Tryptamine prodrug

Abstract

Provided herein is technology relating to prodrugs of psychedelic tryptamine compounds and particularly, but not exclusively, to psychedelic tryptamine prodrug compounds, compositions comprising psychedelic tryptamine prodrug compounds, methods of making psychedelic tryptamine prodrug compounds, and methods of treating a subject with a psychedelic tryptamine prodrug compound.

Description

TRYPTAMINE PRODRUGSTATEMENT OF RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 692,510, filed September 9, 2024, the entire contents of which are incorporated herein by reference for all purposes.TECHNICAL FIELD

[0002] Provided herein is technology relating to prodrugs of psychedelic tryptamine compounds and particularly, but not exclusively, to psychedelic tryptamine prodrug compounds, compositions comprising psychedelic tryptamine compounds, methods of making psychedelic tryptamine prodrug compounds, and methods of treating a subject with a psychedelic tryptamine prodrug compound.BACKGROUND OFTHE INVENTION

[0003] Psilocybin is a naturally occurring prodrug of the psychedelic tryptamine psilocin, which exerts psychoactive effects through action at numerous serotonin (5- HT) receptors. Psilocybin is produced by mushrooms of the genus Psilocybe, e.g., P. azurescens, P. semilanceata, and P. cyanescens. These mushrooms produce other tryptamines such as norbaeocystin, baeocystin, norpsilocin, and aeruginascin. See, e.g., Sherwood (2020) “Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin” J. Nat. Prod. 83: 461-67, incorporated herein by reference. Similarly to the prodrug-active compound relationship between psilocybin and psilocin, norpsilocin is the active compound produced from the prodrug baeocystin. Psilocin and norpsilocin are structurally related, differing only in the presence of one methyl group in the tertiary amine present in psilocin relative to the secondary amine present in norpsilocin. However, while psilocin and norpsilocin are both potent 5-HT agonists, norpsilocin does not produce psychedelic effects in vivo. Some attempts have been made to increase the bioavailability and psychoactivity of norpsilocin analogs and other tryptamines. See, e.g., U.S. Pat. App. Pub. No. 20230406824 and Sherwood (2024) “Psychedelic-like Activity of Norpsilocin Analogues” ACS Chem. Neurosci. 15: 315-27, each of which is incorporated herein by reference. Despite these advances, new compounds are needed.SUMMARY OF THE INVENTION

[0004] Accordingly, provided herein is technology relating to prodrugs of psychedelic tryptamine compounds and particularly, but not exclusively, to psychedelic tryptamine prodrug compounds, compositions comprising psychedelic tryptamine compounds, methods of making psychedelic tryptamine prodrug compounds, and methods of treating a subject with a psychedelic tryptamine prodrug compound. In some embodiments, the technology provides psychedelic tryptamine compounds that have improved characteristics related to oral and / or sub-lingual administration. In some embodiments, the technology provides psychedelic tryptamine compounds that have a shortened duration of psychedelic effects relative to psilocybin and psilocin.

[0005] In some embodiments, the technology provides a compound of formula (I):

[0007] wherein:

[0008] each of R1, R2, and R3is independently selected from hydrogen, substituted or unsubstituted straight chain or branched Ci-C6alkyl, substituted or unsubstituted straight chain or branched C2-C6alkenyl, -(CH2)n-Ar, or -(CH2)rr,-heteroaryl, wherein each of n and m is independently an integer selected from 0, 1 , 2, 3, and 4;

[0009] Ar is substituted or unsubstituted aryl;

[0010] R4is H or COR2; and

[0011] X = O or S.

[0012] In some embodiments, the straight chain or branched Ci-C6alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, and sec-hexyl.

[0013] In some embodiments, the straight chain or branched C2-C6alkenyl is selected from vinyl (CH2=CH-), allyl (CH2=CHCH2-), 1 -butenyl (CH2=CH-CH2CH2-), 2-butenyl (CH3-CH=CH-CH2-), 3-butenyl (CH3CH2-CH=CH-), 1 -pentenyl (CH2=CH-CH2CH2CH2- ), 2-pentenyl (CH3-CH=CH-CH2CH2-), 3-pentenyl (CH3CH2-CH=CH-CH2-), 4-pentenyl(CH3CH2CH2-CH=CH-)11 -hexenyl (CH2=CH-CH2CH2CH2CH2-), 2-hexenyl (CH3- CH=CH-CH2CH2CH2-), 3-hexenyl (CH3CH2-CH=CH-CH2CH2-), 4-hexenyl (CH3CH2CH2- CH=CH-CH2), 5-hexenyl (CH3CH2CH2CH2CH=CH-), and structural isomers thereof.

[0014] In some embodiments, for-(CH2)n-Ar, n is 1 and Ar is phenyl.

[0015] In some embodiments, the heteroaryl can be substituted or unsubstituted and is selected from 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl,2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyL

[0016] In some embodiments, the compound of formula (I) is selected from:

[0018] In some embodiments, the compound of formula (I) is:

[0020] In some embodiments, the technology provides a compound of formula (II):

[0022] wherein:

[0023] R1is selected from hydrogen, substituted or unsubstituted straight chain or branched Ci-C6alkyl, substituted or unsubstituted straight chain or branched C2-C6alkenyl, -(CH2)n-Ar, or-(CH2)m-heteroaryl, wherein each of n and m is independently an integer selected from 0, 1 , 2, 3, and 4;

[0024] Ar is substituted or unsubstituted aryl; and

[0025] X = O or S.

[0026] In some embodiments, the straight chain or branched Ci-C6alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, and sec-hexyl.

[0027] In some embodiments, the straight chain or branched C2-C6alkenyl is selected from vinyl (CH2=CH-), allyl (CH2=CHCH2-), 1 -butenyl (CH2=CH-CH2CH2-), 2-butenyl (CH3-CH=CH-CH2-), 3-butenyl (CH3CH2-CH=CH-), 1 -pentenyl (CH2=CH-CH2CH2CH2- ), 2-pentenyl (CH3-CH=CH-CH2CH2-), 3-pentenyl (CH3CH2-CH=CH-CH2-), 4-pentenyl (CH3CH2CH2-CH=CH-), 1 -hexenyl (CH2=CH-CH2CH2CH2CH2-), 2-hexenyl (CH3- CH=CH-CH2CH2CH2-), 3-hexenyl (CH3CH2-CH=CH-CH2CH2-), 4-hexenyl (CH3CH2CH2- CH=CH-CH2), 5-hexenyl (CH3CH2CH2CH2CH=CH-), and structural isomers thereof.

