Azocino[4,5,6-CD]indoles as serotonin receptor modulators

Abstract

The present disclosure provides azocino[4,5,6-cd]indoles as serotonin receptor modulators. Uses of said compounds in the treatment of medical disorders, such as neurological or psychiatric disorders, and processes of synthesizing said compounds are also provided.

Description

[0001] AZOCINO[4,5,6-CD]INDOLES AS SEROTONIN RECEPTOR MODULATORS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to United States Provisional Patent Application No. 63 / 676,553 filed July 29, 2024, and United States Provisional Patent Application No. 63 / 697,103 filed September 20, 2024, the disclosures of which are incorporated herein by reference in their entireties.

[0004] BACKGROUND

[0005] Psychiatric illnesses, including depression, anxiety, and posttraumatic stress, represent a serious detriment to health and effective human functioning worldwide. Although a number of psychiatric medications are available and extensively prescribed, they fail to deliver relief for many individuals. The prevalence of psychiatric disorders, particularly depression and anxiety, is on an upward trajectory despite a concomitant increase in prescriptions for psychiatric standards of care approved to address those conditions. For those patients who do respond, changes in mood and behavior are often slow to manifest, patients can return to baseline after discontinuation of pharmacotherapy, and tapering is often required when discontinuing use of these pharmacotherapies. In recent years, these persistent unmet needs for improved pharmacotherapies to treat psychiatric disorders have led to the consideration of previously maligned options. For example, classical serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT), have been considered experimental therapeutics for a variety of psychiatric indications. The FDA has granted two breakthrough treatment designations for psilocybin-related pharmaceutical offerings and one breakthrough treatment designation for an LSD formulation, indicating the willingness of regulatory agencies to approve psychedelic agents showing sufficient psychiatric utility.

[0006] However, such compounds induce profound hallucinogenic effects, which can temporarily inhibit the normal functioning of individuals so treated. Accordingly, these compounds are currently classified in Schedule I under the UN Single Convention on Narcotic Drugs and the US Controlled Substances Act due to their alleged high abuse potential, lack of currently approved medical use, and alleged lack of established safety. Such effects, therapeutic and hallucinogenic, are mediated largely through the engagement of serotonin (5-HT) receptors. Of particular importance is the modulation of the serotonin 2A receptor (5-HT2A R), which is responsible for the problematic hallucinogenic activity of these compounds but is also thought to be critical for their purported therapeutic effects. In 5-HT2A affecting compounds, interaction with the Gq / Gll signaling pathway for the 2A R at a threshold efficacy is fully predictive of hallucinogenic activity, while interaction with BDNF TrkB receptors facilitates cortical neuronal dendritic arborization defining of serotonergic psychoplastigens. Additionally, because high synaptic 5-HT concentrations cause hallucinations and many compounds that interact with 5-HT2A are 5-HT-releasing agents, affinity for SERT can also impact hallucinogenic potential and alter effects. Accordingly, serotonergic compounds that can deliver therapeutic benefits while limiting hallucinogenic activity are desirable in instances when hallucinations are therapeutically undesirable. Both hallucinogenic and non- hallucinogenic psychoplastigenic compounds in this class are showing themselves to be of high therapeutic value.

[0007] At several points in the past, the derivatization of known serotonergic compounds facilitated the discovery of principally dopaminergic rather than serotonergic agents when serotonergic agents were initially expected. Examples include Pergolide, a structural analog of LSD, and Eli Lilly’s / V-dimethyl- 1 ,3,4,5-tetrahydrobenzo[c<i]indol-4-amine, a structural analog of DMT. Direct or indirect (i.e., serotonergic) modulation of the dopamine system can be used therapeutically in dopamine-related disorders, including Parkinson’s disease, restless legs syndrome, depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). These conditions have unmet needs for improved pharmacotherapies that include both selective (Parkinson’s disease) and dual receptor activation (depression) that cannot be met with the currently available treatments.

[0008] Additional drugs are urgently needed in a broad range of psychiatric and neurological conditions. This disclosure addresses this as well as other needs.

[0009] SUMMARY

[0010] The present disclosure provides azocino[4,5,6-cd]indole compounds and derivatives thereof, processes of making said compounds, as well as their use in the treatment of medical disorders.

[0011] In one aspect, a compound is provided of Formula I:

[0012] or a pharmaceutically acceptable salt or derivative thereof; wherein all variables are as defined herein.

[0013] In another aspect, a compound is provided of Formula II: or a pharmaceutically acceptable salt or derivative thereof; wherein all variables are as defined herein.

[0014] In another aspect, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0015] In another aspect, a method of treating a medical disorder, such as a neurological or psychiatric disorder, in a subject is also provided. In some aspects, the method comprises administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof.

[0016] In another aspect, a process is provided for synthesizing a compound of Formula Ila:

[0017] the process comprising irradiating a compound of Formula III: to form the compound of Formula Ila, wherein all variables are as defined herein.

[0018] A process for the synthesis of a compound of Formula Ila:

[0019] the process comprising irradiating a compound of Formula Illa: to form the compound of Formula Ila, wherein all variables are as defined herein.

[0020] In another aspect, a compound of Formula Ila is provided prepared according to a process described herein.

[0021] The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description, the drawings, and the claims.

[0022] DESCRIPTION OF DRAWINGS

[0023] FIG. 1 is a scheme depicting pharmacophoric similarities between phenethylamine and tryptamine compounds and the compounds described herein. FIGs. 2A and 2B provides (FIG. 2A) representative structures of an ergoline (LSD-25) and phenethylamine compound (25CN-NBOH) and shows the representative binding of said compounds to the 5-HT2A receptor and (FIG. 2B) the representative binding of an azocinoindole structure along with that of an ergoline (LSD-25) and phenethylamine (25CN- NBOH) to the 5-HT2A receptor.

[0024] FIG. 3 provides an exemplary scheme for the synthesis of compounds described herein.

[0025] FIG. 4 provides a proposed mechanism for the photochemical cyclization used in the preparation of compounds described herein.

[0026] FIGs. 5A to 5D provide photographs of an exemplary reaction setup for the photochemical cyclization used in the preparation of compounds described herein.

[0027] FIG. 6 provides a comparison of the structure of serotonin and related azocinoindole compounds described herein.

[0028] FIG. 7 provides a comparison of the structure of DMT, psilocin, and the azocinoindole compounds described herein to explain the potential resistance of said compounds to MAO deamination.

[0029] FIG. 8 provides a comparison of the structure of pergolide and related azocinoindole compounds described herein.

[0030] FIG. 9 provides computationally determined binding scores for representative compounds of the present disclosure. Coded numerical scale where a low score indicates stronger binding interactions in-silico, while a higher score indicates weaker binding interactions in-silico. Comparators were built and docked alongside the described compounds. Note docking scores are calculated based on electronic interactions only and do not take into account the potency of activation of downstream receptor-linked pathways (such as Gq).

[0031] FIGs. lOA to 10D provide (FIG. 10A) In-vitro 5-HT2A mediated Gqactivation dose-response curves for azocinoindole compounds shown as measured by BRET dissociation of the receptor and G protein. (FIG. 10B) Dose-response curves plotted together for comparison (FIG. IOC) In-silico docking results in the 5-HT2A / LSD receptor ligand co-crystal (PDB ID 7WC6) highlighting shared residue interactions in the orthosteric binding pocket between the full agonist ligand C -Met-CFLNH-Tmn and partial agonist ligand LSD. (FIG. 10D) 5- HT2A / Gqactivation potency versus efficacy of D1-D5 azocinoindoles alongside known 5- HT2Aligands. The gradient bar on the x-axis shows variable potency, while the gradient bar on the y-axis shows the pharmacologic class associated with ligand efficacy. FIGs. 11 A to 11C provide schemes depicting a comparison of (FIG. 11 A) Witkop’s seminal work, (FIG. 11B) Dillon’s extension to dipeptides, and (FIG. 11C) the reactions as described herein in the experimental examples.

[0032] FIG. 12 depicts the effect of added acid on reaction conversion of Gly-Tmn Bl to C4-Gly- CONH-TMN Cl.

[0033] FIG. 13 depicts the effect of methanol on conversion of Bl to Cl at 4 h.

[0034] FIG. 14 provides a scheme depicting the substrate scope for photocyclization of a- aminotryptamides. All reactions performed at 0.01 M on a 2 mmol scale. Irradiation times varied. ^Carried out at a concentration of 0.025 M on a 17 mmol scale without added methanol. Yield over 2 steps from Cbz-protected amine. Isolated as a mixture of diastereomers. '7Yield based on recovered starting material. 'The reaction was carried out on a 1 mmol scale.fConcentration 0.005 M.

[0035] FIG. 15 provides a comparison of substituent effects on photocylization.

[0036] FIG. 16 depicts the effect of chromophores on the photocylization.

[0037] FIG. 17 depicts the effect of N-methylation on photocyclization.

[0038] FIG. 18 provides a comparison of Lucent 360 LC-MS yields with the isolated yields of product from the Rayonet reactor.

[0039] FIG. 19 provides a scheme depicting a proline transamidation product.

[0040] FIG. 20 provides a scheme depicting formation of a C2 isomer.

[0041] FIG. 21 provides a scheme depicting the irradiation of tryptophan ester dipeptide.

[0042] FIG. 22 provides a scheme depicting irradiation of a-hydroxytryptamides.

[0043] FIG. 23 provides a scheme depicting irradiation of a-acetoxytryptamides. "All reactions performed at 0.005 on a 2 mmol scale. Irradiation times varied. ^Reaction performed at a concentration of 0.01 M.cReaction performed with acetonitrile as cosolvent on a 5 mmol scale. ^Isolated as a mixture of diastereomers.

[0044] FIG. 24 provides a scheme depicting irradiation of a-lactone tryptamides.

[0045] FIG. 25 depicts azocinoindoles as structural hybrids of 5-HT2A ligands.

[0046] FIG. 26 provides a scheme depicting compounds reduced for in vitro testing.

[0047] FIG. 27 provides a scheme depicting a comparison of formation of C2 or C4 isomers during irradiation of a-aminotryptamides, a-acetoxytryptamides, a-chlorotryptamides, and a- bromotryptamides . DETAILED DESCRIPTION

[0048] The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known aspects. Many modifications and other aspects disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain, benefiting from the teachings presented in the descriptions herein and the associated drawings. Therefore, it is understood that the disclosures are not limited to the specific aspects disclosed and that modifications and other aspects are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0049] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0050] As apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure.

[0051] Any recited method can be carried out in the order of events recited or any other order that is logically possible. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not explicitly state in the claims or descriptions that the steps are to be limited to a particular order, it is in no way intended that an order be inferred in any respect. This holds for any possible non-express basis for interpretation, including logic concerning the arrangement of steps or operational flow, meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0052] All publications mentioned herein are incorporated by reference to disclose and describe the methods or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure before the filing date of the present application. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0053] It is also to be understood that the terminology herein describes particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0054] Before describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

[0055] Definitions

[0056] As used herein, “comprising” is interpreted as specifying the presence of the stated features, integers, steps, or components but does not preclude the presence or addition of one or more features, integers, steps, components, or groups thereof. Moreover, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.”

[0057] As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context dictates otherwise.

[0058] Ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. Further, the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. There are many values disclosed herein, and each value is also disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value and to “about” another particular value. Similarly, when values are expressed as approximations, using the antecedent “about,” the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0059] When a range is expressed, a further aspect includes from the one particular value and to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z’ as well as the ranges of Tess than x,’ Tess than y.’ and Tess than z.’ Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z’ as well as the ranges of ‘greater than x,’ greater than y,’ and ‘greater than z.’ In addition, the phrase “about ‘x’ to ‘y’,” where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’.”

[0060] Such a range format is used for convenience and brevity and, thus, should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. To illustrate, a numerical range of “about 0. 1 % to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5% but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0061] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate, larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement error, and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, as used herein, “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter, or other quantity or characteristic is “about,” “approximate,” or “at or about,” whether or not expressly stated to be such. Where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself unless expressly stated otherwise.

[0062] As used herein, the term “therapeutically effective amount” refers to an amount sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the particular compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to permanently halt the progression of the disease. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition can also be delaying the onset or even preventing the onset.

[0063] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to increase the dosage gradually until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration. Consequently, single-dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The individual physician can adjust the dosage in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the disclosure (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. However, a patient may insist on a lower or tolerable dose for medical reasons, psychological reasons, or virtually any other reason.

[0064] A response to a therapeutically effective dose of a disclosed compound or composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following the administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied, for example, by increasing or decreasing the amount of a disclosed compound or pharmaceutical composition, changing the disclosed compound or pharmaceutical composition administered, changing the route of administration, changing the dosage timing, and so on. Dosage can vary and can be administered in one or more doses daily for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. As used herein, “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur. The description includes instances where said event or circumstance occurs and those where it does not.

[0065] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g., human). “Subject” can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to a human and constituents thereof.

[0066] As used herein, “treating” and “treatment” generally refer to obtaining a desired pharmacological or physiological effect. The effect can he but does not necessarily have to be prophylactic in preventing or partially preventing a disease, symptom, or condition. The effect can be therapeutic regarding a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a disorder in a subject, particularly a human. It can include any one or more of the following: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e.. arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease or its symptoms or conditions. The term “treatment,” as used herein, can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (i.e., subjects in need thereof) can include those already with the disorder or those in whom the disorder is to be prevented. As used herein, the term “treating” can include inhibiting the disease, disorder, or condition, e.g., impeding its progress, and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such an agent does not treat the cause of the pain.

[0067] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0068] As used herein, “therapeutic” can refer to treating, healing, or ameliorating a disease, disorder, condition, or side effect or decreasing the rate of advancement of a disease, disorder, condition, or side effect. As used herein, the term or phrase “effective,” “effective amount,” or “conditions effective to” refers to such amount or condition that is capable of performing the function or property for which an effective amount or condition is expressed. As will be pointed out below, the exact amount or particular condition required will vary from one aspect to another, depending on recognized variables such as the materials employed and the processing conditions observed. Thus, it is not always possible to specify an exact “effective amount” or “condition effective to.” However, it should be understood that an appropriate effective amount will be readily determined by one of ordinary skill in the art using only routine experimentation. Although the operations of exemplary aspects of the disclosed method may be described in a particular sequential order for convenient presentation, it should be understood that disclosed aspects can encompass an order of operations other than the particular sequential order disclosed. For example, operations described sequentially may, in some cases, be rearranged or performed concurrently. Further, descriptions and disclosures provided in association with one particular aspect are not limited to that aspect and may be applied to any aspect disclosed. As used herein, the term "substantially" means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance generally, typically, or approximately occurs.

[0069] Still further, the term “substantially” can, in some aspects, refer to at least about 90 %, at least about 91 %, at least about 92 %, at least about 93 %, at least about 94 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, or about 100 % of the stated property, component, composition, or other condition for which substantially is used to characterize or otherwise quantify an amount.

[0070] As used herein, the term “substantially,” in, for example, the context “substantially identical” or “substantially similar,” refers to a method or a system, or a component that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% by similar to the method, system, or the component it is compared to.

[0071] “Antagonism” refers to the inactivation of a receptor or enzyme by a modulator or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur.

[0072] “Antagonist” or “neutral antagonist” refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response. “Hallucinogenic” or “hallucinogen” refers herein to an agonist ligand of the 5-HT2A receptor that elicits greater than 75% of the efficacy of serotonin in activation of specifically the Gqeffector protein-coupled serotonin 2A receptor and its associated downstream signaling pathway. By this definition, 70-75% efficacy ligands are considered “partially hallucinogenic,” and <70% efficacy ligands are considered “non-hallucinogenic.” This is consistent with the most up-to-date literature definition and will be comprehensible to a person with sufficient skill in the art.

[0073] “IC50” refers to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process. For example, IC50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. In some aspects, an IC50 is determined in an in vitro assay system. In some aspects, IC50 refers to the concentration of a modulator (e.g., an antagonist or inhibitor) that is required for 50% inhibition of a receptor, for example, 5HT2A-

[0074] “Ligand” refers to a compound with activity at a receptor site target, including agonism, partial agonism, antagonism (competitive, noncompetitive, and covalent), inverse agonism, allosteric modulation (positive and negative), and chaperone-like effects (promoter of a stable receptor subunit dimer, etc.).

[0075] “Modulation” or “modulator” includes any change of basal function induced by a drug at a receptor target, including but not limited to antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0076] “Psychoplastigen” or “psychoplastigenic” refers herein to an agonist or partial agonist ligand of the 5-HT2A receptor and / or the brain-derived neurotrophic factor (BDNF) tyrosine receptor kinase beta (TrkB) receptor that elicits dendritic arborization in cortical neurons, while simultaneously possessing <70% efficacy in activation of specifically the Gqeffector protein- coupled 5-HT2A receptor and its associated downstream signaling pathway. This is consistent with the most up-to-date literature definition and will be comprehensible to a person with sufficient skill in the art.

[0077] “Positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.

[0078] “Releaser” or “releasing agent” refers to a compound that increases the synaptic availability of a neurotransmitter by facilitating exocytosis of neurotransmitter vesicles and / or affecting the neurotransmitter’s reuptake transporter (i.e., reversing its direction of transport).

[0079] Chemical Definitions Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0080] The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as rotamers, as if each is specifically described unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (7?) or (5) configuration. The compounds provided herein may either be enantiomerically pure or be diastereomeric or enantiomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its ( ) form is equivalent, for compounds that undergo epimerization in vivo, to the administration of the compound in its (S) form. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture.

[0081] Compounds described herein may contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, all such possible isomers are contemplated, as well as mixtures of such isomers. Compounds described herein may also exist as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form. Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, all possible tautomers of the compounds described herein are contemplated.

[0082] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=0)NH2 is attached through the carbon of the keto (C=O) group.

[0083] The term “substituted,” as used herein, means that any one or more hydrogen atoms on the designated atom or group are replaced with a moiety selected from the indicated group, provided that the designated atom’s normal valence is not exceeded and the resulting compound is stable. For example, when the substituent is oxo (i.e., =0), two hydrogen atoms on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridine. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and / or can be formulated into a form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. A stable moiety or substituent group is one that does not degrade, react, or fall apart within the period necessary for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art.

[0084] Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to: halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2- C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, AxO-(C0-C6alkyl)-, AxS-(C0-C6alkyl)-, (AW)-(C0-C6alkyl)-, AzC(0)-(C0-C6alkyl)-, AzC(N)-(C0-C6alkyl)-, and AZS(0)-(C0-C6alkyl)-, and AzS(0)2-(C0-C6alkyl)-, wherein Axand A-’’ are independently selected at each occurrence from A“, AZC(O)-, AZC(N)-, AZS(O)-, and AZS(O)2-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) B groups as allowed by valency; wherein Azis independently selected at each occurrence from hydrogen, halo, Ci- C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6-membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -OA“, -SA“, and -NA“Ab', each of which may be optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) B groups as allowed by valency; wherein Aaand Abare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6-membered heterocycle)-(C0-C3alkyl)-, (5- to 10- membered monocyclic or bicyclic aryl)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more (e.g., 1, 2, 3, 4, or 5) B groups as allowed by valency; and wherein B is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, APO-, ApS-, AW, A°C(O)-, A°C(O)-O-, A°C(O)-NA’-, A°S(O)2-, A°S(O)2-O-, and A°S(0)2-NAq-, wherein A" is independently selected at each occurrence from Ap, halo, APQ- , and APA9N-, and wherein A1’ and Aqare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(Co- C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-.

[0085] The terms for various functional groups as used herein are not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent groups, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person in the context in which said functional groups are recited.

[0086] _ 1

[0087] As used herein, the symbol “ ?” (which hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, “ Xy _ s ” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the nondepicted chemical entity can be specified by inference. For example, the compound CH3-R3, Xy _ i wherein R3is H or “ s ,” implies that when R3is “XY,” the point of attachment bond is the same bond as the bond by which R3is depicted as being bonded to CH3.

[0088] “Halo” or “halogen” indicates, independently, any of fluoro, chloro, bromo, or iodo.

[0089] The term “nitro,” as used herein, is represented by the formula — NO2.

[0090] The term “cyano,” as used herein, is represented by the formula — CN

[0091] The term “azido,” as used herein, is represented by the formula -N3.

[0092] The term “oxo,” as used herein, is represented by the formula =0.

[0093] “Alkyl” is a straight chain or branched saturated aliphatic hydrocarbon group. In certain aspects, the alkyl is C1-C2, C1-C3, or C1-C6(i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length). The specified ranges as used herein indicate an alkyl group with the length of each member of the range described as an independent species. For example, C1-C6alkyl, as used herein, indicates an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species, and Ci-C4 lkyl, as used herein, indicates an alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When Co-Cnalkyl is used herein in conjunction with another group, for example (Cs-CvcycloalkyljCo-Cralkyl, or -Co- C4(C3-C?cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (Coalkyl), or attached by an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups, such as heteroatoms, such as -O-Co- C4alkyl(C3-C?cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3- dimethylbutane. In some aspects, the alkyl group is optionally substituted as described herein. “Haloalkyl” refers to an alkyl group that is substituted with one or more halo groups, e.g., fluoro, chloro, bromo, iodo, or combinations thereof.

[0094] “Cycloalkyl” is a saturated or partially unsaturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused or bridged fashion. Non-limiting examples of typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some aspects, the cycloalkyl group is optionally substituted as described herein.

[0095] “Alkenyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, each of which is independently either cis or trans, that may occur at a stable point along the chain. Non-limiting examples include C2-C4alkenyl and C2- Cealkenyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkenyl group, with each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one aspect, the alkenyl group is optionally substituted as described herein.

[0096] “Alkynyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C4alkynyl or C2-C6alkynyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges, as used herein, indicate an alkynyl group with each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5- hexynyl. In one aspect, the alkynyl group is optionally substituted as described herein.

[0097] “Aryl” indicates an aromatic group containing only carbon in the aromatic ring or rings. In one aspect, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 4- to 7- or 5- to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, B, P, Si, and S to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1 -naphthyl and 2-naphthyl. In one aspect, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one aspect, the aryl group is optionally substituted as described herein.

[0098] The term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, O, and S. The term heterocycle includes monocyclic 3- to 12-membered rings, as well as bicyclic 5- to 16-membered ring systems (which can include fused, bridged, or spiro bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, and -S-S- portions. Examples of saturated heterocycle groups include saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]: saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2, 3, 4, 4a, 9,9a- hexahydro-lH-3-aza- fluorenyl, 5,6,7-trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro- 2H-benzo[l,4]oxazinyl, benzofl, 4]dioxanyl, 2,3,-dihydro-lH-benzo[d]isothazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Bicyclic heterocycle includes groups wherein the heterocyclic radical is fused with an aryl radical and the point of attachment is the heterocycle ring. Bicyclic heterocycle also includes heterocyclic radicals that are fused with a carbocyclic radical. Representative examples include, but are not limited to, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indoline and isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms. In one aspect, the heterocycle group is optionally substituted as described herein.

[0099] “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring containing from 1 to 4, or, in some aspects, 1, 2, or 3, heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 4, or in some aspects from 1 to 3 or from 1 to 2, heteroatoms selected from N, O, S, B, or P, with remaining ring atoms being carbon. In one aspect, the only heteroatom is nitrogen. In one aspect, the only heteroatom is oxygen. In one aspect, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 to 6 ring atoms. In some aspects, bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is groups containing 8 or 10 ring atoms in which one 5-, 6-, or 7-membered aromatic ring which contains from 1 to 4 heteroatoms selected from N, O, S, B, or P is fused to a second aromatic or non-aromatic ring, wherein the point of attachment is an aromatic ring. When the total number of S and O atoms in the heteroaryl ring exceeds 1, these heteroatoms are not adjacent to one another within the ring. In one aspect, the total number of S and O atoms in the heteroaryl ring is not more than 2. In another aspect, the total number of S and O atoms in the heteroaryl ring is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In one aspect, the heteroaryl group is optionally substituted as described herein.

[0100] A “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like) or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water, an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include salts that are acceptable for human consumption and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic salts. Examples of such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)I-4-COOH, and the like, or using a different acid that produced the same counterion. Suitable counterions found in pharmaceutically acceptable salts described herein include, but are not limited to, cations such as calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, meglumine, potassium, procaine, sodium, triethylamine, and zinc, and anions such as acetate, aspartate, benzenesulfonate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, teoclate, and tosylate. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, PA., p. 1418 (1985).

[0101] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compound. Exemplary derivatives include, but are not limited to, salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0102] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high- performance liquid chromatography (HPLC) and mass spectrometry (MS), gaschromatography mass spectrometry (GC-MS), and similar, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Both traditional and modem methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers.

[0103] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers, such as Sigma- Aldrich (formally MilliporeSigma, Burlington, MA) or Thermo Fisher Scientific Inc. (Waltham, MA), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons, 2007); Organic Reactions (John Wiley and Sons, 2004); March's Advanced Organic Chemistry, (John Wiley and Sons, 8thEdition); and Larock's Comprehensive Organic Transformations (John Wiley and Sons, 3rdedition, 2017).

[0104] Compounds

[0105] The present disclosure provides compounds useful in treating medical disorders. The disclosed compounds can be used as modulators of serotonin receptors and can be useful for the treatment of diseases and disorders that may be affected by such activity, such as neurological and psychiatric disorders.

[0106] In some aspects, a compound is provided of Formula I

[0107] or a pharmaceutically acceptable salt or derivative thereof; wherein:

[0108] R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0109] R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, C1- C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(O)-(C0-C6alkyl)-, and RzS(O)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0110] R3, R7, and R8are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RzC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6 alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from Y as allowed by valency;

[0111] R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, Cz-Ce alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(N)-(C0-C6alkyl)-, RzS(O)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from

[0112] Y as allowed by valency;

[0113] R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0114] R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(CI-C6 alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RZC(N)-(C1-C6alkyl)-, RZS(O)- (C1-C6alkyl)-, and RzS(O)2-(C1-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0115] R4and R5or R7and R8are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0116] R3and R4or R4and R7or R7and R9are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4)

[0117] Y groups as allowed by valency; or

[0118] R3and R6or R4and R6or R6and R7or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0119] Rxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)- , and RZS(O)2-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0120] Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C?cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0121] Raand Rbare independently selected at each occurrence from hydrogen, Ci-G>alkyl, C1- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- memberedheterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0122] Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°C(O)-NRq-, R°S(O)2-, ROS(O)2-O-, and R°S(0)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2- Ce alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, with the proviso that if R10is methoxy, at least one of R1, R2, R3, Rs, R5, R6, R7, R8, R9, R11, or R12is not hydrogen.

[0123] In another aspect, a compound is provided of Formula II

[0124] or a pharmaceutically acceptable salt or derivative thereof; wherein:

[0125] R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0126] R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, Ci- Ce alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(O)-(C0-C6alkyl)-, and RzS(O)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0127] R3is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, Ci- C6 alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6 alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from Y as allowed by valency;

[0128] R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, Cz-Ce alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, or (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1 , 2, 3, or 4) groups selected from Y as allowed by valency;

[0129] R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0130] R9is selected from, hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(CI-C6 alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RZC(N)-(C1-C6alkyl)-, RZS(O)- (C1-C6alkyl)-, and RzS(O)2-(C1-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0131] R4and R5are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0132] R3and R4are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0133] R3and R6or R4and R6or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; Rxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)- , and RzS(O -, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0134] Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- memberedheterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more (e.g., 1 , 2, 3, or 4) Y groups as allowed by valency; and

[0135] Raand Rbare independently selected at each occurrence from hydrogen, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C?cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0136] Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°C(O)-NRq-, R°S(O)2-, ROS(O)2-O-, and R°S(O)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6alkyl, Ci-G, haloalkyl, C2-C6alkenyl, C2- G, alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, with the proviso that if R10is methoxy, at least one of R1, R2, R3, R5, R5, R6, R9, R11, or R12is not hydrogen.

[0137] In some aspects of Formula I or Formula II, R1is selected from hydrogen and C1-C6alkyl. In some aspects of Formula I or Formula II, R1is hydrogen. In some aspects of Formula I or Formula II, R1is G-G, alkyl. In some aspects of Formula I or Formula II, R1is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3 -methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In any of the above aspects, R1may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0138] In some aspects of Formula I or Formula II, R2is selected from hydrogen, halo, Ci-Cs alkyl, C1-C6haloalkyl, and -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some aspects of Formula I or Formula II, R2is hydrogen. In some aspects of Formula I or Formula II, R2is halo. In some aspects of Formula I or Formula II, R2is selected from fluoro, chloro, or bromo. In some aspects of Formula I or Formula II, R2is C1-C6alkyl. In some aspects of Formula I or Formula II, R2is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2- methylpentane, 3 -methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In some aspects of Formula I or Formula II, R2is G-G> haloalkyl. In some aspects of Formula I or Formula II, R2is selected from trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl. In some aspects of Formula I or Formula II, R2is -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some aspects of Formula I or Formula II, R2is -ORX, wherein Rxis selected from hydrogen, methyl, ethyl, isopropyl, and trifluoromethyl. In any of the above aspects, R2may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0139] In some aspects of Formula I or Formula II, R10is selected from hydrogen, halo, G-G> alkyl, C1-C6haloalkyl, and -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some aspects of Formula I or Formula II, R10is hydrogen. In some aspects of Formula I or Formula II, R10is halo. In some aspects of Formula I or Formula II, R10is selected from fluoro, chloro, or bromo. In some aspects of Formula I or Formula II, R10is C1-C6alkyl. In some aspects of Formula I or Formula II, R10is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2- methylpentane, 3 -methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In some aspects of Formula I or Formula II, R10is C1-C6haloalkyl. In some aspects of Formula I or Formula II, R10is selected from trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl. In some aspects of Formula I or Formula II, R10is -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some aspects of Formula I or Formula II, R10is -ORX, wherein Rxis selected from hydrogen, methyl, ethyl, isopropyl, and trifluoromethyl. In any of the above aspects, R10may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0140] In some aspects of Formula I or Formula II, R11is selected from hydrogen, halo, G-G> alkyl, C1- 5 haloalkyl, and -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some aspects of Formula I or Formula II, R11is hydrogen. In some aspects of Formula I or Formula II, R11is halo. In some aspects of Formula I or Formula II, R11is selected from fluoro, chloro, or bromo. In some aspects of Formula I or Formula II, R11is Ci-Cs alkyl. In some aspects of Formula I or Formula II, R11is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2- methylpentane, 3 -methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In some aspects of Formula I or Formula II, R11is C1-C6haloalkyl. In some aspects of Formula I or Formula II, R11is selected from tri fluoromethyl, trifluoroethyl, and hexafluoroisopropyl. In some aspects of Formula I or Formula II, R11is -ORX, wherein Rxis hydrogen, Ci-Cs alkyl, or C1-C6haloalkyl. In some aspects of Formula I or Formula II, R11is -ORX, wherein Rxis selected from hydrogen, methyl, ethyl, isopropyl, and trifluoromethyl. In any of the above aspects, R1may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0141] In some aspects of Formula I or Formula II, R12is selected from hydrogen, halo, Ci-CY alkyl, C1-C6haloalkyl, and -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some aspects of Formula 1 or Formula 11, R12is hydrogen. In some aspects of Formula 1 or Formula II, R12is halo. In some aspects of Formula I or Formula II, R12is selected from fluoro, chloro, or bromo. In some aspects of Formula I or Formula II, R12is C1-C6alkyl. In some aspects of Formula I or Formula II, R12is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2- methylpentane, 3 -methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In some aspects of Formula I or Formula II, R12is C1-C6haloalkyl. In some aspects of Formula I or Formula II, R12is selected from trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl. In some aspects of Formula I or Formula II, R12is -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some aspects of Formula I or Formula II, R12is -ORX, wherein Rxis selected from hydrogen, methyl, ethyl, isopropyl, and trifluoromethyl. In any of the above aspects, R12may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0142] In some aspects, the compound of Formula I is selected from:

[0143]

[0144] In some aspects, the compound of Formula II is selected from:

[0145]

[0146] In some aspects of Formula I or Formula II, R6is selected from hydrogen, C1-C6alkyl, 6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-.

