.4ppm (m, 1H, aromatic CH), 10.7ppm (m, 1H, NH).

[0104] Inhibition was determined in the functional GCPR assay for adrenergic alpha1A and alpha2A: IC50(A1A): 1800 nM; IC50(A2A): 1700 nM.

[0105] Example 2 - 5HT1A competitive binding assay Competitive binding assays (Eurofins Cerep) were performed using human recombinant 5-HT1A, [3H]8-OHDPAT (0.5 nM) transfected into HEK-293 cells and the test compound from Example 1 was tested at eight concentrations ranging from 0.01 mM to 30 mM (Choi DS et al. FEBS Letters 1994, 352, 393). Analysis was performed using software developed at Cerep (Hill software) and run on a Windows (R) Commercially available software for SigmaPlot (R) 4.0 ((C)1997 SPSS Inc). The binding constant (Ki 540 nM) was calculated using the Cheng-Prusoff equation. The compound is a moderate agonist at the 5HT1A receptor, but is approximately 5-fold more selective at the 5HT2A receptor (Ki 110 nM).

[0106] Example 3 - 5HT2A competitive binding assay Competitive binding assays (Eurofins Cerep) were performed using human recombinant 5-HT2A transfected into HEK-293 cells, 125I-DOI (0.1 nM), and the test compound from Example 1 was tested at eight concentrations ranging from 0.01 mM to 30 mM (Choi DS et al. FEBS Letters 1994, 352, 393). Analysis was performed using software developed at Cerep (Hill software) and run on a Windows (R) Commercially available software for SigmaPlot (R) 4.0 ((C)1997 SPSS Inc). Binding constants (Ki 110 nM) were calculated using the Cheng-Prusoff equation. Based on data from http: / PDSP.unc.edu / databases / pdsp.php, the compound is approximately equipotent to psilocybin.

[0107] Example 4 - 5HT2A Functional Assay Competitive binding assays (Eurofins Cerep) were performed using human recombinant 5-HT2A transfected into HEK-293 cells, serotonin (30 nM), and the test compound from Example 1 was tested at eight concentrations ranging from 0.01 mM to 30 mM (Choi DS et al. FEBS Letters 1994, 352, 393). Analysis was performed using software developed at Cerep (Hill software) and run on a Windows (R) Commercially available software for SigmaPlot (R) 4.0 ((C)1997 SPSS Inc.) The results showed agonism at 5HT2A with an EC50 of 520 nM, reaching 80% maximal efficacy at the highest concentration.

[0108] Example 5 - 5HT2B competitive binding assay Competitive binding assays were performed (Eurofins Cerep) using human recombinant 5-HT1A transfected into CHO cells, 125I-DOI (0.2 nM), and the test compound from Example 1 was tested at eight concentrations ranging from 0.01 mM to 30 mM (Choi DS et al. FEBS Letters 1994, 352, 393). Analysis was performed using software developed at Cerep (Hill software) and run on a Windows (R) Commercially available software for SigmaPlot (R) 4.0 ((C)1997 SPSS Inc). The binding constant could not be determined using the Cheng-Prusoff equation (Ki 180 nM). The compound binds to the 5HT2B receptor with similar strength to the 5HT2A receptor (Ki 110 nM).

[0109] Example 6 - 5HT2B (isotol phosphate, IP1) functional assay Functional assays were performed using human recombinant 5-HT2B transfected into CHO cells (Eurofins Cerep) and the test compound from Example 1 was tested at eight 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. Analysis was performed using software developed at Cerep (Hill software) and run on Windows (R) Commercially available software for SigmaPlot (R) 4.0 ((C)1997 SPSS Inc). The lack of activity of the compound at the receptor meant that the EC50 could not be determined. Combined with the results of Example 4, this suggests that the compound binds to the 5HT2B receptor but does not cause any functional activity of the receptor, and therefore acts as a neutral agonist or antagonist at therapeutic levels.

[0110] Example 7 - 5HT2B Functional Antagonist Assay Antagonist functional assays were performed using human recombinant 5-HT2B transfected into CHO cells (Eurofins Cerep) with background serotonin (10 uM) and test compounds from Example 1 were tested at eight concentrations ranging from 0.01 mM to 30 mM (see Porter, RHP et al. Brit. J. Pharmacol. 1999, 128, 13). Quantification of myo-inositol-1-phosphate was performed using HTRF. Analysis was performed using software developed at Cerep (Hill software) and run on a Windows (R) Commercially available software for SigmaPlot (R) 4.0 ((C) 1997 SPSS Inc.) These results show that the compound from Example 1 is a full antagonist with an IC50<10 uM as determined using the Cheng-Prusoff equation.

[0111] Example 8 -5HT2C competitive binding assay Competitive binding assays were performed (Eurofins Cerep) using human recombinant 5-HT1A transfected into CHO cells, 125I-DOI (0.2 nM), and the test compound from Example 1 was tested at eight concentrations ranging from 0.01 mM to 30 mM (Choi DS et al. FEBS Letters 1994, 352, 393). Analysis was performed using software developed at Cerep (Hill software) and run on a Windows (R) Commercially available software for SigmaPlot (R) 4.0 ((C)1997 SPSS Inc). The binding constant could not be determined using the Cheng-Prusoff equation (Ki 680 nM). The compound is a moderate agonist at the 5HT2C receptor, but is approximately six-fold more selective for the 5HT2A receptor (Ki 110 nM).