[0028] In some embodiments, for-(CH2)n-Ar, n is 1 and Ar is phenyl.

[0029] In some embodiments, the heteroaryl can be substituted or unsubstituted and is selected from 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl,2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl.

[0030] In some embodiments, the compound of formula (II) is selected from:

[0032] In some embodiments, the compound of formula (II) is:

[0034] In some embodiments, the technology provides a compound (4-HO-N(R’)T) having structure (III):

[0036] In some embodiments, the technology provides a prodrug of a 4-HO-N(R1)T compound, e.g., a prodrug having a structure according to structure (I) or structure (II).In some embodiments, the technology provides a prodrug of a 4-HO-N(R1)T compound, e.g., a prodrug that has a structure according to one of the following:

[0052] Without being bound by theory, it is contemplated that a prodrug as described herein is converted rapidly in human plasma to a 4-HO-N(R’)T compound having structure (III). Accordingly, the prodrugs described herein (e.g., a compound of formula (I) or a compound of formula (II)) are prodrugs of and are converted by metabolic processes to their associated 4-HO-N(R1)T compound (e.g., a compound of formula (III)). The R1group of the prodrugs provided herein (e.g., a compound of formula (I) or a compound of formula (II)) is present in the active tryptamine (e.g., a compound of formula (III)) after metabolism.

[0053] Some portions of this description describe the embodiments of the technology in terms of algorithms and symbolic representations of operations on information. These algorithmic descriptions and representations are commonly used by those skilled in the data processing arts to convey the substance of their work effectively to others skilled in the art. These operations, while described functionally, computationally, or logically, are understood to be implemented by computer programs or equivalent electrical circuits, microcode, or the like. Furthermore, it has also proven convenient at times to refer to these arrangements of operations as modules, without loss of generality. The described operations and their associated modules may be embodied in software, firmware, hardware, or any combinations thereof.

[0054] Certain steps, operations, or processes described herein may be performed or implemented with one or more hardware or software modules, alone or in combination with other devices. In some embodiments, a software module is implemented with a computer program product comprisinga computer-readable medium containing computer program code, which can be executed by a computer processor for performing any or all steps, operations, or processes described.

[0055] In some embodiments, systems comprise a computer and / or data storage provided virtually (e.g., as a cloud computing resource). In particular embodiments, the technology comprises use of cloud computing to provide a virtual computer system that comprises the components and / or performs the functions of a computer as described herein. Thus, in some embodiments, cloud computing provides infrastructure, applications, and software as described herein through a network and / or over the internet. In some embodiments, computing resources (e.g., data analysis, calculation, data storage, application programs, file storage, etc.) are remotely provided over a network (e.g., the internet; and / or a cellular network).

[0056] Embodiments of the technology may also relate to an apparatus for performing the operations herein. This apparatus may be specially constructed for the required purposes (e.g., an application-specific integrated circuit or a field-programmable gate array) and / or it may comprise a general-purpose computing device (e.g., a microcontroller, microprocessor, and the like) selectively activated or reconfigured by a computer program stored in the computer. The apparatus may be configured to perform one or more steps, actions, and / or functions described herein, e.g., provided as instructions of a computer program. Such a computer program may be stored in a non-transitory, tangible computer readable storage medium or any type of media suitable for storing electronic instructions, which may be coupled to a computer system bus. Furthermore, any computing systems referred to in the specification may include a single processor or may be architectures employing multiple processor designs for increased computing capability.

[0057] Additional embodiments will be apparent to persons skilled in the relevant art based on the teachings contained herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0059] These and otherfeatures, aspects, and advantages of the present technology will become better understood with regard to the following drawings.

[0060] FIG. 1 shows exemplary tryptamine prodrug compounds provided herein.

[0061] FIG. 2 summarizes the synthesis of a number of 4-hydroxy-tryptamines.

[0062] It is to be understood that the figures are not necessarily drawn to scale, nor are the objects in the figures necessarily drawn to scale in relationship to one another. The figures are depictions that are intended to bring clarity and understanding to various embodiments of apparatuses, systems, and methods disclosed herein. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. Moreover, it should be appreciated that the drawings are not intended to limit the scope of the present teachings in any way.DETAILED DESCRIPTION

[0063] Provided herein is technology relating to prodrugs of psychedelic tryptamine compounds and particularly, but not exclusively, to psychedelic tryptamine prodrug compounds, compositions comprising psychedelic tryptamine compounds, methods of making psychedelic tryptamine prodrug compounds, and methods of treating a subject with a psychedelic tryptamine prodrug compound.

[0064] In this detailed description of the various embodiments, for purposes of explanation, numerous specific details are set forth to provide a thorough understanding of the embodiments disclosed. One skilled in the art will appreciate, however, that these various embodiments may be practiced with orwithout these specific details. In other instances, structures and devices are shown in block diagram form. Furthermore, one skilled in the art can readily appreciate that the specific sequences in which methods are presented and performed are illustrative and it is contemplated that the sequences can be varied and still remain within the spirit and scope of the various embodiments disclosed herein.

[0065] All literature and similar materials cited in this application, including but not limited to, patents, patent applications, articles, books, treatises, and internet web pages are expressly incorporated by reference in their entirety for any purpose. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which belongs the various embodiments described herein. When definitions of terms in incorporated references appear to differ from the definitions provided in the present teachings, the definition provided in the present teachings shall control. The section headings used herein are for organizational purposes only and are not to be construed as limiting the described subject matter in anyway.Definitions

[0066] To facilitate an understanding of the present technology, a number of terms and phrases are defined below. Additional definitions are set forth throughout the detailed description.

[0067] Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrase “in one embodiment” as used herein does not necessarily refer to the same embodiment, though it may. Furthermore, the phrase “in another embodiment” as used herein does not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention.

[0068] In addition, as used herein, the term “or” is an inclusive “or” operator and is equivalent to the term “and / or” unless the context clearly dictates otherwise. The term “based on” is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of “a”, “an”, and “the” include plural references. The meaning of “in” includes “in” and “on.”

[0069] As used herein, the terms “about”, “approximately”, “substantially”, and “significantly” are understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of these terms that are not clear to persons of ordinary skill in the art given the context in which they are used, “about” and “approximately” mean plus or minus less than or equal to 10% of the particular term and “substantially” and “significantly” mean plus or minus greater than 10% of the particular term.