[0147] In some aspects of Formula I or Formula II, R6is hydrogen. In some aspects of Formula I or Formula II, R6is C i -C> alkyl. In some aspects of Formula I or Formula II, R6is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3 -methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0148] In some aspects of Formula I or Formula II, R6is (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-. In some aspects of Formula I or Formula II, R6is (R6a)-(C0-C6alkyl)-, wherein R6ais selected from phenyl, 1 -naphthyl, and 2-naphthyl. In some aspects of Formula I or Formula II, R6is selected from (6- to 10-membered monocyclic or bicyclic aryl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Ci alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Cz alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C4 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Cs alkyl)-, and (6- to 10-membered monocyclic or bicyclic aryl)-(C6 alkyl)-.

[0149] In some aspects of Formula I or Formula II, R6is (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-. In some aspects of Formula I or Formula II, R6is (R6a)-(C0-C6alkyl)-, wherein R6ais selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some aspects of Formula I or Formula II, R6is selected from (5- to 10-membered monocyclic or bicyclic heteroaryl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Ci alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C2 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C4 alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Cs alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C6 alkyl)-.

[0150] In any of the above aspects, R6may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0151] In some aspects of Formula I or Formula II, R9is selected from hydrogen, C1-C6alkyl, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C1-C6alkyl)-, RxS-(C1-C6alkyl)-, (RxRyN)-(Ci- C6alkyl)-, and RZC(O)-(C1-C6alkyl)-.

[0152] In some aspects of Formula I or Formula II, R9is hydrogen.

[0153] In some aspects of Formula I or Formula II, R9is C1-C6alkyl. In some aspects of Formula I or Formula II, R9is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3- methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0154] In some aspects of Formula I or Formula II, R9is (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-. In some aspects of Formula I or Formula II, R9is (R9a)-(C0-C6alkyl)-, wherein R9ais selected from phenyl, 1 -naphthyl, and 2-naphthyl. In some aspects of Formula I or Formula II, R9is selected from (6- to 10-membered monocyclic or bicyclic aryl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Ci alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C2 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C4 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Cs alkyl)-, and (6- to 10-membered monocyclic or bicyclic aryl)-(Ce alkyl)-. In some aspects of Formula I or Formula II, R9is (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-. In some aspects of Formula I or Formula II, R9is (R9a)-(C0-C6alkyl)-, wherein R9ais selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzo thiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some aspects of Formula I or Formula II, R9is selected from (5- to 10-membered monocyclic or bicyclic heteroaryl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Ci alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C2 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C3alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C4 alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Cs alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Ce alkyl)-.

[0155] In some aspects of Formula I or Formula II, R9is RxO-(C1-C6alkyl)-. In some aspects of Formula I or Formula II, R9is RXO-(CI-C6 alkyl)-, wherein Rxis selected from Raand RZC(O)- , wherein Rais selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and benzyl, and wherein Rzis selected from hydrogen, chloro, bromo, -OH, -O(Ci-C6 alkyl), -NH2, -N(independently Ci- Ce alkyl or hydrogen), methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some aspects of Formula I or Formula II, R9is selected from RxO-(Ci alkyl)-, RXO-(C2alkyl)-, RXO-(C3alkyl)-, RXO-(C4alkyl)-, RXO-(C5alkyl)-, and RXO-(C6alkyl)-.

[0156] In some aspects of Formula I or Formula II, R9is RxS-(C1-C6alkyl)-. In some aspects of Formula I or Formula II, R9is RxS-(C1-C6alkyl)-, wherein Rxis selected from Raand RZC(O)- , wherein Rais selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and benzyl, and wherein Rzis selected from hydrogen, chloro, bromo, -OH, -O(Ci-C6 alkyl), -NH2, -N(independently Ci- G> alkyl or hydrogen), methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some aspects of Formula I or Formula II, R9is selected from RxS-(Ci alkyl)-, RXS-(C2alkyl)-, RXS-(C3alkyl)-, RXS-(C4alkyl)-, RXS-(C5alkyl)-, and RxS-(Ce alkyl)-. In some aspects of Formula I or Formula II, R9is (RxRyN)-(Ci-C6 alkyl)-. In some aspects of Formula I or Formula II, R9is (RxRyN)-(C1-C6alkyl)-, wherein Rxand Ryare independently selected from Ra, RZC(O)-, and RZC(N)-, wherein Rais independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and benzyl, and wherein Rzis independently selected from hydrogen, chloro, bromo, -OH, -O(Ci-C6 alkyl), -NH2, -N(independently Ci-G, alkyl or hydrogen), methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some aspects of Formula I or Formula II, R9is selected from (RxRyN)-(Ci alkyl)-, (RxRyN)- (C2 alkyl)-, (RxRyN)-(C3alkyl)-, (RxRyN)-(C4alkyl)-, (RxRyN)-(C5alkyl)-, and (RxRyN)-(C6alkyl)-.

[0157] In some aspects of Formula I or Formula II, R9is RzC(O)-(C1-C6alkyl)-. In some aspects of Formula I or Formula II, R9is RZC(O)-(CI-C6 alkyl)-, wherein Rzis selected from hydrogen, chloro, bromo, -OH, -O(C1-C6alkyl), -NH2, -N(independently C1-C6alkyl or hydrogen), methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some aspects of Formula I or Formula II, R9is selected from RzC(O)-(Ci alkyl)-, RZC(O)-(C2alkyl)-, RZC(O)-(C3alkyl)-, RZC(O)-(C4alkyl)-, RZC(O)-(C5alkyl)-, and RZC(O)-(C6alkyl)-.

[0158] In any of the above aspects, R9may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0159] In some aspects of Formula I or Formula II, R3is selected from hydrogen and C1-C6alkyl. In some aspects of Formula I or Formula II, R3is hydrogen. In some aspects of Formula I or Formula II, R3is C1-C6alkyl. In some aspects of Formula I or Formula II, R3is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3 -methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In any of the above aspects, R3may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0160] In some aspects of Formula I, R4is selected from hydrogen or C1-C6alkyl. In some aspects of Formula I, R4is hydrogen. In some aspects of Formula I, R4is C1-C6alkyl. In some aspects of Formula I, R4is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3- methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In any of the above aspects, R4may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency. In some aspects of Formula I, R5is selected from hydrogen and C i -Q> alkyl. In some aspects of Formula I, Rsis hydrogen. In some aspects of Formula I, R5is C1-C6alkyl. In some aspects of Formula I, R5is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3- methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In any of the above aspects, R5may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0161] In some aspects of Formula I, R3and R4are brought together with the carbons to which they are attached to form a 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency. In some aspects of Formula I, R3and R4are brought together with the carbons to which they are attached to form a heterocycle selected from pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, pyrazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, indolinyl, and isoindolinyl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0162] In some aspects of Formula II, R4is selected from hydrogen and C1-C6alkyl. In some aspects of Formula II, R4is hydrogen. In some aspects of Formula II, R4is C1-C6alkyl. In some aspects of Formula II, R4is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2- methylpentane, 3 -methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In any of the above aspects, R4may be optionally substituted with one or more (e.g., 1 , 2, 3, or 4) Y groups as allowed by valency.

[0163] In some aspects of Formula II, R5is selected from hydrogen and C1-C6alkyl. In some aspects of Formula II, R5is hydrogen. In some aspects of Formula II, Rsis C1-C6alkyl. In some aspects of Formula II, R5is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2- methylpentane, 3 -methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In any of the above aspects, R5may be optionally substituted with one or more (e.g., 1 , 2, 3, or 4) Y groups as allowed by valency.

[0164] In some aspects of Formula II, R3and R4are brought together with the carbons to which they are attached to form a 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency. In some aspects of Formula II, R3and R4are brought together with the carbons to which they are attached to form a heterocycle selected from pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, pyrazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, indolinyl, and isoindolinyl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency.

[0165] In some aspects of Formula I, R7is selected from hydrogen and C1-C6alkyl. In some aspects of Formula I, R7is hydrogen. In some aspects of Formula I, R7is C1-C6alkyl. In some aspects of Formula I, R7is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3- methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0166] In some aspects of Formula I, R8is selected from hydrogen and C i -Co alkyl. In some aspects of Formula I, R8is hydrogen. In some aspects of Formula I, R8is C1-C6alkyl. In some aspects of Formula I, Rsis selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3- methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane.

[0167] Representative compounds of the present disclosure include, but are not limited to:

[0168] or a pharmaceutically acceptable salt or derivative thereof.

[0169] Further representative compounds of the present disclosure include, but are not limited to: or a pharmaceutically acceptable salt thereof.

[0170] Even further representative compounds of the present disclosure include, but are not limited

[0171] or a pharmaceutically acceptable salt or derivative thereof.

[0172] In an alternative aspect, a compound is provided selected from:

[0173] or a pharmaceutically acceptable salt or derivative thereof.

[0174] The present disclosure also includes compounds described herein with at least one desired isotopic substitution of an atom at an amount above the natural abundance of the isotope, i.e., enriched.

[0175] Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as2H,3H,nC,13C,15N,17O,18O,18F,31P'32P,35S,36C1, and125I, respectively. In one aspect, isotopically labeled compounds can be used in metabolic studies (with14C), reaction kinetic studies (with, for example,2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug and substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F-labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0176] By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H), may optionally be used anywhere in described structures that achieve the desired result. Alternatively, or in addition, isotopes of carbon, e.g.,13C and14C, may be used. In one aspect, the isotopic substitution is replacing hydrogen with deuterium at one or more locations on the molecule to improve the performance of the molecule as a drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in the allocation of bond breakage during metabolism (an alpha-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a beta-deuterium kinetic isotope effect).

[0177] Isotopic substitutions, such as deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain aspects, the isotope is 80, 85, 90, 95, or 99% or more enriched in an isotope at any location of interest. In some aspects, deuterium is 80, 85, 90, 95, or 99% enriched at a desired location. Unless otherwise stated, enrichment at any point is above natural abundance and, in an aspect, is enough to alter a detectable property of the compounds as a drug in a human. The compounds of the present disclosure may form a solvate with solvents (including water). Therefore, in one aspect, the disclosure includes a solvated form of the active compound. The term “solvate” refers to a molecular complex of a compound of the present disclosure (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a disclosed compound and water. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, de-acetone, or de-DMSO. A solvate can be in a liquid or solid form.

[0178] It is known that chemical substances may form solids present in different states of order, termed polymorphic forms or modifications. The different forms of a polymorphic substance can differ greatly in their physical properties. The compounds disclosed herein can be present in different polymorphic forms, with it possible for particular forms to be metastable. Unless stated to the contrary, the present disclosure includes all such polymorphic forms.

[0179] A “prodrug,” as used herein, means a compound which, when administered to a host in vivo, is converted into a parent drug. As used herein, the term “parent drug” means any of the presently described compounds herein. Prodrugs can be used to achieve any desired effect, including to enhance the properties of the parent drug or to improve the pharmaceutical or pharmacokinetic properties of the parent, including to increase the half-life of the drug in vivo. Prodrug strategies provide choices in modulating the conditions for in vivo generation of the parent drug. Non-limiting examples of prodrug strategies include covalent attachment of removable groups or removable portions of groups, for example, but not limited to, acylating, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydrides, among others. In certain aspects, the prodrug renders the parent compound more lipophilic. In certain aspects, a prodrug can be provided that has several prodrug moieties in a linear, branched, or cyclic manner. For example, nonlimiting aspects include the use of a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or other compounds that have at least two functional groups that can link the parent compound with another prodrug moiety and are typically biodegradable in vivo. In some aspects, 2, 3, 4, or 5 prodrug biodegradable moieties are covalently bound in a sequence, branched, or cyclic fashion to the parent compound. Non-limiting examples of prodrugs according to the present disclosure are formed with: a carboxylic acid on the parent drug and a hydroxylated prodrug moiety7to form an ester; a carboxylic acid on the parent drug and an amine prodrug to form an amide; an amino on the parent drug and a carboxylic acid prodrug moiety to form an amide; an amino on the parent drug and a sulfonic acid to form a sulfonamide; a sulfonic acid on the parent drug and an amino on the prodrug moiety to form a sulfonamide; a hydroxyl group on the parent drug and a carboxylic acid on the prodrug moiety to form an ester; a hydroxyl on the parent drug and a hydroxylated prodrug moiety' to form an ester; a phosphonate on the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester; a phosphoric acid on the parent drug and a hydroxylated prodrug moiety to form a phosphate ester; a hydroxyl on the parent drug and a phosphonate on the prodrug to form a phosphonate ester; a hydroxyl on the parent drug and a phosphoric acid prodrug moiety to form a phosphate ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2- 24 alkyl) to fonn an ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-S-(C2-24 alkyl) to form a thioester; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an ether; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an thioether; and a carboxylic acid, oxime, hydrazide, hydrazine, amine or hydroxyl on the parent compound and a prodrug moiety that is a biodegradable polymer or oligomer including but not limited to polylactic acid, polylactide-co-glycolide, polyglycolide, polyethylene glycol, polyanhydride, polyester, polyamide, or a peptide.

[0180] In some aspects, a prodrug is provided by attaching a natural or non-natural amino acid to an appropriate functional moiety on the parent compound, for example, oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually in a manner such that the amino acid is cleaved in vivo to provide the parent drug. The amino acid can be used alone or covalently linked (straight, branched, or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve the desired performance, such as increased half-life, lipophilicity, or other drug delivery or pharmacokinetic properties. The amino acid can be any compound with an amino group and a carboxylic acid, which includes an aliphatic amino acid, alkyl amino acid, aromatic amino acid, heteroaliphatic amino acid, heteroalkyl amino acid, heterocyclic amino acid, or heteroaryl amino acid.

[0181] Synthetic Processes Processes for the preparation of compounds described herein are also provided. In one aspect, a process is provided for the synthesis of a compound of Formula Ila: the process comprising irradiating a compound of Formula III: to form the compound of Formula Ila, wherein: X1is selected from -

[0182] R13is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; m is 0, 1, or 2; and all other variables are as defined herein.

[0183] In some aspects of Formula 111, X1is -NH?. In some aspects of Formula III, X1is -OH. In some aspects of Formula III, X1is -O(C=O)R13, wherein R13is selected from methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some aspects of Formula III, X1is selected from:

[0184] In an alternative aspect, a process is provided for the synthesis of a compound of Formula Ila: the process comprising irradiating a compound of Formula Illa:

[0185] to form the compound of Formula Ila, wherein:

[0186] Xlais selected from halo, -N(R13a)2, -N(R13a)3+, -OH, -O(C=O)R13,

[0187] R13ais independently selected at each occurrence from hydrogen, Ci-G> alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, and RXO-, each of which may be optionally substituted with one or more Y groups as allowed by valency; and all other variables are as defined herein.

[0188] In some aspects of Formula Illa, Xlais chloro. In some aspects of Formula llla, Xlais bromo. In some aspects of Formula IIIa, Xlais -NH2. In some aspects of Formula IIIa, Xlais -N(R13a)2, wherein R13ais independently selected at each occurrence from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -OH, - OCH3, and -OCH2CH3. In some aspects of Formula IIIa, Xlais -N(R13a)3+, wherein R13ais independently selected at each occurrence from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -OH, -OCH3, and -OCH2CH3. In some aspects of Formula ma, Xlais -OH. In some aspects of Formula IIP, Xlais - O(C=O)R13, wherein R13ais selected from methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some aspects of Formula IIP, Xlais selected from:

[0189] In some aspects, irradiating the compound of Formula III or Formula IIP comprises irradiating the compound with ultraviolet or visible light. In some aspects, the ultraviolet light is of a wavelength from about 240 nanometers to about 320 nanometers, including exemplary values of about 240 nanometers, about 250 nanometers, about 260 nanometers, about 270 nanometers, about 280 nanometers, about 290 nanometers, about 300 nanometers, about 310 nanometers, about 320 nanometers, or any subrange formed from those above exemplary values.

[0190] In some aspects, the process is carried out in the presence of an acid. In some aspects, the acid comprises a mineral acid (e.g., hydrochloric acid) or an organic acid. In some aspects, the acid comprises an organic acid, such as a carboxylic acid, for example, acetic acid. The acid may be present in an amount from about 1 molar equivalent to about 30 molar equivalents relative to the compound of Formula III or Formula IIP. As used herein, a “molar equivalent” refers to the ratio of moles of one compound (e.g., the acid) to the moles of another compound (e.g., the compound of Formula III or Formula IIP). In some aspects, the acid is present in an amount of about 10 molar equivalents relative to the compound of Formula III (for example, when an organic acid is used). In other aspects, the acid is present in an amount of about 1 molar equivalent relative to the compound of Formula III or Formula IIP (for example, when a mineral acid is used). In some aspects, the acid may be present in an amount of about 30 molar equivalents or more relative to the compounds of Formula III or Formula IIP.

[0191] The described processes, or reactions to produce the compounds used in the described processes, can be carried out in solvents indicated herein or in solvents which can be selected by one of skill in the art of organic synthesis. Solvents can be substantially nonreactive with the starting materials (reactants), intermediates, or products under the conditions at which the reaction is carried out, i.e., temperature and pressure. Reactions can be carried out in one solvent or a mixture of more than one solvent. Product or intermediate formation can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., *H and13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0192] In some aspects, the processes described herein may be carried out in the presence of an alcoholic solvent. In particular aspects, the processes described herein are carried out in methanol. However, other suitable solvents or mixtures of solvents may be readily determined by a person of ordinary skill in the art of organic synthesis.

[0193] Variations on compounds used in the processes described herein can include the addition, subtraction, or movement of various constituents as described for each compound. Similarly, when one or more chiral centers are present in a molecule, the chirality of the molecule can be changed. Additionally, the synthesis of the compounds used in these processes can involve the protection of various chemical groups, and further, the compounds prepared by the disclosed processes may be subsequently deprotected as appropriate. The use of protection and deprotection and the selection of appropriate protecting groups would be readily known to one skilled in the art. “Protecting group”, as used herein, refers to any conventional functional group that allows one to obtain chemoselectivity in a subsequent chemical reaction. Protecting groups are described, for example, in Peter G. M. Wuts, Greene’s Protective Groups in Organic Synthesis, 5thEd., Wiley & Sons, 2014. For a particular compound and / or a particular chemical reaction, a person skilled in the art knows how to select and implement appropriate protecting groups and their associated synthetic methods. Examples of amine protecting groups include acyl and alkoxy carbonyl groups, such as t-butoxycarbonyl (BOC) and [2-(trimethylsilyl)ethoxy]methoxy (SEM). Examples of carboxyl protecting groups include C1-C6alkoxy groups, such as methyl, ethyl, and t-butyl. Examples of alcohol protecting groups include benzyl, trityl, silyl ethers, and the like.

[0194] Pharmaceutical Compositions

[0195] The compounds described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the active components described herein can be formulated in a physiologically- or pharmaceutically- acceptable form and administered by any suitable route known in the art, including, for example, oral and parenteral routes of administration. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrastemal administration, such as by injection. Administration of the active components of the compositions can be a single administration, or at continuous and distinct intervals as can be readily determined by a person skilled in the art.

[0196] Compositions, as described herein, comprising an active compound and a pharmaceutically acceptable carrier or excipient of some sort, may be useful in a variety of medical and nonmedical applications.

[0197] "Pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate-buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion), and / or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, or other material well known in the art for use in pharmaceutical formulations and as described further herein.

[0198] “Excipients” include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. General considerations in formulation and / or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0199] Exemplary excipients include, but are not limited to, any non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type. Some examples of materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. As would be appreciated by one of skill in this art, the excipients may be chosen based on what the composition is useful for. For example, with a pharmaceutical composition or cosmetic composition, the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and / or to animals, orally, rectally, parenterally, intracistemally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray. In some aspects, the active compounds disclosed herein are administered topically.

[0200] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.

[0201] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.

[0202] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and / or combinations thereof.

[0203] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxy toluene, mono thioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0204] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0205] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0206] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl. In certain aspects, the preservative is an antioxidant. In other aspects, the preservative is a chelating agent.

[0207] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer’s solution, ethyl alcohol, etc., and combinations thereof.

[0208] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.

[0209] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black currant seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0210] Additionally, the composition may further comprise a polymer. Exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar gum, gum arabic, gum karaya, gum ghatti, konjac and gum tragacanth, glycosaminoglycans and proteoglycans such as hyaluronic acid and its salts, proteins such as gelatin, collagen, albumin, and fibrin, other polymers, for example, polyhydroxyacids such as polylactide, polyglycolide, polyl(lactide-co-glycolide) and poly(.epsilon.-caprolactone-co-glycolide)-, carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, polyacrylic acid / acrylamide copolymer, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxidepropylene oxide), and a Pluronic polymer, polyoxy ethylene (polyethylene glycol), poly anhydrides, polyvinylalchol, polyethyleneamine and polypyrridine, polyethylene glycol (PEG) polymers, such as PEGylated lipids (e.g., PEG-stearate, l,2-Distearoyl-sn-glycero-3- Phosphoethanolamine-N- [Methoxy(Polyethylene glycol)- 1000] , 1 ,2-Distearoyl-sn-glycero- 3-Phosphoethanolamine-N- [Methoxy (Polyethylene glycol)-2000], and 1,2-Distearoyl-sn- glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-5000]), copolymers and salts thereof.

[0211] Additionally, the composition may further comprise an emulsifying agent. Exemplary emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate |Myrj 451, polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. In certain aspects, the emulsifying agent is cholesterol.

[0212] Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable compositions, such as injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be an injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In certain aspects, the particles are suspended in a carrier fluid comprising 1% (w / v) sodium carboxymethyl cellulose and 0.1% (v / v) Tween 80. The injectable composition can be sterilized, for example, by filtration through a bacteria- retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0213] Compositions for rectal or vaginal administration may be in the form of suppositories, which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.

[0214] Solid compositions include capsules, tablets, pills, powders, and granules. In such solid compositions, the particles are mixed with at least one excipient and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents.

[0215] Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0216] Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is admixed with an excipient and any needed preservatives or buffers as may be required.

[0217] The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0218] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0219] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the particles in a polymer matrix or gel.

[0220] Methods of Use

[0221] The compounds or compositions described herein may be used in the treatment of medical disorders, such as neurological or psychiatric disorders.

[0222] Thus, in some aspects, methods for treating neurological or psychiatric disorders in a subject in need thereof. In some aspects, the methods comprise administering to the subject a therapeutically effective amount of a compound or composition described herein. In some aspects, the compound or composition described herein may be administered in combination or alternation with an additional therapeutic agent.

[0223] In one aspect, a method is provided for treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or composition described herein.

[0224] Representative examples of neurological disorders to be treated include, but are not limited to: a brain dysfunction (such as apraxia, agnosia, amnesia, aphasia, or dysarthria); a spinal cord disorder (such as a spinal pathology, injury, or inflammation); peripheral neuropathy or other peripheral nervous system disorder; a cranial nerve disorder (such as trigeminal neuralgia); an autonomic nervous system disorder (such as dysautonomia or multiple system atrophy); a seizure disorder (such as epilepsy); a movement disorder of the central or peripheral nervous system (such as Parkinson’s disease, essential tremor, amyotrophic lateral sclerosis, or Tourette’s syndrome); multiple sclerosis and related disorders; a sleep disorder (such as narcolepsy); a speech disorder (such as stuttering); headaches (such as migraines, cluster headache, or tension headache); pain (such as complex regional pain syndrome or fibromyalgia); delirium or dementia (such as Alzheimer’s disease); coma or impaired consciousness (including stupor); a stroke; tumors of the nervous system (including cancer); multiple sclerosis or other demyelinating diseases; a brain infection; meningitis; or prion diseases.

[0225] In another aspect, a method is provided for treating a psychiatric disorder (i.e., a mental disorder) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or composition described herein.

[0226] Representative examples of psychiatric disorders to be treated include, but are not limited to: anxiety disorders; dissociative disorders (such as dissociative identity disorder, dissociative amnesia, depersonalization-derealization disorder, dissociative fugue, dissociative neurological symptom disorder including psychogenic non-epileptic seizures, other specified dissociative disorder, unspecified dissociative disorder, or Ganser syndrome); mood disorders, including depressive disorders (such as disruptive mood dysregulation disorder, major depressive disorder, dysthymia, premenstrual dysphoric disorder, pervasive refusal syndrome, or unspecified depressive disorder), bipolar disorders (such as bipolar I disorder, bipolar II disorder, bipolar disorder not otherwise specified, and cyclothymia); trauma and stressor related disorders (such as reactive attachment disorder, disinhibited social engagement disorder, post-traumatic stress disorder, post-traumatic embitterment disorder, acute stress disorder, adjustment disorder, complex post-traumatic stress disorder, or prolonged grief disorder); a neurodevelopmental disorder (such as an intellectual disability, language disorder, sensory processing disorder, speech sound disorder, stuttering, aphasia, social communication disorder, pervasive developmental disorder, auditory processing disorder, autism spectrum disorder, attention deficit hyperactivity disorder, developmental coordination disorder, Tourette syndrome, Down syndrome, tic disorder, dyslexia, dyscalculia, dysgraphia, or nonverbal learning disorder); sleep-wake disorders (such as insomnia, hypersomnia, idiopathic hypersomnia, Kleine-Levin syndrome, insufficient sleep syndrome, narcolepsy, restless legs syndrome, sleep apnea, night terrors, and exploding head syndrome), parasomnias (such as nightmare disorder, rapid eye movement sleep behavior disorder, confusional arousals, sleepwalking, hypnagogic hallucinations, or hypnopompic hallucinations), or circadian rhythm sleep disorders (such as circadian rhythm sleep disorder, delayed sleep phase disorder, advanced sleep phase disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake disorder, circadian rhythm sleep-wake disorder caused by irregular work shifts, or jet lag); neurocognitive disorders (such as delirium, dementia, traumatic brain injury, HIV-associated neurocognitive disorder, amnesia, chronic traumatic encephalopathy, or agnosia); substance-related and addictive disorders (such as substance-induced disorders; substance intoxication; substance withdrawal: substance dependence; disorders due to use of alcohol, cannabis, synthetic cannabinoids, opioids, sedatives, hypnotics, anxiolytics, cocaine, amphetamines, synthetic cathinone, caffeine, hallucinogens, nicotine, volatile inhalants, or dissociative drugs; addictive personality; gambling disorder; video game addiction; internet addiction disorder; sexual addiction; food addiction; exercise addiction; addiction to social media; pornography addiction; or shopping addiction); paraphilias; somatic symptom related disorders (such as hypochondriasis; cyberchondria; somatization disorder; conversion disorder; factitious disorder imposed on self; factitious disorder imposed on another; pain disorder; or medically unexplained physical symptoms); sexual dysfunctions (such as delayed ejaculation, erectile dysfunction, anorgasmia, vaginismus, male hypoactive sexual desire disorder, female sexual arousal disorder, persistent genital arousal disorder; hypoactive sexual desire disorder, sexual arousal disorder, premature ejaculation, dyspareunia, or sexual dysfunction); elimination disorders (such as enuresis, nocturnal enuresis, or encopresis); feeding and eating disorders (such as pica, rumination syndrome, avoidant / restrictive food intake disorder, anorexia nervosa, binge eating disorder, bulimia nervosa, purging disorder, diabulimia, night eating syndrome, orthorexia nervosa, atypical anorexia nervosa, or other specified feeding or eating disorder); disruptive impulse-control and conduct disorders (such as intermittent explosive disorder, oppositional defiant disorder, conduct disorder, antisocial personality disorder, pyromania, kleptomania, mythomania, or disruptive mood dysregulation disorder); obsessive-compulsive and related disorders (such as obsessive-compulsive disorder, body dysmorphic disorder, body integrity dysphoria, trichotillomania, excoriation disorder, body-focused repetitive behavior disorder, olfactory reference syndrome, phantom limb syndrome, primarily obsessional obsessive-compulsive disorder, or hoarding disorder); schizophrenia spectrum and other psychotic disorder (such as brief psychotic disorder, delusional disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, schizotypal personality disorder, paraphrenia, or shared delusional disorder); personality disorders including cluster A personality disorders (such as paranoid personality disorder, schizoid personality disorder, or schizotypal personality disorder), cluster B personality disorders (such as antisocial personality disorder, borderline personality disorder, histrionic personality disorder, or narcissistic personality disorder), cluster C personality disorders (such as avoidant personality disorder, dependent personality disorder, or obsessive-compulsive personality disorder), or not otherwise specified personality disorders (such as depressive personality disorder, passive-aggressive personality disorder, sadistic personality disorder, or self-defeating personality' disorder); gender dysphoria; medication-induced movement disorder or other adverse effects of medication; catatonia; or a culture-bound syndrome.