[0112] Example 9 - Pharmacokinetics after intravenous (iv) administration in rats The compound of Example 1 was dispersed in water containing phosphate buffered saline at a ratio of 1 mg / ml, and then acidified to pH 4 to form a solution. This solution was administered to each of three rats (approximately 300 g each) at a ratio of 1.0 mg / kg (approximate dose 0.33 ml, dose volume 0.33 mg) via a catheter placed in the carotid artery. The animals were observed for 12 hours, counting the cumulative number of head-twitch movements over a 10-minute period up to 2 hours, and then for 10 minutes at 3, 3.5, and 4 hours. Blood samples (0.25 ml) were collected via the catheter using a 1 ml syringe into 0.8 ml K2EDTA tubes at 0.0833, 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours after administration, and placed on ice water until processing. Saline (0.25 ml) was reinjected into the animals via the catheter after each blood draw to flush the catheter and replenish the blood volume. Collected blood samples were centrifuged (3200g, 5 min, 4C) within 5 min of collection, and plasma was collected and frozen in cryovials in liquid nitrogen and stored at -80 C until further analysis. A bioanalytical method was developed for the quantification of compounds in plasma after calibration with example compounds using a Sciex 6500 Q-trap MSMS equipped with a standard LC system.

[0113] The plasma profile is shown in Figure 1. The mean plasma half-life was 66 minutes. There was no significant head-twitching during the duration of the rat intravenous PK study, indicating reduced hallucinogenicity of the compound despite the 5HT2A receptor binding and functional assays (Examples 3 and 4 above). Non-hallucinogenic 5HT2A agonists may have significant potential utility in treating mood disorders and may overcome the need for monitoring requirements typical of similar 5HT2A agonists of the same class that produce hallucinogenic states.

[0114] Example 10 - Synthesis of 2-(N-(3-methoxybenzyl)-N-methyl)aminoethyl)-1H-indole [ka] The two-step synthetic process of amide coupling followed by reduction in Example 1 was carried out using 3-methoxy-N-methylbenzylamine (2.0 equiv.) instead of the 2-methoxy modified amine described in Example 1. Yield step 1: 85%; yield step 2: 20%. Purity UPLC: 98%, QNMR (using 1,4-dinitrobenzene; peak at 6.7 (1H) from compound in example): 96%. Accurate mass by MS (MH+): 295.0. 1H NMR (dmso-d6): 2.3ppm (s, 3H, NMe), 2.6ppm (m, 2H, -CH2N), 2.8ppm (m, 2H, indole-CH 2-), 3.5ppm(s, 2H, NCH2Ph), 3.7ppm(s, 3H, OMe), 3.75ppm(s, 3H, OMe), 6.8ppm(m, 1H , aromatic CH), 6.9ppm (m, 2H, aromatic CH), 6.95ppm (m, 1H, aromatic CH), 7.05ppm (s, 1H, aromatic CH), 7. 13ppm (m, 2H, aromatic CH), 7.2 (d, 1H, aromatic CH), 7.4ppm (m, 1H, aromatic CH), 10.7ppm (m, 1H, NH). 5HT1A binding Ki 510nM. 5HT2A Ki 14nM. 5HT2B binding Ki 380nM. 5HT2B functional agonist mode IC50 1050nM (efficiency <20% down to 30uM). 5HT2C binding Ki 42nM.

[0115] Examples 11-29 Details regarding the synthesis and testing of the following compounds are provided below: Results of testing of various compounds below are reported in Table 1 below (all units in Table 1 are in nM).

[0116] [Table 2]

[0117] [Table 3]

[0118] [Table 4]

[0119] [Table 5]

[0120] [Table 6]

[0121] [Table 7]

[0122] [Table 8]

[0123] Example 11 - Synthesis of N-ethyl-2-(5-methoxy-1H-indol-3-yl)-N-(2-methoxybenzyl)ethan-1-amine The following reaction scheme was used: [ka]

[0124] To a stirred solution of 2-methoxybenzaldehyde (3.0 g, 1.0 equiv.) in EtOH (20 mL) was added ethylamine (0.99 g, 1.0 equiv.) at room temperature. The reaction mixture was cooled to 0° C., stirred for 5 min, and NaBH4 (1.63 g, 2.0 equiv.) was added portionwise. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (50 mL), extracted with EtOAc (2×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give N-(2-methoxybenzyl)ethanamine (2, 2.7 g, 74%) as a colorless viscous syrup.

[0125] 1H NMR (400MHz, DMSO-d6) δppm7.29 (dd, J=7.25, 0.88Hz, 1H, aromatic CH), 7.15 - 7.23(m, 1H, aromatic CH), 6.95(d, J=8.13Hz, 1H, aromatic CH), 6.89(t, J=7.38Hz, 1H, aromatic CH), 3.77(s, 3 H, OMe), 3.66 (s, 2H, -CH2N), 2.53 (q, J=7.21Hz, 2H, -CH2N), 1.02 (t, J=7.13Hz, 3H, -CH2Me).

[0126] 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 a 50% solution of T3P in EtOAc (3.9 mL, 2.0 equiv.) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), and extracted with EtOAc (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography (20-30% EtOAc in heptane) to give N-ethyl-2-(5-methoxy-1H-indol-3-yl)-N-(2-methoxybenzyl)acetamide (0.7 g, 65%) as a colorless viscous syrup. LCMS: Not done.

[0127] 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 dropwise a solution of 2M LiAlH4 (2.0 equiv.) in THF (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The 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), the white precipitate was filtered through a pad of Celite and extracted with EtOAc (100 mL). The filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was triturated with heptane (10 mL) to give N-ethyl-2-(5-methoxy-1H-indol-3-yl)-N-(2-methoxybenzyl)ethan-1-amine (0.45 g, 67%) as an off-white solid.

[0128] MS(ESI) m / e[M+H] + :339;HPLC purity: 99.84% (RT=5.9 minutes), 1 H NMR (400MHz, DMSO-d6) δppm10.56(s, 1H, indole-NH) 7.40 (dd, J=7.38, 1.38Hz, 1H, aromatic CH) 7.15 - 7.21(m, 2H, aromatic CH), 7.05 (d, J=2.13Hz, 1H, aromatic CH), 6.81 - 6.98(m, 3H, aromatic CH), 6.68(dd, J=8.76, 2.38Hz, 1H, aromatic CH), 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=7.05Hz, 2H, CH2), 1.04(t, J=7.07Hz, 3H, -CH2Me).