[0070] As used herein, disclosure of ranges includes disclosure of all values and further divided ranges within the entire range, including endpoints and sub-ranges given for the ranges. As used herein, the disclosure of numeric ranges includes the endpoints and each intervening numbertherebetween with the same degree of precision. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and forthe range 6.0-7.0, the numbers 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0071] As used herein, the suffix “-free” refers to an embodiment of the technology that omits the feature of the base root of the word to which “-free” is appended. That is, the term “X-free” as used herein means “without X”, where X is a feature of the technology omitted in the “X-free” technology. For example, a “calcium-free” composition does not comprise calcium, a “mixing-free” method does not comprise a mixing step, etc.

[0072] Although the terms “first”, “second”, “third”, etc. may be used herein to describe various steps, elements, compositions, components, regions, layers, and / or sections, these steps, elements, compositions, components, regions, layers, and / or sections should not be limited by these terms, unless otherwise indicated. These terms are used to distinguish one step, element, composition, component, region, layer, and / or section from another step, element, composition, component, region, layer, and / or section. Terms such as “first”, “second”, and other numerical terms when used herein do not imply a sequence or order unless clearly indicated by the context. Thus, a first step, element, composition, component, region, layer, or section discussed herein could be termed a second step, element, composition, component, region, layer, or section without departing from technology.

[0073] As used herein, the word “presence” or “absence” (or, alternatively, “present” or “absent”) is used in a relative sense to describe the amount or level of a particular entity (e.g., component, action, element). For example, when an entity is said to be “present”, it means the level or amount of this entity is above a pre-determined threshold; conversely, when an entity is said to be “absent”, it means the level or amount of this entity is below a pre-determined threshold. The pre-determined threshold may be the threshold for detectability associated with the particular test used to detect the entity or any other threshold. When an entity is “detected” it is “present”; when an entity is “not detected” it is “absent”. Further, when a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as being “absent”, the named atom is replaced by a direct bond.

[0074] As used herein, an “increase” or a “decrease” refers to a detectable (e.g., measured) positive or negative change, respectively, in the value of a variable relative to a previously measured value of the variable, relative to a pre-established value, and / or relative to a value of a standard control. An increase is a positive change preferably at least 10%, more preferably 50%, still more preferably 2-fold, even more preferably atleast 5-fold, and most preferably at least 10-fold relative to the previously measured value of the variable, the pre-established value, and / or the value of a standard control. Similarly, a decrease is a negative change preferably at least 10%, more preferably 50%, still more preferably at least 80%, and most preferably at least 90% of the previously measured value of the variable, the pre-established value, and / or the value of a standard control. Other terms indicating quantitative changes or differences, such as “more” or “less”, are used herein in the same fashion as described above.

[0075] As used herein, a “system” refers to a plurality of real and / or abstract components operating together for a common purpose. In some embodiments, a “system” is an integrated assemblage of hardware and / or software components. In some embodiments, each component of the system interacts with one or more other components and / or is related to one or more other components. In some embodiments, a system refers to a combination of components and software for controlling and directing methods. For example, a “system” or “subsystem” may comprise one or more of, or any combination of, the following: mechanical devices, hardware, components of hardware, circuits, circuitry, logic design, logical components, software, software modules, components of software or software modules, software procedures, software instructions, software routines, software objects, software functions, software classes, software programs, files containing software, etc., to perform a function of the system or subsystem. Thus, the methods and apparatus of the embodiments, or certain aspects or portions thereof, may take the form of program code (e.g., instructions) embodied in tangible media, such as floppy diskettes, CD-ROMs, hard drives, flash memory, or any other machine-readable storage medium wherein, when the program code is loaded into and executed by a machine, such as a computer, the machine becomes an apparatus for practicingthe embodiments. In the case of program code execution on programmable computers, the computing device generally includes a processor, a storage medium readable by the processor (e.g., volatile and non-volatile memory and / or storage elements), at least one input device, and at least one output device. One or more programs may implement or utilize the processes described in connection with the embodiments, e.g., through the use of an application programming interface (API), reusable controls, or the like. Such programs are preferably implemented in a high-level procedural orobject-oriented programming language to communicate with a computer system. However, the program(s) can be implemented in assembly or machine language, if desired. In any case, the language may be a compiled or interpreted language, and combined with hardware implementations.

[0076] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2nd edition, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7th Edition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rd Edition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0077] As used herein, the term “alkyl” refers to a univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom and having the general formula that is -CnH2n+i. An alkyl group derived by removal of a hydrogen atom from a terminal carbon atom of an unbranched alkane form a subclass of normal alkyl (n-alkyl) groups having the general formula of -(CH2)n-H. The groups -CH2-R, -CH-(R)2(R * H), and -C(R)s (R * H) are primary, secondary, and tertiary alkyl groups, respectively.

[0078] An alkyl can be a straight chain (i.e . , unbranched) or a branched acyclic hydrocarbon having the number of carbon atoms designated (e.g., Ci-C20inclusive, including 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons. In particular embodiments, the alkyl is a Ci-C6alkyl, including 1 , 2, 3, 4, 5, and 6 carbons. In other embodiments, the alkyl is a C1-C4 alkyl, including 1 , 2, 3, and 4 carbons.

[0079] In certain embodiments, “alkyl” refers to straight chain alkyls. In other embodiments, “alkyl” refers to branched alkyls. In certain other embodiments, “alkyl” refers to straight-chain and / or branched alkyls. “Branched” refers to an alkyl group inwhich a lower alkyl group, such as methyl, ethyl, propyl, or butyl, is attached to a linear alkyl chain.

[0080] Representative alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, and dodecyl. In particular embodiments, representative Ci-C6branched or straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, and sec-hexyl.

[0081] As used herein, the term “alkene” refers to a cyclic branched or unbranched hydrocarbon having one carbon-carbon double bond and the general formula CnH2n. An “alkenyl group” refers to a monovalent group having the general formula -CnH2n-i formed from an alkene by removal of one hydrogen atom from any carbon atom.

[0082] Representative C2-C6branched or straight chain alkenyl groups include, but are not limited to, vinyl (CH2=CH-), allyl (CH2=CHCH2-), 1 -butenyl (CH2=CH-CH2CH2-), 2- butenyl (CH3-CH=CH-CH2-), 3-butenyl (CH3CH2-CH=CH-), 1 -pentenyl (CH2=CH- CH2CH2CH2-), 2-pentenyl (CH3-CH=CH-CH2CH2-), 3-pentenyl (CH3CH2-CH=CH-CH2- ), 4-pentenyl (CH3CH2CH2-CH=CH-), 1 -hexenyl (CH2=CH-CH2CH2CH2CH2-), 2-hexenyl (CH3-CH=CH-CH2CH2CH2-), 3-hexenyl (CH3CH2-CH=CH-CH2CH2-), 4-hexenyl (CH3CH2CH2-CH=CH-CH2), 5-hexenyl (CH3CH2CH2CH2CH=CH-), and structural isomers thereof.