[0227] Further representative examples of disorders which can be treated by the compounds or compositions described herein include, but are not limited to, addiction, alcohol use disorder or substance use disorder, Alzheimer’s disease, anxiety, Attention-Deficit / Hyperactivity Disorder, bipolar disorder, borderline personality disorders, depression, dementia, headache disorders including migraine or cluster headaches, major depressive disorder, Parkinson’s disease, personality disorders, post-traumatic stress disorder, schizophrenia and related disorders, spectrum disorder, stereotypic movement disorder, stroke, suicidal ideation, tic disorders, Tourette’s disorder, and treatment-resistant depression.

[0228] In some aspects, the compounds, methods, and compositions may be used to increase synaptic serotonin levels, modulate serotonergic and other neurologic receptors, control neurotransmission, as an inhibitor of dopamine uptake, or as a direct releaser of dopamine, either directly or indirectly via serotonergic modulation.

[0229] In some aspects, the compounds, methods, and compositions may be used to treat or prevent pharmacoresistant seizures, acutely or as a prophylactic.

[0230] In some aspects, the compounds, methods, and compositions may be used as dopamine receptor modulators, dopamine-releasing agents, or inhibitors of the dopamine transporter and used for the treatment of Parkinson's disease, Restless Legs Syndrome, and / or hyperprolactinemic conditions.

[0231] In some aspects, the compounds, methods, and compositions may be used as an anxiolytic to reduce anxiety associated with terminal and non-terminal cancers, agitation associated with dementia due to Alzheimer’s disease, and irritability associated with autism.

[0232] In some aspects, the compounds, methods, and compositions may be used as serotonin or dopamine receptor modulators for weight loss in obese patients. In some aspects, the compounds, methods, and compositions may be used to treat or prevent idiopathic age-related decline in mental capacity, both typical and atypical, as well as for the decline in mental function associated with both Alzheimer’s disease and late-stage Parkinson’s disease.

[0233] In some aspects, the compounds or compositions described herein may be used as a nootropic or supplement.

[0234] The active ingredient may be administered in such amounts, at such a time, and by such a route as deemed necessary in order to achieve the desired result. The exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the medical disorder, the particular active ingredient, its mode of administration, its mode of activity, and the like. The active ingredient, whether the active compound itself or the active compound in combination with another agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0235] The active ingredient may be administered by any route. In some aspects, the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors, including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc. The exact amount of an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or a person skilled in the art and can be lower or the same as that administered to an adult.

[0236] Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice and other animals to humans are known to the art.

[0237] The dosage ranges for the administration of the compositions are those large enough to produce the desired effect, in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the patient's age, condition, sex, and extent of the disease, and it can be determined by one skilled in the art. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary and can be administered in one or more doses daily for one or several days.

[0238] Additional Particular Aspects

[0239] In view of the described compounds, compositions, and methods, hereinbelow are described certain more particular aspects of the disclosure. These particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein, or that the “particular” aspects are somehow limited in some way other than the inherent meanings of the language and formulae literally used therein.

[0240] Aspect 1. A compound of Formula I or a pharmaceutically acceptable salt or derivative thereof; wherein:

[0241] R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0242] R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, Ci- Ce alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(O)-(C0-C6alkyl)-, and RzS(O)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0243] R3, R7, and Rsare independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RzC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from Y as allowed by valency;

[0244] R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from Y as allowed by valency;

[0245] R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0246] R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(CI-C6 alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RZC(N)-(C1-C6alkyl)-, RZS(O)- (Ci-Cs alkyl)-, and RZS(O)2-( C1-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0247] R4and Rsor R7and R8are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0248] R3and R4or R4and R7or R7and R9are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0249] R3and R6or R4and R6or R6and R7or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency

[0250] Rxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)- , and RZS(O)2-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0251] Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C?cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0252] Raand Rbare independently selected at each occurrence from hydrogen, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0253] Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3 alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°C(O)-NRq-, R°S(O)2-, ROS(O)2-O-, and R°S(O)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2- Ce alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, with the proviso that if R10is methoxy, at least one of R1, R2, R3, R5, R5, Rc, R7, R8, R9, R11, or R12is not hydrogen.

[0254] Aspect 2. The compound of aspect 1 , or a pharmaceutically acceptable salt or derivative thereof, wherein R7is selected from hydrogen and C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

[0255] Aspect 3. The compound of aspect 1 or aspect 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R8is selected from hydrogen and C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

[0256] Aspect 4. The compound of any one of aspects 1-3, or a pharmaceutically acceptable salt or derivative thereof, wherein R3is selected from hydrogen and C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

[0257] Aspect 5. The compound of any one of aspects 1-4, or a pharmaceutically acceptable salt or derivative thereof, wherein R4is selected from hydrogen or C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

[0258] Aspect 6. The compound of any one of aspects 1 -3, or a pharmaceutically acceptable salt or derivative thereof, wherein R3and R4are brought together with the carbons to which they are attached to form a 3- to 8 -membered monocyclic or bicyclic heterocycle optionally substituted with one or more Y groups as allowed by valency. Aspect 7. The compound of any one of aspects 1-6, or a pharmaceutically acceptable salt or derivative thereof, wherein Rsis selected from hydrogen and C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

[0259] Aspect 8. A compound of Formula II or a pharmaceutically acceptable salt or derivative thereof; wherein:

[0260] R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0261] R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, Ci- Ce alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0262] R3is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, Ci- C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from Y as allowed by valency;

[0263] R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, or (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g.. 1, 2, 3, or 4) groups selected from Y as allowed by valency;

[0264] R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0265] R9is selected from, hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C1-C6alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RZC(N)-(C1-C6alkyl)-, RZS(O)- (C1-C6alkyl)-, and RzS(O)2-(C1-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0266] R4and R5are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0267] R3and R4are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or R3and R6or R4and R6or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0268] Rxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)- , and RZS(O)2-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0269] Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- memberedheterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0270] Raand Rbare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0271] Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°C(O)-NRq-, ROS(0)2-, ROS(O)2-O-, and R°S(O)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6alkyl, Ci-C<> haloalkyl, C2-C6alkenyl, C2- Ce alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, with the proviso that if R10is methoxy, at least one of R1, R2, R3, R5, R5, R6, R9, R11, or R12is not hydrogen. Aspect 9. The compound of aspect 8, or a pharmaceutically acceptable salt or derivative thereof, wherein R3is selected from hydrogen and C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

[0272] Aspect 10. The compound of aspect 8 or aspect 9, or a pharmaceutically acceptable salt or derivative thereof, wherein R4is selected from hydrogen or C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

[0273] Aspect 11. The compound of aspect 8, or a pharmaceutically acceptable salt or derivative thereof, wherein R3and R4are brought together with the carbons to which they are attached to form a 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more Y groups as allowed by valency.

[0274] Aspect 12. The compound of any one of aspects 8-11, or a pharmaceutically acceptable salt or derivative thereof, wherein R5is selected from hydrogen and C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

[0275] Aspect 13. The compound of any one of aspects 1-12, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from hydrogen and C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

[0276] Aspect 14. The compound of any one of aspects 1-13, or a pharmaceutically acceptable salt or derivative thereof, wherein R2is selected from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, and -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalky 1, each of which may be optionally substituted with one or more Y groups as allowed by valency.

[0277] Aspect 15. The compound of any one of aspects 1-14, or a pharmaceutically acceptable salt or derivative thereof, wherein R10is selected from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, and -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl, each of which may be optionally substituted with one or more Y groups as allowed by valency.

[0278] Aspect 16. The compound of any one of aspects 1-15, or a pharmaceutically acceptable salt or derivative thereof, wherein R11is selected from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, and -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl, each of which may be optionally substituted with one or more Y groups as allowed by valency.

[0279] Aspect 17. The compound of any one of aspects 1-16, or a pharmaceutically acceptable salt or derivative thereof, wherein R12is selected from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, and -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl, each of which may be optionally substituted by one or more Y groups as allowed by valency.

[0280] Aspect 18. The compound of any one of aspects 1-17, or a pharmaceutically acceptable salt or derivative thereof, wherein R6is selected from hydrogen, C1-C6alkyl, 6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted by one or more Y groups as allowed by valency.

[0281] Aspect 19. The compound of any one of aspects 1-18, or a pharmaceutically acceptable salt or derivative thereof, wherein R9is selected from hydrogen, G-G> alkyl, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(C1-C6alkyl)-, RXS-(C1-C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, and RzC(O)-(C1-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency.

[0282] or a pharmaceutically acceptable salt or derivative thereof.

[0283] Aspect 21. A compound selected from: or a pharmaceutically acceptable salt thereof.

[0284] Aspect 22. A compound selected from:

[0285] or a pharmaceutically acceptable salt or derivative thereof.

[0286] Aspect 23. A pharmaceutical composition comprising a compound of any one of aspects 1-22, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient.

[0287] Aspect 24. A method of treating a psychiatric disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 1-22, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of aspect 23. Aspect 25. A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 1-22, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of aspect 23. Aspect 26. A method of treating a medical disorder in a subject in need thereof, wherein the medical disorder is selected from addiction, alcohol use disorder or substance use disorder,

[0288] Alzheimer’s disease, anxiety, Attention-Deficit / Hyperactivity Disorder, bipolar disorder, borderline personality disorders, depression, dementia, headache disorders including migraine or cluster headaches, major depressive disorder, Parkinson’s disease, personality disorders, post-traumatic stress disorder, schizophrenia and related disorders, spectrum disorder, stereotypic movement disorder, stroke, suicidal ideation, tic disorders, Tourette’s disorder, and treatment resistant depression, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 1-22, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of aspect 23.

[0289] Aspect 27. A process for the synthesis of a compound of Formula Ha: the process comprising irradiating a compound of Formula III:

[0290] to form the compound of Formula Ila, wherein:

[0291] R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0292] R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, C1- C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0293] R3is selected from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RXS-(C0-C6alkyl)-, (RxR>'N)-(C0-C6alkyl)-, RzC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from Y as allowed by valency; R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalky IXC0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from Y as allowed by valency;

[0294] R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0295] R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(CI-C6 alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RZC(N)-(C1-C6alkyl)-, RZS(O)- (C1-C6alkyl)-, and RzS(O)2-(C1-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0296] R4and R5are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0297] R3and R4are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0298] R3and R6or R4and R6or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; X1is selected from -

[0299] R13is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; m is 0, 1, or 2;

[0300] Rxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)- , and RZS(O)2-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0301] Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, Ci-Cealkynyl, (C3-C?cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0302] Raand Rbare independently selected at each occurrence from hydrogen, C1-C6alkyl, Ci- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0303] Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, Ci -Co alkyl, CI-CG haloalkyl, C2-C6alkenyl, C2-CG alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-Co alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°C(O)-NRq-, R°S(O)2-, R°S(O)2-O-, and R°S(O)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, CI-CG alkyl, CI-CG haloalkyl, C2-C6alkenyl, C2- Ge alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-.

[0304] Aspect 28. The process of aspect 27, wherein X1is -NIT. Aspect 29. The process of aspect 27 or aspect 28, wherein irradiating the compound of Formula III comprises irradiating the compound with ultraviolet or visible light, preferably ultraviolet light.

[0305] Aspect 30. The process of any one of aspects 27-29, wherein the process is carried out in the presence of an acid. Aspect 31. The process of aspect 30, wherein the acid comprises a mineral acid (such as hydrochloric acid) or an organic acid (such as acetic acid).

[0306] Aspect 32. The process of any one of aspects 27-31, wherein the process is carried out in the presence of an alcoholic solvent.

[0307] Aspect 33. A compound of Formula Ila prepared according to the process of any one of aspects 27-32.

[0308] Aspect 34. A process for the synthesis of a compound of Formula Ila: the process comprising irradiating a compound of Formula Illa:

[0309] to form the compound of Formula Ila, wherein:

[0310] R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0311] R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, Ci- Ce alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0312] R3is selected from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RXS-(C0-C6alkyl)-, (RxR>'N)-(C0-C6alkyl)-, RzC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from Y as allowed by valency; R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalky IXC0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups selected from Y as allowed by valency;

[0313] R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0314] R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(CI-C6 alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RZC(N)-(C1-C6alkyl)-, RZS(O)- (C1-C6alkyl)-, and RzS(O)2-(C1-C6alkyl)-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0315] R4and R5are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0316] R3and R4are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; or

[0317] R3and R6or R4and R6or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; Xlais selected from halo, -N(R13a)2, -N(R13a)3+, -OH, -O(C=O)R13,

[0318] R13ais independently selected at each occurrence from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, and RXO-, each of which may be optionally substituted with one or more Y groups as allowed by valency; m is 0, 1, or 2;

[0319] Rxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)- , and RZS(O)2-, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency;

[0320] Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, Ci- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0321] Raand Rbare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- memberedheterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more (e.g., 1, 2, 3, or 4) Y groups as allowed by valency; and

[0322] Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°C(O)-NRq-, R°S(O)2-, R°S(O)2-O-, and R°S(O)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, Ci-O, alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2- G> alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-Cf, alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-.

[0323] Aspect 35. The process of aspect 34, wherein X1is -NH2.

[0324] Aspect 36. The process of aspect 34 or aspect 35, wherein irradiating the compound of Formula Illa comprises irradiating the compound with ultraviolet or visible light, preferably ultraviolet light.

[0325] Aspect 37. The process of any one of aspects 34-36, wherein the process is carried out in the presence of an acid.

[0326] Aspect 38. The process of aspects 37, wherein the acid comprises a mineral acid (such as hydrochloric acid) or an organic acid (such as acetic acid).

[0327] Aspect 39. The process of any one of aspects 34-38, wherein the process is carried out in the presence of an alcoholic solvent.

[0328] Aspect 40. A compound of Formula Ila prepared according to the process of any one of aspects 34-39.

[0329] A number of aspects of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other aspects are within the scope of the following claims.

[0330] By way of non-limiting illustration, examples of certain aspects of the present disclosure are given below.

[0331] EXAMPLES

[0332] The following examples are set forth below to illustrate the compounds, compositions, and methods claimed herein, along with associated methods and results according to the disclosed subject matter. These examples are not intended to include all aspects of the subject matter disclosed herein but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present disclosure, which are apparent to one skilled in the art.

[0333] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, the temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions, that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.

[0334] Example 1. Conversion of Amino Acids to SHTIAR Agonists Using UV Light

[0335] A light-induced cyclization that results in the direct functionalization of the indole ring at the C4 position is developed into a practical method for the synthesis of tricyclic tryptamines of medicinal interest. The full set of essential and non-essential amino acids were coupled to tryptamine and irradiation of these a-amino-tryptamides using UV light produced a library of lactams bridging the C3 and C4 positions of the indole nucleus via Dillon’s variant of the Witkop cyclization. These products belong to the class of lactams originally described by Witkop (2,8,9,10-tetrahydroazocino[4,5,6-cd]indol-7(6H)-ones) resulting from irradiation of a-haloamides of tryptophan and tryptamine. After optimization of the irradiation wavelength, reaction temperature, solvent, substrate loading, and acid additive, the yield and synthetic ease of this cyclization establishes it as a valuable synthetic method. A photocyclization is also presented here that employs a-acetoxyamides of tryptamine to give lactams in high yield. In a special case of this chemistry, it is shown that irradiation of a-lactone-substituted amides of tryptamine leads to a cyclization where the lactone is exchanged for the azocino-lactam with complete atom economy. Using these conditions and a variety of easily accessed precursors, C3 to C4 bridged indoles were produced in good to excellent yields, free of the C2-regioisomers that are often seen using standard Witkop substrates. Due to the structural similarities of the reduced lactams (azocinoindoles) with known psychoactive tryptamines and phenethylamines, their binding at 5-HT2AR, a G-protein-coupled receptor where simple n-alkytryptamines and phenethylamines are known to act, was investigated both in-silico and in-vitro. BRET receptor binding assays show that these azocinoindoles bind to 5-HT2AR and activate the Gctq pathway with both psychedelic- and non-hallucinogenic psychoplastigen- like efficacies.

[0336] Introduction

[0337] The functionalization of indole at the C4 position, generally to produce compounds of medicinal value, continues to capture the interest of synthetic chemists. Indole compounds display a broad range of biological activities ranging from anti-Parkinsonian, anti-migraine, and anti-nausea to chemotherapeutic. There are eight indole compounds on the WHO Model List of Essential Medicines and of these, two are C4 substituted. (See World Health Organization, WHO Model List of Essential Medicines - 23rd list, 2023. https: / / pubs.acs.org / doi / full / 10.1021 / acsguide.40303 (accessed 2024-07-06)). C4- substituted indoles are often produced semisynthetically from naturally derived precursors because direct substitution of the C4 position is generally not possible. The reactivity of indole is largely governed by the electronics of the pyrrole moiety, favoring electrophilic addition at C3, accompanied by migration to C2 in some cases, followed by re-aromatization. (See Biswas, K. M.; Jackson, A. H. Electrophilic substitution in indoles — V: Indolenines as intermediates in the benzylation of 3-substituted indoles. Tetrahedron 1968, 25 (1), 227-241). Methods to alter this selectivity have involved the reduction of electron density in the pyrrole ring, achieved by incorporating electron- withdrawing groups onto the N1 and / or C3-position or by obstructing the pyrrole portion of the molecule with large groups on N 1 such as benzyl or triisopropylsilyl (TIPS). A pivaloyl group on N1 offers a synergistic effect between sterics and electronics that encourages C4 substitution of indole, however, this method of functionalization has been unsuccessful on tryptophan and its derivatives. (See Teranishi, K.; Hayashi, S.; Nakatsuka, S.-i.; Goto, T. A facile biomimetic synthesis of Uhle's Ketone by the regioselective Friedel-Crafts cyclization of Indole-3 -ylpropionyl Chloride. Tetrahedron Lett. 1994, 35 (44), 8173-8176).

[0338] Methods that have been developed to access C4 indoles include the directed lithiation of gramine and quenching with various electrophiles at low temperature and cine-substitution of 5-indolyl carbamates. (See Fukuda, T.; Akashima, H.; Iwao, M. Synthesis of 3,4,5- trisubstituted indoles via iterative directed lithiation of l-(triisopropylsilyl)gramines. Tetrahedron 2005, 61 (28), 6886-6891 ; Masatomo, I. Directed Lithiation of 1- Triisopropylsilylgramine. A Short Acess to 3,4-disubstituted Indoles. Heterocycles 1993, 36 (1), 29-32; Chauder, B.; Larkin, A.; Snieckus, V. Rapid Route to 3,4-Substituted Indoles via a Directed Ortho Metalation-Retro-Mannich Sequence. Org. Lett. 2002, 4 (5), 815-817. DOI: 10.1021 / ol017310m; Griffen, E. J.; Roe, D. G.; Snieckus, V. Benzenoid Ring Functionalization of Indoles and Tryptophols via Combined Directed Ortho Metalation-Cross Coupling Methodology. J. Org.Chem. 1995, 60, 1484-1485; and Mesganaw, T.; Nathel, N. F. F.; Garg, N. K. Cine Substitution of Arenes Using the Aryl Carbamate as a Removable Directing Group. Org. Lett. 2012, 14 (11), 2918-2921). A combinatorial approach of Nl- protecting groups on 3-formyl / keto indoles has led to several recent publications that showcase directed C-H activation of the C4 position using noble metals rather than traditional thallium and mercury activators. (See Salim, V. M.; Seidl, M. C. Thallation- Iodination Studies of Heterocyclic Systems. J. Heterocyclic Chem. 1979, 16, 993-996; Lanke, V.; Ramaiah Prabhu, K. Regioselective Synthesis of 4-Substituted Indoles via C-H Activation: A Ruthenium Catalyzed Novel Directing Group Strategy. Org. Lett. 2013, 15 (24), 6262- 6265; Sherikar, M. S.; Devarajappa, R.; Prabhu, K. R. Weak Coordinating Carbonyl-Directed Rhodium(III)-Catalyzed C-H Activation at the C4-Position of Indole with Allyl Alcohols. J. Org. Chem. 2020, 85 (8), 5516-5524; Kuang, G.; Liu, D.; Chen, X.; Liu, G.; Fu, Y.; Peng, Y.; Li, H.; Zhou, Y. Transient Directing Group Strategy as a Unified Method for Site Selective Direct C4-H Halogenation of Indoles. Org. Lett. 2021, 23 (21), 8402-8406; Singh, A.; Dey, A.; Pal, K.; Dash, O. P.; Voila, C. M. R. Pd(II)-Catalyzed Transient Directing Group- Assisted Regioselective Diverse C4-H Functionalizations of Indoles. Org. Lett. 2022, 24 (10), 1941-1946; Basak, S.; Paul, T.; Punniyamurthy, T. Palladium-Catalyzed 2-fold C-H Activation / C-C Coupling for C4-Arylation of Indoles Using Weak Chelation. Org. Lett. 2022, 24 (2), 554-558; and Taskesenligil, Y.; Aslan, M.; Cogurcu, T.; Saracoglu, N. Directed C-H Functionalization of C3-Aldehyde, Ketone, and Acid / Ester-Substituted Free (NH) Indoles with lodoarenes via a Palladium Catalyst System. The J. Org. Chem. 2023, 88 (3), 1299-1318). Rapoport developed a high-yielding, multi-step, enantioselective route to D-(+)- 4-bromotryptophan, a desirable starting material for C4 indole alkaloid synthesis that circumvents the issue of C2 / C4 selectivity. (See Hurt, C. R.; Lin, R.; Rapoport, H. Enantiospecific Synthesis of (R)-4-Amino-5-oxo-l,3,4,5-tetrahydrobenz[cd]indole, an Advanced Intermediate Containing the Tricyclic Core of the Ergots. J. Org. Chem 1999, 64 (1), 225-233; and Nettekoven, M.; Psiorz, M.; Waldmann, H. Synthesis of enantiomeric ally pure 4-Alkylsubstituted Tryptophan Derivatives by a Combination of Organometallic Reactions with Enantioselective Enzymatic Transformations. Tetrahedron Lett. 1995, 36, 1425-1428). Despite scattered advancements in accessing these highly sought-after indoles, there remains a need to access the C4-position of tryptophan and tryptamines efficiently and without limitations.

[0339] In 1966, Witkop et al. serendipitously discovered a photocyclization of V-chloroacetyl- tryptophan that produced an eight-membered lactam bridging the C3- and C4-positions of the indole nucleus (FIG. 11 A). (See Yonemitsu, O.; Cerutti, P.; Witkop, B. Photoreductions and Photocyclizations of Tryptophan. J. Am. Chem. Soc. 1966, 88 (17), 3941-3945). This photoinduced cyclization has been recognized as a valuable method for accessing C4- substituted indoles due to the absence of directing groups, protecting groups, noble metals, or toxic metals. (See Gritsch, P. J.; Leitner, C.; Pfaffenbach, M.; Gaich. The Witkop Cyclization: A Photoinduced C-H Activation of the Indole System. Angew. Chem. Int. Ed. 2014, 53, 1208- 1217; and Kalepu, J.; Gandeepan, P.; Ackermann, L.; Pilarski, L. T. C4-H indole functionalisation: precedent and prospects. Chem. Sci. 2018, 9 (18), 4203-4216). Even with these advantageous attributes, the Witkop photocyclization of a-chloroalkylamides of tryptophan or tryptamine has seen limited synthetic use as it generally suffers from low yields and often involves tedious purification requirements due to competing C2 cyclization and unproductive homolysis of the carbon-chlorine bond. In 1992, Moody and coworkers showed that a,a-dichloroamides cyclize in acceptable yields while providing a functional handle at the reaction center that can be used for further elaboration. (See Beck, A. L.; Mascal, M.; Moody, C. J.; Slawin, A. M. Z.; Williams, D. J.; Coates, W. J. Synthesis of 3,4-bridged indoles by photocyclisation reactions. Part 1. Photocyclisation of halogenoacetyl tryptophan derivatives. J. Chem. Soc., Perkin Trans. 1 1992, (7), 797). a, a-Dichloroamides have thus been used in the key step of the total synthesis of decursivine, indolelactam V, and dragmacidin D. (See Mascal, M.; Modes, K. V.; Durmus, A. Concise Photochemical Synthesis of the Antimalarial Indole Alkaloid Decursivine. Angew Chem. 2011, 123 (19), 4537-4538; Mascal, M.; Moody, C. J. Synthesis of (-)-indolactam V. J. Chem. Soc., Chem. Commun. 1988, (9), 589-590; and Feldman, K. S.; Ngemmeesri, P. Total Synthesis of (+)- Dragmacidin E. Org. Lett. 2011, 13 (20), 5704-5707).

[0340] Following Witkop’ s seminal work, Dillon published two papers that have received little attention from the synthetic community. They showed that two dipeptides of tryptophan, Gly- Trp and Ala-Trp, undergo photocyclization to give products identical to the Witkop lactams but in substantially higher yields, estimated to be between 70 and 80% (FIG. 11B). (See Dillon, J. The Anaerobic Photolysis of Tryptophan Containing Peptides. Photochem. Photobiol. 1980, 32 (1), 37-39; and Dillon, J. The Anaerobic Photolysis of Tryptophan Containing Peptides - II, Photochem. Photobiol. 1981, 33 (2), 137-142). For the last several decades, Dillion’s work has remained untapped in terms of synthetic utility. Using readily available amino acids to access intermediates of pharmaceutical interest presents an advantageous approach to drug discovery, and a high-yielding route to C4 substituted indoles would represent a significant advancement in this field. The initial step of the process, amide bond formation, is one of the most well-studied and commonly applied transformations in organic chemistry. (See Pattabiraman, V. R.; Bode, J. W. Rethinking amide bond synthesis. Nature. 2011, 480, 471-479). Indeed, amino acid coupling has become so routine that it is generally automated in the pharmaceutical industry. Utilizing amino acids as the substrate and light as the only reagent, with water as the solvent, the Witkop variant described by Dillon aligns well with the principles of green chemistry. The potential of this cyclization motivated us to develop it into a mainstream method for accessing azocinoindoles bearing both the tryptamine and phenethylamines pharmacophores. We have thus undertaken extensive efforts to explore the synthetic potential of this remarkable excited state reaction. After optimizing for solvent, acid additive, light source / wavelength, temperature, and concentration, using an advanced photochemical reactor, the Lucent 360, the cyclization was successfully scaled up to multi-gram quantities with high selectivity. During the course of this investigation, three substrates were discovered in which the amine leaving group was replaced with hydroxy, acetoxy, and lactone functionalities (FIG. 11C). These reactions are efficacious for smallmolecule synthesis and drug development as shown by our investigation into ring-constrained analogs of well-known 5-HT2A ligands, as described below.

[0341] Results and Discussion

[0342] To simplify naming in this example, tryptamine will be abbreviated as Tmn and the three letter representation code for amino acids will be used. For example, Cbz-Gly-Tmn Al refers to N-benzyloxycarbonyl-glycine tryptamide. (Amides of tryptamine are known as tryptamides and can be named from the carboxylic acid used to make them.) Glycine tryptamide is denoted as Gly-Tmn Bl and so forth. Cyclized analogs that bridge the C3 and C4 position of the indole nucleus and form an azocine system are denoted with the prefix C4-, followed by the three letter amino acid code used to make them, followed by CO or CH2 to represent the amide carbonyl or its reduction to a methylene group, respectively, then NR to denote the tryptamine nitrogen, and finally the abbreviated form of tryptamine. C4-Xxx-C(Rn)NR-Tmn represents the generic formula. For example, the cyclized analog of Gly-Tmn Bl is C4-Gly-CONH-Tmn Cl. The reduced form of this lactam is C4-Gly-CH2NH-Tmn DI.

[0343] The 20 amino acids that comprise proteins, along with norleucine (Nle), tert-leucine (Tie), and theanine (GlnNHEt) were coupled to tryptamine. Glycine was coupled to A-methyl tryptamine (NMe-Tmn), a,a-dimethyltryptamine (a,a-diMeTmn), a, a, N- tri methyl tryptamine (NMe-a,a-diMeTmn), 5-methoxy- tryptamine (5-MeOTmn), 5 -methoxy -TV- methyltryptamine (NMe-5-MeOTmn), a-ethyltryptamine (a-EtTmn), and P-ethyltryptamine (P-EtTmn), (compounds A1-A30).

[0344] All of the protected pseudo-dipeptides of tryptamine were synthesized using the same EDC coupling procedure except for the coupling of Cbz-Gly with a, a, N- tri methyl trypta ine which required a more activated ester. Crystallization was used as the means of purification in 22 of the 30 coupling reactions. Removal of the protecting group (compounds A1-A30 to B1-B30) gave the unprotected amines which were of sufficient purity to carry forward in all cases with the exception of Met-Tmn B18 which required chromatography. Prolonged storage of AspOMe-Tmn B21 and GluOMe-Tmn B22 resulted in some P- and y-lactam impurities, respectively. Photocyclization of B1-B30 gave compounds C1-C30. All protected precursors, deprotected tryptamide substrates, and cyclized products were characterized by ' l l NMR,13C NMR, ME-HSQC, and high-resolution mass spectrometry. Photocyclization was optimized with the Lucent 360 photoreactor using Gly-Tmn (Bl to Cl) and GlnNHEt-Tmn (B24 to C24) as model substrates.

[0345] Dillon used highly dilute solutions (26 mg / L) for the two photocyclizations they studied. While this is advantageous for intramolecular and photochemical reactions in general, it is unreasonable for product synthesis. At 0.005 M, the concentration explored here was 50 times that of Dillon’s. An attempt was made to optimize the reaction in a Rayonet reactor using solutions between 0.005 M and 0.025 M and reaction volumes between 60 mL and 400 mL. Initial results for the irradiation of Gly-Tmn Bl were promising but yields of C4-Gly-CONH- Tmn Cl never exceeded 50%. Optimization of a photochemical reaction using a single vessel reactor is a slow and tedious process, especially for reaction times longer than 12 hours. While LEDs have been used for visible light photocatalysis for some time, UV-LEDs for classic photochemistry have been slow to emerge. Hepatochem recently marketed the Lucent 360, with a capacity to run 16 reactions side by side, and agreed to develop UV-LED lights for our purposes, which greatly facilitated optimization of the photocyclization reactions described here. The reactor allowed for consistent reaction conditions and easily quantifiable results, strengthening reliability and reproducibility.

[0346] The effect of added acid was investigated. The addition of strong acid, hydrochloric (HC1) or trifluoroacetic (TFA) acid, beyond the single equivalent used to protonate the amine, was detrimental to the reaction (FIG. 12). TFA gave better yields than HC1. In contrast, acetic acid (AcOH) showed an opposite trend where conversion increased over time with additional equivalents of acid. No negative effects were observed at up to 20 equivalents but the beneficial effect plateaued at 10 equivalents and therefore this amount was used for all subsequent reactions. A single equivalent of TFA gave comparable results to the chosen condition and would provide a less acidic environment; however, this more expensive additive was not further investigated. Addition of sodium chloride had no effect on reaction conversion. It should be noted that this data was obtained using the Lucent 360 in a single 4- hour experiment. To acquire the same data using a single vessel reactor with standard low- pressure mercury lamps, it would have required 15 days of irradiation time, which is more than 10% of the bulbs lifespan.