[0129] Example 12 - Synthesis of N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-(2-methoxybenzyl)propan-2-amine The following reaction scheme was used: [ka]

[0130] To a stirred solution of 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 LiAlH4 in THF (6.8 mL, 5.03 equiv.) at 0°C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0°C and quenched with saturated aqueous Na2SO4 (10 mL). The white precipitate was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (50 mL) and the separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography (1-5% MeOH in EtOAc) to give N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-(2-methoxybenzyl)propan-2-amine (0.34 g, 35%) as a colorless viscous oil.

[0131] MS(ESI) m / e [M+H] + :353;HPLC purity:97.03%(RT=1.8min); 1 H NMR (400MHz, DMSO-d6) δppm10.54(s, 1H, indole NH), 7.49(dd, J=7.50, 1.50Hz, 1H, aromatic CH), 7.14-7.22(m, 2H, aromatic CH), 7.03(d, J=2.25Hz, 1H, aromatic CH), 6.87-6.96(m, 2H, aromatic CH), 6.81(d, J=2.38Hz, 1H, aromatic CH), 6.67(dd, J=8.69, 2.44Hz, 1H, aromatic CH), 3.77(s, 3H, OMe), 3.69(s, 3H, OMe), 3.61(s, 2 H, CH2), 2.97-3.05(m, 1H, CH), 2.62-2.76(m, 4H, CH2), 1.01(d, J=6.63Hz, 6H, CH(CH3)2).

[0132] Example 13 - Synthesis of N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-(2-methoxybenzyl)prop-2-en-1-amine The following reaction scheme was used: [ka]

[0133] 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 at room temperature for 12 h. The reaction mixture was cooled to 0° C., stirred for 5 min, and NaBH4 (0.45 g, 1.6 equiv.) was added in portions. The reaction mixture was stirred at room temperature for 12 h. The 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), and extracted with EtOAc (2×100 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give N-(2-methoxybenzyl)prop-2-en-1-amine (0.7 g, 54%) as a colorless viscous syrup.

[0134] 1 H NMR (400MHz, DMSO-d6) δppm7.28-7.33(m, 1H, aromatic CH) 7.18-7.27(m, 1H, aromatic CH) 6.88-6.99(m, 2H, aromatic CH) 5.87(ddt, J=16.93, 11.07, 5.32, 5.32Hz, 1H, alkene CH) 5.11-5.25(m, 1H, alkene CH) 5.07(d, J=10.27Hz, 1H, alkene CH) 3.79(s, 3H, OMe) 3.66(s, 2H, NCH2) 3.17(d, J=4.89Hz, 2H, NCH2).

[0135] 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 a 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. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo to give the crude material, diluted with water (30 mL), and extracted with EtOAc (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography (20-30% EtOAc in heptane) to give N-allyl-2-(5-methoxy-1H-indol-3-yl)-N-(2-methoxybenzyl)acetamide (0.8 g, 55%) as a colorless viscous syrup. MS(ESI) m / e [M+H]: 365.

[0136] To a stirred solution of LAH (2M in THF, 7.7 mL, 3.9 equiv.) in THF (50 mL) was added AlCl3 (2.04 g, 4.0 equiv.) portionwise 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. and then at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0° C. and quenched with 20% NaOH solution (10 mL). The precipitate was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was purified by combi flash (50-100% EtOAc in heptane) to give N-ethyl-2-(5-methoxy-1H-indol-3-yl)-N-(2-methoxybenzyl)ethan-1-amine (0.8 g, 59%) as an off-white solid.

[0137] MS(ESI) m / e [M+H] + :351;HPLC purity:99.43%(RT=6.06min) 1 H NMR (400 MHz, DMSO-d6) δppm10.55 (s, 1H, Indole NH), 7.40 (d, J = 7.38 Hz, 1H, aromatic CH), 7.19 (d, J = 8.76 Hz, 2H, aromatic CH), 7.00-7.06 (m, 1H, aromatic CH), 6.96 (d, J = 8.13 Hz, 1H, aromatic CH), 6.90 (t, J = 7.38 Hz, 1H, aromatic CH), 6.8 5 (d, J = 2.13 Hz, 1H, aromatic CH), 6.67 (dd, J = 8.69, 2.31 Hz, 1H, aromatic CH), 5.86-5.97 (m, 1H, alken CH), 5.24 (s, 1H, alken CH), 5.14 (d, J = 10.26 Hz, 1H, alken CH), 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).

[0138] Example 14 - Synthesis of 2-(1H-indol-3-yl)-N-(4-methoxybenzyl)-N-methylethan-1-amine The following are used in the following countermeasures:

change

[0139] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (0.85 g, 1.0 equiv.) and 1-(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, and a 50% solution of T3P in EtOAc (6.1 mL, 2.02 equiv.) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), and extracted with EtOAc (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography (20-30% EtOAc in heptane) to give 2-(1H-indol-3-yl)-N-(4-methoxybenzyl)-N-methylacetamide (3, 1.1 g, 73%) as a colorless oil.

[0140] MS(ESI) m / e [M+H] + :308.9; 1 H NMR (400MHz, chloroform-d) δppm8.24(s, 1H, indole NH), 7.58-7.67(m, 1H, aromatic CH), 7.35(d, J=8.00Hz, 1H, aromatic CH), 7.05-7.22(m, 5H, aromatic CH) , 6.82(d, J=8.25Hz, 2H, aromatic CH), 4.33-4.62(m, 2H, CH2), 3.89(s, 2H, CH2), 3.79(s, 3H, OMe), 2.93(s, 3H, NMe).

[0141] 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 2M LiAlH4 solution in THF (4.46 mL, 2.5 equiv.) at 0°C. The reaction mixture was stirred at room temperature for 16 h. The 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). The white precipitate was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material obtained was triturated with n-heptane (10 mL) to give 2-(1H-indol-3-yl)-N-(4-methoxybenzyl)-N-methylethan-1-amine (FT165, 0.47 g, 44%) as an off-white solid.