[0083] Alkyl and alkenyl groups can optionally be substituted (a “substituted alkyl” or a “substituted alkenyl”) with one or more substituents, which can be the same or different. Such substituent groups include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, alkenyl, halogen, acyl, carboxyl, oxo, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.

[0084] As used herein, the term “aryl” refers to a group derived from an arene by removal of a hydrogen atom from a ring carbon atom. As used herein, an “arene” refers to monocyclic and polycyclic aromatic hydrocarbons.

[0085] As used herein, the term “heteroaryl” refers to a heterocyclyl group derived from a heteroarene by removal of a hydrogen atom from any ring atom. As used herein, the term “heteroarene” refers to a heterocyclic compound derived from an arene by replacement of one or more methine (-C=) and / or vinylene (-CH=CH-) groups bytrivalent or divalent heteroatoms, respectively, in such a way as to maintain the continuous n-electron system characteristic of aromatic systems.

[0086] Non-limiting examples of aryl and heteroaryl groups include phenyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2- quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.

[0087] The above noted aryl and heteroaryl ring systems can be substituted with one or more substituents, which can be the same or different including, but not limited to, alkyl, substituted alkyl, cycloalkyl, alkenyl, halogen, acyl, carboxyl, oxo, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto, and any of the substituent groups defined immediately herein below.

[0088] As used herein, the term “acyl” refers to a group formed by removing one or more hydroxy groups from oxoacids that have the general structure RkE(=O)i(OH)m(I * 0), and replacement analogues of such acyl groups. In organic chemistry an unspecified acyl group is commonly a carboxylic acyl group. For example, in some embodiments, the term acyl includes an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent and has the general formula RC(=O)-, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocylic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes arylacyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also are intended to include amides, -RC(=O)NR’, esters, -RC(=O)OR’, ketones, -RC(=O)R’, and aldehydes, -RC(=O)H.

[0089] The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl”, “alkenyl”, and “alkynyl” are as previously described and can include Ci-20inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbonchains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec- butoxyl, fert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, and the like.

[0090] The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group.

[0091] “Aryloxyl” refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.

[0092] “Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0093] “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl, i.e., C6H5-CH2-O-. An aralkyloxyl group can optionally be substituted.

[0094] “Alkoxycarbonyl” refers to an alkyl-O-C(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tertbutyloxycarbonyl.

[0095] “Aryloxycarbonyl” refers to an aryl-O-C(=O)- group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

[0096] “Aralkoxycarbonyl” refers to an aralkyl-O-C(=O)- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

[0097] The term “acyloxyl” refers to an oxygen-centered radicals consisting of an acyl radical bonded to an oxygen atom, e.g., an acyl-O- group wherein acyl is as previously described.

[0098] The term “amine” refers to a compound formally derived from ammonia by replacing one, two or three hydrogen atoms by hydrocarbyl groups, and having the general structures RNH2(primary amines), R2NH (secondary amines), R3N (tertiary amines). In some embodiments, the term amino refers to the -NH2group. More generally, the amino group is -NR'R”, wherein R' and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0099] The terms “acylamino” and “alkylamino” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.

[0100] An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR’ wherein R’ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR’R”, wherein R’ and R” are each independently selected from alkyl groups. The term trialkylamino refers to a group having the structure -NR’R”R”’, wherein R’, R”, and R’” are each independently selected from alkyl groups. Additionally, R’, R”, and / or R’” taken together may optionally be -(CH2)k- where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.

[0101] The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S-and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0102] “Acylamino” refers to an acyl-NH- group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described.

[0103] The term “carbonyl” refers to a compound containing the carbonyl group, - C(=O)-. The term is commonly used in the restricted sense of aldehydes (R-C(=O)H) and ketones, although it actually includes carboxylic acids and derivatives.

[0104] The term “carboxylic acid” refers to an oxoacid having the structure RC(=O)OH. The term is used as a suffix in systematic name formation to denote the -C(=O)OH group including its carbon atom. In some embodiments, the term “carboxyl” refers to the -COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.

[0105] “Carbamoyl” refers to an amide group of the formula -C(=O)NH2.

[0106] “Alkylcarbamoyl” refers to a R’RN-C(=O)- group wherein one of R and R’ is hydrogen and the other of R and R’ is alkyl and / or substituted alkyl as previously described.

[0107] “Dialkylcarbamoyl” refers to a R’RN-C(=O)- group wherein each of R and R’ is independently alkyl and / or substituted alkyl as previously described.

[0108] The term carbonyldioxyl, as used herein, refers to a carbonate group of the formula -O-C(=O)-OR.

[0109] The term “cyano” refers to the -C=N group.

[0110] The terms “halo,” “halide,” or “halogen” as used herein refer to fluoro, chloro, bromo, and iodo groups. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyL For example, the term “halo(Ci-4)alkyl” is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.

[0111] The term “hydroxyl” refers to the -OH group.

[0112] The term “hydroxyalkyl” refers to an alkyl group substituted with an -OH group.

[0113] The term “mercapto” refers to the -SH group.

[0114] The term “oxo compound” refers to a compounds containing an oxygen atom, =O, doubly bonded to carbon or another element. The term thus embraces aldehydes, carboxylic acids, ketones, sulfonic acids, amides and esters. Oxo used as an adjective (and thus separated by a space) modifying another class of compound, as in oxo carboxylic acids, indicates the presence of an oxo substituent at any position. To indicate a double-bonded oxygen that is part of a ketonic structure, the term keto is sometimes used as a prefix, but such use has been abandoned by IUPAC for naming specific compounds. Atraditional use of keto is for indicating oxidation of CHOH to C=O in a parent compound that contains OH groups, such as carbohydrates, e.g. 3- ketoglucose. In some embodiments, the term “oxo” as used herein means an oxygen atom that is double bonded to a carbon atom or to another element.

[0115] The term “nitro” refers to the -NO2group.

[0116] The term “thio” refers to replacement of an oxygen by a sulfur, e.g., PhC(=S)NH2, thiobenzamide.

[0117] The term “thiol” refers to a compounds having the structure RSH (R * H), e.g., MeCH2SH ethanethiol. A thiol also is known by the term “mercaptan.”

[0118] The term “thiohydroxyl” or “thiol,” as used herein, refers to a group of the formula -SH.

[0119] The term “sulfate” refers to the -SO4group.

[0120] The term “sulfide” refers to a compound having the structure RSR (R * H) and also are referred to as “thioethers.”