[0347] While the literature for the Witkop cyclization utilizes a variety of wavelengths, it was found in this study that 310 nm light consistently gave better result than 254 nm light with the amines substrates. Based on the absorption spectra of tryptophan, it was predicted that 275 nm wavelength light would further improve the efficiency of the reaction. Side by side experiments confirmed that 275 nm light was more efficient than 300 nm light. Due to current limitations, 300 nm light was used for all other experiments.

[0348] The effect of temperature was investigated, and it was determined that an increase from room temperature to 45° C had no effect on the product formation during the first six hours of the reaction, by which time it was observed to be more than 80% complete. Lowering the reaction temperature to 5°C, decreased conversion by 10-15% at all time points tested. Product formation was measured as a function of substrate concentration over time. It was found that product formation increased linearly with substrate concentration up to about 0.01 M at which point linearity was lost. At the highest concentration tested, 0.08 M, only a 20% increase in productivity was observed based on the amount of added substrate. No intermolecular reactions were observed at any of the concentrations tested, as determined by LC-MS.

[0349] The effect of cosolvent was investigated and an increase in conversion was seen when 10% methanol was added to the aqueous solution (FIG. 13). A methanol concentration of 20% produced a conversion at four hours similar to when no methanol was added and conversion decreased rapidly at methanol concentrations above 20%. The use of acetonitrile as a cosolvent gave inferior results.

[0350] The addition of 10 equivalents of acetic acid to 10% aq. methanol allowed the reactions to go to completion in the shortest amount of time and in the highest yield. The conditions optimized in the Lucent 360 transferred to the Rayonet reactor well and at 0.01 M, Gly-Tmn Bl, underwent cyclization to give C4-Gly-CONH-Tmn Cl in 90% yield within 20 hours on a 2 mmol scale. The product could be purified by simple trituration with methanol; however, the reaction mixture was subjected to chromatography to ensure that the product was free of polymeric material and other trace impurities and to show conclusively that trituration was an effective purification method. By increasing the concentration and irradiation time, the same cyclization could be performed on a multi-gram scale (10 mmol) in a yield of 83% without chromatography. Representative examples are shown in FIG. 14.

[0351] The effect of branching alpha and beta to the amine leaving group was investigated (FIG. 15). In contrast to the Witkop cyclization, the reaction gave no product when performed on tertiary amines. (See Nagata, R.; Endo, Y.; Shudo, K. Photocyclization of y-Chlorotiglyl-L- tryptophan Methyl ester Yields Azocinoindole and Azepinoindole Derivatives. Chem Pharm Bull. 1993, 41, 369-372; and Szantay, C.; Boelcskei, H.; Gacs-baitz, E. Synthesis of Vinca Alkaloids and Related Compounds. XLVIII Synthesis of (+)-Cathamthine and (+)- Allocatharanthine. Tetrahedron. 1990, 46. 1711-1732). Glycine tryptamides reacted faster than tryptamines made from more substituted amino acids. Branching beta to the reacting center was poorly tolerated. Val-Tmn BIO and Ile-Tmn B13 have methyl groups adjacent to the reacting center and gave nearly identical poor yields of C4-Val-C0NH-Tmn CIO and C4- Ile-CONH-Tmn C13, respectively. The isolated yields of these compounds improved with longer irradiation times or lower concentrations. Irradiation of Tle-Tmn B14, which has a quaternary center adjacent to the leaving group, gave C4-Tle-C0NH-Tmn C14 in 4% isolated yield. Attempts to increase this yield were unsuccessful. The alcohol functionality was tolerated in the irradiation of Ser-Tmn B15 to give C4-Ser-C0NH-Tmn CIS and Thr-Tmn B16 to give C4-Thr-C0NH-Tmn C16. The branching effect was also apparent here but not as detrimental to the reaction as alkyl branching. Branching gamma to the reaction center had no effect, typified by the comparison between the reaction of Nle-Tmn Bll to give C4-Nle- CONH-Tmn Cll and Leu-Tmn B12 to give C4-Leu-C0NH-Tmn C12. Relative rates of cyclization thus depend largely on branching beta to the reacting center as follows: R = Me > 'Bu « "Bu » 'Pr «sBu > 'Bu.

[0352] The presence of other chromophores was shown to have a detrimental effect on reaction conversion (FIG. 16). The irradiation of Trp-Tmn B27 to give C4-Trp-C0NH-Tmn C27 stopped at 25% conversion. Extending the reaction times and decreasing the concentration of the substrate failed to improve the yield. This can be explained by the inner filter effect or product inhibition where the product absorbs light more strongly than the substrate. The isolated yield based on recovered starting material, however, is good. The irradiation of Tyr- Tmn B26 to give C4-Tyr-C0NH-Tmn C26 follows a similar course as Trp-Tmn B27 but with a less defined endpoint; yields could be slightly increased by extending the irradiation time. The cyclization of Phe-Tmn B25 to give C4-Phe-C0NH-Tmn C25 similarly stalled around 50% conversion.

[0353] The effect of A-melhylation on the tryptamide nitrogen was investigated. In the three cases studied, the methyl group slightly decreased the amount of product formed over time as determined by LC-MS (FIG. 17). The presence of a 5-methoxy substituent on tryptamine significantly enhanced product formation, exemplified by the conversion of Gly-5-MeOTmn B5 to C4-Gly-CONH-5-MeOTmn C5. The most detrimental A-methyl effect was observed with the methyl derivative of this substrate in the reaction of Gly-5-MeO-Tmn B6 to C4-Gly- C0NMe-5-Me0Tmn C6. This A-methyl effect was also observed with the Rayonet reactor but to a greater extent. All of the isolated yields for the A-methyl derivatives were significantly lower than the yields determined by LC-MS. Gly-C0NMe-5Me0Tmn C5 could be isolated in only 25% yield after repeated chromatography and triturations. Taking into consideration the yield reduction and difficulty in purification, methylation post cyclization would be considered the preferred route.

[0354] The photocyclization was performed in flow using the Lucent 360. With a residence time of 1 hour and a concentration of 0.005M, GlnNHEt-Tmn B24 underwent cyclization to C4- GlnNHEt-CONH-Tmn C24 in a yield of 74%. This shows that the reaction is amenable to flow and can be scaled up beyond the multi-gram quantities available through batch reactions. (See Elliot, L. D.; Berry, M.; Haqi, B.; Klauber, D.; Leonard, J.; Brooker-Milburn, K.I. A Small-Footprint, High-Capacity Flow Reactor for UV Photochemical Synthesis on the Kilogram Scale. Org. Process Res. Dev. 2016, 20, 1806-1811).

[0355] A comparison of the results using the Lucent 360 and the isolated yields using the Rayonet reactor is presented graphically in FIG. 18. Isolated yields generally corresponded well with the LC-MS yields obtained in the Lucent 360, with the largest discrepancies arising from the A-methyl compounds as mentioned previously. The slightly higher yields observed for C4- Val-CONH-Tmn CIO and C4-Ile-C0NH-Tmn C13 using the Rayonet reactor were obtained using extended reaction times. Purification of C4-Arg-CONH-Tmn C29 necessitated silica gel chromatography under acidic conditions, and this could account for the slightly lower isolated yield of this compound. It should be noted that this substrate was irradiated as the NOz-protected guanidine and the nitro protecting group was lost during irradiation.

[0356] Pro-Tmn B19 underwent cyclization to give C4-Pro-CONH-Tmn C19-2, with concurrent ring opening of the pyrrolidine. This result shows that the reaction works similarly well on secondary amines. Isolation of C19-2, however proved challenging. The freebase could be crystallized from methanol consistently in 30% yield. The Boc-protected amine C4-Boc-Pro- CONH-Tmn C19 could be isolated in 53% yield after carbmoylation. Photocyclization followed by acetylation of the free amine gave C19-3 in 23% yield along with the interesting trans amidation product C19-4 in 15% yield (FIG. 19).

[0357] Cyclization onto the entropically favored and reactive C2 position of indole, which gives the corresponding azepine system, creates difficult-to-separate mixtures that have historically plagued the Witkop cyclization. The C2 isomer was seen only once in the course of hundreds of trials; the irradiation of GlnNHEt-Tmn B24 to give C4-GlnNHEt-CONH-Tmn C34 also gave C2-GlnNHEt-CONH-Tmn C34-2 in 2% isolated yield (FIG. 20). This reaction was used to optimize the wavelength of light, solvent, temperature, and concentration in hope of elucidating the source of this unwanted isomer. None of the parameters investigated significantly affected its formation but the isomer was found at a maximum of 4% (LC-MS yield) during the wavelength screen when 254nm light was used. It could be argued that substitution alpha to the tryptamide nitrogen could promote formation of this other isomer through a conformation change during cyclization. The high isolated yield of C4-Gly-C0NH-aEtTmn C7 shows that alkyl substitution at the alpha position does not promote its formation. It was considered that tryptophan derivatives could be prone to C2 cyclization as these are the more common substrates used in the Witkop cyclization. To test this, Gln-TrpOMe B31 was irradiated to give a moderate 55% yield of / « / / ?.v-4-Gln-CONH- D-TrpOMe C31 along with 15% of the diketopiperazine product (FIG. 21). No evidence of the C2 isomer was seen in this case either and the product was exclusively trans.

[0358] In an attempt to increase the versatility of this photo-induced cyclization, other leaving groups were explored. Irradiation of (trifhioroacetyl)alanine tryptamide A32 gave no product. Lactic acid tryptamide A33, however, gave a 19% yield of C4-Ala-Tmn C9 after 24 hours of irradiation under neutral conditions. The addition of HC1 to the reaction led to no isolated product. Adopting the conditions used for the amines gave a viable reaction using dilute solutions and extended reaction times (FIG. 22).

[0359] Excellent results were achieved when a-acetoxytryptamides were irradiated (FIG. 23). The a-acetoxy acids were obtained by diazotization of the corresponding amino acids in acetic acid prior to coupling. All couplings were performed using a standard EDC procedure to give compounds A34-A42. Because compounds A32-A40 cyclize to previously made azocinoindoles, the products are not given separate C-designations.

[0360] The irradiation of 2-acetoxypropanoic acid tryptamide A36 to give C4-Ala-C0NH-Tmn C9 also produced a small amount of acrylic acid tryptamide which was determined by independent synthesis and comparison of the resulting1H NMR spectra. Irradiation of acrylic acid tryptamide gave no reaction. Partial hydrolysis of the esters to give the alcohol was also observed during irradiation of many of the a-acetoxytryptamides. Continued irradiation resulted in cyclization of this by-product albeit at a lower rate. The C2 isomer was not observed during the irradiation of the a-acetoxytryptamides or a-hydoxytryptamides.

[0361] None of the effects studied altered the high C4 selectivity of this reaction. It is tempting to say that the lack of homolysis of the C-N or C-0 bond is connected to this high selectivity as homolysis is not observed with the irradiation of the amines or acetates but is a minor side product formed during the irradiation of the a-chloroamides. Homolysis could results in an indiscriminate radical that could attack either C2 or C4. Further investigations are being performed to test this hypothesis.

[0362] Irradiation of methyl (2-acetoxypropanoyl)-D-tryptophanate A41 to give C4-Ala-C0NH-D- TrpOMe C41 demonstrates one of the advantages of the acetoxy derivatives. Ala-TrpOMe would present procedural challenges similar to Gln-TrpOMe B31, where rapid isolation of the free amine and immediate irradiation was necessary to minimize diketopiperazine formation. Compound A41 could be stored indefinitely and cyclized in moderate yield.

[0363] The irradiation of 2-acetoxy-2-phenylacetic acid tryptamide A42 gave C4-Phg-C0NH-Tmn C42 in 37% yield (FIG. 23). The amine version of this reaction was unsuccessful after many attempts. C4-Phg-C0NH-Tmn C42 gives poor]H and13C NMR spectra where all peaks show up as broad singlets and the product has low solubility in all solvents. Methyl ether byproducts resulting from attack of the solvent on the benzylic position were detected by LC-MS during the course of this reaction. To show if these substrates could go on to products similar to the alcohols, alpha-ether tryptamides were synthesized independently but failed to cyclize under standard conditions.

[0364] The a-acetoxytryptamides required one less step to reach the product after coupling than the corresponding amines, making them more atom-economical. Met-Tmn A18 required chromatography after removal of the Boc group and the Cbz protecting group could not be easily utilized with the thioether present. (See Abiraj, K.; Gowda, D. C. Heterogeneous catalytic transfer hydrogenation in peptide synthesis. Lett. Pept. Sci. 2003, 9, 153-165). Using the acetoxy leaving group made this reaction more convenient.

[0365] Diazotization of y-oxo amino acids produces 5-oxotetrahydrofuran-2-carboxylic acid through intramolecular attack. The coupling of this compound to tryptamine gave A44. Irradiation of A44 produced C4-Glu-C0NH-Tmn C44. This is an atom-efficient reaction that goes in good yield and does not require chromatography (FIG. 24). The product contains the versatile carboxylic acid functional group in a desirable location making it a useful precursor to unexplored polycycles and ergoline-like molecules of potential pharmaceutical value. The tryptophanate version of this reaction also proceeded well. The resulting acid was directly coupled toe diethylamine under standard conditions to give C4-GlnNEt2-CONH-TrpOMe C45 as a separable mixture of diastereomers (1 :1) in 48% yield over two steps.

[0366] All photocyclizations involving amino or oxygen leaving groups maintained complete C4 selectivity regardless of substitution or conditions employed. Additionally, while dehalogenation is a known side reaction of the Witkop cyclization, photolytic deamination or deoxygenation was not observed. It is suggested that two different mechanistic pathways are operating (FIG. 4). We propose that irradiation at 310 nm leads to an indole+:e“ contact ion pair as described by Kumar and coworkers in a study of the photoionization dynamics of indole in aqueous solution (FIG. 4). Direct reduction of the leaving group is possible in the case of the a-halo amides considering the bond dissociation energies, which are 71 kcal / mol, 83 kcal / mol, and 112 kcal / mol for CI L-Br. CH3-CI and CH3-NH4+respectively. The direct reduction of the halogen would result in a weakly stabilized and moderately selective radical, leading to a mixture of the C2- and C4-regioisomers. Single electron transfer (SET) to the amide on the other hand is believed to lead exclusively to the C4 product through what is suggested to be a spin-center shift (SCS) mechanism, that results in an electrophilic and therefore more selective radical.

[0367] The direct reduction pathway in FIG. 4 would be supported if the more easily reducible a- haloacetyl tryptamide (a-bromoacetyl vs a-chloroacetyl) gives a higher C2 / C4 ratio and a higher yield of the C2 product. Thus, N-chloroacetyl tryptamine and Mbromoacetyl tryptamine were subjected to the optimized reaction conditions (FIG. 27). Irradiation of N- bromoacetyl tryptamine indeed produced a higher C2 / C4 ratio (0.18 vs 0.11), and a higher yield of the C2 product, lending support to the proposed pathways. Furthermore, the ratio of C2 products (Br / Cl = 1.25) aligns well with the ratio of previously calculated reduction potentials (Br / Cl = 1.26), again supporting that direct reduction leads to the C2 product.

[0368] While precedent exists for radical formation occurring though an SCS mechanism for a- acetoxy ketones and heterobenzylic ammonium groups, we believe this is the first example of a simple protonated a-amino amide group being used as a selective radical precursor. Furthermore, we propose that the electrophilic nature of the radical resulting from both the a- acetoxy and protonated a-amino amides will find use in other photochemical transformations related to those of the synthetically versatile a-haloamides, due to the abundance of readily available a-amino amide precursors and the high electrophilicity of the resulting radical.

[0369] Given the structural similarity of the azocinoindole core to known serotonergic psychedelics 2,5-dimethoxy-4-methylamphetamine (DOM) and dimethyltryptamine (DMT), it was hypothesized that the azocinoindole core could serve as a serotonergic drug development platform (FIG. 25).

[0370] There has been renewed interest in the use of psychedelic drugs to treat various psychiatric disorders including depression and anxiety. Despite an increase in available medications used to treat these conditions, there remain unmet needs for improved pharmacotherapies. Many of the current regimes used to treat depression produce the desired effect only over extended time periods and include a variety of side effects. Often, multiple medications and continued use are required to treat patients and monitoring is necessary when starting or tapering off many selective serotonin reuptake inhibitors (SSRIs).

[0371] The use of the non-selective 5-HT receptor (5-HTR) agonist classic psychedelics, including lysergic acid diethylamide (LSD), psilocybin, and DMT, along with medications in the entactogen and dissociative classes, is once again gaining traction with popular culture and studies have supported their utility in the treatment of depression and anxiety. There are, however, drawbacks that include severe distortions to perception, which can interfere with daily routines and the feeling of euphoria that is associated with the potential for abuse. While classic psychedelics are resurgent in basic scientific research, their therapeutic development is hampered by hallucinogenic potential, the cost of concomitant psychotherapy, suboptimum acute durations of action, and the lack of selectivity amongst 5-HT2A receptor subtypes.

[0372] Studies of 5-HTZA ligands have been limited over the last half century due to federal regulations and the stigma created during the counter-culture movement. The mention of the words “hallucinogen” and “psychedelic” still causes apprehension in segments of the population. Regardless of personal stance on this topic, it is without question that separating the hallucinogenic and euphoric effects from the therapeutic effects that include positive changes in self-perception and outlook on life, long term reduction in depression through single administration and treatment of post-traumatic stress disorder (PTSD), amongst others, would be beneficial. There are also the well-studied neuroplastigenic effects for which non- hallucinogenic drugs are desired.

[0373] Due to high sequence homology, ligand selectivity amongst the 5-HT2R subtypes is notoriously difficult to achieve. While the phenethylamine class of psychedelics is the most well-studied and highly selective members exist, there has been minimal selectivity observed with the 5 HT2A tryptamine therapeutics. Applying conformational constraints to flexible parent molecules is a strategy often leveraged to increase ligand selectivity and to elucidate the active binding pose. While the ethylamine side-chain of tryptamine has been constrained in various ways, the current azocino system presented here has not been investigated, mainly due to synthetic inaccessibility. Investigation into the binding of this class of compounds, that contains not only the ring-constrained tryptamine system but also the phenethylamine system, will lead to a better understanding of the selectivity requirements of the 5-HT2A receptor and other 5-HT2 subtypes.

[0374] We have demonstrated the feasibility of this serotonergic drug development platform using both in-.silico and in-vitro screening against the 5-HT2A receptor which is a G-protein-coupled receptor (GPCR) target that is attracting increasing pharmaceutical interest for its antidepressant, anxiolytic, antiaddictive, and neurogenic effects. The 5-HT2AR couples to Gq / Gn and beta-arrestin2, with signaling efficacy at Gqdefining hallucinogen- like versus psychoplastigen-like effects. In addition, it is implicated in various physiological processes including perception, cognition, mood regulation, self-perception, and processing of novel stimuli.

[0375] As proof of concept, 100 synthetically accessible azocinoindoles were screened in-silico on two cryo-EM derived 5-HToA / ligand cocrystal structures (LSD / 2A and 25CN-NBOH / 2A; PDB codes 7WC6 and 6WHA, respectively). In-silico results are indicative of active ligands at both conformations of the 2A receptor, however, residue-level insight indicates a strong preference for LSD-like binding. In the LSD / 2A cocrystal, all 100 compounds were docked without constraints and compared to the docking scores with contact constraints to D155332and W3366'48individually as well as to both residues simultaneously. The D155332residue is believed to guide molecules towards W336648and contact with W336648is believed to be necessary for full activation of the 5-HT2AR. Binding poses and scores remained largely unchanged when the D155332constraint was applied, indicating strong LSD-like binding. There was no observed stereochemical preference or preference for substitution on the nitrogen, however, large groups (R in FIG. 26) that extended into the gap between transmembrane 4 and 5, reaching up toward the extracellular binding pocket known to incorporate and interact with the diethylamide of LSD, helped guide the molecule into realistic binding poses. When the W3366'48constraint was applied, many of the molecules suffered large decreases in binding scores. The molecules that did not have large decreases in docking scores and also had realistic binding poses were largely the R-enatiomer and contained methyl groups that were used to meet the W336648contact constraint.

[0376] In the 25-CNBOH / 2A cocrystal, residue level insights indicate strong interactions with the critical D155332residue, with some ligands interacting concurrently with S159336, a residue known to be involved in phenethylamine-type ligand binding. Constraints involving W3366'48with either D155332or S1593 6simultaneously led to unrealistic binding poses in almost all cases. Taken together, in-silico results indicate that the azocinoindoles trend toward LSD- like, rather than / V-benzyl phenethylamine-like docking. Azocinoindoles appear to bind in the orthosteric binding pocket and may stabilize conformational ensembles similar to those observed with known agonist / partial agonist ligands, suggesting similar signaling outputs. Based on these encouraging results, measurements of in-vitro S-l I Gq coupled pathway signaling efficacy and activation potency were obtained for five azocinoindoles as doseresponse curves by BRET dissociation assay, with serotonin (5-HT) defining 100% efficacy. This assay was recently demonstrated to be strongly predictive of hallucinogenic versus non- hallucinogenic ligand effects in-vivo and was selected for this reason. Reduction of the lactams C4-Gly-C0NH-Tmn Cl, C4-Gly-C0NMe-Tmn C2, C4-Gly- C0NH-5Me0Tmn C5, C4-Ser-C0NH-Tmn C15, and C4-Met-C0NH-Tmn C18, produced a small library of freebase molecules D1-D5 (FIG. 26). Given that these compounds were tested as proof of concept rather than for high potency and efficacy, it was striking that C4- Met-CFFNH-Tmn D5 displayed full agonist activity at the receptor, an efficacy rare in tryptamine-based 5-HT2A ligands. The predicted binding pose maps well over the pose of cocrystallized ligand LSD, with the same three residue interactions known to be crucial in LSD’s binding (FIG. IOC). Both S242546and the main chain carbonyl of G2385'42are known to form hydrogen bonds with the indole nitrogen of LSD at distances of 4.3 and 3.0 A, respectively. The calculated binding pose only deviates by 0.1 A at S242546(4.4 A). The critical residue for interaction with the basic (tryptamine) nitrogen of LSD, D 1553-32, measures 2.6 A for LSD and 3.5 A for C4-Met-CH2NH-Tmn D5 (FIG. 10C).

[0377] Potencies ranged from high nM to pM as follows in order from least to most potent; C4-Ser- CHzNH-Tmn D4 at 7.1 pM, C4-Gly- CH2NH-5MeOTmn D3 at 6.3 pM, C4-Gly-CH2NH- Tmn DI at 1.3 pM, C4-Met-CH2NH-Tmn D5 at 502 nM, and C4-Gly-CH2NMe-Tmn C2 at 402 nM. Efficacies ranged from 61% (non-hallucinogenic partial agonist) to 93% (full agonist) (FIGs. 6A-6B). Efficacies for each compound in order from lowest to highest efficacy were C4-Gly-CH2NMe-Tmn D2 at 61%, C4-Gly- CH2NH-5MeOTmn D2 at 77%, C4-Ser-CH2NH-Tmn D4 at 81%, C4-Gly-CH2NH-Tmn DI at 81%, and C4-Met-CH2NH- Tmn D5 at 93%.

[0378] Despite relatively low potency, the five compounds derived from the azocinoindole core, demonstrate a range of efficacies indicative of unique pharmacologies, including psychoplastigen-like partial agonism, classic psychedelic-like, hallucinogenic partial agonism, and full agonism comparable to the efficacy of mescaline. This suggests that this class contains compounds with oneirogenic, psychedelic, or psychoplastigenic effects. The azocinoindole core provides a framework for serotonergic drug development, an area under active investigation. A full panel screen of all 5-HT receptor subtypes may reveal additional possibilities.

[0379] Conclusion

[0380] The current methods of C4 indole activation lack both synthetic accessibility and sustainability. Installing protecting groups and directing groups to alter regioselectivity is neither step- nor atom-economical. These cumbersome means of accessing C4 indoles have hindered drug discovery, on one of the most prolific heterocycles studied, for decades. A method is presented here that relies neither on protecting nor directing groups. No expensive catalysts or special reagents are required. The solvents are benign, and the reactants are either amino acids or derived from amino acids. The reactions presented are efficient and the C2 isomer is not formed to a significant extent. The workup is simple, and the process is amendable to scale-up. Leaving groups have been developed including the hydroxyl and acetoxy groups, and awareness has been brought to the versatile amine leaving group that has seen little interest in the past ca. 50 years. Direct access to azocinoindoles through photolysis and reduction provides an efficient and versatile platform for serotonergic drug development.

[0381]

[0382] References for Example 1

[0383] Horowski R. Lisuride: An 8-Alpha-Ergoline with Ergot Antagonistic Properties. In NeuroPsychopharmacotherapy, Springer, Cham. 2021, 1-43. Johnston, M. M.; Rapoport, A. M. Triptans for the Management of Migraine. Drugs 2010, 70, 1505-1518. Dhiman, A.; Sharma, R.; Singh, R. K. Target-based anticancer indole derivatives and insight into structure-activity relationship: A mechanistic review update (2018-2021). Acta. Pharm. Sin B. 2022, 12, 3006-3027.

[0384] World Health Organization, WHO Model List of Essential Medicines - 23rd list, 2023. https: / / pubs.acs.org / doi / full / 10.1021 / acsguide.40303 (accessed 2024-07-06).

[0385] Biswas, K. M.; Jackson, A. H. Electrophilic substitution in indoles — V: Indolenines as intermediates in the benzylation of 3-substituted indoles. Tetrahedron 1968, 25, 227-241.

[0386] Liu, Q.; Li, Q. Ma, Y.; Jia, Y. Direct Olefination at the C-4 position of Tryptophan via C-H activation: Application to Biomimetic Synthesis of Claviciptic Acid. Org Lett. 2013, 15, 4528-4531.

[0387] Fukuda, T.; Akashima, H.; Iwao, M. Synthesis of 3,4,5-trisubstituted indoles via iterative directed lithiation of l-(triisopropylsilyl)gramines. Tetrahedron 2005, 61 (28), 6886-6891.

[0388] Masatomo, I. Directed Lithiation of 1 -Triisopropylsilylgramine. A Short Access to 3,4- disubstituted Indoles. Heterocycles 1993, 36, 29-32.

[0389] Chauder, B.; Larkin, A.; Snieckus, V. Rapid Route to 3,4-Substituted Indoles via a Directed Ortho Metalation-Retro-Mannich Sequence. Org. Lett. 2002, 4, 815-817.

[0390] Teranishi, K.; Hayashi, S.; Nakatsuka, S.-i.; Goto, T. A facile biomimetic synthesis of Uhle's Ketone by the regioselective Friedel-Crafts cyclization of Indole-3-ylpropionyl Chloride. Tetrahedron Lett. 1994, 35 (44), 8173-8176.

[0391] Griffen, E. J.; Roe, D. G.; Snieckus, V. Benzenoid Ring Functionalization of Indoles and Tryptophols via Combined Directed Ortho Metalation-Cross Coupling Methodology. J. Org. Chem. 1995, 60, 1484-1485. DOI: 10.1021 / jo00111a003

[0392] Mesganaw, T.; Nathel, N. F. F.; Garg, N. K. Cine Substitution of Arenes Using the Aryl Carbamate as a Removable Directing Group. Org. Lett. 2012, 14 (11), 2918-2921.

[0393] Salim, V. M.; Seidl, M. C. Thallation-Iodination Studies of Heterocyclic Systems. J. Heterocyclic Chem. 1979, 16, 993-996.

[0394] Lanke, V.; Ramaiah Prabhu, K. Regioselective Synthesis of 4-Substituted Indoles via C-H Activation: A Ruthenium Catalyzed Novel Directing Group Strategy. Org. Lett. 2013, 15 (24), 6262-6265.

[0395] Sherikar, M. S.; Devaraj appa, R.; Prabhu, K. R. Weak Coordinating Carbonyl-Directed Rhodium(III)-Catalyzed C-H Activation at the C4-Position of Indole with Allyl Alcohols. J. Org. Chem. 2020, 85, 5516-5524. Kuang, G.; Liu, D.; Chen, X.; Liu, G.; Fu, Y.; Peng, Y.; Li, H.; Zhou, Y. Transient Directing Group Strategy as a Unified Method for Site Selective Direct C4-H Halogenation of Indoles. Org. Lett. 2021, 23 (21), 8402-8406.

[0396] Basak, S.; Paul, T.; Punniyamurthy, T. Palladium-Catalyzed 2- fold C-H Activation / C-C Coupling for C4-Arylation of Indoles Using Weak Chelation. Org. Lett. 2022, 24, 554-558. Taskesenligil, Y.; Aslan, M.; Cogurcu, T.; Saracoglu, N. Directed C-H Functionalization of C3 -Aldehyde, Ketone, and Acid / Ester-Substituted Free (NH) Indoles with lodoarenes via a Palladium Catalyst System. J. Org. Chem. 2023, 88, 1299-1318.

[0397] Hurt, C. R.; Lin, R.; Rapoport, H. Enantiospecific Synthesis of (R)-4-Amino-5-oxo-l,3,4,5- tetrahydrobenz[cd]indole, an Advanced Intermediate Containing the Tricyclic Core of the Ergots. J. Org. Chem 1999, 64, 225-233.

[0398] Nettekoven, M.; Psiorz, M.; Waldmann, H. Synthesis of enantiomerically pure 4- Alkylsubstituted Tryptophan Derivatives by a Combination of Organometallic Reactions with Enantioselective Enzymatic Transformations. Tetrahedron Lett. 1995, 36, 1425-1428. Kalepu, J.; Gandeepan, P.; Ackermann, L.; Pilarski, L. T. C4-H indole functionalisation: precedent and prospects. Chem. Sci. 2018, 9, 4203-4216.

[0399] Yonemitsu, O.; Cerutti, P.; Witkop, B. Photoreductions and Photocyclizations of Tryptophan. J. Am. Chem. Soc. 1966, 88, 3941-3945.

[0400] Gritsch, P. J.; Leitner, C.; Pfaffenbach, M.; Gaich. The Witkop Cyclization: A Photoinduced C_H Activation of the Indole System. Angew. Chem. Int. Ed. 2014, 53, 1208-1217.