[0142] MS(ESI) m / e [M+H] + :295;HPLC purity:98.04%(RT=5.2min); 1 H NMR (400MHz, DMSO-d6) δppm10.73(s, 1H, indole NH), 7.42(d, J=7.8Hz, 1H, aromatic CH), 7.31(d, J=8Hz, 1H, aromatic aromatic CH), 7.28-7.17(m, 2H, aromatic CH), 7.11(s, 1H), 7.04(t, J=7.6Hz, 1H, aromatic CH), 6. 93(t, J=7.6Hz, 1H, aromatic CH), 6.86(d, J=7.8Hz, 2H, aromatic CH), 3.73(s, 3H, OMe), 3.4 8(s, 2H, CH2), 2.94-2.77(m, 2H, CH2), 2.67-2.55(m, 2H, CH2), 2.21(s, 3H, NMe).

[0143] Example 15 - Synthesis of N-(2,3-dimethoxybenzyl)-2-(1H-indol-3-yl)-N-methylethan-1-amine The following reaction scheme was used: [ka]

[0144] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (0.87 g, 1.0 equiv.) and compound 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 EtOAc 50% T3P solution (3.16 mL, 2.0 equiv.) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (50 mL), and extracted with EtOAc (2×100 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude material. The crude material obtained was purified by combi flash chromatography (20-30% EtOAc in heptane) to give N-(2,3-dimethoxybenzyl)-2-(1H-indol-3-yl)-N-methylacetamide (3, 1.0 g, 59%) as a colorless oil.

[0145] MS(ESI) m / e [M+H] + :339; 1 H NMR (400MHz, DMSO-d6) δppm10.88(d, J=9.78Hz, 1H, indole NH), 7.53-7.61(m, 1H, aromatic CH), 7.49(d, J =7.34Hz, 1H, aromatic CH), 7.27-7.40(m, 1H, aromatic CH), 7.19(d, J=13.20Hz, 1H, aromatic C H), 6.87-7.10(m, 3H, aromatic CH), 6.54-6.67(m, 1H, aromatic CH), 4.45-4.65(m, 2H, C H2), 3.76-3.85(m, 6H, OMe), 3.70(d, J=15.16Hz, 3H, NMe), 2.96(s, 2H, CH2).

[0146] To a stirred 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 dropwise a solution of 2M LiAlH4 in THF (4.88 mL, 2.02 equiv.) at 0°C. The reaction mixture was stirred at room temperature for 16 h. The 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) and the white precipitate was filtered through a pad of Celite and washed with EtOAc (70 mL). The filtrate was washed with water (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography (40-60% EtOAc in heptane) to give N-(2,3-dimethoxybenzyl)-2-(1H-indol-3-yl)-N-methylethan-1-amine (0.37 g, 38%) as a colorless viscous oil.

[0147] MS(ESI) m / e [M+H] + :325;HPLC purity:97.62%(RT=5.9min); 1 H NMR (400MHz, DMSO-d6) δppm10.73(s, 1H, indole NH), 7.43(d, J=7.88Hz, 1H, aromatic CH), 7.31(d, J=8.13Hz, 1H, aromatic CH), 7.09-7.13(m, 1H, aromatic CH), 6.97-7.06(m, 2H, aromatic CH), 6 .90-6.97(m, 3H, aromatic CH), 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).

[0148] Example 16 - Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(2,3-dimethoxybenzyl)prop-2-an-1-amine The following reaction scheme was used: [ka]

[0149] To a stirred solution of 2,3-dimethoxybenzaldehyde (3.0 g, 1.0 equiv.) in EtOH (90 mL) was added isopropylethylamine (1.5 g, 1.5 equiv.). The reaction mixture was stirred at room temperature for 12 h, cooled to 0° C., and NaBH4 (1.33 g, 2.0 equiv.) was added portionwise. The reaction mixture was stirred at room temperature for 12 h. The 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), and extracted with EtOAc (2×100 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give N-(2,3-dimethoxybenzyl)propan-2-amine (2.4 g, 63%) as a colorless oil.

[0150] To a stirred solution of N-(2,3-dimethoxybenzyl)propan-2-amine (2.4 g, 1.0 equiv.) and compound 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 a 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. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo to give the crude material, diluted with water (50 mL), and extracted with EtOAc (2×100 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude material. The crude material obtained was purified by combi flash chromatography (20-30% EtOAc in heptane) to give N-(2,3-dimethoxybenzyl)-2-(1H-indol-3-yl)-N-isopropylacetamide (2.5 g, 59%) as a colorless viscous oil.

[0151] To a stirred solution of N-(2,3-dimethoxybenzyl)-2-(1H-indol-3-yl)-N-isopropylacetamide (1.5 g, 1.0 equiv.) in THF (50 mL) was added a solution of 2M LiAlH4 in THF (10.2 mL, 5.1 equiv.) dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h. The 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). A white precipitate was formed, which was filtered through a pad of Celite and the cake was washed with EtOAc (100 mL). The filtrate was washed with water (50 mL) and the separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material. The resulting crude material was purified by preparative HPLC which was triturated with MeOH (5 mL) to give N-(2-(1H-indol-3-yl)ethyl)-N-(2,3-dimethoxybenzyl)propan-2-amine (0.4 g, 28%) as an off-white solid.

[0152] MS(ESI) m / e [M+H] + :353;HPLC purity:98.36%(RT=8.23min); 1 H NMR (400MHz, DMSO-d6) δppm10.70(s, 1H, indole NH), 7.21-7.38(m, 2H, aromatic CH), 6.93-7.11(m, 4H, aromatic CH), 6.87-6.93(m, 2H, aromatic CH), 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=6.85Hz, 6H, NCHMe).