[0121] The term “sulfone” refers to a compound having the structure, RS(=O)2R (R * H), e.g., C2H5S(=O)2CH3 ethyl methyl sulfone.

[0122] The term “sulfoxide” refers to a compound having the structure R2S=O (R * H), e.g., Ph2S=O diphenyl sulfoxide.

[0123] The term “ureido” refers to a urea group of the formula -NH — CO — NH2.

[0124] One of ordinary skill in the art would recognize that a structure represented generally by, for example, the formula:

[0126] as used herein refers to a ring structure, for example, but not limited to a 3- carbon, a 4-carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and / or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and number of R groups is determined by the value of the variable “n,” which is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution. Each R group, if more than one, is substituted on an available carbon of the ring structure rather than on another R group. For example, the structure above where n is 0 to 2 would comprise compound groups including, but not limited to:

[0127] the like.

[0128] A dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is, a dashed line representinga bond in a cyclic ring structure indicates that the ring structure is selected from a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

[0129] As used herein, the term “substituent” refers to a group substituted on an atom of the indicated group. When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1 , 2, 3, 4, 5, or 6; in some embodiments 1 , 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof.

[0130] As used herein in chemical structures, the indication

[0132] represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the core compound).

[0133] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0134] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH2O- optionally also recites -OCH2-, and -OC(O)NH- also optionally recites -NHC(O)O-.

[0135] Further, throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0136] Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L-for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E andZ geometric isomers.

[0137] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0138] As used herein, the term “congener” refers to one of two or more substances related to each other by origin, structure, or function.

[0139] The term “enantiomer” refers to one of a pair of molecular entities which are mirror images of each other and non-superposable.

[0140] The term “stereoisomer” refers to an isomer that possess identical constitution, but which differ in the arrangement of their atoms in space.

[0141] The term “racemate” refers to an equimolar mixture of a pair of enantiomers. It does not exhibit optical activity. The chemical name or formula of a racemate is distinguished from those of the enantiomers by the prefix (±)- or rac- (or racem-) or by the symbols RS and SR.

[0142] The term “diastereoisomerism” refers to stereoisomerism other than enantiomerism. Diastereoisomers (or diastereomers) are stereoisomers not related as mirror images. Diastereoisomers are characterized by differences in physical properties, and by some differences in chemical behavior towards achiral as well as chiral reagents.

[0143] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0144] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C- enriched carbon are within the scope of this disclosure.

[0145] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125l) or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0146] The terms “administer”, “administering”, “administered”, or “administration” referto any manner of providing a compound or a pharmaceutical composition (e.g., one described herein), to a subject or patient. Routes of administration can be accomplished through any means known by those skilled in the art. Such means include, but are not limited to, oral, buccal, intravenous, subcutaneous, intramuscular, transdermal, by inhalation and the like.

[0147] “Effective amount”, as used herein, refers to a dosage of a compound or a composition effective for eliciting a desired effect. This term as used herein may also referto an amount effective at bringing about a desired in vivo effect in a subject, such as a human.

[0148] As used herein, the term “subject” is intended to include human and nonhuman animals. Exemplary human subjects include a human patient having a disorder, e.g., a neurological or psychiatric disorder. The term “non-human animals” includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals (such as sheep, dogs, cats, cows, pigs, etc.), and rodents (such as mice, rats, hamsters, guinea pigs, etc.).

[0019] As used herein, the term “treat” or “treating” a subject having a disorder refers to administering a compound or a composition described herein to the subject, such that at least one symptom of the disorder is cured, healed, alleviated, relieved, altered, remedied, ameliorated, or improved. Treating includes administering an amount effective to alleviate, relieve, alter, remedy, ameliorate, cure, improve or affect the disorder or the symptoms of the disorder. The treatment may inhibit deterioration or worsening of a symptom of a disorder.Description

[0150] The technology described herein relates to prodrugs of psychedelic tryptamine compounds. See, e.g., FIG. 1 . In addition to tryptamine compounds and tryptamine prodrug compounds, also disclosed herein are compositions (e.g., pharmaceutical compositions) comprising psychedelic tryptamine compounds, methods of making psychedelic tryptamine prodrug compounds, and methods of treating a subject with a psychedelic tryptamine prodrug compound.

[0151] For instance, representative alkyl tryptamine compounds are disclosed in U.S. Patent Application Publication No. US20240083848, to Chadeayne, published March 14, 2024, which is incorporated herein by reference in its entirety. Int’l Pat. App. No. PCT / US2023 / 029799, to Kruegel, published February 15, 2024, which is incorporated herein by reference, also describes some tryptamine compounds for use in treating mood disorders.

[0152] More particularly, in some embodiments, the provided herein is a compound of formula (I):

[0154] wherein:

[0155] each of R1, R2, and R3is independently selected from hydrogen, substituted or unsubstituted straight chain or branched Ci-C6alkyl, substituted or unsubstituted straight chain or branched C2-C6alkenyl, -(CH2)n-Ar, or -(CH2)m-heteroaryl, wherein each of n and m is independently an integer selected from 0, 1 , 2, 3, and 4;

[0156] Ar is substituted or unsubstituted aryl; and

[0157] R4is H or COR2; and X = O or S.

[0158] In particular embodiments, the compound of formula (I) is one of:

[0160] .

[0161] In other embodiments, the compound is a compound of formula (II):

[0163] wherein:

[0164] R1is selected from hydrogen, substituted or unsubstituted straight chain or branched Ci-Ce alkyl, substituted or unsubstituted straight chain or branched C2-C6 alkenyl, -(CH2)n-Ar, or-(CH2)m-heteroaryl, wherein each of n and m is independently an integer selected from 0, 1 , 2, 3, and 4;

[0165] Ar is substituted or unsubstituted aryl; and

[0166] X = O or S.

[0167] In some embodiments, the compound of formula (II) is one of:

[0169] The compounds of the present disclosure may have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituent groups. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this disclosure.

[0170] The independent syntheses of the enantiomerically ordiastereomerically enriched compounds, ortheir chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. The absolute stereochemistry of a compound may be determined by using X-ray crystallography to determine the crystal structure of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

[0171] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0172] The compound (e.g., a compound of structure (I), (II), or (III)) may possess tautomeric forms, and tautomers also constitute embodiments of the disclosure.

[0173] The present disclosure also includes isotopically-labeled compounds (e.g., an isotopically-labeled compound of structure (I), (II), or (III)), which are identical to those recited in structure (I), (II), or (III), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,180,31P,35S,18F, and36Cl, respectively. Substitution with heavier isotopes such as deuterium (i.e.,2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of structure (I), (II), or (III) are11C,13N,15O, and18F. Isotopically-labeled compounds of structure (I), (II), or (III) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent.