[0401] Naruto, S.; Yonemitsu, O. Photochemical Synthesis of Azepinoindoles and Azocinoindoles from N-Chloroacetylindolylethylamines, and a Mechanistic Study based on the Correlation between Quantum Yields and Calculated Frontier Electron Densities of Indole Radicals. Chem. Pharm. Bull. 1980, 28, 900-909.

[0402] Beck, A. L.; Mascal, M.; Moody, C. J.; Slawin, A. M. Z.; Williams, D. J.; Coates, W. J. Synthesis of 3,4-bridged indoles by photocyclisation reactions. Part 1. Photocyclisation of halogenoacetyl tryptophan derivatives. J. Chem. Soc., Perkin Trans. 1 1992,, 797.

[0403] Feldman, K. S.; Ngernmeesri, P. Total Synthesis of (±)-Dragmacidin E. Org. Lett. 2011, 13 (20), 5704-5707.

[0404] Mascal, M.; Moody, C. J. Synthesis of (-)-indolactam V. J. Chem. Soc., Chem. Commun. 1988, 589-590.

[0405] Mascal, M.; Modes, K. V.; Durmus, A. Concise Photochemical Synthesis of the Antimalarial Indole Alkaloid Decursivine. Angew Chem. 2011, 123 (19), 4537-4538. Dillon, J. The Anaerobic Photolysis of Tryptophan Containing Peptides. Photochem. Photobiol. 1980, 32, 37-39.

[0406] Dillon, J. The Anaerobic Photolysis of Tryptophan Containing Peptides - II, Photochem. Photobiol. 1981, 33, 137-142.

[0407] Elliot, L. D.; Berry, M.; Haqi, B.; Klauber, D.; Leonard, J.; Brooker-Milburn, K.I. A Small- Footprint, High-Capacity Flow Reactor for UV Photochemical Synthesis on the Kilogram Scale. Org. Process Res. Dev. 2016, 20, 1806-1811.

[0408] Kuhn, H.J.; Braslavsky, S.E.; Schmidt, R. Chemical Actinometry; IUPAC Technical Report: Pure Appl. Chem., 2004, 76, 2105-2146.

[0409] Nagata, R.; Endo, Y.; Shudo, K. Photocyclization of y-Chlorotiglyl-L-tryptophan Methyl ester Yields Azocinoindole and Azepinoindole Derivatives. Chem Pharm Bull. 1993, 41 , 369- 372.

[0410] Szantay, C.; Boelcskei, H.; Gacsbaitz, E. Synthesis of Vinca Alkaloids and Related Compounds. XL VIII Synthesis of (+)-Catharnthine and (±)-Allocatharanthine. Tetrahedron. 1990, 46, 1711-1732.

[0411] Abiraj, K.; Gowda, D. C. Heterogeneous catalytic transfer hydrogenation in peptide synthesis. Lett. Pept. Sci. 2003, 9, 153-165.

[0412] Kumar, G.; Kellogg, M.; Dey, S.; Oliver, T. A. A.; Bradforth, S. E. Unraveling the Photoionization Dynamics of Indole in Aqueous and Ethanol Solutions. J. Phys. Chem. B. 2024, 128, 4158-4170.

[0413] Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic Chemistry, John Wiley & Sons, New York, 1995.

[0414] Zhang, F. -L.; Li, B.; Houk, K. N.; Wang, Y. -F. Application of the Spin-Center Shift in Organic Synthesis. JACS AU 2022, 5, 1032-1042.

[0415] Isse, A. A.; Lin, C. Y.; Coote, M. L.; Gennaro, A. Estimation of Standard Reduction Potentials of Halogen Atoms and Alkyl Halides. J. Phys. Chem. B. 2011, 115, 4, 678-684.

[0416] Nguyen, J. D.; Matsuura, B. S. Stephenson, C. R. J. A Photochemical Strategy for Lignin Degradation at Room Temperature. J. Am. Chem. Soc. 2014, 136, 1218.

[0417] Nacsa, E. D.; MacMillan, D. W. C. Spin-Center Shift-Enabled Direct Enantioselective a- Benzylation of Aldehydes with Alcohols. J. Am. Chem. Soc. 2018, 140, 9, 3322-3330.

[0418] Fantinati, A.; Zanirato, V.; Marchetti, P.; Trapella, C. The Fascinating Chemistry of a- Haloamides. ChemistryOpen 2020, 9, 100-170.

[0419] Zabolotna, Y.; Volochnyuk, D. M.; Ryabukhin, S. V.; Horvath, D.; Gavrilenko, K. S.;

[0420] Marcou, G.; Moroz, Y. S.; Oksiuta, O.; Var-nek, A. J. A Close-up Look at the Chemical Space of Commercially Available Building Blocks for Medicinal Chemistry. Chem. Inf. Model. 2022, 62, 9, 2171-2185.

[0421] Johnson, M. W.; Griffiths, R. R. Potential Therapeutic Effects of Psilocybin. Neurotherapeutics. 2017, 14, 734-740.

[0422] Borissova, A.; Rucker, J. J. The development of psilocybin therapy for treatment-resistant depression: an update. BJPsych Bull. 2023, 48, 38-44.

[0423] Sharp, T.; Collins, H. Mechanisms of SSRI Therapy and Discontinuation. Curr. Top. Behav. Neurosci. 2024, 66, 21-47.

[0424] Cameron, L. P.; Benetatos, J. Lewis, V.; Bonniwell, E. M.; Jaster, A. M.; Moliner, R.; Castren, E.; McCorvy, J. M.; Palner, M.; Aguilar- Valles, A. Beyond the 5-HT2A Receptor: Classic and Nonclassic Target in Psychedelic Drug Action. J. Neurosci. 2023, 43, 7472-7482. Heifets, B. D.; Olsen, D. E.; Therapeutic mechanism of psychedelics and entactogens. Neuropsychopharmacology. 2024, 49, 104-118.

[0425] Simon, I. A.; Bjprn-Yoshimoto, W. E.; Harpspe, K.; Iliadis, S.; Svensson, B.; Jensen, A. A.; Gloriam D. E. Ligand selectivity hotspots in serotonin GPCRs. 2023, 44, 978-990.

[0426] Juncosa, J. L; Hansen, M.; Bonner, L. A.; Cueva, J. P.; Maglathlin, R.; McCorvy, J. D.; Marona-Lewicka, D.; Lili, M. A.; Nichols, D. E. Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands. ACS Chem. Neurosci. 2013, 4, 1, 96-109.

[0427] Lewis, V.; Bonniwell, E. M.; Lanham, J. K.; Ghaffari, A.; Sheshbaradaran, H.; Cao, A. B.; Calkins, M. M.; Bautista-Carro, M. A.; Arsenault, E.; Telfer, A.; Taghavi-Abkuh, F.; Malcom, N. J.; Sayegh, F. L.; Abizaid, A.; Schmid, Y.; Morton, K.; Halberstadt, A. L.; Aguilar-Valles, A. McCorvy, J. D. A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Rep. 2023, 42, 112203.

[0428] Wallach, J.; Cao, A. B.; Calkins, M. M.; Heim, A. J.; Lanham, J. K.; Bonniwell, E. M.; Hennessey, J. J.; Bock, H. A.; Anderson, E. I.; Sherwood, A. M.; Morris, H.; de Klein, R.; Klein, A. K.; Cuccurazzu, B.; Gamrat, J.; Fannana, T.; Zauhar, R.; Halberstadt, A. L.; McCorvy, J. D. Identification of 5-HT2A Receptor Signaling Pathways Associated with Psychedelic Potential. Nat. Commun. 2023, 14, 1-19.

[0429] Example 2. Chemistry

[0430] General

[0431] Anhydrous dichloromethane was purchased from Millipore-Sigma and used as received. THF was purchased from Millipore-Sigma and distilled from sodium prior to use. Tryptamine, 5- methoxytryptamine, amino acids and coupling reagents were purchased from Oakwood chemical and used as received. Protected amino acids were synthesized using known procedures or purchased from Oakwood chemical or Millipore-Sigma. X-melhyllryptamine and 5-methoxy-A-methyltryptamine were prepared in an analogous manner to a,a,N“- trimethy Itryptamine .

[0432] Reactions were monitored using thin layer chromatography (TLC) on Sorbtech XG TLC plates with fluorescent indicator (TLC Silica gel 60 F254). Plates were visualized using ultraviolet light (254 nm) and / or KMnO4 solution as appropriate. Flash chromatography was performed using silica gel (Fisher Chemical, 230-400 Mesh, Grade 60). Solvent mixtures given in the description of each reaction refer to v / v composition. Rf values are optimized for TLC. Typically, columns were run using gradients that ended at solvent ratio listed for with the Rf value unless free amines or alcohols were present. In these cases, the gradient end point was past the listed solvent strength for the reported Rf value.

[0433] A Broker Avance NEO 300 MHz spectrometer was used to record 1H, 13C and HSQCDEPT spectra in the indicated deuterated solvent. All chemical shifts (5) are reported in parts per million (ppm) relative to residual solvent peaks as follows: CDCL (5H = 7.26 ppm, 6C = 77.16 ppm) or CD3OD (5H = 3.31 ppm, 6C = 49.00 ppm) or DMSO-ffc (5H = 2.50 ppm, 6C = 39.52 ppm) Coupling constants (J) are averaged. The multiplicity of a 1H NMR signal is designated by one of the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. The 13C NMR spectra are 1H decoupled.

[0434] High-resolution mass spectra were recorded on a Thermo Fisher Hybrid LTQ-Orbitrap XL mass spectrometer. HRMS data were obtained by direct infusion and mass calibration was performed using Pierce ESI positive and negative calibration standard solution (Thermo Fisher Inc.). Molecular formula assignments were performed using the Molecular Formula Calculator published by the National High Magnetic Field Laboratory (https: / / nationalmaglab.org / ). The [M + Na]+ and [M + H]+ ions were observed.

[0435] General procedure for recrystallization using a binary solvent system

[0436] The crude product was dissolved in a moderate amount the more polar solvent and heated to a gentle reflux. The less polar solvent was then added slowly until a slight change in transparency was observed. The mixture was then removed from the heat and stirred at room temperature for about an hour before being placed in a freezer at -20°C. Once cooled the product was collected by suction filtration and air dried. In some cases, the product was further dried using vacuum.

[0437] General procedure for recrystallization using a single solvent system Recrystallization using a single solvent system consisted of dissolving the product in an excess amount of the desired boiling solvent and filtering. The filtrate was then heated on a hotplate with stream of argon to assist evaporation until a change in transparency was noticed. The mixture was then removed from the heat and stirred at room temperature for roughly an hour before being placed in a freezer at -20 °C. Once cooled the product was collected by suction filtration and air dried.

[0438] (Sl)«,« dimethyltryptamine a,a-dimethyltryptamine was obtained from gramine using a known procedure.O0Gramine (1 .0 g, 69.0 mmol) and sodium hydroxide (2.8 g, 72.0 mmol) were refluxed in nitropropane (60 mL) for 18 hours. The resulting solution was cooled to room temperature and 10% aqueous citric acid (60 mL) was added. The solution was stirred for several hours before water (80 mL) was added. The solution was extracted with diethyl ether (3 x 80 mL). The organic extracts were washed with 0.1 M HC1, followed by saturated sodium bicarbonate, and brine. The organic layer was dried over sodium sulphate and the solvent was removed to give (15.1 g, 69 mmol) 3-(2-methyl-2-nitropropyl)-lH-indole in quantitative yield. Rf= 0.32 (20% EtOAc:80% hexanes)

[0439] The crude nitro product from above was dissolved in methanol (340 mL) and transferred to a Parr pressure vessel. Pd / C / 10% (0.5 g) was added and a hydrogen pressure of 260 psi was applied. After 16 hours the solution was filtered through celite, and the solvent was removed. The crude solid was recrystallized from isopropanol and hexanes to give the product (10.0 g, 53 mmol) as a white powder in 77% yield. The spectra matched the literature report.

[0440] (S2) A-formyl a,a-dimethyltryptamide. a,a-dimethyltryptamine (5.65 g, 30.0 mmol) was refluxed in ethyl formate (50 mL) and ethanol (8 mL) for one week under an argon atmosphere. The reaction mixture was filtered to remove remaining starting material and the solvent was removed. The crude product was chromatographed using ethyl acetate to provide the product (4.06 g, 18.8 mmol) as a white solid in 63% yield. Rf= 0.33 (100% EtOAc) ’H NMR (300 MHz, DMSO-d6) (rotamers observed): 5 10.94 - 10.82 (m, 1H), 8.03 - 7.87 (m, 1H), 7.70 - 7.46 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.11 - 6.99 (m, 2H), 7.00 - 6.91 (m, 1H), 2.96 (d, 7= 579.4 Hz, 2H), 1.28 - 1.19 (m, 6H).13C{]H} NMR (76 MHz, DMSO-d6) (rotamers observed): 5 162.81, 160.76, 135.88, 135.86, 128.49, 128.24, 124.74, 124.32, 120.65, 120.57, 118.89, 118.82, 118.41, 118.29, 1 1 1.30, 1 11.27, 1 10.49, 109.84, 53.79, 53.04, 38.44, 34.54, 28.07, 26.95. HRMS: (ESI+) C13H16N2O [M+H] m / z calcd. 217.1263, found 217.1337.

[0441] (S3) «,a,2V“-trimethyltryptamine.

[0442] N-formyl-a,a-dimethyltryptamine (3.69 g, 17.1 mmol) was dissolved in anhydrous THF (50 mL) under argon. A separate, oven dried, 2 neck flask, equipped with a reflux condenser was filled with solid LAH (2.75 g, 72.5 mmol,) and THF (20 mL) was added. The 2 neck was cooled to 0°C before the tryptamine containing flask was cannula transferred onto the LAH slurry. The mixture was brought to room temperature and then refluxed for 4 hours. The reaction was carefully quenched at 0°C with wet THF (7 mL H2O in 66 mL THF) and stirred overnight. The resulting white slurry was filtered, and the filter cake was washed with additional THF. The solvent was removed to provide the product as a white solid (3.35 g, 16.6 mmol) in 97% yield. H NMR (300 MHz, CDCh): 5 8.29 (s, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.36 (d, 7 = 7.8 Hz, 1H), 7.22 - 7.15 (m, 1H), 7.15 - 7.08 (m, 1H), 7.04 (s, 1H), 2.87 (s, 2H), 2.41 (s, 3H), 1.67 (s, 1H), 1.13 (s, 6H).13C{]H} NMR (76 MHz, CDCh): 5 5 136.18, 128.72, 123.60, 121.70, 119.55, 119.30, 112.13, 111.19, 53.79, 36.40, 28.88, 26.35. HRMS: (ES1+) C13H18N2 |M+H] m / z calcd 203.1470, found 203.1541.

[0443] General procedure 1 for amide bond formation

[0444] Tryptamides were synthesized using standard liquid phase peptide synthesis. Tryptamine or its derivatives (1.0 equiv.), 1 -Hydroxybenzotriazole HOBt (1.1 equiv.) and -protected amino acid (1.0 equiv.) were placed into a flask with a stir bar and purged with argon. Anhydrous DCM was added via cannula to give approximately a 0.1 M solution. The suspension was cooled in an ice bath and to this was added EDC1 HC1 (1.2 eq) in one portion. After 30 minutes NMM (2.2 equiv.) was added drop wise via syringe. The solution was slowly allowed to come to room temperature as the ice melted and the reaction was stirred overnight (minimum 12 hours). The solvent was removed and resulting oil was transferred to a sep funnel with a minimum of 20 ml of ethyl acetate per mmol of starting material and 20 mL 0. IM HC1 per mmol of starting material. The aqueous layer was separated and the organic layer was washed 2 additional times with 0.1M HC1, followed by saturated sodium bicarbonate and brine. The organic layer was dried with sodium sulfate, filtered and the solvent was removed. Compounds were purified by recrystallization from EtOAc / hexanes or isopropanol or methanol or by column chromatography (EtOAc / hexanes).

[0445] (Al) A -Cbz-glycine tryptamide. Cbz-Gly-Tmn

[0446] Tryptamine (3.20 g, 20.0 mmol) and N-Cbz-glycine (4.18 g, 20.0 mmol) were reacted using GP 1. Note: 40 mL of ethyl acetate per mmol is required to dissolve the crude product during work up. The crude product was recrystallized from 150 mL of ethyl acetate to produce Al (6.38 g, 18.2 mmol) as a white solid in 91% yield.0 Rf= 0.15 (65% EtOAc:35% hexanes) H NMR (300 MHz, DMSO- e): 5 10.81 (s, 1H), 7.95 (t, J = 5.5 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.43 (t, 7 = 6.1 Hz, 1H), 7.39 - 7.27 (m, 6H), 7.15 (d, 7 = 1.8 Hz, 1H), 7.06 (t, 7 = 6.9 Hz, 2H), 6.98 (t, 7 = 7.4 Hz, 1H), 5.04 (s, 2H), 3.60 (d, 7 = 6.1 Hz, 2H), 3.34 (d, 7 = 8.7 Hz, 3H), 2.82 (t, 7 = 7.4 Hz, 2H).13C{ *H} NMR (76 MHz, DMSO-d6): 5 168.90, 156.50, 137.06, 136.25, 128.35, 127.79, 127.75, 127.21, 122.66, 120.93, 118.25, 111.73, 111.38, 65.51, 43.65, 25.23. HRMS: (ESI+) C20H21N3O3 [M+H] m / z calcd. 352.1583, found 352.1654.

[0447] (A2) A-Cbz-glycine N“-methyltryptamide. Cbz-Gly-NMe-Tmn N"-methyltryptamine (1.74 g, 10.0 mmol) and Cbz-glycine (2.09 g, 10.0 mmol) were reacted using GP l.The crude product was recrystallized from ethyl acetate to produce A2 (3.02 g, 8.27 mmol) as a snow like white solid in 83% yield. Rf = 0.34 (50% EtOAc:50% hexanes) H NMR (300 MHz, DMSO-d6) (rotamers observed): 8 10.88 - 10.82 (m, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.42 - 7.17 (m, 7H), 7.15 (s, 1H), 7.08 (t, 7 = 7.5 Hz, 1H), 6.99 (t, 7 = 7.3 Hz, 1H), 5.06 - 5.02 (m, 2H), 3.82 - 3.76 (m, 2H), 3.58 - 3.47 (m, 2H), 3.00 - 2.81 (m, 5H).13C{ ’H] NMR (76 MHz, DMSO-d6) (rotamers observed): 6 168.24, 168.18, 156.57, 156.49, 137.19, 137.16, 136.31 , 136.24, 128.36, 127.78, 127.70, 127.68, 127.26, 127.06, 123.26, 122.72, 121.07, 121.02, 118.49, 118.34, 118.12, 111.53, 111.46, 110.76, 65.44, 65.41, 49.13, 48.61, 42.25, 41.65, 34.14, 33.23, 23.69, 22.95. HRMS: (ESI+) C21H23N3O3 [M+H] m / z calcd. 366.1739, found 366.1809.

[0448] (A3) A-Cbz-glycine «, ( / -dimethyl tryptamide. Cbz-Gly-a,a-DiMeTmn a, a dimethyltryptamine (1.88 g, 10.0 mmol) and Cbz-glycine (2.09 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A3 (2.59 g, 6.83 mmol) as a white foam in 68% yield. Rf= 0.40 (65% EtOAc:35% hexanes) ’H NMR (300 MHz, CDCI3): 8 8.00 (s, 1H), 7.57 (d, 7 = 7.8 Hz, 1H), 7.38 - 7.30 (m, 6H), 7.17 (td, 7 = 8.1, 7.6, 1.3 Hz, 1H), 7.10 (td, 7 = 7.5, 7.1, 1.2 Hz, 1H), 6.95 (s, 1H), 5.64 (s, 1H), 5.26 (s, 1H), 5.09 (s, 2H), 3.69 (d, 7 = 4.8 Hz, 2H), 3.12 (s, 2H), 1.40 (s, 6H).13C{JH} NMR (76 MHz, CDCh): 8 168.51, 156.69, 136.28, 136.02, 128.62, 128.44, 128.30, 128.12, 123.92, 121.75, 1 19.40, 119.08, 111.34, 67.08, 54.91, 45.10, 35.30, 27.25. HRMS: (ESI+) C22H25N3O3 [M+H] m / z calcd. 352.1583, found 352.1654.

[0449] (A4) A-Cbz-glycine a,a,N“-trimethy!tryptamide. Cbz-Gly-NMe-a,a-DiMeTmn GP1 worked in all cases except here: a, a-dimethyl-Na-methyltryptamine (1.88 g, 10.0 mmol) and Cbz-glycine (1.05 g, 5.00 mmol) were dissolved in anhydrous THF (50 mL) and cooled in an icebath. To this was added oxalyl chloride (0.45 mL, 0.667 g, 5.25 mmol) and DMF (0.1 mL). The solution was stirred for 3 hours before being cannula transferred into an ice cold solution of a, a dimethyl-N“-methyltryptamine (1.01 g, 5.00mmol) in THF (20 mL) containing / V-methyl morpholine (1.27 mL, 1.17 g, 11.6 mmol, 2.3 equiv.) and DMAP (17.5 mg, 0.15 mmol). The solution was slowly allowed to warm to room temperature and was determined complete by TLC after 6 hours. The solvent was removed, and the crude product was dissolved in ethyl acetate (100 mL) and washed with 0.1M HC1 (3x50 mL), saturated NaHCCL (50 mL) and brine. The organic layer was dried over sodium sulfate and the solvent was removed. The crude product was chromatographed using ethyl acetate and hexanes to produce A4 (1.1 g, 2.78 mmol) as a yellow glass in 56% yield. Rf = 0.40 (40% EtOAc:60% hexanes) ’H NMR (300 MHz, DMSO-6): 5 10.87 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.45 - 7.25 (m, 7H), 7.10 - 6.91 (m, 3H), 5.09 (s, 2H), 3.80 (d, J = 5.7 Hz, 2H), 3.26 (s, 2H), 2.50 (d, J = 2.1 Hz, 3H), 1.38 (s, 6H).13C{ ’H} NMR (76 MHz, DMSO-d6): 5 168.86, 156.73, 137.21, 135.82, 128.46, 128.35, 127.76, 127.68, 124.14, 120.51, 118.81, 118.36, 111.23, 110.86, 65.42, 60.48, 44.54, 32.68, 31.32, 27.05. HRMS: (ESI+) C23H27N3O3 [M+H] m / z calcd. 394.2052, found 391.2125.

[0450] (A5) A-Cbz-glycine 5-methoxytryptamide. Cbz-Gly-NMe-5-MeOTmn

[0451] 5-Methoxytryptamine (1.90g, 10.0 mmol) and Cbz-glycine (2.09 g, 10.0 mmol) were reacted using GP 1. The product was a scaly tan solid and determined pure by TLC and NMR (3.49 g, 9.14 mmol, 91%). Rf= 0.36 (80% EtOAc:20% hexanes) NMR (300 MHz, CDCI3): 5 7.83 (s, 1H), 7.35 (s, 5H), 7.24 (d, 7 = 8.8 Hz, 1H), 7.O1 (d, 7 = 2.3 Hz, 1H), 6.94 (s, 1H), 6.87 (dd, 7 = 8.8, 2.4 Hz, 1H), 5.99 (s, 1H), 5.29 (s, 1H), 5.09 (s, 2H), 3.85 (s, 3H), 3.79 (d, 7 = 5.7 Hz, 2H), 3.59 (q, J = 6.5 Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H).13C{1H} NMR (76 MHz, CDCh): 3 168.93, 156.66, 154.15, 136.27, 131.63, 128.71, 128.43, 128.28, 127.69, 123.12, 112.47, 112.31, 112.17, 100.56, 67.27, 56.07, 44.72, 39.58, 25.22. HRMS: (ESI+) C21H23N3O4 [M+H] m / z calcd. 382.1689, found 382.1757.

[0452] (A6) A-Cbz-glycine 5-methoxy-N“-methyltryptamide. Cbz-Gly- NMe-5MeOTmn

[0453] 5-methoxy-Na-methyltryptamine (2.04 g, 10.0 mmol) and Cbz-glycine (2.09 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes to produce A6 (3.17, 8.06 mmol) as a bleach white powder in 81% yield. Rf = 0.30 (65% EtOAc:35% hexanes) 'H NMR (300 MHz, DMSO- e) (rotamers observed): 5 10.81 - 10.45 (m, 1H), 7.40 - 7.17 (m, 7H), 7.16 - 7.02 (m, 2H), 6.75 - 6.68 (m, 1H), 5.04 (d, J = 11.2 Hz, 2H), 3.86 (d, J = 5.9 Hz, 1H), 3.80 - 3.68 (m, 4H), 3.57 - 3.45 (m, 2H), 2.98 - 2.76 (m, 5H).13C{]H] NMR (76 MHz, DMSO-d6) (rotamers observed): 5 168.27, 168.18, 156.55, 156.48, 153.17, 153.08, 137.20, 137.17, 131.48, 131.37, 128.35, 127.77, 127.70, 127.67, 127.59, 127.42, 123.86, 123.36, 112.18, 112.09, 111.21, 111.08, 110.57, 100.27, 99.95, 65.44, 65.40, 55.39, 55.33, 49.09, 48.36, 42.27, 41.65, 34.13, 33.25, 23.75, 23.00. HRMS: (ESI+) C22H25N3O4 [M+H] m / z calcd. 396.1845, found 396.1917.

[0454] (A7) A-Cbz-glycine a-ethyl tryptamide. Cbz-Gly-aEtTmn

[0455] 3-(2-nitrobutyl)-lH-indole (25 mmol) was reduced over several days with 10% Pd / C and H2 at 1 atm. The crude product was reacted with Cbz-glycine (5.23g, 25 mmol) using GP 1. The crude product was recrystallized from ethyl acetate and hexanes using the general procedure with modification. The crystallization was performed at room temperature and then placed in the freezer whereupon it oiled out. On warming crystals formed and the solution was placed back in the freezer. The product A7 (6.34g g, 16.7 mmol) was isolated as a white solid. The yield was 67% over two steps. Rf = 0.27 (65% EtOAc:35% hexanes)]H NMR (300 MHz, DMSO-de): 5 10.79 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.43 - 7.25 (m, 7H), 7.11 (d, J = 1.9 Hz, 1H), 7.09 - 7.02 (m, 1H), 6.97 (t, 7 = 7.3 Hz, 1H), 5.05 (s, 2H), 3.98 - 3.80 (m, 1H), 3.70 - 3.48 (m, 2H), 2.79 (qd, J = 14.3, 6.5 Hz, 2H), 1.62 - 1.40 (m, 1H), 1.31 (dq, J= 14.5, 7.4 Hz, 1H), 0.81 (t, J = 7.3 Hz, 3H).13C{ ’H] NMR (76 MHz, DMSO- dd): 5 168.64, 156.52, 137.13, 136.21, 128.35, 127.79, 127.73, 127.64, 127.17, 123.24, 120.82, 118.47, 1 18.26, 11 1.35, 65.49, 51.09, 43.62, 30.20, 26.43, 10.56. HRMS: (ESI+) C22H25N3O3[M+H] m / z calcd. 380.1896, found 380.1971.

[0456] (A8) A-Cbz-glycine 0-ethyl tryptamide. Cbz-Gly-fi-EtTmn

[0457] P-ethyl tryptamine (1.17g, 6.21 mmol) and Cbz-glycine (1.3 g, 6.21 mol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A8 (1.96 g, 5.17 mmol) as an opaque solid in 83% yield. Rf= 0.33 (65% EtOAc:35% hexanes) ’H NMR (300 MHz, DMSO-d6): 6 10.84 (s, 1H), 7.77 (t, J = 5.6 Hz, 1H), 7.57 (d, 7= 7.8 Hz, 1H), 7.44 - 7.25 (m, 7= 5.6, 5.2 Hz, 7H), 7.11 (d, 7 = 2.1 Hz, 1H), 7.09 - 7.01 (m, 1H), 6.96 (t, J = 7.4 Hz, 1H), 5.03 (s, 2H), 3.58 (d, J = 6.1 Hz, 2H), 3.34 (s, 2H), 2.95 (p, 7 = 7.8, 7.3 Hz, 1H), 1.85 - 1.68 (m, 1H), 1.61 (dq, 7= 14.6, 7.4 Hz, 1H), 0.78 (t, 7= 7.3 Hz, 3H).13C{ ’H] NMR (76 MHz, DMSO-d6): 6 169.02, 156.51, 137.09, 136.50, 128.36, 127.80, 127.75, 127.12, 126.97, 122.00, 120.84, 1 18.70, 1 18.18, 115.69, 1 11.49, 65.53, 43.74, 43.63, 38.06, 25.13, 25.13, 11.94. HRMS: (ESI+) C22H25N3O3 [M+H] m / z calcd. 380.1896, found 380.1976.

[0458] (A9) N-Cbz-L-alanine tryptamide. Cbz-L-Ala-Tmn

[0459] Tryptamine (1.60 g, 10.0 mmol) and Cbz-alanine (2.23 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes with the aid of a seed crystal to produce A9 (2.74, 7.50 mmol) a white solid in 75% yield.O Rf = 0.22 (50% EtOAc:50% hexanes)1H NMR (300 MHz, DMSO-d6): 8 10.81 (s, 1H), 7.94 (t, J = 5.7 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.42 - 7.25 (m, 7H), 7. 14 (d, J = 2.3 Hz, 1H), 7.06 (td, J = 7.4, 1.2 Hz, 1H), 6.97 (td, J= 1A, 0.9 Hz, 1H), 5.11 - 4.94 (m, 2H), 4.01 (p, 7 = 7.2 Hz, 1H), 3.43 - 3.22 (m, 2H), 2.81 (t, 7 = 7.4 Hz, 2H), 1.19 (d, 7 = 7.1 Hz, 3H). ^Cf ’H} NMR (76 MHz, DMSO-d6): 8 172.30, 155.67, 137.06, 136.26, 128.33, 127.77, 127.21 , 122.70, 120.91 , 118.27, 118.23, 111.72, 111.36, 65.41, 50.21, 25.16, 18.38. HRMS: (ESI+) C21H23N3O3 [M+H] m / z calcd. 366.1739, found 366.1811.