[0153] Example 17 - Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(benzyl)methan-1-amine The following reaction scheme was used: [ka]

[0154] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (1 g, 1.0 equiv.) in 10 ml of ACN was added N-methyl-1-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 room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL) and extracted with EtOAc (2x50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by combi flash chromatography to give the desired product as a white solid (1.2 g, 75% yield).

[0155] 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 dropwise a solution of 2M LAH (0.3 g, 2.0 equiv.). The reaction mixture was stirred at 0° C. for 4 h under N2 atmosphere. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated Na2SO4 solution (10 mL) and the white precipitate was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by combi flash chromatography to give N-benzyl-2-(1H-indol-3-yl)-N-methylethan-1-amine (FT232, 0.6 g, 52%) as a brown solid.

[0156] MS(ESI) m / e [M+H] + :265; HPLC purity: 99.6% (RT=5.7 min), 1H NMR (400MHz, DMSO-d6) δ=10.74(s, 1H, indole NH), 7.42(d, J=7.75Hz, 1H, aromatic CH), 7.39-7.26(m, 5H, aromatic CH), 7.25(s, 1H, aromatic CH), 7.12(d, J=2.0Hz, 1H, aromatic CH), 7.04(dt, J= 2.0Hz, 8.0Hz, 1H, aromatic CH), 6.93(dt, J=2.0Hz, 8.0Hz, 1H, aromatic CH), 3.56(s, 2H, CH2), 2.88(t, J=4.0Hz, 2H, CH2), 2.64(s, 2H, CH2), 2.24(s, 3H, NMe).

[0157] Example 18 - Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(3-ethylbenzyl)prop-2-en-1-amine 3-(aminoethyl)-1H-indole (1 eq.) was reacted with 3-methoxybenzoic anhydride (1.2 eq.) in ethanol at 65 C for 7 h to form an intermediate imine, which was then cooled to room temperature and reacted in situ by adding NaBH4 (2 eq.). After quenching, extraction and evaporation of the solvent, the desired 3-(3-methoxybenzylaminoethyl)-1H-indole (1.1 g, 62%) was obtained. This (0.6 g, 1 eq.) was then reacted with trans-1-bromo-2-butene (1.1 eq.) in a minimum of DMF using K2CO3 (2 eq.) at room temperature for 2 h. The product was extracted and subsequently isolated after flash chromatography to give a semi-solid (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( mm, 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).

[0158] Example 19 - Synthesis of (Z)-N-(2-(1H-indol-3-yl)ethyl)-N-(3-methoxybenzyl)but-2-en-1-amine The following reaction scheme was used: [ka]

[0159] To a stirred solution of 2-(1H-indol-3-yl)ethan-1-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 in portions and stirred for another 4 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice water and extracted with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (Combi-Flash column, 24 g redisep cartridge) using 100% DCM to 2% MeOH in DCM to give the desired product as a viscous orange syrup (1.8 g, 69% yield).

[0160] To a solution of but-2-yn-1-ol (2.0 g, 1.0 equiv.) in 50 mL of methanol was added Lindlar's catalyst (0.2 g, 0.04 equiv.) at room temperature under 50 psi hydrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum to give the crude compound ((Z)-but-2-en-1-ol) (1.8 g, 67% yield). The crude compound was used directly in the next step.

[0161] To a stirred solution of (Z)-but-2-en-1-ol (1.8 g, 1.0 equiv.) in 40 ml of diethyl ether was added PBr3 (0.9 ml, 0.4 equiv.) dropwise at 0° C. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice water and the aqueous layer was extracted with diethyl ether (50 ml×2). The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a yellow liquid which was used directly in the next step (0.6 g, 16% yield).

[0162] To a stirred solution of 2-(1H-indol-3-yl)-N-(3-methoxybenzyl)ethan-1-amine (1.0 g, 1.0 equiv.) in 8 ml of DMF, K2CO3 was added and (Z)-1-bromobut-2-ene (0.5 g, 1.1 equiv.) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. Completion of the reaction was confirmed by TLC. The reaction mixture was diluted with water (30 ml) and DCM (50 ml). The organic layer was separated and washed with water (30 ml x 2). The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Combi-Flash column, 24 g redisep cartridge) using 100% DCM to 2% MeOH in DCM to give the desired product as a viscous orange syrup (0.5 g, 37% yield).

[0163] MS(ESI) m / e [M+H] + :335; HPLC purity: 98% (RT=6.2 min), 1 H NMR (400MHz, DMSO-d6) δ=10.74(s, 1H, indole NH), 7.39-7.29(m, 2H, aromatic CH), 7.23(s, 1H, aromatic CH), 7.12-6.99(m, 2H, aromatic CH), 6.93(d, J=6.8Hz, 3H, aromatic CH), 6.81(s, 1H, aromatic CH) ), 5.82-5.46(m, 2H, alkene CH), 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, alkene Me).

[0164] Example 20 - Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(3-methoxybenzyl)2-methylprop-2-en-1-amine 3-(3-Methoxybenzylaminoethyl)-1H-indole (0.61 equiv, 1 equiv) from Example 18 was alkylated with 3-bromo-2-methylpropene (1.1 equiv) in the same manner as described in Example 18 to give the desired compound (0.5 g, 60%). Purity (UPLC) 99.8%. M.S. 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).

[0165] Example 21 - Synthesis of 2-(1H-indol-3-yl)-N-(3-ethylbenzyl)-N-methylethan-1-amine 3-Ethylbenzaldehyde (1 eq) was reacted with methylamine (1.2 eq) in ethanol at room temperature overnight, followed by reductive amination using NaBH4 (2.5 eq) at room temperature for 2 h. After quenching the excess hydride, the amine was collected after extraction into aqueous acid, washed repeatedly with DCM, extracted back into DCM, washed with basic bicarbonate solution, dried over K2CO3, and the solvent was evaporated to dryness to give an oil (1 g, 91%). Coupling of the amine (1.2 eq) with 3-indoleacetic acid (1 eq) was carried out using polyphosphonic anhydride (2 eq) and triethylamine (4 eq) in acetonitrile at 0 C, which was allowed to warm to room temperature overnight. Workup included evaporation of the solvent, redissolving in DCM, washing with aqueous weak acid and weak base to remove starting material, drying over K2CO3, and evaporation of the solvent to give a semi-solid (1.1 g, 54%), which was then reduced with LIA1H4 (2 eq.) in THF at 0 C for 4 h. After reduction of the solvent, the compound was separated by flash chromatography EtOAc / heptane gradient to give the desired compound as a semi-solid (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 (mm, 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).