[0174] Compounds of structure (I), (II), or (III) can be synthesized by a variety of methods, includingthose illustrated in the Examples as Scheme 1 and Scheme 2.

[0175] Compounds and intermediates may be isolated and purified by methods well- known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific &Technical, Essex CM202JE, England.

[0176] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

[0177] Standard experimentation, including appropriate manipulation of the reaction conditions, reagents, and sequence of the synthetic route; protection of any chemical functionality that cannot be compatible with the reaction conditions; and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art, examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference.

[0178] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0179] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described herein using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0180] The synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure or the claims. Alternatives,modifications, and equivalents of the synthetic methods and specific examples are contemplated.

[0181] Compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the disclosure may also exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0182] The present disclosure also provides compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds disclosed herein (e.g., a compound of structure (I), (II), or (III)). Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0183] Pharmaceutical Compositions

[0184] The disclosed compounds (e.g., compounds of structure (I), (II), or (III)) may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the disclosure are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used insubjects prior to or at an earlier stage of disease or condition, the prophylactically effective amount will be less than the therapeutically effective amount.

[0185] For example, a therapeutically effective amount of a compound of structure (I), (II), or (III) may be approximately 1 mg / kg to approximately 1000 mg / kg, approximately 5 mg / kg to approximately 950 mg / kg, approximately 10 mg / kg to approximately 900 mg / kg, approximately 15 mg / kg to approximately 850 mg / kg, approximately 20 mg / kg to approximately 800 mg / kg, approximately 25 mg / kg to approximately 750 mg / kg, approximately 30 mg / kg to approximately 700 mg / kg, approximately 35 mg / kg to approximately 650 mg / kg, approximately 40 mg / kg to approximately 600 mg / kg, approximately 45 mg / kg to approximately 550 mg / kg, approximately 50 mg / kg to approximately 500 mg / kg, approximately 55 mg / kg to approximately 450 mg / kg, approximately 60 mg / kg to approximately 400 mg / kg, approximately 65 mg / kg to approximately 350 mg / kg, approximately 70 mg / kg to approximately 300 mg / kg, approximately 75 mg / kg to approximately 250 mg / kg, approximately 80 mg / kg to approximately 200 mg / kg, approximately 85 mg / kg to approximately 150 mg / kg, and approximately 90 mg / kg to approximately 100 mg / kg.

[0186] The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a nontoxic, inert solid, semi-solid, or liquid filler; diluent; encapsulating material; or formulation auxiliary of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose, and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; and phosphate buffer solutions; and other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, and coloring agents, releasing agents, coating agents,sweetening agents, flavoring agents, and perfuming agents. Preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0187] Thus, the compounds may be formulated for administration, for example, by solid dosing, in an eye drop, in a topical oil-based formulation, by injection, by inhalation (either through the mouth or the nose), in an implant, or by parenteral or rectal administration. In some embodiments, the compounds are formulated for oral, sublingual, and / or buccal administration. Techniques and formulations may generally be found in “Remington’s Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0188] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0189] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

[0190] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically approximately 50 to approximately 90%.

[0191] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate, and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma. The amount of lubricant(s) in a systemic ortopical composition is typically approximately 5 to approximately 10%.

[0192] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose,methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically approximately 5 to approximately 50%.

[0193] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically approximately 0.1 to approximately 10%.

[0194] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically approximately 0.005 to approximately 0.1 %.

[0195] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically approximately 0.1 to approximately 1 .0%.

[0196] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically approximately 0.001 to approximately 1%.

[0197] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically approximately 0.1 to approximately 5%.

[0198] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically approximately 0.01 to approximately 5%.

[0199] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically approximately 1 to approximately 5%.

[0200] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from approximately 0 to approximately 100%.

[0201] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, Pennsylvania) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically approximately 1 to approximately 8%.

[0202] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington’s Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon’s Volume 1 , Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically approximately 0.1% to approximately 5%.

[0203] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01 % to 50% of an active compound (e.g., a compound of structure (I), (II), or (III)), and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1 % to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0204] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, dissolvable films, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least approximately 5%, and more particularly from approximately 25% to approximately 50% of actives. The oral dosage compositions include approximately 50% to approximately 95% of carriers, and more particularly, from approximately 50% to approximately 75%.

[0205] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0206] Capsules (including implants, time released, and sustained release formulations) typically include an active compound (e.g., a compound of structure (I), (II), or (III)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0207] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this disclosure.

[0208] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the mouth or the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0209] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non- effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0210] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal, and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Suchcompositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0211] The disclosed compounds can be topically administered, e.g., on the skin or mucosa. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of structure (I), (II), or (III)), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0212] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this disclosure are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0213] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0214] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0215] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1 ,2-diol, butane-1 ,3-diol, mink oil, cetyl alcohol, isopropylisostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically approximately 5% to approximately 95%.

[0216] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically approximately 0% to approximately 95%.

[0217] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically approximately 0% to approximately 95%.

[0218] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5- carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.

[0219] The amount of thickener(s) in a topical composition is typically approximately 0% to approximately 95%.

[0220] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0221] The amount of fragrance in a topical composition is typically approximately 0% to approximately 0.5%, particularly, approximately 0.001 % to approximately 0.1%.

[0222] Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

[0223] Methods of Use

[0224] The present disclosure provides methods of using the compounds and compositions described herein (e.g., compounds of structure (I), (II), or (III)). In some embodiments, the methods include methods of treating a neurological condition.

[0225] Compounds described herein are agonists of the 5-HT receptor, e.g., the 5-HT2A receptor. Further, it is contemplated that the prodrug compounds of formula (II) possess acetylcholinesterase inhibitory activity prior to metabolic conversion of the prodrug to the active psychedelic form. Such potential activity would categorize these compounds as pleiotropic prodrugs with dual therapeutic applications. That is, in some embodiments, the prodrug compounds described herein are acetylcholine esterase inhibitors and, after metabolic conversion of the prodrug to a psychedelic tryptamine drug, the psychedelic tryptamine drug compound is an agonist of the 5-HT receptor.