[0460] (A10) N-Cbz-L- valine tryptamide. Cbz-L-Val-Tmn

[0461] Tryptamine (1.60 g, 10.0 mmol) and Cbz-L-valine (2.51 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes to produce A10 (2.89 g, 7.34 mmol) a white solid in 74% yield.O Rf = 0.40 (50% EtOAc:50% hexanes) H NMR (300 MHz, CDCh): 8 8.31 (s, 1H), 7.57 (d, 7 = 7.8 Hz, 1H), 7.39 - 7.28 (m, 6H), 7.19 (t, 7 = 7.6 Hz, 1H), 7.11 (t, 7 = 7.4 Hz, 1H), 6.90 (s, 1H), 6.34 (s, 1H), 5.55 (d, 7 = 8.8 Hz, 1H), 5.11 - 4.92 (m, 2H), 4.06 - 3.91 (m, 1H), 3.66 - 3.45 (m, 7 = 6.5 Hz, 2H), 2.93 (t, 7 = 6.6 Hz, 2H), 2.07 (dq, 7 = 13.1, 6.5 Hz, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.87 (d, 7 = 6.7 Hz, 3H).13C{!H} NMR (76 MHz, CDCh): 8 171.43, 156.59, 136.48, 136.33, 128.62, 128.27, 128.10, 127.24, 122.33, 122.15, 119.42, 118.63, 112.51, 111.42, 67.01, 60.61, 39.72, 31.18, 25.35, 19.33, 17.83. HRMS: (ESI+) C23H27N3O3 [M+H] m / z calcd. 394.2052, found 394.2123.

[0462] (All) / V-Cbz-L-norleucine tryptamide. Cbz-L-Nle-Tmn

[0463] Tryptamine (1.60 g, 10.0 mmol) and Cbz-L-norleucine (2.65 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes to produce Al 1 (2.68 g, 6.59 mmol) as a white solid in 66% yield.!H NMR (300 MHz, DMSO-d6): 8 10.80 (s, 1H), 7.97 (t, 7 = 5.6 Hz, 1H), 7.54 (d, 7 = 7.7 Hz, 1H), 7.41 - 7.25 (m, 7H), 7.13 (d, 7 = 1.8 Hz, 1H), 7.06 (Id, 7 = 7.2, 1.1 Hz, 1H), 6.97 (td, 7 = 7.6, 1.0 Hz, 1H), 5.09 - 4.95 (m, 2H), 3.93 (td, 7 = 8.5, 5.7 Hz, 1H), 3.43 - 3.21 (m, 3H), 2.81 (t, 7 = 7.3 Hz, 2H), 1.67 - 1.38 (m, 2H), 1.28 - 1.10 (m, 4H), 0.83 (t, 7 = 6.6 Hz, 3H).13C{!H] NMR (76 MHz, DMSO-d6): 5 171.82, 155.95, 137.12, 136.26, 128.31, 127.75, 127.69, 127.21, 122.67, 120.90, 118.26, 118.21, 111.72, 111.36, 65.37, 54.79, 31.82, 27.67, 25.17, 21.85, 13.87. HRMS: (ESI+) C23H27N3O3 [M+H] m / z calcd. 408.2209, found 408.2284.

[0464] (A12) / V-Cbz-L-leucine tryptamide. Cbz-L-Leu-Tmn

[0465] Tryptamine (1.60g, 10.0 mmol) and Cbz-L-leucine (2.65 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes with the aid of a seed crystal to produce A 12 (2.96 g, 7.26 mmol) as a white solid in 73% yield.O 'H NMR (300 MHz, DMSO-d6): 8 10.81 (s, 1H), 7.99 (t, 7 = 5.6 Hz, 1H), 7.55 (d, 7 = 7.7 Hz, 1H), 7.42 - 7.24 (m, 7H), 7.13 (d, 7 = 1.6 Hz, 1H), 7.06 (td, 7 = 8.0, 0.9 Hz, 1H), 6.97 (td, 7 = 8.0, 0.8 Hz, 1H), 5.10 - 4.95 (m, 2H), 4.04 - 3.92 (m, 1H), 3.42 - 3.24 (m, 3H), 2.81 (t, 7 = 7.3 Hz, 2H), 1.65 - 1.48 (m, 1H), 1.47 - 1.30 (m, 2H), 0.85 (t, 7 = 6.5 Hz, 6H).13C{ ‘H} NMR (76 MHz, DMSO-d6): 8 172.13, 155.93, 137.10, 136.24, 128.31, 127.75, 127.67, 127.21, 122.67, 120.88, 118.26, 118.20, 111.72, 111.34, 65.38, 53.25, 40.94, 25.13, 24.25, 22.98, 21.52.HRMS: (ESI+) C23H27N3O3 [M+H] m / z calcd. 408.2209, found 408.2282.

[0466] (A13) V-Cbz-L-isoleucine tryptamide. Cbz-L-Ile-Tmn

[0467] Tryptamine (1.60 g, 10.0 mmol) and Cbz-L-isoleucine (2.65 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes to produce A13 (2.61 g, 6.40 mmol) as a white solid in 64% yield. 'H NMR (300 MHz, DMSO-de) 8 10.80 (s, 1H), 8.04 (t, J = 5.4 Hz, 1H), 7.54 (d, 7 = 7.7 Hz, 1H), 7.39 - 7.20 (m, 7H), 7.14 (d, 7 = 1.9 Hz, 1H), 7.06 (Id, 7= 7.0, 1.1 Hz, 1H), 6.97 (td, 7= 8.0, 1.1 Hz, 1H), 5.10 - 4.95 (m, 2H), 3.85 (t, 7 = 8.3 Hz, 1H), 3.46 - 3.21 (m, 2H), 2.81 (t, 7 = 7.4 Hz, 2H), 1.70 (d, 7 = 6.0 Hz, 1H), 1.47 - 1.31 (m, 1H), 1.17 - 0.99 (m, 1H), 0.81 (t, 7 = 7.4, 3.5 Hz, 3H), 0.78 (t, 7 = 4.4 Hz). ^Cf ’H} NMR (76 MHz, DMSO-cfc): 171.06, 156.02, 137.11, 136.25, 128.30, 127.74, 127.65, 127.16, 122.66, 120.89, 118.20, 111.67, 111.34, 65.38, 59.31, 39.40, 36.38, 25.17, 24.39, 15.42, 10.95. HRMS: (ESH) C23H27N3O3 [M+H] m / z calcd. 408.2209, found 408.2283.

[0468] (A14) IV-Cbz-L-tert-leucine tryptamide. Cbz-L-Tle-Tmn

[0469] Tryptamine (1.60g, 10.0 mmol) and Cbz-L-tert-leucine (2.65 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A14 (2.30 g, 5.64 mmol) as a white foam in 56% yield. Ri = 0.45 (40% EtOAc:60% hexanes)JH NMR (300 MHz, DMSO-d6) 5 10.81 (s, 1H), 8.11 (t, 7 = 5.2 Hz, 1H), 7.55 (d, 7 = 7.8 Hz, 1H), 7.40 - 7.26 (m, 6H), 7. 15 (d, 7 = 1.5 Hz, 1H), 7.07 (t, 7 = 7.5 Hz, 2H), 6.98 (t, 7 = 7.3 Hz, 1H), 5.12 - 4.99 (m, 2H), 3.92 (d, 7= 9.5 Hz, 1H), 3.50 - 3.24 (m, 4H), 2.85 (t, 7 = 7.7 Hz, 2H), 0.92 (s, 9H).13C{]H} NMR (76 MHz, DMSO-d6): 5 169.96, 156.04, 137.10, 136.25, 128.31, 127.73, 127.62, 127.16, 122.65, 120.90, 118.23, 118.21, 111.68, 111.34, 65.44, 62.59, 39.39, 33.94, 26.68, 25.17. HRMS: (ESI+) C23H27N3O3 [M+H] m / z calcd. 408.2209, found 408.2283.

[0470] (A15) N-Cbz-L-serine tryptamide. Cbz-L-Ser-Tmn

[0471] Tryptamine (1.60g, 10.0 mmol) and Cbz-L-serine (2.39 g, 10.0 mmol) were reacted using GP

[0472] 1. The crude product was recrystallized from ethyl acetate and hexanes to produce A15 (2.61 g, 6.85 mmol) as a white solid in 69% yield.!H NMR (300 MHz, DMSO-cfe): 5 10.80 (s, 1H), 7.98 (t, J = 5.5 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.40 - 7.29 (m, 7H), 7.17 - 7.12 (m, 2H), 7.06 (td, 7 = 7.0, 1.1 Hz, 1H), 6.97 (td, 7 = 7.9, 1.0 Hz, 1H), 5.11 - 4.97 (m, 2H), 4.84 (t, J = 5.7 Hz, 1H), 4.08 - 3.96 (m, 1H), 3.64 - 3.48 (m, 2H), 3.40 - 3.24 (m, 2H), 2.81 (t, J = 7.4 Hz, 2H).13C{‘H} NMR (76 MHz, DMSO-cfc): 5 169.95, 155.95, 137.01, 136.26, 128.36, 127.78, 127.21, 122.72, 120.93, 118.25, 111.74, 111.39, 65.56, 61.90, 57.41, 39.65, 25.18. HRMS: (ESI+) C21H23N3O4 [M+H] m / z calcd. 382.1689, found 382.1761.

[0473] (A16) V-Cbz-L- threonine tryptamide. Cbz-L-Thr-Tmn

[0474] Tryptamine (1.60g, 10.0 mmol) and Cbz-L-threonine (2.53 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes to produce A 16 (3.31 g, 8.37 mmol) as a white solid in 84% yield. ’H NMR (300 MHz, DMSO-d6): 8 (s, 1H), 7.96 (t, 7 = 5.5 Hz, 1H), 7.55 (d, 7 = 7.7 Hz, 1H), 7.42 - 7.24 (m, 6H), 7.15 (d, 7 = 1.3 Hz, 1H), 7.06 (td, 7 = 7.3, 1.1 Hz, 1H), 6.98 (td, 7 = 7.0, 1.1 Hz, 1H), 6.88 (d, 7 = 8.4 Hz, 1H), 5.14 - 4.97 (m, 2H), 4.77 (d, 7 = 5.7 Hz, 1H), 3.93 (td, 7 = 12.1, 11.3, 4.7 Hz, 2H), 3.49 - 3.19 (m, 3H), 2.82 (t, 7 = 7.4 Hz, 2H), 1.04 (d, 7 = 6.0 Hz, 3H).13C{ ’H} NMR (76 MHz, DMSO-cfc): 8 170.16, 156.15, 137.03, 136.28, 128.36, 127.81, 127.70, 127.20, 122.73, 120.94, 118.26, 111.74, 111.39, 66.73, 65.61, 60.79, 25.18, 20.16. HRMS: (ESI+) C22H25N3O4 [M+H] m / z calcd. 396.1845, found 396.1915.

[0475] (A17) Boc-S-Benzyl-L-cysteine tryptamide. Boc-CysBn-Tmn

[0476] Tryptamine (1.60 g, 10.0 mmol) and Boc-S-Benzyl-L-cysteine (3.11 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes to produce A17 (3.96 g, 8.73 mmol) as white solid in 87% yield.O Ri = 0.50 (50% EtOAc:50% hexanes) 'H NMR (300 MHz, DMSO-d6): 6 10.81 (s, 1H), 8.09 (t, J = 5.5 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.37 - 7.18 (m, 6H), 7.15 (d, 7 = 2.1 Hz, 1H), 7.07 (dt, 7 = 7.8, 2.4, 1.0 Hz, 2H), 6.98 (td, 7 = 7.9, 1.0 Hz, 2H), 6.92 (d, 7 = 8.6 Hz, 1H), 4.16 (q, 7 = 8.4 Hz, 1H), 3.74 (s, 2H), 3.34 (d, 7= 7.2 Hz, 3H), 2.83 (t, 7 = 7.4 Hz, 2H), 2.71 (dd, 7 = 13.6, 5.4 Hz, 1H), 2.60 - 2.51 (m, 1H), 1.41 (s, 9H).13C{ ’H} NMR (76 MHz, DMSO-d6): 5 170.36, 155.24, 138.41, 136.25, 128.89, 128.32, 127.17, 126.80, 122.65, 120.91, 118.23, 111.65, 111.37, 78.23, 53.78, 35.16, 33.55, 28.19, 25.14. HRMS: (ESI+) C25H31N3O3S [M+H] m / z calcd. 454.2086, found 454.2160.

[0477] (A 18) N-Boc-L- methionine tryptamide. Boc-L-Met-Tmn

[0478] Tryptamine (1.60g, 10.0 mmol) and Boc-L-methionine (2.49g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes to produce Al 8 (2.18, 5.56 mmol) as white solid, with a small particle size, in 58% yield. Rf = 0.43 (50% EtOAc:50% hexanes) ' H NMR (300 MHz, DMSO-d6): 5 10.81 (s, 1H), 7.89 (t, 7 = 5.3 Hz, 1 H), 7.54 (d, 7 = 7.7 Hz, 1 H), 7.33 (d, 7 = 8.0 Hz, 1 H), 7. 13 (d, 7 = 2.2 Hz, 1 H), 7.06 (td, 7 = 7.2, 1.0 Hz, 1H), 6.97 (td, 7 = 7.9, 1.1 Hz, 1H), 6.91 (d, 7 = 8.1 Hz, 1H), 3.99 (dt, 7 = 13.3, 7.7 Hz, 1H), 3.44 - 3.22 (m, 2H), 2.81 (t, 7 = 7.3 Hz, 2H), 2.46 - 2.28 (m, 2H), 2.01 (s, 3H) 1.88 - 1.64 (m, 2H), 1.38 (s, 9H).13C{ ’H} NMR (76 MHz, DMSO-<fc): 5 171.51, 155.36, 136.27, 127.18, 122.61, 120.91, 118.25, 118.22, 11 1.69, 111.36, 78.09, 53.63, 39.47, 31.87, 29.81, 28.20, 25.17, 14.64. HRMS: (ESI+) C20H29N3O3S [M+H] m / z calcd. 392.1930, found 392.2006.

[0479] (A19) M-Cbz-L-proline tryptamide. Cbz.-L-Pro-Tmn Tryptamine (1.60g, 10.0 mmol) and Cbz-L-proline (2.49 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A19 (2.09 g, 5.34 mmol) as a white foam in 53% yield.O Rf = 0.35 (80% EtOAc:20% hexanes) ' H NMR (300 MHz, DMSO-c / e) (rotamers observed): 5 10.80 (s, 1H), 8.10 - 7.96 (m, 1H), 7.58 - 7.18 (m, 1H), 7.41 - 7.22 (m, 6H), 7.17 - 7.03 (m, 2H), 6.98 (td, J = 6.8, 0.7 Hz, 1H), 5.16 - 4.93 (m, 2H), 4.23 - 4.08 (m, 1H), 3.53 - 3.23 (m, 5H), 2.79 (dt, 7= 15.1, 7.0 Hz, 2H), 2.08 (dddd, 7 = 20.6, 17.3, 11.3, 4.3 Hz, 1H), 1.86 - 1.72 (m, 3H).13C{]H} NMR (76 MHz, DMSO-d6) (rotamers observed): 5 171.99, 171.75, 154.18, 153.95, 137.05, 136.30, 128.40, 128.22, 127.78, 127.56, 127.52, 127.27, 127.06, 122.77, 122.55, 120.94, 118.28, 118.24, 111.78, 111.40, 65.98, 65.82, 60.25, 59.76, 47.16, 46.55, 31.28, 30.17, 25.25, 25.17, 23.90, 23.10. HRMS: (ESI+) C23H25N3O3 [M+H] m / z calcd. 392.1986, found 392.1967.

[0480] (A20) V-Cbz-D-asparagine tryptamide. Cbz-D-Asn-Tmn

[0481] Tryptamine (1.60 g, 10.0 mmol) and Cbz-D-asparagine (2.66 g, 10.0 mmol) were reacted using GP 1. Note: the product is extracted as a suspension and not dried chemically. The crude product was recrystallized from methanol (75 mL) to produce A20 (2.25g, 5.51 mmol) as white solid in 55% yield. ’H NMR (300 MHz, DMSO-d6): 8 10.81 (s, 1H), 7.95 (s, 1H), 7.55 (d, 7= 7.7 Hz, 1H), 7.34 (d, 7= 11.6 Hz, 8H), 7.14 (s, 1H), 7.O6 (t, 7 = 7.4 Hz, 1H), 6.98 (t, 7 = 7.4 Hz, 1H), 6.88 (s, 1H), 5.03 (d, 7 = 3.0 Hz, 2H), 4.32 (q, 7 = 8.0 Hz, 1H), 3.29 (d, 7 = 7.2 Hz, 1H), 2.80 (t, 7 = 7.2 Hz, 2H), 2.40 (td, 7 = 15.1, 14.5, 6.7 Hz, 2H).13C{1H } NMR (76 MHz, DMSO-d6): 8 171.55, 171.11, 155.77, 136.97, 136.29, 128.36, 127.79, 127.21, 122.71, 120.95, 118.27, 111.72, 111.41, 65.56, 51.91, 37.58, 25.18. HRMS: (ESI+) C22H24N4O4 [M+H] m / z calcd. 409.1798, found 409.1872. (A21) N-Boc-L- aspartic acid P-methyl ester tryptamide. Cbz-L-AspOMe-Tmn

[0482] Tryptamine (1.60 g, 10.0 mmol) and Boc-L-aspartic acid- -methyl ester (2.47 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A21 (2.88 g, 7.38 mmol) as an orange glass in 74% yield. Rf = 0.32 (50% EtOAc:50% hexanes)!H NMR (300 MHz, CDCh): 8 (s, 1H), 7.60 (d, 7 = 7.8 Hz, 1H), 7.36 (d, 7= 8.0 Hz, 1H), 7.19 (1, 7 = 7.3, 1.0 Hz, 1H), 7.12 (t, 7 = 7.8, 1.0 Hz, 1H), 7.O3 (d, 7= 2.1 Hz, 1H), 6.59 (s, 1H), 5.64 (d, 7 = 7.6 Hz, 1H), 4.47 (s, 1H), 3.64 (s, 3H), 3.58 (qd, 7 = 6.9, 2.1 Hz, 2H), 2.97 (q, 7 = 7.6, 6.8 Hz, 3H), 2.65 (dd, 7 = 17.0, 6.0 Hz, 1H), 1.41 (s, 9H).13C{]H] NMR (76 MHz, CDCh): 8 172.35, 170.69, 155.56, 136.47, 127.28, 122.32, 122.05, 119.35, 118.61, 112.50, 111.35, 80.50, 52.00, 50.78, 40.01, 36.16, 28.30, 25.24. HRMS: (ESI+) C20H27N3O5 [M+H] m / z calcd. 390.1951, found 390.2020.

[0483] (A22) V-Cbz-L-glutamic acid 5-methyl ester tryptamide. Cbz-L-GluOMe-Tmn

[0484] Tryptamine (1.60 g, 10.0 mmol) and A-Cbz-E-glutamic acid 5-methyl ester (2.95 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes to produce A22 (3.27 g, 7.47 mmol) as white solid in 75% yield.]H NMR (300 MHz, DMSO-< / 6): 8 (s, 1H), 8.02 (t, 7 = 5.6 Hz, 1H), 7.55 (d, 7 = 7.7 Hz, 1H), 7.45 - 7.25 (m, 7H), 7.14 (s, 1H), 7.06 (t, 7 = 7.2 Hz, 1H), 6.98 (t, 7= 7.5 Hz, 1H), 5.11 - 4.94 (m, 2H), 4.00 (ddd, 7 = 13.7, 7.7, 5.3 Hz, 1H), 3.58 (s, 3H), 3.45 - 3.24 (m, 2H), 2.82 (t, 7 = 7.3 Hz, 2H), 2.31 (t, 7 = 7.7 Hz, 2H), 1.92 (dq, 7 = 13.3, 7.7 Hz, 1H), 1.77 (dq, 7 = 16.1, 7.9 Hz, 1H).13C{!H] NMR (76 MHz, DMSO-d6): 8 172.74, 171.03, 155.91, 136.99, 136.23, 128.32, 127.78, 127.71, 127.15, 122.65, 120.89, 118.23, 118.20, 111.64, 111.34, 65.47, 53.98, 51.33, 29.93, 27.25, 25.14. HRMS: (ESI+) C24H27N3O5 [M+H] m / z calcd. 438.1951, found 438.2025. (A23) V-Cbz-L-glutamine tryptamide. Cbz-L-Gln-Tmn

[0485] Tryptamine (1.60g, 10.0 mmol) and Cbz-L-glutamine (2.80 g, 10.0 mmol) were reacted using GP 1. Note: the product is extracted as a suspension and not dried chemically. The crude product was recrystallized from methanol and ethyl acetate to produce A23 (2.43, 5.75 mmol) as white solid in 58% yield.!H NMR (300 MHz, DMSO-d6): 8 10.81 (s, 1H), 7.98 (t, 7 = 5.6 Hz, 1H), 7.55 (d, 7 = 7.7 Hz, 1H), 7.42 - 7.21 (m, 8H), 7.14 (s, 1H), 7.06 (t, 7 = 7.5 Hz, 1H), 6.98 (t, 7 = 7.4 Hz, 1H), 6.75 (s, 1H), 5.10 - 4.94 (m, 2H), 3.94 (q, 7 = 8.4 Hz, 1H), 2.81 (t, 7 = 7.4 Hz, 2H), 2.16 - 2.02 (m, 2H), 1.87 (dt, 7 = 14.4, 6.8 Hz, 1H), 1.72 (dt, 7 = 14.9, 8.4 Hz, 1H).13C{ ’H} NMR (76 MHz, DMSO-d6): 8 173.70, 171.40, 155.90, 137.02, 136.24, 127.78, 127.72, 127.16, 122.65, 120.91, 118.26, 118.22, 111.69, 111.36, 65.44, 54.55, 31.53, 27.84, 25.23. HRMS: (ESI+) C23H26N4O4 [M+H] m / z calcd. 423.1954, found 423.2028.

[0486] (A24) V-Cbz-L-theanine tryptamide. Cbz-L-GlnEt-Tmn

[0487] Tryptamine (1.60 g, 10.0 mmol) and Cbz-L-theanine (3.08g, 10.0 mmol) were reacted using GP 1. Note: 40 mL of ethyl acetate per mmol is required to dissolve the crude product during work up. The crude product was recrystallized from ethyl acetate to produce A24 (2.23 g,

[0488] 7.15 mmol) as a white solid in 72% yield. H NMR (300 MHz, CD3OD): 5 7.56 (d, J = 7.8 Hz, 1H), 7.38 - 7.20 (m, 6H), 7.08 (td, 7 = 7.0, 1.1 Hz, 1H), 7.05 (s, 1H), 7.00 (t, 7 = 7.4 Hz, 1H), 5.13 - 4.98 (m, 2H), 4.06 (dd, 7 = 8.6, 4.9 Hz, 1H), 3.49 (dq, 7 = 12.7, 6.3, 5.8 Hz, 2H),

[0489] 3.15 (q, 7 = 7.2 Hz, 2H), 2.93 (t, 7 = 7.0 Hz, 2H), 2.18 (t, 7 = 7.5 Hz, 2H), 2.00 (dt, 7 = 11.7, 7.0 Hz, 1H), 1.82 (dt, 7= 14.9, 7.9 Hz, 1H), 1.07 (t, 7= 7.3 Hz, 3H).13C{]H } NMR (76 MHz, CD3OD): 8 174.61, 174.16, 158.30, 138.13, 138.06, 129.46, 129.04, 128.93, 128.69, 123.57, 122.31, 119.61, 119.27, 113.02, 112.22, 67.77, 56.20, 48.72, 48.43, 48.15, 41.35, 41.23, 35.25, 33.20, 29.36, 26.17, 14.73. HRMS: (ESI+) C25H30N4O4 [M+H] m / z calcd. 451.2267, found 451.2336.

[0490]

[0491] (A25) V-Cbz-L-phenylalanine tryptamide. Cbz-L-Phe-Tmn

[0492] Tryptamine (1.60 g, 10.0 mmol) and Cbz-E-phenylalanine (2.99 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate to produce A25 (3.25 g, 7.36 mmol) as a white solid in 74% yield.O *H NMR (300 MHz, DMSO-d6): 5 10.81 (s, 1H), 8.10 (t, J = 5.5 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.37 - 7.16 (m, 11H), 7.13 (d, J = 2.0 Hz, 1H), 7.07 (ddd, 7 = 23.4, 7.0, 1.2 Hz, 1H), 6.98 (td, 7 = 7.9, 1.0 Hz, 1H), 5.01 - 4.86 (m, 2H), 4.21 (td, 7 = 10.0, 4.5 Hz, 1H), 3.47 - 3.22 (m, 2H), 2.95 (dd, 7 = 13.7, 4.5 Hz, 1H), 2.82 - 2.67 (m, 3H).13C{ *H} NMR (76 MHz, DMSO-< / 6): 5 171.27, 155.86, 138.20, 137.07, 136.28, 129.23, 128.29, 128.05, 127.68, 127.47, 127.22, 126.24, 122.72, 120.94, 118.27, 111.72, 111.39, 65.25, 56.36, 37.77, 25.12. HRMS: (ESI+) C27H27N3O3 [M+H] m / z calcd. 442.2052, found 442.2130.

[0493] (A26) V-Cbz-L-tyrosine tryptamide. Cbz-L-Tyr-Tmn

[0494] Tryptamine (1.60g, 10.0 mmol) and Cbz-L- tyrosine (3.15g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes and then triturated from DCM to produce A26 (2.03 g, 4.44 mmol) as a white solid in 44% yield. Rf= 0.22 (50% EtOAc:50% hexanes) *H NMR (300 MHz, DMSO-d6): 8 10.80 (s, 1H), 9.17 (s, 1H), 8.04 (t, 7 = 5.5 Hz, 1H), 7.54 (d, 7 = 7.7 Hz, 1H), 7.41 - 7.21 (m, 7H), 7.16 - 7.10 (m, 1H), 7.10 - 6.92 (m, 4H), 6.70 (d, 7 = 8.4 Hz, 2H), 5.06 - 4.86 (m, 2H), 4.12 (td, 7 = 9.8, 4.6 Hz, 1H), 3.44 - 3.33 (m, 2H), 2.80 (q, 7 = 9.2, 7.2 Hz, 3H), 2.62 (dd, 7 = 13.5, 10.3 Hz, 1H).13C{]H} NMR (76 MHz, DMSO-d6): 8 171.48, 155.90, 155.85, 137.15, 136.32, 130.22, 128.33, 128.27, 127.70, 127.47, 127.26, 126.86, 122.75, 121.00, 118.33, 115.22, 114.94, 111.80, 111.44, 65.26, 56.76, 39.59, 37.10, 25.18. HRMS: (ESI+) C27H27N3O4 [M+H] m / z calcd. 458.2002, found 458.2078.

[0495] (A27) V-Cbz-L- tryptophan tryptamide. Cbz-L-Trp-Tmn

[0496] Tryptamine (1.60 g, 10.0 mmol) and Cbz-L-tryptophan (3.38 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A27 (4.28 g, 7.04 mmol) as a white foam in 70% yield.O Rf= 0.37 (65% EtOAc:35% hexanes)]H NMR (300 MHz, DMSO-d6): 5 10.81 (s, 2H), 8.09 (t, 7 = 5.5 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.40 - 7.21 (m, 8H), 7.14 (d, J = 2.7 Hz, 2H), 7.06 (t, J = 7.5 Hz, 2H), 7.02 - 6.92 (m, 2H), 4.96 (s, 2H), 4.25 (td, J = 9.0, 4.9 Hz, 1H), 3.38 (d, J = 7.4 Hz, 2H), 3.08 (dd, J = 14.5, 4.7 Hz, 1H), 2.91 (dd, J = 14.5, 9.5 Hz, 1H), 2.78 (t, J = 7.4 Hz, 2H).13C{]H} NMR (76 MHz, DMSO-d6): 5 171.77, 155.91, 137.09, 136.33, 136.18,

[0497] 128.36, 127.74, 127.56, 127.39, 127.28, 126.91, 123.85, 122.73, 121.01, 120.94, 118.63,

[0498] 118.36, 118.33, 118.30, 111.85, 111.45, 111.38, 110.37, 65.36, 55.80, 28.09, 25.16. HRMS: (ESI+) C29H28N4O3 [M+H] m / z calcd. 481.2161, found 481.2244.

[0499] (A28) A-Cbz-L- histidine tryptamide. Cbz-L-His-Tmn

[0500] Tryptamine (1.60g, 10.0 mmol) and Cbz-L-histidine (2.89 g, 10.0 mmol) were reacted using GP 1. The work up was modified by using 1 % citric acid (30 ml) in place of the three HC1 washes during work up. The crude product was chromatographed using methanol and DCM to produce A28 (1.60 g, 3.71 mmol) as a white solid in 37% yield. Rf= 0.22 (6% MeOH:94% DCM) ’H NMR (300 MHz, DMSO-d6): 5 11.78 (s, 1H), 10.80 (s, 1H), 7.97 (t, J = 5.7 Hz, 1H), 7.54 (d, J = 6.3 Hz, 2H), 7.43 - 7.21 (m, 7H), 7.11 (d, J = 2.0 Hz, 1H), 7.09 - 7.03 (m, 1H), 6.98 (Id, J = 7.5, 7.1, 1.1 Hz, 1H), 6.77 (s, 1H), 5.07 - 4.92 (m, 2H), 4.21 (td, J = 8.5, 5.1 Hz, 1H), 3.40 - 3.22 (m, 2H), 2.89 (dd, J= 14.8, 5.0 Hz, 1H), 2.82 - 2.66 (m, 3H).13C{!H] NMR (76 MHz, DMSO-d6): 8 171.23, 155.82, 137.05, 136.29, 134.76, 133.67, 128.36, 127.77, 127.64, 127.22, 126.97, 122.68, 120.96, 118.31, 118.27, 111.75, 111.41, 65.45, 55.10, 39.59, 29.81, 25.18. HRMS: (ESI+) C24H25N5O3 [M+H] m / z calcd. 432.1957, found 432.2032.

[0501] (A29) g yp

[0502] Tryptamine (1.60 g, 10.0 mmol) and g (3.53 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from isopropanol and ethyl acetate to produce A29 (3.89g, 7.85 mmol) as a white solid in 79% yield.!H NMR (300 MHz, DMSO-de): 8 10.79 (s, 1H), 8.02 (t, J = 5.6 Hz, 1H), 7.55 (d, J= 9.0 Hz, 1H), 7.43 - 7.25 (m, 7H), 7.15 (d, J = 1.7 Hz, 1H), 7.07 (td, 7 = 7.1, 1.0 Hz, 1H), 6.98 (td, 7 = 8.0, 0.9 Hz, 1H), 5.11 - 4.94 (m, 2H), 4.04 - 3.90 (m, 1H), 3.47 - 3.23 (m, 2H), 3.13 (d, 7 = 5.6 Hz, 2H), 2.82 (t, 7 = 7.3 Hz, 2H), 1.74 - 1.38 (m, 4H).13C{ ’H] NMR (76 MHz, DMSO-d6): 8 171.56, 159.31, 155.99, 137.05, 136.28, 128.38, 127.83, 127.77, 127.21, 122.76, 120.96, 118.29, 111.71, 111.41, 65.52, 54.50, 29.36, 25.25. HRMS: (ESI+) C24H29N7O5 [M+H] m / z calcd. 496.2230, found 496.2312.