[0166] Example 22 - 3-(((2-(1H-indol-3-yl)ethyl)(methyl)amino)methyl)phenol The following reaction scheme was used: [ka]

[0167] To a stirred solution of 2-(1H-indol-3-yl)-N-methylethan-1-amine (0.7 g, 1.0 eq.) in 25 ml of DCE was added 3-methoxybenzaldehyde (0.6 g, 1.0 eq.) and NaBH(OAc)3 (1.3 g, 1.5 eq.). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM and quenched with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with DCM (30 ml x 2). The organic layer was then washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Combi-Flash column, 24 g redisep cartridge) using 100% DCM to 2% MeOH in DCM to give the desired product as a viscous orange syrup (0.5 g, 44% yield).

[0168] To a stirred solution of 2-(1H-indol-3-yl)-N-(3-methoxybenzyl)-N-methylethan-1-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 the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated NaHCO3 solution and the aqueous layer was extracted with DCM (50 ml×2). The organic layer was then washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Combi-Flash column, 24 g redisep cartridge) using 100% DCM to 5% MeOH in DCM, washed with n-heptane to give the desired product as an off-white solid (0.1 g, 25% yield).

[0169] MS(ESI) m / e [M+H] + :281;HPLC purity: 97.5% (RT=7.9 minutes), 1H NMR (400MHz, DMSO-d6) δ=10.76(s, 1H, indole NH), 9.28(s, 1H, aromatic OH), 7.44(d, J=7.9Hz, 1H, aromatic CH), 7.32(d, J=7.9Hz, 1H, aromatic CH), 7.28-6.98(m, 3H, aromatic CH), 6.97-6.90 (m, 1H, aromatic CH), 6.88-6.71(m, 2H, aromatic CH), 6.65(d, J=6.1Hz, 1H, aromatic CH), 3.52(s, 2H, CH2), 2.90(s, 2H, CH2), 2.67(s, 2H, CH2), 2.27(s, 3H, NMe).

[0170] Example 23 - Synthesis of N-(3-bromobenzyl)-2-(1H-indol-3-yl)-N-methylethan-1-amine The following reaction scheme was used: [ka]

[0171] To a stirred solution of 2-(1H-indol-3-yl)ethan-1-amine (5 g, 1.0 equiv.) in 50 ml of DCM was 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 room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction was quenched with ice water and the aqueous layer was extracted with DCM (50 ml×2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Combi-Flash column, 24 g redisep cartridge) using 30% ethyl acetate in n-heptane to give the desired product as a white solid (4.8 g, 70% yield).

[0172] To a stirred solution of N-(2-(1H-indol-3-yl)ethyl)propionamide (4.8 g, 1.0 equiv.) in 100 ml of THF was added dropwise a 2M solution of LAH (3.9 ml, 3.0 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated Na2SO4 solution (10 mL) and the white precipitate was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by combi flash chromatography to give 2-(1H-indol-3-yl)-N-methylethan-1-amine (3.2 g, 82% yield) as a viscous orange syrup.

[0173] 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 was added 3-bromobenzaldehyde (1.3 g, 1.2 equiv.) and NaBH(OAc)3 (1.8 g, 1.5 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM and quenched with saturated NaHCO3 solution. The organic layer was separated and washed with water followed by brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Combi-Flash column, 24 g redisep cartridge) using 10-40% ethyl acetate in n-heptane to give the desired product as a viscous orange syrup (0.6 g, 30% yield).

[0174] MS(ESI) m / e [M+H] + :343;HPLC purity: 98.6% (RT=5.4 minutes), 1H NMR (400MHz, DMSO-d6) δ=10.75(s, 1H, indole NH), 7.51(s, 1H, aromatic CH), 7.43(d, J=7.9Hz, 2H, aromatic CH), 7.37-7. 17(m, 3H, aromatic CH), 7.12(s, 1H, aromatic CH), 7.04(t, J=7.5Hz, 1H, aromatic CH), 6.94(t, J=8.0Hz 1H, aromatic CH), 3.56(s, 2H, CH2), 2.88(t, J=8.0Hz, 2H, CH2), 2.63(t, J=8.0Hz, 2H, CH2), 2.24(s, 3H, NMe).

[0175] Example 24 - Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(3-hydroxymethylbenzyl)methan-1-amine To a stirred solution of 2-(1H-indol-3-yl)-N-methylethan-1-amine (0.9 g, 1.2 eq.) and isophthalic acid monomethyl ester (1.0 eq.) and triethylamine (4 eq.) in 25 ml ACN at 0° C., polyphosphonic anhydride (2 eq.) was added and the reaction mixture was allowed to warm slowly to room temperature over 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by combi flash chromatography to give the desired product as an off-white solid (1.3 g, 76%). In a second step, the solid was reduced with LiAlH4 (3 eq.) in 30 ml THF at reflux for 16 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with saturated Na2SO4 solution (10 mL), the white precipitate was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by combi flash chromatography to give 2-(1H-indol-3-yl)-N-(3-hydroxymethylbenzyl)-N-methylethan-1-amine as a semi-solid (0.35 g, 30%).

[0176] MS(ESI) m / e [MH+] 295. HPLC purity: 98% (RT=7.56 min), 1 H NMR (400MHz, 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), 7.0 5(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).