[0226] Activity of compounds described herein can be assessed using several methods, including in vitro and in vivo methods including receptor binding assays and biological assays. Assays for testing the efficacy and safety of psychoactive drugs are described in, e.g., Roth, National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP) ASSAY PROTOCOL BOOK Version III, which is available at pdsp.unc.edu and which is incorporated herein by reference. In vivo assays using a mouse model are described in, e.g., Sherwood (2024), ACS Chem. Neurosci. 15: 315-27, which is incorporated herein by reference. In vitro and in vivo assays for evaluating receptor agonist activity at serotonin receptors are described in Glatfelter (2022) ACS Pharmacol. Transl. Sci. 5: 1181-96, which is incorporated herein by reference.

[0227] Additional assays that find use in testing compounds described herein include, e.g., incubating a compound with human liver and / or intestinal microsomes; testing a compound described herein using a head-twitch response in mice; testing a compound described herein for plasma stability and / or Caco-2 permeability; and testingcompounds described herein using an off-target GPCR screen and / or to assay hERG inhibition.

[0228] In some embodiments, the technology described herein provides a method of treating a disease or malady in a subject in need of treatment for the disease or malady (e.g., a subject suffering from a disease or malady described herein). For example, in some embodiments, methods comprise administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of structure (I), (II), or (III)), or a pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising a compound of structure (I), (II), or (III)). Accordingly, in some embodiments, the technology provides a method of treating a disease or malady in a subject in need thereof, e.g., a subject suffering from depression, psychotic disorder, schizophrenia, schizophreniform disorder (acute schizophrenic episode), schizoaffective disorder, bipolar I disorder (mania, manic disorder, manic-depressive psychosis), bipolar II disorder, major depressive disorder, major depressive disorder with psychotic feature (psychotic depression), delusional disorders (paranoia), Shared Psychotic Disorder (Shared paranoia disorder), Brief Psychotic disorder (Other and Unspecified Reactive Psychosis), Psychotic disorder not otherwise specified (Unspecified Psychosis), paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, anxiety disorder, social anxiety disorder, substance- induced anxiety disorder, selective mutism, panic disorder, panic attacks, agoraphobia, attention deficit syndrome, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and premenstrual syndrome (PMS).

[0229] In some embodiments, compounds described herein are used to prevent and / or treat a brain disorder. For example, embodiments of methods provide treatments for preventing and / or treating a brain disorder by administering to a subject in need thereof a therapeutically effective amount of a compound described herein. The brain disorder may be chosen from Huntington's disease, Alzheimer's disease, dementia, and Parkinson's disease.

[0230] In some embodiments, a compound described herein finds use in preventing and / or treating developmental disorders, delirium, dementia, amnestic disorders and other cognitive disorders, psychiatric disorders due to a somatic condition, drug- related disorders, schizophrenia and other psychotic disorders, mood disorders,anxiety disorders, somatoform disorders, factitious disorders, dissociative disorders, eating disorders, sleep disorders, impulse control disorders, adjustment disorders, or personality disorders. The technology described herein provides a method for preventing and / or treating these disorders by administering to a subject in need thereof a therapeutically effective amount of a compound described herein including, but not limited to, the exemplary embodiments discussed herein.

[0231] In some embodiments, compounds described herein are used to modulate neurogenesis by administering a compound or composition described herein. As used herein, the term “modulating neurite outgrowth” refers to changing, manipulating, and / or adjusting the growth and development of neural projections (“neurites”). In some embodiments, neurogenesis comprises modulating the growth of new neurites, modulating the number of neurites per neuron, and / or modulating neurite length. In some embodiments, modulating neurite outgrowth comprises increasing and / or enhancingthe rate and / or length at which neurites develop. Thus, embodiments of the technology provide methods of modulating neurite outgrowth by administering a compound or composition described herein. As used herein, the term "modulating neurogenesis" refers to changing, manipulating, and / or adjusting the growth and development of neural tissue. In some embodiments, neurogenesis comprises adult neurogenesis in which new neural stem cells are generated from neural stem cells in an adult animal. In some embodiments, modulating neurogenesis comprises increasing and / or enhancingthe rate at which new neural tissue is developed.

[0232] The disclosure also relates to a method of generating a tryptamine compound (e.g., a psychedelic tryptamine compound) in situ in a patient, the method comprising administering a tryptamine prodrug described herein to a patient. The disclosure also relates to methods of generating a tryptamine compound (e.g., a psychedelic tryptamine compound) comprising contacting at least one tryptamine prodrug as described herein with an enzyme in vitro or in vivo.

[0233] Dosages

[0234] It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatmentsdescribed herein. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and / or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician or therapist, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.

[0235] Administration in vivo can be effected in one dose, continuously, or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.

[0236] Combination Therapies

[0237] A compound or composition described herein may be used in combination with other known therapies. Administered “in combination”, as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured oreliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation isseen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

[0238] A compound or composition described herein and the at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the compound described herein can be administered first, and the additional agent can be administered subsequently, or the order of administration can be reversed.

[0239] The compounds of the disclosure can also be used in combination with other drugs. For example, dosing a patient with a compound of the disclosure (e.g., a compound of structure (I), (II), or (III)) and a second drug may provide a greater clinical benefit than dosing the patient either with the serotonergic drug or a compound as described herein alone. In some embodiments, the second drug is a serotonergic drug. In some embodiments, the serotonergic drug is an antidepressant, an anxiolytic, a selective serotonin reuptake inhibitor, or a selective serotonin norepinephrine reuptake inhibitor. Examples of serotonergic drugs that find use in combination with a compound as described herein include but are not limited to alprazolam, amphetamine, aripiprazole, azapirone, a barbiturate, bromazepam, bupropion, buspirone, a cannabinoid, chlordiazepoxide, citalopram, clonazepam, clorazepate, dextromethorphan, diazepam, duloxetine, escitalopram, fluoxetine, flurazepam, fluvoxamine, lorazepam, lysergic acid diethylamide, lysergamide, 3,4- methylenedioxymethamphetamine, milnacipran, mirtazapine, naratriptan, paroxetine, pethidine, phenethylamine, psicaine, oxazepam, reboxetine, serenic, serotonin, sertraline, temazepam, tramadol, triazolam, a tryptamine, venlafaxine, and vortioxetine. Further examples of serotonergic drugs include psilocybin, psilocybin derivatives, MDMA, and LSD.