[0503] (A30) , y yp z y

[0504] Tryptamine (1.60 g, 10.0 mmol) and (4.14 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate and hexanes to produce A30 (4.94 g, 8.86 mmol) as a white solid in 89% yield.!H NMR (300 MHz, DMSO-d6): 8 10.79 (s, 1H), 7.97 (t, J = 5.6 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.39 - 7.25 (m, 11H), 7.22 (t, J = 5.7 Hz, 1H), 7.13 (d, J = 1.7 Hz, 1H), 7.09 - 7.01 (m, 1H), 7.01 - 6.93 (m, 1H), 5.08 - 4.94 (m, 4H), 3.97 - 3.82 (m, 1H), 3.46 - 3.19 (m, 2H), 2.95 (q, J = 6.5 Hz, 2H), 2.81 (t, J = 7.3 Hz, 2H), 1.65 - 1.11 (m, 6H).13C{ ’H} NMR (76 MHz, DMSO-d6): 8 171.79, 156.13, 155.99, 137.29, 137.08, 136.27, 128.34, 127.73, 127.22, 122.70, 120.92, 118.29, 118.24, 111.74, 111.38, 65.43, 65.16, 54.83, 39.90, 39.19, 31.75, 29.14, 25.19, 22.84. HRMS: (ESI+) C32H36N4O5 [M+H] m / z calcd. 557.2686, found 557.2770.

[0505] (A31) V-Cbz-methyl L-glutaminyl-D-tryptophanate. Cbz-L-Gln-TrpOMe

[0506] Tryptamine (1.60 g, 10.0 mmol) and Cbz-E-glutamine (2.80 g, 10.0 mmol) were reacted using GP 1. Note: the product is extracted as a suspension and not dried chemically. The crude product was triturated with ethyl acetate to produce A31 (3.70, 7.70 mmol) as white solid in 77% yield.]H NMR (300 MHz, DMSO-d6): 8 10.88 (s, 1H), 8.24 (d, 7 = 7.7 Hz, 1H), 7.47 (d, 7 = 7.7 Hz, 1H), 7.42 - 7.26 (m, 7H), 7.19 (s, 1H), 7.11 (d, J = 1.9 Hz, 1H), 7.10 - 7.02 (m, 1 H), 7.02 - 6.93 (m, 1 H), 6.74 (s, 1 H), 5.02 (d, J = 1 .9 Hz, 2H), 4.51 (dd, J = 6.0, 4.6 Hz, 1H), 4.09 - 3.96 (m, 1H), 3.57 (s, 3H), 3.18 - 3.02 (m, 2H).13C{ ’H} NMR (76 MHz, DMSO- d6): 8 173.64, 172.11, 171.64, 155.86, 136.96, 136.07, 128.34, 127.79, 127.72, 127.01, 123.69, 120.97, 118.43, 117.95, 111.42, 109.17, 65.47, 54.26, 52.96, 51.84, 31.38, 27.78, 27.15.

[0507] (A32) (trifluoroacetyl)alanine tryptamide. Tryptamine (1.60g, 10.0 mmol) and (trifluoroacetyl)analine (1.85 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A32 (2.69 g, 7.94 mmol) as a white solid in 79% yield Rf= 0.44 (50% EtOAc:50% hexanes)1!! NMR (300 MHz, CD3OD): 5 7.60 - 7.53 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.99 (t, 7 = 7.1 Hz, 1H), 4.36 (q, 7 = 7.1 Hz, 1H), 3.50 (td, 7 = 7.0, 3.1 Hz, 2H), 3.03 - 2.88 (m, 2H), 1.35 (d, 7 = 7.2 Hz, 3H).13C{ *H} NMR (76 MHz, CD3OD): 5 173.41, 158.88, 158.38, 138.15, 128.70, 123.56, 122.30, 119.59, 119.23, 113.01, 112.20, 50.97, 41.42, 26.12, 17.83. HRMS: (ESI+) C15H16F3N3O2 [M+H] m / z calcd. 328.1195, found 328.1266.

[0508] (A33) Lactic acid tryptamide. Lac-Tmn

[0509] Tryptamine (1.60 g, 10.0 mmol) and lactic acid (0.90 g, 10.0 mmol) were reacted using GP 1. The crude product was recrystallized from ethyl acetate to produce A33 (0.94 g, 4.10 mmol) as a white solid that quickly melted in 41% yield. 01H NMR (300 MHz, DMSO-dr,): 6 10.80 (s, 1H), 7.74 (t, 7 = 5.5 Hz, 1H), 7.56 (d, 7 = 7.8 Hz, 1H), 7.33 (d, 7 = 8.0 Hz, 1H), 7.14 (d, 7 = 2.1 Hz, 1H), 7.06 (t, 7 = 8.0 Hz, 1H), 6.97 (t, 7 = 7.0 Hz, 1H), 5.45 (d, 7 = 5.0 Hz, 1H), 4.04 - 3.86 (m, 1H), 3.39 (d, 7 = 6.9 Hz, 2H), 2.83 (t, 7 = 7.5 Hz, 2H), 1.20 (d, 7 = 6.8 Hz, 3H).O Other analytical data matched previous report.

[0510] (A34) acetoxyacetic acid tryptamide.

[0511] Tryptamine (1.60 g, 10.0 mmol) and acetoxyacetic acid (1.18 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A34 (1.87 g, 7.17 mmol) as a tan solid in 72% yield 'H NMR (300 MHz, CDCI3): 5 8.14 (s, 1H), 7.61 (d, 7 = 7.7 Hz, 1H), 7.39 (d, 7 = 8.0 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 7.10 (m, 1H), 7.06 (d, 7 = 2.3 Hz, 1H), 6.18 (s, 1H), 4.52 (s, 2H), 3.70 - 3.57 (m, 2H), 3.02 (t, 7 = 6.6 Hz, 2H), 1.97 (s, 3H).13C{]H} NMR (76 MHz, CDCh): 5 169.53, 167.11, 136.48, 127.36, 122.37, 122.21, 119.55, 118.55, 112.47, 111.48, 62.96, 39.75, 25.07, 20.59. Rf= 0.22 (65% EtOAc:35% hexanes) HRMS: (ESH) C14H16N2O3 [M+H] m / z calcd. 261.2930, found 261.1237.

[0512] (A35) acetoxyacetic acid 5-methoxytryptamide.

[0513] 5-methoxytryptamine (1.90 g, 10.0 mmol) and acetoxyacetic acid (1.18 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A35 (2.17 g, 7.17 mmol) as a tan solid in 72% yield Rf= 0.23 (65% EtOAc:35% hexanes) 'H NMR (300 MHz, CDCh): 5 8.00 (s, 1H), 7.23 (s, 1H), 7.00 (s, 2H), 6.85 (dd, J = 8.8, 2.4 Hz, 1H), 6.17 (s, 1H), 4.49 (s, 2H), 3.83 (s, 3H), 3.61 (q, J = 6.5 Hz, 2H), 2.95 (t, J = 6.6 Hz, 2H), 1.94 (s, 3H). ^CpH} NMR (76 MHz, CDCh): 8 169.56, 167.12, 154.00, 131.61, 127.70, 123.14, 112.26, 112.20, 112.03, 100.34, 62.89, 55.89, 39.64, 25.01, 20.44. HRMS: (ESI+) C15H18N2O4 [M+H] m / z calcd. 291.1267, found 291.1339.

[0514] (A36) 2-acetoxypropanoic acid tryptamide.

[0515] 2-acetoxy propionic acid (3.96 g, 30.0 mmol was dissolved in anhydrous THF (30 mL) and cooled to -20°C. To this was added / V-methyl morpholine (3.4 mL, 30.0 mmol) and isobutyl chloroformate (4.2 mL, 30.0 mmol). The solution was stirred for 5 minutes before a solution of tryptamine (4.8 g, 30.0 mmol) and A-methyl-morpholine (3.4 mL, 30.0 mmol) in THF (30 mL) was added dropwise. The solution was stirred overnight. The work up procedure for GP 1 was followed. The crude product was chromatographed using ethyl acetate and hexanes to produce A36 (6.50 g, 23.7 mmol) as a white solid in 79% yield. 0 Rf = 0.28 (65% EtOAc:35% hexanes)!H NMR (300 MHz, CD3OD): 3 7.56 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 5.7 Hz, 2H), 7.00 (t, J = 7.4 Hz, 1H), 4.98 (q, J = 6.9 Hz, 1H), 3.48 (tt, J = 8.8, 4.6 Hz, 2H), 2.94 (t, J = 7.1 Hz, 2H), 2.04 (s, 3H), 1.35 (d, J = 6.9 Hz, 3H).13C{ *H} NMR (76 MHz, CDiOD): 5 173.40, 171.71, 138.04, 128.69, 123.58, 122.30, 119.61, 119.25, 112.96, 112.21, 71.50, 41.12, 25.99, 20.70, 18.14. HRMS: (ESI+) C17H18N2O5 [M+H] m / z calcd. 331.1216, found 331.1296.

[0516] (A37) 2-acetoxy-4-methyIpentanoic acid tryptamide.

[0517] Tryptamine (1.60 g, 10.0 mmol) and 2-acetoxy-4-methylpentanoic acid (1.74 g, 10.0 mmol) were reacted using GP 1 . The crude product was chromatographed using ethyl acetate and hexanes to produce A37 (2.44 g, 7.70 mmol) as a thick amber oil 77% yield. Rf= 0.23 (50% EtOAc:50% hexanes)JH NMR (300 MHz, CD3OD): 5 7.56 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.08 (t, 7 = 7.1 Hz, 1H), 7.05 (s, 1H), 7.00 (t, 7 = 7.5 Hz, 1H), 4.98 (dd, 7 = 9.3, 4.0 Hz, 1H), 3.59 - 3.39 (m, 2H), 2.94 (t, 7 = 7.1 Hz, 2H), 2.04 (s, 3H), 1.69 - 1.59 (m, 2H), 1.52 - 1.43 (m, 1H), 0.89 (dd, 7 = 8.2, 6.5 Hz, 6H). ^CfH] NMR (76 MHz, CD3OD): 8 3 173.27, 171.96, 138.12, 128.77, 123.61, 122.29, 119.61, 119.27, 112.98, 112.21, 41.97, 41.13, 26.00, 25.67, 23.44, 21.99, 20.64. HRMS: (ESI+) C18H24N2O3 [M+H] m / z calcd. 317.1787 found 317.1865.

[0518] (A38) (3S)-2-acetoxy-3-methylpentanoic acid tryptamide.

[0519] Tryptamine (1.60 g, 10.0 mmol) and (3S)-2-acetoxy-3-methylpentanoic acid (1.74 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A38 (2.69 g, 8.51 mmol) as a light amber oil 85% yield. Rf = 0.36 (50% EtOAc:50% hexanes) ’H NMR (300 MHz, CD3OD): 8 7.57 (d, 7 = 7.8 Hz, 1H), 7.32 (d, 7 = 8.0 Hz, 1H), 7.12 - 7.03 (m, 2H), 7.03 - 6.96 (m, 1H), 4.83 (s, 1H), 3.50 (tt, 7 = 9.0, 4.7 Hz, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.06 (s, 3H), 1.87 (tdd, J = 9.3, 6.2, 4.8 Hz, 1H), 1.46 (did, J = 14.9, 7.5, 4.0 Hz, 1H), 1.27 - 1.09 (m, 1H), 0.91 - 0.82 (m, 6H).13C{ *H} NMR (76 MHz, CD3OD): 5 5 172.00, 171.97, 138.08, 128.66, 123.57, 122.29, 119.61, 119.23, 112.93, 112.21, 78.98, 40.99, 38.12, 26.08, 25.27, 20.59, 15.41, 11.71. HRMS: (ESI+) C18H24N2O3 [M+H] m / z calcd. 317.1787 found 317.1862.

[0520] (A39) 2-acetoxy-4-(methylthio)butanoic acid tryptamide.

[0521] Tryptamine (1.60 g, 10.0 mmol) and 2-acetoxy-4-(methylthio)butanoic acid (1.92 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A39 (1.80 g, 5.38 mmol) as a light amber oil 54% yield. Rf = 0.20 (50% EtOAc:50% hexanes) ’H NMR (300 MHz, CD3OD): 5 7.56 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7. 12 - 7.04 (m, 2H), 7.04 - 6.96 (m, 1H), 5.04 (t, J = 6.3 Hz, 1H), 3.59 - 3.42 (m, 2H), 2.95 (t, J = 7.0 Hz, 2H), 2.49 - 2.40 (m, 2H), 2.06 (s, 3H), 2.02 (s, 3H), 2.01 - 1.93 (m, 2H).13C{!H] NMR (76 MHz, CD3OD): 5 172.32, 171.80, 138.08, 128.70, 123.61, 122.31, 119.63, 1 19.26, 112.94, 112.23, 73.93, 41.09, 32.61, 30.24, 26.00, 20.63, 15.13. HRMS: (ESI+) C17H22N2O3S [M+H] m / z calcd. 335.1351 found 335.1422.

[0522] (A40) 2-acetoxy-3-phenylpropanoic acid tryptamide.

[0523] Tryptamine (1.60 g, 10.0 mmol) and 2-acetoxy-3-phenylpropanoic acid (2.08 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using methanol and DCM to produce A40 (2.18 g, 6.23 mmol) as a light amber semi-solid 62% yield. Rf = unknown (2% MeOH:98% DCM) ’H NMR (300 MHz, CD3OD): 7.52 (d, J= 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.27 - 7.16 (m, 5H), 7.08 (t, 7 = 7.0 Hz, 1H), 7.03 - 6.96 (m, 2H), 5.16 (dd, 7 = 7.8, 4.9 Hz, 1H), 3.44 (t, J = 7.2 Hz, 2H), 3.01 (qd, 7 = 14.0, 6.4 Hz, 2H), 2.91 - 2.76 (m, 2H), 1.96 (s, 3H).13C{ ’H} NMR (76 MHz, CD3OD): 5 171.89, 171.56, 138.11, 137.54, 130.55, 129.36, 128.71, 127.88, 123.54, 122.31, 119.63, 119.25, 112.95, 112.22, 75.70, 41.14, 38.94, 25.97. HRMS: (ESI+) C21H22N2O3 [M+H] m / z calcd. 351.1630 found 351.1701.

[0524] (A42) (R)-2-acetoxy-2-phenylacetic acid tryptamide.

[0525] Tryptamine (1.60 g, 10.0 mmol) and 2-acetoxy-2-phenylacetic acid (1.94 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A42 (2.18 g, 6.53 mmol) as a light amber gum in 65% yield. Rf= unknown (50% EtOAc:50% hexanes)!H NMR (300 MHz, CD3OD): 5 7.53 (d, J = 7.8 Hz, 1H), 7.43 - 7.27 (m, 6H), 7.08 (t, J = 7.3 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 6.90 (s, 1H), 5.89 (s, 1H), 3.49 (hept, J = 7.0, 6.5 Hz, 2H), 2.92 (t, 7 = 7.0 Hz, 2H), 2.10 (s, 3H).nC{]H} NMR (76 MHz, CD3OD): 5 171.48, 171.29, 138.10, 136.99, 129.88, 129.59, 128.66, 128.57, 123.68, 122.26, 1 19.61, 119.21, 112.85, 112.19, 76.94, 41.24, 25.93, 20.69. HRMS: (ESI+) C20H20N2O3 [M+H] m / z calcd. 337.1474, found 337.1542.

[0526] (A43) 5-oxotetrahydrofuran-2-carboxylic acid tryptamide.

[0527] Tryptamine (8.01 g, 50.0 mmol) and 5-oxotetrahydrofuran-2-carboxylic acid (6.50 g, 50.0 mmol) were reacted using GP 1. The crude product was chromatographed using methanol and DCM to produce A43 (9.52 g, 35.0 mmol) as off white solid in 70% yield. Rf = 0.25 (5% MeOH:95% DCM) ’H NMR (300 MHz, CD3OD): 5 7.57 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.12 - 7.04 (m, 2H), 7.00 (t, 7 = 7.4 Hz, 1H), 4.81 (s, 1H), 3.54 (d, 7 = 8.3 Hz, 2H), 2.98 (s, 2H), 2.45 (d, 7 = 10.4 Hz, 3H), 1.98 (d, 7 = 9.4 Hz, 1H).13C{ ’H] NMR (76 MHz, CD3OD): 8 178.63, 172.13, 138.06, 128.83, 123.56, 122.32, 119.64, 119.30, 112.94, 112.24, 78.77, 41.18, 28.17, 26.90, 25.98. HRMS: (ESI+) C15H16N2O3 [M+H] m / z calcd. 272.3040, found 273.1233.

[0528] (A44) methyl (5-oxotetrahydrofuran-2-carbonyl)-D-tryptophanate.

[0529] Methyl-D-tryptophanate (2.18 g, 10.0 mmol) and 5-oxotetrahydrofuran-2-carboxylic acid (1.30 g, 10.0 mmol) were reacted using GP 1. The crude product was chromatographed using ethyl acetate and hexanes to produce A44 (2.34g, 7.2 mmol) as a white solid in 72% yield. Rf = 0.24 (50% EtOAc:50% hexanes)]H NMR (300 MHz, CD3OD): 5 7.52 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.13 - 7.05 (m, 2H), 7.01 (td, J = 7.6, 7.1, 1.1 Hz, 1H), 4.84 - 4.73 (m, 2H), 3.71 (s, 3H), 3.37 (dd, J = 15.0, 5.0 Hz, 1H), 3.22 (dd, J = 14.7, 8.1 Hz, 1H), 2.48 - 2.29 (m, 3H), 2.06 - 1.82 (m, 1H). ^CpH} NMR (76 MHz, CD3OD): 5 178.70, 173.42, 172.10, 137.96, 128.61, 124.50, 122.52, 119.91, 119.11, 112.36, 110.48, 78.42, 54.45, 52.88, 28.17, 27.98, 26.91. HRMS: (ESI+) C17H18N2O5 [M+H] m / z calcd. 331.1216, found 331.1296.

[0530] General procedure 2 for Cbz group removal

[0531] The Cbz-protected tryptamide was dissolved in methanol to make a 0.1 M solution. To the flask was added 5 wt. % of palladium (10 wt. % on activated carbon) followed by a septum and a balloon of hydrogen. The reaction typically was complete by 4 hours as determined by TEC. The resulting mixture was filtered through celite, the solvent was removed, and 20-50 mL of DI water was added to the resulting residue. After sufficient mixing the resulting solution was lyophilized.

[0532] (Bl) Glycine tryptamide. Gly-Tmn -Cbz-glycine tryptamide (6.38 g, 18.2 mmol) was subjected to GP2 to produce Bl (3.86 g, 18.2 mmol) as a white solid in quantitative yield.1'H NMR (300 MHz, CDCI3): 8 8.23 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.20 (ddd, J = 22.1, 7.1, 1.1 Hz, 1H), 7.12 (td, 7 = 8.0, 1.1 Hz, 1H), 7.04 (d, 7 = 2.3 Hz, 1H), 3.64 (q, 7 = 6.7 Hz, 2H), 3.30 (s, 2H), 3.00 (t, 7 = 6.9 Hz, 2H).13C{!H} NMR (76 MHz, CDCI3): 8 173.01, 136.47, 122.24, 121.88, 119.13, 118.57, 112.61, 111.42, 77.16, 44.72, 39.46, 25.35. HRMS: (ESI+) C12H15N3O [M+H] m / z calcd. 218.1215, found 218.1283.

[0533] (B2) Glycine N“-methyltryptamide. Gly-NMe-Tmn

[0534] IV-Cbz-glycine Na-methyltryptamide (1.09g, 3.00 mmol) was subjected to GP2 to produce B2 (0.690g, 2.98 mmol) as a white solid in 99% yield.1H NMR (300 MHz, CD3OD) (rotamers observed): 5 7.62 - 7.51 (m, 1H), 7.37 - 7.29 (m, 1H), 7.15 - 6.96 (m, 3H), 3.70 - 3.51 (m, 2H), 3.39 (s, 1H), 3.06 - 2.94 (m, 5H), 2.82 (s, 1H).13C{ 'H] NMR (76 MHz, CD3OD) (rotamers observed): 8 173.89, 173.42, 138.09, 138.04, 128.77, 128.40, 124.12, 123.48, 122.56, 122.34, 119.98, 119.64, 119.23, 118.92, 113.03, 112.48, 112.28, 112.25, 50.72, 43.10, 42.42, 35.04, 33.95, 24.63, 24.12. HRMS: (ESI+) C13H17N3O [M+H] m / z calcd. 232.1372, found 232.1445.

[0535] (B3) Glycine a,«-dimethyltryptamide. Gly-a,a-DiMeTmn

[0536] N-Cbz-glycine a,a-dimethyltryptamide (1.71 g, 4.51 mmol) was subjected to GP2 to produce B3 (1.06 g 4.31 mmol) as a semi-sticky white solid that melted after several days, in 96% yield. ’H NMR (300 MHz, DMSO-d6): 8 10.87 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.36 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.06 (d J = 2.4 Hz) 7.04 (td, J = 8.1, 1.3 Hz, 1H), 6.96 (td, 7 = 7.5, 7.0, 1.1 Hz, 1H), 3.32 (s, 1H), 3.06 (s, 2H), 2.97 (s, 2H), 1.79 (s, 2H), 1.27 (s, 6H).I3C{ ’H] NMR (76 MHz, DMSO-d6): 8 172.36, 135.87, 128.46, 124.28, 120.57, 118.75, 118.26, 111.26, 110.51, 53.32, 45.27, 34.72, 26.89. HRMS: (ESI+) C14H19N3O [M+H] m / z calcd. 246.1528, found 246.1598.

[0537] (B4) Glycine a,«,N“-trimethyltryptamide. Gly-NMe-a,a-DiMeTmn

[0538] N-Cbz-glycine a,a,N“-trimethyltryptamide (1.71 g, 4.51 mmol) was subjected to GP2 to produce B4 (1.06g 4.31 mmol) as a semi-sticky white solid that melted after several days, in 96% yield.]H NMR (300 MHz, DMSO-cfo): 5 10.87 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.32 (d, 7= 7.9 Hz, 1H), 7.06 - 6.98 (m, 1H), 6.98 - 6.91 (m, 2H), 3.27 (s, 2H), 3.21 (s, 2H), 2.45 (s, 3H), 1.38 (s, 6H).13C{1H } NMR (76 MHz, DMSO-d6): 513C NMR (76 MHz, DMSO) 6 173.21 , 135.77, 128.40, 123.90, 120.50, 1 18.69, 1 18.19, 1 1 1.23, 1 10.93, 60.03, 45.26, 32.78, 30.97, 27.05. HRMS: (ESI+) C15H21N3O [M+H] m / z calcd. 260.1685, found 160.1756.

[0539] (B5) Glycine 5-methoxytryptamide. Gly-5MeOTmn

[0540] N-Cbz-glycine 5-methoxytryptamide (1.15 g, 3.01 mmol) was subjected to GP2 to produce B5 (0.746 g, 3.01 mmol) as a dark transparent oil in quantitative yield.O 'H NMR (300 MHz, CDCh): 5 8.06 (s, 1H), 7.31 (s, 1H), 7.26 (d, 7 = 8.8 Hz, 1H), 7.04 (dd, 7 = 7.7, 2.3 Hz, 2H), 6.86 (dd, 7 = 8.8, 2.4 Hz, 1H), 3.86 (s, 3H), 3.63 (q, 7 = 6.8 Hz, 2H), 3.32 (s, 2H), 2.96 (t, 7 = 6.8 Hz, 2H), 1.29 (s, 2H).13C{ ’H] NMR (76 MHz, CDCh): 5 173.02, 153.82, 131.66, 127.73, 123.00, 112.37, 112.11, 112.06, 100.49, 55.97, 44.78, 39.33, 25.39. HRMS: (ESI+) C13H17N3O2 [M+H] m / z calcd. 248.1321, found 248.1393.

[0541] (B6) Glycine 5-methoxy-N“-methyltryptamide. Gly-NMe-5MeOTmn / V-Cbz-glycine 5-methoxy-Af-methyltryptamide (1.83 g, 4.63 mmol) was subjected to GP2 to produce B6 (1.19g 4.55 mmol) as a sticky grey solid in 98% yield. 'H NMR (300 MHz, CDiOD) (rotamers observed): 5 7.26 - 7.18 (m, 1H), 7.11 - 6.98 (m, 2H), 6.79 - 6.72 (m, 1H), 3.83 (s, 3H), 3.69 - 3.50 (m, 2H), 3.40 - 2.91 (m, 6H), 2.84 (s, 1H).13C{ *H} NMR (76 MHz, CD3OD) (rotamers observed): 6 174.07, 173.57, 155.15, 154.93, 133.28, 133.17, 129.07, 128.71, 124.85, 124.26, 113.17, 112.95, 112.80, 112.76, 112.50, 112.10, 101.36, 100.89, 56.32, 56.26, 50.59, 50.46, 48.72, 48.43, 48.15, 43.15, 42.45, 34.93, 33.93, 24.58, 24.13. HRMS: (EST+) C14H19N3O2 [M+H] m / z calcd. 262.1477, found 262.1552.

[0542] (B7) Glycine a-ethyl tryptamide. Gly-aEtTmn

[0543] N-Cbz-glycine a-ethyl tryptamide (3.79 g 10.0 mmol) was subjected to GP2 to produce B7 (2.08, 8.48 mmol) as a white solid in 85% yield. ’H NMR (300 MHz, DMSO-d6): 5 10.80 (s, 1H), 7.62 (d, 7= 8.6 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.32 (d, 7 = 7.9 Hz, 1H), 7.11 (s, 1H), 7.05 (t, 7 = 7.3 Hz, 1H), 6.97 (t, 7 = 7.3 Hz, 1H), 3.91 (t, 7 = 9.6 Hz, 1H), 3.25 (s, 4H), 2.80 (qd, 7 = 14.3, 6.6 Hz, 3H), 1.60 - 1.43 (m, 1H), 1.34 (dp, 7 = 15.8, 7.7 Hz, 1H), 0.82 (t, 7 = 7.3 Hz, 3H). ^CfH] NMR (76 MHz, DMSO-d6): 5 172.35, 136.18, 127.63, 123.21, 120.79, 118.46, 118.19, 111.32, 111.29, 50.50, 44.73, 30.17, 26.53, 10.53. HRMS: (ESI+) C14H19N3O [M+H] m / z calcd. 246.1528, found 246.1594.

[0544] (B8) Glycine P-ethyl tryptamide. Gly-PEtTmn

[0545] N-Cbz-glycine [3 -ethyl tryptamide (1.80 g 4.74 mmol) was subjected to GP2 to produce B8 (1.14 g, 4.67 mmol) as a white solid in 98% yield. H NMR (300 MHz, DMSO-d6): 5 10.85 (s, 1H), 7.74 (t, 7 = 5.7 Hz, 1H), 7.57 (d, 7 = 7.9 Hz, 1H), 7.34 (d, 7 = 8.0 Hz, 1H), 7.14 (d, 7 = 2.3 Hz, 1H), 7.06 (t, 7 = 7.1, 1.1 Hz, 1H), 6.95 (td, 7 = 7.5, 7.1, 1.0 Hz, 1H), 3.38 (dhept, 7 = 13.0, 6.7, 6.2 Hz, 3H), 3.01 - 2.90 (m, 1H), 1.70 (dddd, 7 = 35.8, 13.5, 10.8, 7.4 Hz, 4H), 0.80 (t, 7 = 7.4 Hz, 3H).13C{ ’H] NMR (76 MHz, DMSO-d6): 5 172.72, 136.51, 126.93, 122.03, 120.83, 118.70, 118.14, 115.69, 111.49, 44.69, 43.20, 38.11, 25.32, 11.96. HRMS: (ESI+) C14H19N3O [M+H] m / z calcd. 246.1528, found 246.1597.

[0546] (B9) L-alanine tryptamide. L-Ma-Tmn

[0547] IV-Cbz-L-alanine tryptamide (1.83 g, 5.00 mmol) was subjected to GP2 to produce B9 (1.16 g, 5.00 mmol) as a transparent gum in quantitative yield.O]H NMR (300 MHz, CDCh): 5 8.22 (s, 1H), 7.62 (d, 7 = 7.9 Hz, 1H), 7.37 (d, 7= 8.0 Hz, 1H), 7.30 (s, 1H), 7.20 (td, 7 = 7.1, 1.2 Hz, l H), 7.12 (td, 7 = 7.5, 7.1 , 1.1 Hz, 1H), 7.04 (d, 7= 2.3 Hz, 1H), 3.60 (qd, 7= 6.9, 1.9 Hz, 2H), 3.44 (q, 7 = 7.0 Hz, 1H), 2.99 (t, 7 = 6.8 Hz, 2H), 1.39 (s, 2H), 1.30 (d, 7 = 7.0 Hz, 3H).13C{]H] NMR (76 MHz, CDCh): 5 175.98, 136.46, 127.37, 122.23, 121.82, 119.08, 118.59, 112.59, 111.41, 50.72, 39.54, 25.34, 21.72. HRMS: (ESI+) C13H17N3O [M+H] m / z calcd. 232.1372, found 232.1442.

[0548] (B10) L-valine tryptamide. L-Val-Tmn

[0549] N-Cbz-L-valine tryptamide (2.76 g, 7.01 mmol) was subjected to GP2 to produce B 10 (1.82 g, 7.01 mmol) as a white solid in quantitative yield.1H NMR (300 MHz, DMSO-ch): 8 10.81 (s, 1H), 7.55 (d, 7 = 7.8 Hz, 1H), 7.33 (d, 7 = 8.0 Hz, 1H), 7.14 (d, 7 = 1.9 Hz, 1H), 7.06 (td, 7 = 7.1, 1.1 Hz, 1H), 6.97 (td, 7= 7.9, 1.0 Hz, 1H), 3.42 - 3.29 (m, 3H), 2.91 (d, 7 = 5.0 Hz, 1H), 2.82 (t, 7 = 7.4 Hz, 2H), 1.93 - 1.79 (m, 1H), 1.56 (s, 2H), 0.86 (d, 7= 6.9 Hz, 3H), 0.76 (d, 7 = 6.8 Hz, 3H). 13CfH] NMR (76 MHz, DMSO-d6): 6 174.50, 136.31, 127.23, 122.63, 120.91, 118.30, 118.20, 111.80, 111.39, 60.15, 39.20, 31.55, 25.43, 19.64, 17.07. HRMS: (ESI+) C15H21N3O [M+H] m / z calcd. 260.1685, found 260.1755.