[0177] Example 25 - Synthesis of 2-(1H-indol-3-yl)-N-(3-ethynylbenzyl)-N-methylethan-1-amine To an ethanolic solution containing 2-(1H-indol-3-yl)-N-methylethan-1-amine (0.5 g, 1.2 eq., as prepared in Example 23) and 3-ethynyl-benzaldehyde (1.1 eq.) stirred at room temperature overnight was added NaBH4 (2.5 eq.). The mixture was stirred for an additional 2 h before workup. The reaction mixture was quenched with ice water and extracted with ethyl acetate (50 ml x 2). The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Combi-Flash column, 24 g redisep cartridge) using 100% DCM to 2% MeOH in DCM to give the desired product as a viscous orange syrup (0.3 g, 22% yield). MS (ESI) m / e [MH+] 289.2. Purity HPLC 99.56%. 1 H NMR (400 MHz, DMSO-d6): Consistent with structure.

[0178] Example 26 - Synthesis of 2-(1H-indol-3-yl)-N-(2,3-methylenedioxybenzyl)-N-methylethan-1-amine To a stirred solution of 2-(1H-indol-3-yl)-N-methylethan-1-amine (0.5 g, 1.2 eq., prepared in Example 23) in 25 ml of acetonitrile, 2,3-methylenedioxy-benzoic acid (1.0 eq.), polyphosphonic anhydride (1.5 eq.) and triethylamine (3 eq.) were added at 0° C. and the reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with DCM and quenched with saturated NaHCO3 solution. The organic layer was separated and washed with water, followed by brine, and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Combi-Flash column, 24 g redisep cartridge) using 10-40% ethyl acetate in n-heptane to give the desired product (0.7 g, 69% yield). The resulting semi-solid was then reduced using 2 equivalents of LiAlH4 in THF at 0 C for 16 h to give the desired product, which was again purified by flash chromatography (0.3 g, 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 (mm, 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).

[0179] Example 27 - Synthesis of 2-(5-methoxy-1H-indol-3-yl)-N-(3-methoxybenzyl)-N-methylethan-1-amine The following reaction scheme was used: [ka]

[0180] To a stirred solution of 2-(5-methoxy-1H-indol-3-yl)acetic acid (0.5 g, 1.0 equiv.) in ACN was added 1-(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. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL) and extracted with EtOAc (2x50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by combi flash chromatography (Combi-Flash column, 24 g redisep cartridge) using 5% DCM:MeOH to give the product as a brown solid (0.62 g, 75% yield).

[0181] 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 dropwise 2M LAH solution (0.14 g, 2.0 equiv.). The reaction mixture was stirred at 0° C. for 4 h under N2 atmosphere. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with saturated Na2SO4 solution (10 mL) and the white precipitate was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography to give 2-(5-methoxy-1H-indol-3-yl)-N-(3-methoxybenzyl)-N-methylethan-1-amine (FT230, 0.35 g, 60%) as an off-white solid.

[0182] MS(ESI) m / e [M+H] + :325; HPLC purity: 96.44% (RT=4.0 min), 1H NMR (400MHz, DMSO-d6) δ=10.59(s, 1H, indole NH), 7.27-7.12(m, 2H, aromatic CH), 7.08(d, J=2.0Hz, 1H, aromatic CH), 6.88(d, J=5.4Hz, 3H, aromatic CH), 6.80(d, J=7.8Hz , 1H, aromatic CH), 6.68(dd, J=2.4, 8.8Hz, 1H, aromatic CH), 3.70(d, J=2.0Hz, 6H, OMe), 3.53(s, 2H, CH2), 2.84(t, , J=4.0Hz 2H, CH2), 2.62(s, 2H,CH2), 2.26(s, 3H, NMe).

[0183] Example 28 - Synthesis of 2-(1H-indol-3-yl)-N-(2-methoxybenzyl)-N-methylethan-1-amine The following reaction scheme was used: [ka]

[0184] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (1 g, 1.0 equiv.) in ACN solvent was added 1-(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 room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL) and extracted with EtOAc (2x50 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by combi flash chromatography to give the desired product (1.2 g, 68% yield).

[0185] 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 dropwise a solution of 2M LAH solution (0.3 g, 2.0 equiv.). The reaction mixture was stirred at 0° C. for 4 h under N2 atmosphere. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated Na2SO4 solution (10 mL) and the white precipitate was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by combi flash chromatography to give 2-(1H-indol-3-yl)-N-(2-methoxybenzyl)-N-methylethan-1-amine (FT231, 0.31 g, 27%) as an off-white solid.

[0186] MS(ESI) m / e [M+H] + :295; HPLC purity: 98% (RT=5.9 minutes), 1 H NMR (400MHz, DMSO-d6) δ=10.74(s, 1H, indole NH), 7.44(d, J=8.0Hz, 1H, aromatic CH), 7.36-7.29(m, 2H, aromatic CH), 7.25-7.17(m, 1H, aromatic CH), 7.12(d, J=2. 3Hz, 1H, aromatic CH), 7.08-7.01(m, 1H, aromatic CH), 6.99-6.86(m, 3H, aromatic CH), 3.76(s, 3H, OMe), 3.55(s, 2H, CH2), 2.88(s, J=4.0Hz) 2H, CH2), 2.65(s,, J=8.0Hz, 2H, CH2), 2.26(s, 3H, NMe).

[0187] Example 29 - Synthesis of N-(2-(1H-indol-3-yl)ethyl)-N-(3-methoxybenzyl)prop-2-en-1-amine The following reaction scheme was used: [ka]

[0188] To a stirred solution of 2-(1H-indol-3-yl)acetic acid (0.6 g, 1.0 equiv.) in 10 ml ACN solvent, N-(3-methoxybenzyl)prop-2-en-1-amine (0.7 g, 1.2 equiv.) was added followed by T3P (2.2 g, 2.0 equiv.) and Et3N (1.0 g, 3.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 16 hours 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 Na2SO4 and concentrated in vacuo. The crude material was purified by combi flash chromatography to give the desired product as an off-white solid (1.1 g, 96% yield).