[0550]

[0551] (Bll) L-norleucine tryptamide hydrochloride. L-Nle-Tmn

[0552] A-Cbz-L-norleucine tryptamide (xx) (1.22 g, 2.99 mmol) was subjected to GP2 with added concentrated HC1 (0.25 ml, 3.03 mmol) to produce Bl 1 (0.928 g, 2.99 mmol) as a white solid in quantitative yield.]H NMR (300 MHz, CD3OD): 5 7.56 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.12 - 7.04 (m, 2H), 7.00 (td, 7 = 7.5, 7.1, 1.0 Hz, 1H), 3.77 - 3.62 (m, 2H), 3.49 (dt, J = 13.4, 6.9 Hz, 1H), 2.99 (td, 7 = 7.0, 2.6 Hz, 2H), 1.79 - 1.61 (m, 2H), 1.35 - 1.15 (m, 4H), 0.87 (t, 7 = 6.9 Hz, 3H).13C{]H} NMR (76 MHz, CD3OD): 5 170.05, 138.03, 128.58, 123.58, 122.26, 119.56, 119.15, 112.66, 112.29, 54.53, 54.45, 48.72, 48.43, 48.15, 41.35, 41.23, 32.31, 27.70, 25.98, 23.25, 14.03. HRMS: (ESH) C16H23N3O [M+H] m / z calcd. 274.1841 , found 274.1920.

[0553] (B12) L-Ieucine tryptamide. L-Leu-Tmn jV-Cbz-L-leucine tryptamide (1.25g, 3.08 mmol), ammonia formate (0.580 g, 9.25 mmol) and Pd / C 10 wt. % (100 mg) were placed in a flask purged with argon. Anhydrous methanol (20 mL) was added, and the mixture was stirred for 18 hours. The mixture was filtered through celite, concentrated, dissolved in DCM and washed twice with sat. NazCCh. The organics were dried over sodium sulphate, filtered and concentrated to produce B12 (0.750g, 2.74 mmol) as a white solid in 89% yield.O ’H NMR (300 MHz, CDCI3): 5 8.75 (s, 1H), 7.62 (d, 7 = 7.8 Hz, 1H), 7.36 (d, 7 = 8.0 Hz, 2H), 7.19 (t, 7 = 7.1 Hz, 1H), 7.11 (t, 7 = 7.1 Hz, 1H), 6.98 (d, 7= 1.9 Hz, 1H), 3.60 (qd, 7 = 6.8, 2.5 Hz, 2H), 3.32 (dd, 7 = 9.7, 3.4 Hz, 1H), 2.98 (t, 7 = 6.9 Hz, 2H), 1.77 - 1.55 (m, 2H), 1.30 (t, 7 = 9.1 Hz, 3H), 0.94 (d, 7 = 6.1 Hz, 3H), 0.90 (d, 7 = 6.0 Hz, 3H). ^CpH} NMR (76 MHz, CDCI3): 5 175.83, 136.49, 127.46, 122.16, 121.93, 119.18, 118.70, 112.85, 111.42, 53.59, 44.18, 39.58, 25.45, 24.89, 23.49, 21.40. HRMS: (ESI+) C16H23N3O [M+H] m / z calcd. 274.1841, found 274.1914.

[0554] (B13) L-isoleucine-tryptamide. L-Ile-Tmn

[0555] N-Cbz-L-isoleucine tryptamide (1.25 g, 3.08 mmol) was subjected to GP2 to produce B13 (0.797g 2.91 mmol) as a white solid in 95% yield. 'H NMR (300 MHz, CDCI3): 5 8.31 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.19 (td, J = 8.1, 7.6, 1.2 Hz, 1H), 7.11 (td, 7 = 7.5, 7.1, 1.1 Hz, 1H), 7.02 (d, 7 = 2.3 Hz, 1H), 3.62 (q, 7 = 6.9 Hz, 2H), 3.22 (d, 7 = 3.9 Hz, 1H), 3.05 - 2.91 (m, 2H), 1.97 (dtq, 7 = 13.9, 6.9, 3.9 Hz, 1H), 1.49 (s, 3H), 1.32 (dtq, 7 = 14.4, 7.0, 3.9 Hz, 1H), 1.12 - 0.96 (m, 1H), 0.93 (d, 7 = 7.0 Hz, 3H), 0.86 (t, 7 = 7.3 Hz, 3H).13C{ ’H} NMR (76 MHz, CDCh): 8 174.47, 136.50, 127.43, 122.20, 121.90, 1 19.16, 118.66, 112.78, 111.40, 59.99, 39.51, 37.98, 25.53, 23.67, 16.18, 11.96. HRMS: (ESI+) C16H23N3O [M+H] m / z calcd. 274.1841, found 274.1911.

[0556] (B14) L-tert-leucine tryptamide. L-Tle-Tmn

[0557] N-Cbz-L-tert-leucine tryptamide (1.22 g, 3.00 mmol) was subjected to GP2 to produce B14 (0.770 g 2.82 mmol) as a white solid in 94% yield. ’H NMR (300 MHz, DMSO-d6): 6 10.80 (s, 1H), 7.85 (t, 7 = 5.5 Hz, 1H), 7.54 (d, 7 = 7.8 Hz, 1H), 7.33 (d, 7 = 8.0 Hz, 1H), 7.15 (d, 7 = 2.2 Hz, 1H), 7.06 (td, 7 = 7.0, 1.0 Hz, 1H), 6.97 (td, 7 = 7.5, 7.1, 1.1 Hz, 1H), 3.44 - 3.33 (m, 2H), 2.86 - 2.74 (m, 3H), 1.59 (s, 2H), 0.87 (s, 9H).13C{1H] NMR (76 MHz, DMSO- d6): 6 173.85, 136.28, 127.20, 122.61, 120.90, 118.26, 118.19, 111.82, 111.37, 63.18, 39.19, 33.85, 26.58, 25.37. HRMS: (ESI+) C16H23N3O [M+H] m / z calcd. 274.1841, found 274.1924.

[0558] (B15) L-serine tryptamide. L-Ser-Tmn

[0559] N-Cbz-L-serine tryptamide (1.89 g, 4.95 mmol) was subjected to GP2 to produce B15 (1.19 g 4.80 mmol) as a sticky beige solid in 97% yield. *H NMR (300 MHz, DMSO-d6): 8 10.81 (s, 1H), 7.95 (t, J = 5.7 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.06 (td, 7 = 7.1, 1.1 Hz, 1H), 6.97 (td, 7 = 7.5, 7.0, 1.1 Hz, 1H), 4.73 (s, 1H), 3.51 (d, 7 = 10.4 Hz, 1H), 3.37 (dd, 7 = 10.3, 4.7 Hz, 3H), 3.18 (dd, 7 = 6.4, 4.7 Hz, 1H), 2.82 (t, 7 = 7.4 Hz, 2H), 1.78 (s, 2H).13C{ *H} NMR (76 MHz, DMSO-d6): 8 173.23, 136.34, 127.28, 122.74, 121.00, 118.39, 118.30, 111.84, 111.45, 64.40, 57.06, 39.32, 25.35. HRMS: (ESI+) C13H17N3O2 [M+H] m / z calcd. 248.1321, found 248.1401.

[0560] (B16) L-threonine tryptamide. L-Thr-Tmn

[0561] N-Cbz.-L- threonine tryptamide (0.994 g, 2.51 mmol) was subjected to GP2 to produce B16 (0.626 g 2.40 mmol) as a white solid in 95% yield.1H NMR (300 MHz, DMSO-d6): 8 10.81 (s, 1H), 7.99 (t, 7 = 5.8 Hz, 1H), 7.56 (d, 7 = 7.8 Hz, 1H), 7.33 (d, 7 = 8.0 Hz, 1H), 7.15 (d, 7 = 2.2 Hz, 1H), 7.06 (td, 7 = 7.1, 1.1 Hz, 1H), 6.97 (td, 7 = 7.5, 7.0, 1.1 Hz, 1H), 4.59 (d, 7 = 5.0 Hz, 1H), 3.82 (h, 7 = 6.2 Hz, 1H), 3.46 - 3.25 (m, 4H), 2.90 (d, 7 = 4.5 Hz, 1H), 2.83 (t, 7 = 7.4 Hz, 2H), 1.73 (s, 2H), 1.04 (d, 7 = 6.4 Hz, 3H). ^CpH} NMR (76 MHz, DMSO-d6): 8 173.34, 136.24, 127.17, 122.63, 120.90, 118.30, 118.19, 111.77, 111.34, 67.58, 60.60, 25.28, 20.25. HRMS: (ESI+) C14H19N3O2 [M+H] m / z calcd. 262.1477, found 262.1554.

[0562] (B17) S-benzyl-L-cysteine tryptamide acetate. L-CysBn-Tmn

[0563] A-Boc-S-benzyLL-cystiene tryptamide (1.29 g, 2.84 mmol) was added as a solid to a mixture of 3:1 methanol: acetyl chloride (40 mL) at 0°C. The solution was stirred at 0°C for 5 hours. The mixture was quenched with solid sodium bicarbonate while maintaining the temperature at 0°C. The mixture was transferred to a separatory funnel, diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined extracts were dried over sodium sulfate before the solvent was removed. The product was lyophilized to give an amber colored gum. Acetic acid (0.19 ml, 3.30 mmol) followed by water (50 mL) was added to the freebase and the resulting mixture lyophilized again to give an amber solid B 17 (1.13 g, 2.73 mmol) in 96% yield. Rf= 0.20 (6% Methanol:94% DCM) freebase. 'H NMR (300 MHz, CD3OD): 5 7.56 (d, 7= 7.7 Hz, 1H), 7.38 - 7.17 (m, 6H), 7.13 - 7.04 (m, 2H), 7.00 (t, J= 1A Hz, 1H), 3.64 - 3.43 (m, 3H), 2.98 (t, 7 = 7.1 Hz, 2H), 2.76 (dd, 7= 13.9, 5.7 Hz, 1H), 2.62 (dd, 7 = 13.9, 7.4 Hz, 1H), 1.95 (s, 3H).13C{]H} NMR (76 MHz, CD3OD): 5 178.12, 171.67, 139.12, 138.10, 129.98, 129.52, 128.64, 128.16, 123.59, 122.37, 119.63, 119.22, 112.88, 112.83, 112.32, 54.18, 41.38, 37.02, 35.17, 26.06, 22.79. HRMS: (ESI+) C20H23N3OS [M+H] m / z calcd. 354.1562, found 354.1633.

[0564] (B18) Methionine tryptamide acetate. L-Met-Tmn

[0565] A-Boc-L-methionine tryptamide (1.02 g, 2.85 mmol) was added as a solid to a mixture of 3: 1 methanol: acetyl chloride (40 mL) at 0°C. The solution was stirred at 0°C for 5 hours before the solvent was removed and the crude residue neutralized with cold saturated sodium bicarbonate. The mixture was transferred to a separatory funnel and extracted with ethyl acetate (3 x 60 mL). The combined extracts were dried over sodium sulfate before the solvent was removed. The product was chromatographed using DCM and methanol to give the freebase as a turbid oil after lyophilization. Note: the freebase elutes cleanly in 3-5% methanol in DCM. Acetic acid (0.15 ml, 2.61 mmol) followed by water (50 mL) was added to the freebase and the resulting mixture lyophilized again to give the acetate salt B18 (0.885g, 2.51 mmol) in 88% yield. Rf= 0.30 (10% Methanol:90% DCM)]H NMR (300 MHz, CD3OD): 5 7.56 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.13 - 7.04 (m, 2H), 7.00 (td, J = 8.0, 0.9 Hz, 1H), 3.78 - 3.58 (m, 2H), 3.49 (dt, J = 13.4, 7.0 Hz, 1H), 2.98 (td, J = 7.0, 2.1 Hz, 2H), 2.41 (t, 7 = 7.7 Hz, 2H), 2.00 (s, 3H), 1.99 - 1.80 (m, 5H).13C{]H} NMR (76 MHz, CD3OD): 6 178.95, 171.70, 138.13, 128.63, 123.73, 123.56, 122.36, 119.63, 119.21, 112.80, 112.32, 54.04, 41.22, 33.04, 32.80, 30.22, 30.12, 26.07, 23.35, 15.07. HRMS: (ESI+) C15H21N3OS [M+H] m / z calcd. 292.1405, found 292.1481.

[0566] (B19) L-proline tryptamide. L-Pro-Tmn

[0567] N-Cbz-L-proline tryptamide (1.96 g, 5.00 mmol) was subjected to GP2 to produce B19 (1.23g, 4.78 mmol) as a white solid in 96% yield. Description of compound in literature does not match.O0 ]H NMR (300 MHz, DMSO-d6): 5 10.80 (s, 1H), 7.97 (t, J = 5.8 Hz, 1H), 7.55 (d, 7 = 7.8 Hz, 1H), 7.33 (dt, 7 = 8.1, 1.0 Hz, 1H), 7.13 (d, 7 = 2.3 Hz, 1H), 7.06 (td, 7 = 6.9, 1.2 Hz, 1H), 6.97 (td, 7= 7.5, 7.0, 1.1 Hz, 1H), 3.47 (dd, 7 = 8.8, 5.4 Hz, 1H), 3.41 - 3.25 (m, 3H), 2.87 - 2.63 (m, 4H), 1.98 - 1.82 (m, 1H), 1.70 - 1.47 (m, 3H).nC{]H} NMR (76 MHz, DMSO-d6): 6 174.25, 136.27, 127.23, 122.62, 120.91, 118.34, 118.19, 111.76, 111.35, 60.30, 46.68, 39.02, 30.47, 25.81, 25.31. HRMS: (ESI+) C15H19N3O [M+H] m / z calcd. 258.1528, found 258.1595. (B20) D-asparagine tryptamide. D-Asn-Tmn

[0568] A-Cbz-D-asparagine tryptamide (2.14 g, 5.24 mmol) was subjected to GP2 to produce B20 (1.44g, 5.24 mmol) as a white solid in quantitative yield. 'H NMR (300 MHz, DMSO-d6): 5 10.81 (s, 1H), 7.99 (t, J = 5.8 Hz, 1H), 7.55 (d, 7 = 7.8 Hz, 1H), 7.38 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.16 (d, 7 = 2.2 Hz, 1H), 7.06 (td, 7 = 7.1, 1.0 Hz, 1H), 6.97 (td, 7 = 7.1, 1.0 Hz, 1H), 6.83 (s, 1H), 3.43 (dd, 7 = 10.8, 5.4 Hz, 1H), 3.38 - 3.34 (m, 1H), 2.82 (t, 7 = 7.4 Hz, 2H), 2.42 (dd, 7 = 14.9, 3.9 Hz, 1H), 2.16 (dd, 7 = 14.9, 9.2 Hz, 1H), 1.84 (s, 2H).13C{ ‘H} NMR (76 MHz, DMSO-d6): 8 174.20, 173.03, 136.34, 127.27, 122.76, 120.99, 118.36, 1 18.29, 111.81, 111.47, 52.30, 40.68, 39.42, 25.29. HRMS: (ESI+) C14H18N4O2 [M+H] m / z calcd. 275.1430, found 275.1505.

[0569] (B21) L-Aspartic acid P-methyl ester tryptamine. L-AspOMe-Tmn

[0570] A-Cbz-L- Aspartic acid P-methyl ester tryptamide (1.03 g, 2.64 mmol) was added as a solid to a mixture of 3: 1 methanol: acetyl chloride (35 mL) at 0°C. The solution was stirred at 0°C for 5 hours and then at room temperature for an additional 18 hours. The mixture was cooled back to 0°C and quenched with solid sodium bicarbonate. The mixture was transferred to a separatory funnel, diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined extracts were dried over sodium sulfate before the solvent was removed. The product was lyophilized to give to give B21 (0.625 g, 2.16 mmol) as an amber colored gum in 82% yield. The product converted to the P-lactam over time. Rf = 0.29 (8% Methanol:92% DCM) ’H NMR (300 MHz, CD3OD): 6 7.57 (d, 7 = 7.7 Hz, 1H), 7.33 (dt, 7 = 8.1, 0.9 Hz, 1H), 7.12 - 7.05 (m, 2H), 7.00 (td, 7 = 7.5, 7.1, 1.1 Hz, 1H), 3.65 (s, 3H), 3.61 (dd, 7 = 7.5, 5.3 Hz, 1H), 3.51 (td, 7 = 7.2, 1.8 Hz, 2H), 2.96 (t, 7 = 7.1 Hz, 2H), 2.68 (dd, 7 = 16.3, 5.3 Hz, 1H), 2.54 (dd, 7= 16.3, 7.5 Hz, 1H).13C{ ’H} NMR (76 MHz, CD3OD): 8 175.86, 173.37, 138.09, 128.70, 123.52, 122.33, 119.59, 119.26, 113.07, 112.25, 52.97, 52.18, 41.22, 40.06, 26.10. HRMS: (ESI+) C15H19N3O3 [M+H] m / z calcd. 290.1426, found 290.1500.

[0571] (B22) 5-methyl L-glutamate tryptamide hydrochloride. L-GluOMe-Tmn

[0572] IV-Cbz 5-methyl L-glutamate-tryptamide (3.82 g, 8.73 mmol) was subjected to GP2, with one equivalent of added HC1, to produce B22 (2.91 g, 8.56 mmol) as a red solid in 98% yield. H NMR (300 MHz, CD3OD): 5 7.56 (d, J = 7.8 Hz...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula Ior a pharmaceutically acceptable salt or derivative thereof; wherein:R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more Y groups as allowed by valency;R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, Ci- Ce alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(O)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(O)-(C0-C6alkyl)-, and RzS(O)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;R3, R7, and R8are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-memberedmonocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(Co-C& alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RzC(O)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RZS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency;R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalky IXC0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(C0-C6alkyl)-, RXS-(CO- C1- aClk6yl)-, (RxRyN)-(C0-C6alkyl)-, RZC(N)-(C0-C6alkyl)-, RzS(O)-(C0-C6alkyl)-, and RzS(O)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency;R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more Y groups as allowed by valency;R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-( C1-C6, alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-( C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RZC(N)-(C1-C6alkyl)-, RZS(O)- (C1-C6alkyl)-, and RzS(O)2-(C1-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; orR4and R5or R7and R8are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more Y groups as allowed by valency; or R3and R4or R4and R7or R7and R9are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more Y groups as allowed by valency; orR3and R6or R4and R6or R6and R7or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more Y groups as allowed by valencyRxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)- , and RZS(O)2-, each of which may be optionally substituted with one or more Y groups as allowed by valency;Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- memberedheterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more Y groups as allowed by valency; andRaand Rbare independently selected at each occurrence from hydrogen, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C?cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°C(O)-NRq-, R°S(O)2-, ROS(O)2-O-, and R°S(O)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2- Ce alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, with the proviso that if R10is methoxy, at least one of R1, R2, R3, R5, R5, R6, R7, R8, R9, R11, or R12is not hydrogen.

2. The compound of claim 1, or a pharmaceutically acceptable salt or derivative thereof, wherein R7is selected from hydrogen and Ci-G, alkyl optionally substituted with one or more Y groups as allowed by valency.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or derivative thereof, wherein R8is selected from hydrogen and Ci-G, alkyl optionally substituted with one or more Y groups as allowed by valency.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or derivative thereof, wherein R3is selected from hydrogen and C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or derivative thereof, wherein R4is selected from hydrogen or C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or derivative thereof, wherein R3and R4are brought together with the carbons to which they are attached to form a 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more Y groups as allowed by valency.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or derivative thereof, wherein R5is selected from hydrogen and Ci-G, alkyl optionally substituted with one or more Y groups as allowed by valency.

8. A compound of Formula IIor a pharmaceutically acceptable salt or derivative thereof; wherein:R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more Y groups as allowed by valency;R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, Ci- Ce alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;R3is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, Ci- C& alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(O)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency;R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalky IXC0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, or (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency;R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2-, each of which may be optionally substituted with one or more Y groups as allowed by valency;R9is selected from, hydrogen, Ci-Cs alkyl, Ci-Cs haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C1-C6alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RZC(N)-(C1-C6alkyl)-, RZS(O)- (C1-C6alkyl)-, and RzS(O)2-(C1-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; orR4and R5are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more Y groups as allowed by valency; orR3and R4are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more Y groups as allowed by valency; or R3and R6or R4and R6or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more Y groups as allowed by valency;Rxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)- , and RZS(O)2-, each of which may be optionally substituted with one or more Y groups as allowed by valency;Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, Ci- C6haloalkyl, C2-C6alkenyl, Cz-Cealkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more Y groups as allowed by valency; andRaand Rbare independently selected at each occurrence from hydrogen, C, -Coalkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- memberedheterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more Y groups as allowed by valency; andY is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°GO)-NRq-, R°S(O)2-, ROS(O)2-O-, and R°S(O)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, G-G> alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2- Ce alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, with the proviso that if R10is methoxy, at least one of R1, R2, R3, R5, R5, R6, R9, R11, or R12is not hydrogen.

9. The compound of claim 8, or a pharmaceutically acceptable salt or derivative thereof, wherein R3is selected from hydrogen and G -G> alkyl optionally substituted with one or moreY groups as allowed by valency.

10. The compound of claim 8 or claim 9, or a pharmaceutically acceptable salt or derivative thereof, wherein R4is selected from hydrogen or G-G> alkyl optionally substituted with one or more Y groups as allowed by valency.

11. The compound of claim 8, or a pharmaceutically acceptable salt or derivative thereof, wherein R3and R4are brought together with the carbons to which they are attached to form a 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more Y groups as allowed by valency.

12. The compound of any one of claims 8-11, or a pharmaceutically acceptable salt or derivative thereof, wherein R5is selected from hydrogen and G-G> alkyl optionally substituted with one or more Y groups as allowed by valency.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or derivative thereof, wherein R1is selected from hydrogen and C1-C6alkyl optionally substituted with one or more Y groups as allowed by valency.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or derivative thereof, wherein R2is selected from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl,and -ORX, wherein Rxis hydrogen, G-G> alkyl, or G-G> haloalkyl, each of which may be optionally substituted with one or more Y groups as allowed by valency.

15. The compound of any one of claims 1- 14, or a pharmaceutically acceptable salt or derivative thereof, wherein R10is selected from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, and -ORX, wherein Rxis hydrogen, C1-C6alkyl, or C1-C6haloalkyl, each of which may be optionally substituted with one or more Y groups as allowed by valency.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or derivative thereof, wherein R11is selected from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, and -ORX, wherein Rxis hydrogen, Ci-G, alkyl, or Ci-G, haloalkyl, each of which may be optionally substituted with one or more Y groups as allowed by valency.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or derivative thereof, wherein R12is selected from hydrogen, halo, G-G> alkyl, C-C6 haloalkyl, and -ORX, wherein Rxis hydrogen, G-G alkyl, or C1-C6haloalkyl, each of which may be optionally substituted by one or more Y groups as allowed by valency.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or derivative thereof, wherein R6is selected from hydrogen, G-Ce alkyl, 6- to 10-membered monocyclic or bicyclic aryl)-(Co-G alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted by one or more Y groups as allowed by valency.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or derivative thereof, wherein R9is selected from hydrogen, G-Ce alkyl, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(G-C6alkyl)-, RXS-(G-C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, and RZC(O)-(G-G alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency.

20. A compound selected from:or a pharmaceutically acceptable salt or derivative thereof.

21. A compound selected from:or a pharmaceutically acceptable salt thereof.

22. A compound selected from:or a pharmaceutically acceptable salt or derivative thereof.

23. A pharmaceutical composition comprising a compound of any one of claims 1-22, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient.

24. A method of treating a psychiatric disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-22, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of claim 23.

25. A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-22, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of claim 23.

26. A method of treating a medical disorder in a subject in need thereof, wherein the medical disorder is selected from addiction, alcohol use disorder or substance use disorder, Alzheimer’s disease, anxiety, Attention-Deficit / Hyperactivity Disorder, bipolar disorder, borderline personality disorders, depression, dementia, headache disorders including migraine or cluster headaches, major depressive disorder, Parkinson’s disease, personality disorders, post-traumatic stress disorder, schizophrenia and related disorders, spectrum disorder, stereotypic movement disorder, stroke, suicidal ideation, tic disorders, Tourette’s disorder, and treatment resistant depression, the method comprising administering to thesubject a therapeutically effective amount of a compound of any one of claims 1-22, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of claim 23.

27. A process for the synthesis of a compound of Formula Ila:the process comprising irradiating a compound of Formula III:to form the compound of Formula Ila, wherein:R1is selected from hydrogen, Ci-C<> alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2-, each of which may be optionally substituted with one or more Y groups as allowed by valency;R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, Ci- Ce alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(O)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(O)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;R3is selected from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RXS-(C0-C6alkyl)-, (RxR>'N)-(C0-C6alkyl)-, RzC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RZS(0)-(CO-C6 alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency;R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalky IXC0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency;R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RzS(Oh- , each of which may be optionally substituted with one or more Y groups as allowed by valency;R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(CI-C6 alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-(C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RzC(N)-(Ci-Cfialkyl)-, RZS(O)- (C1-C6alkyl)-, and RzS(O)2-(C1-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; orR4and R5are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more Y groups as allowed by valency; orR3and R4are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more Y groups as allowed by valency; or R3and R6or R4and R6or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more Y groups as allowed by valency;X1is selected from -R13is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; m is 0, 1, or 2;Rxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)- , and RZS(O)2-, each of which may be optionally substituted with one or more Y groups as allowed by valency;Rzis independently selected at each occurrence from hydrogen, halo, Ci-Csalkyl, C1- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- memberedheterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa,and -NRaRb, each of which may be optionally substituted with one or more Y groups as allowed by valency; andRaand Rbare independently selected at each occurrence from hydrogen, Ci-C6alkyl, Ci- Cehaloalkyl, C2-C6lkenyl, C2-C6alkynyl, (C3-C7cycloalkyl -(C0-C3alkyl)-, (4- to 6- memberedheterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, Ci -Co alkyl, CI-CG haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°C(O)-NRq-, R°S(O)2-, ROS(O)2-O-, and R°S(O)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2- G> alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-.

28. The process of claim 27, wherein X1is -NH2.

29. The process of claim 27 or claim 28, wherein irradiating the compound of Formula III comprises irradiating the compound with ultraviolet or visible light, preferably ultraviolet light.

30. The process of any one of claims 27-29, wherein the process is carried out in the presence of an acid.

31. The process of claim 30, wherein the acid comprises a mineral acid (such as hydrochloric acid) or an organic acid (such as acetic acid).

32. The process of any one of claims 27-31, wherein the process is carried out in the presence of an alcoholic solvent.

33. A compound of Formula Ila prepared according to the process of any one of claims 27-32.

34. A process for the synthesis of a compound of Formula Ila:the process comprising irradiating a compound of Formula Illa:to form the compound of Formula Ila, wherein:R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more Y groups as allowed by valency;R2, R10, R11, and R12are independently selected from hydrogen, halo, nitro, cyano, azido, Ci- Ce alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-memberedmonocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(0)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;R3is selected from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RXO-(C0-C6alkyl)-, RXS-(C0-C6alkyl)-, (RxR>'N)-(C0-C6alkyl)-, RzC(O)-(C0-C6alkyl)-, RzC(N)-(C0-C6alkyl)-, RzS(0)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency;R4and R5are independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalky IXC0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-(C0-C6alkyl)-, RxS-(C0-C6alkyl)-, (RxRyN)-(C0-C6alkyl)-, RZC(N)-(C0-C6alkyl)-, RzS(O)-(C0-C6alkyl)-, and RzS(0)2-(C0-C6alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency;R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2- , each of which may be optionally substituted with one or more Y groups as allowed by valency;R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RxO-( C1-C6alkyl)-, RxS-(Ci- C6alkyl)-, (RxRyN)-( C1-C6alkyl)-, RZC(O)-(C1-C6alkyl)-, RZC(N)-( C1-C6alkyl)-, RZS(O)- (C1-C6alkyl)-, and RzS(O)2-(C1-C6alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; orR4and R5are brought together with the carbon to which they are attached to form a C3-C6cycloalkyl or 3- to 8-membered monocyclic or bicyclic heterocycle, each of which may be optionally substituted with one or more Y groups as allowed by valency; orR3and R4are brought together with the atoms to which they are attached to form C3-C6cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more Y groups as allowed by valency; or R3and R6or R4and R6or R6and R9are brought together with the atoms to which they are attached to form 3- to 8-membered monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which may be optionally substituted with one or more Y groups as allowed by valency;Xlais selected from halo, -N(R13a)2, -N(R13ah+, -OH, -O(C=O)R13,R13ais independently selected at each occurrence from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C6alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, and RXO-, each of which may be optionally substituted with one or more Y groups as allowed by valency; m is 0, 1, or 2;Rxand Ryare independently selected at each occurrence from Ra, RZC(O)-, RZC(N)-, RZS(O)-, and RZS(O)2-, each of which may be optionally substituted with one or more Y groups as allowed by valency;Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- memberedheterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORa, -SRa, and -NRaRb, each of which may be optionally substituted with one or more Y groups as allowed by valency; andRaand Rbare independently selected at each occurrence from hydrogen, Ci -Chalky I, Ci- Cehaloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C?cycloalkyl)-(C0-C3alkyl)-, (4- to 6-membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RPO-, RPS-, RpRqN-, R°C(O)-, R°C(O)-O-, R°C(O)-NRq-, R°S(O)2-, ROS(O)2-O-, and R°S(O)2-NRq-, wherein R° is independently selected at each occurrence from Rp, halo, RPO-, and RpRqN-, and wherein Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2- C6 alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-.

35. The process of claim 34, wherein X1is -NH2.

36. The process of claim 34 or claim 35, wherein irradiating the compound of Formula Illa comprises irradiating the compound with ultraviolet or visible light, preferably ultraviolet light.

37. The process of any one of claims 34-36, wherein the process is carried out in the presence of an acid.

38. The process of claim 37, wherein the acid comprises a mineral acid (such as hydrochloric acid) or an organic acid (such as acetic acid).

39. The process of any one of claims 34-38, wherein the process is carried out in the presence of an alcoholic solvent.

40. A compound of Formula Ila prepared according to the process of any one of claims 34-39.

Images