[0189] 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.) in portions. The reaction mixture was then stirred continuously at 0° C. to room temperature for 1 h. After 1 h, 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 room temperature for 12 h. After completion, the reaction mixture was quenched with saturated Na2SO4 solution (10 mL) and the white precipitate was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography to give N-(2-(1H-indol-3-yl)ethyl)-N-(3-methoxybenzyl)prop-2-en-1-amine (FT233, 0.6 g, 59%) as a brown solid. MS(ESI) m / e [M+H] + :321;HPLC purity: 99% (RT=5.8 min), 1H NMR (400MHz, DMSO-d6) δ=10.73(s, 1H, indole NH), 7.38(d, J=7.75Hz, 1H, aromatic CH), 7.3(d, J=8.0Hz, 1H, aromatic CH), 7.22(t, J=7.8 8Hz, 1H, aromatic CH), 7.11-6.98(m, 2H, aromatic CH), 6.91(s, 3H, aromatic CH), 6.8(d, J=7.5Hz, 1H, aromatic CH), 6.00-5.8 0 (m, 1H, alkene CH), 5.24 (d, J = 17.3 Hz, 1H, alkene CH), 5.15 (d, J = 10.26 Hz, 1H, alkene CH), 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).

[0190] Comparative examples A~C Using methods similar to those described above for the compounds of Examples 1 and 8, the following compounds were synthesized and tested:

[0191] [Table 9]

[0192] [Table 10]

[0193] The compounds of Comparative Examples A to C are outside the scope of the present invention. The results are reported in Table 1.

[0194] [Table 11]

[0195] It is therefore proposed that serotonin-2A agonists can be tested and used to treat a number of mood disorders with new mechanisms of action, thereby rescuing patients who are not treatable by current medical options. However, agonists of serotonin 2A are often also agonists of the mostly homologous serotonin-2B receptor. As mentioned above, agonism of the serotonin 2B receptor can cause valve stiffening by fibrotic mechanisms, and was exemplified by the compound fenfluramine, which was withdrawn from the weight loss pharmaceutical market due to this adverse reaction in overweight patients. The present invention provides new molecules, methods and uses of these molecules based on benzyl-functionalized tryptamines that show potent serotonin-2A receptor agonism and are atypical serotonin-2B antagonists, and therefore do not show the potential for cardiotoxic adverse reactions. The present invention may find utility in novel mood indications, neurorecovery / repair (neuroplasticity), and potential as a frequent or chronic daily medicine used by patients. Furthermore, the present invention may enable patients with pre-existing cardiovascular vulnerability, and who are otherwise precluded from the use of classical serotonin agonists that more traditionally activate serotonin-2B, to use these molecules after their efficacy and safety for treating these disorders of the brain have been adequately demonstrated.

[0196] While the present invention has been described with reference to exemplary embodiments and examples, this description is not intended to be construed in a limiting sense. Thus, various modifications of the exemplary embodiments, as well as other embodiments of the invention, will be apparent to those skilled in the art upon reference to this description. It is therefore intended that the appended claims cover any such modifications and embodiments.

[0197] All publications, patents, and patent applications referenced in this specification are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

Claims

1. Formula I: 【Chemistry 1】 [In the formula, R is hydrogen; R 1 is hydrogen or methoxy; R 2 is selected from methyl, 2-propenyl, cis-2-butenyl, trans-2-butenyl, 2-methyl-2-propenyl, and i-propyl; R 3 is hydrogen or methoxy; R 4 is selected from hydroxyl, halogen, methoxy, ethynyl, ethyl, and methyl substituted with hydroxyl; R 5 is hydrogen; and R 6 is hydrogen, however, (a)R 1 is hydrogen, and R 2 is methyl, R 3 and R 4 are both not methoxy, and (b)R 1 is hydrogen and R 2 is methyl and R 3 is hydrogen, and R 4 When is a halo, R 4 is bromo] or a pharmaceutically acceptable salt thereof.

2. R 2 The compound of claim 1, wherein is methyl.

3. R 4 is methoxy or halogen.

4. R 4 The compound of claim 1, wherein is bromo.

5. The compound is 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

6. The compound is 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

7. The compound is 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

8. The compound is 【Transformation 5】 or a pharmaceutically acceptable salt thereof.

9. The compound is 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

10. The compound is 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

11. The compound is 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

12. The compound is 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

13. The compound is 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. 15. The pharmaceutical composition of claim 14, wherein the composition is suitable for oral administration.

16. 15. The pharmaceutical composition of claim 14, wherein the composition is suitable for subcutaneous injection.

17. 15. The pharmaceutical composition of claim 14, wherein the composition is suitable for intravenous injection.

18. 15. The pharmaceutical composition of claim 14, wherein the composition is suitable for administration to the nasal mucosa.

19. A parenteral injection kit for reconstitution comprising a vial containing a lyophilized compound according to any one of claims 1 to 13.

20. 15. The pharmaceutical composition of claim 14 for treating a central nervous system (CNS) disease or disorder.

21. CNS disease or disorder 2A The pharmaceutical composition of claim 20, wherein the agonism is relieved.

22. 21. The pharmaceutical composition of claim 20, wherein the disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression, medication-resistant depression, alcohol dependence, tobacco addiction, cocaine addiction, opioid dependence, inflammation, cluster headache, gambling disorder, eating disorders, chronic pain, chronic fatigue, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

23. 21. The pharmaceutical composition of claim 20, wherein the disease or disorder is selected from generalized anxiety disorder (GAD), depression, major depressive disorder (MDD), postpartum depression, medication-resistant depression, cluster headache, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).

24. 21. The pharmaceutical composition of claim 20, wherein the composition is administered in combination with a further antidepressant.

25. 21. The pharmaceutical composition of claim 20, administered in conjunction with psychotherapy.

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