[0240] In some embodiments, the second drug is a cannabinoid. Examples of cannabinoids that find use in combination with a compound as described herein include but are not limited to Cannabichromene (CBC), Cannabichromenic acid(CBCA), Cannabichromevarin (CBCV), Cannabichromevarinic acid (CBCVA), Cannabicyclol (CBL), Cannabicyclolic acid (CBLA), Cannabicyclovarin (CBLV), Cannabidiol (CBD), Cannabidiol monomethylether (CBDM), Cannabidiolic acid (CBDA), Cannabidiorcol (CBD-C1 ), Cannabidivarin (CBDV), Cannabidivarinic acid (CBDVA), Cannabielsoic acid B (CBEA-B), Cannabielsoin (CBE), Cannabielsoin acid A (CBEA-A), Cannabigerol (CBG), Cannabigerol monomethylether (CBGM), Cannabigerolic acid (CBGA), Cannabigerolic acid monomethylether (CBGAM), Cannabigerovarin (CBGV), Cannabigerovarinic acid (CBGVA), Cannabinodiol (CBND), Cannabinodivarin (CBDV), Cannabinol (CBN), Cannabinol methylether (CBNM), Cannabinol-C2 (CBN-C2), Cannabinol-C4 (CBN-C4), Cannabinolic acid (CBNA), Cannabiorcool (CBN-C1 ), Cannabivarin (CBV), Cannabitriol (CBT), Cannabitriolvarin (CBTV), 1 O-Ethoxy-9- hydroxy-delta-6a-tetrahydrocannabinol, Cannbicitran (CBT), Cannabiripsol (CBR), 8,9- Dihydroxy-delta-6a-tetrahydrocannabinol, Delta-8-tetrahydrocannabinol (A8-THC), Delta-8-tetrahydrocannabinolic acid (A8-THCA), Delta-9-tetra hydrocannabinol (THC), Delta-9-tetrahydrocannabinol-C4 (THC-C4), Delta-9-tetrahydrocannabinolic acid A (THCA-A), Delta-9-tetrahydrocannabinolic acid B (THCA-B), Delta-9- tetrahydrocannabinolic acid-C4 (THCA-C4), Delta-9-tetrahydrocannabiorcol (THC-C1 ), Delta-9-tetrahydrocannabiorcolic acid (THCA-C1 ), Delta-9-tetrahydrocannabivarin (THCV), Delta-9-tetrahydrocannabivarinic acid (THCVA), 10-Oxo-delta-6a- tetrahydrocannabinol (OTHC), Cannabichromanon (CBCF), Cannabifuran (CBF), Cannabiglendol, Delta-9-cis-tetrahydrocannabinol (cis-THC), Tryhydroxy-delta-9- tetrahydrocannabinol (triOH-THC), Dehydrocannabifuran (DCBF), and 3, 4,5,6- Tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-1 - benzoxocin-5-methanol. In some embodiments, the term “cannabinoid” refers to a compound chosen from THC, THCA, THCV, THCVA, CBC, CBCA, CBCV, CBCVA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBGV, or CBGVA.

[0241] In some embodiments, the second drug is a terpene. Examples of terpenes that find use in combination with a compound as described herein include but are not limited to acetanisole, acetyl cedrene, anethole, anisole, benzaldehyde, bornyl acetate, borneol, cadinene, cafestol, caffeic acid, camphene, camphor, capsaicin, carene, carotene, carvacrol, carvone, alpha-caryophyllene, beta-caryophyllene, caryophyllene oxide, cedrene, cedrene epoxide, cecanal, cedrol, cembrene,cinnamaldehyde, cinnamic acid, citronellal, citronellol, cymene, eicosane, elemene, estragole, ethyl acetate, ethyl cinnamate, ethyl maltol, eucalyptol / 1 ,8-cineole, eudesmol, eugenol, euphol, farnesene, farnesol, fenchone, geraniol, geranyl acetate, guaia-1 (10),11-diene, guaiacol, guaiol, guaiene, gurjunene, herniarin, hexanaldehyde, hexanoic acid, humulene, ionone, ipsdienol, isoamyl acetate, isoamyl alcohol, isoamyl formate, isoborneol, isomyrcenol, isoprene, isopulegol, isovaleric acid, lavandulol, limonene, gamma-linolenic acid, linalool, longifolene, lycopene, menthol, methyl butyrate, 3-mercapto-2-methylpentanal, beta-mercaptoethanol, mercaptoacetic acid, methyl salicylate, methylbutenol, methyl-2-methylvalerate, methyl thiobutyrate, betamyrcene, gamma-muurolene, nepetalactone, nerol, nerolidol, neryl acetate, nonanaldehyde, nonanoic acid, ocimene, octanal, octanoic acid, pentyl butyrate, phellandrene, phenylacetaldehyde, phenylacetic acid, phenylethanethiol, phytol, pinene, propanethiol, pristimerin, pulegone, retinol, rutin, sabinene, squalene, taxadiene, terpineol, terpine-4-ol, terpinolene, thujone, thymol, umbelliferone, undecanal, verdoxan, and vanillin. In some embodiments, the terpene is bornyl acetate, alpha-bisabolol, borneol, camphene, camphor, carene, beta-caryophyllene, cedrene, cymene, elemene, eucalyptol, eudesmol, farnesene, fenchol, geraniol, guaiacol, humulene, isoborneol, limonene, linalool, menthol, beta-myrcene, nerolidol, ocimene, phellandrene, phytol, pinene, pulegone, sabinene, terpineol, terpinolene, or valencene.

[0242] In some embodiments, the second drug is an adrenergic drug. In some embodiments, the adrenergic drug is an antidepressant, an alpha-adrenergic antagonist, a norepinephrine transporter inhibitor, or a vesicular monoamine transporter inhibitor. Examples of adrenergic drugs that find use in combination with a compound as described herein include but are not limited to adrenaline, agmatine, amoxapine, aptazapine, atomoxetine, bupropion, clonidine, doxepin, duloxetine, esmirtazpine, mianserin, ketanserin, mirabegron, mirtazapine, norepinephrine, phentolamine, phenylephrine, piperoxan, reserpine, ritodrine, setiptiline, tesofensine, timolol, trazodone, trimipramine, or xylazine.

[0243] In some embodiments, the second drug is a dopaminergic drug. In some embodiments, the dopaminergic drug is a vesicular monoamine transporter inhibitor or a dopamine transporter inhibitor. In some embodiments, the dopaminergic drug isamineptine, apomorphine, benzylpiperazine, bromocriptine, cabergoline, chlorpromazine, clozapine, dihydrexidine, domperidone, dopamine, fluphenazine, haloperidol, ketamine, loxapine, methamphetamine, olanzapine, pemoline, perphenazine, pergolide, phencyclidine, phenethylamine, phenmetrazine, pimozide, piribedil, a psychostimulant, reserpine, risperidone, ropinirole, tetrabenazine, or thioridazine.

[0244] Examples of greater clinical benefits could include a larger reduction in symptoms and / or a faster time to alleviation of symptoms.

[0245] Other agents that may be used in combination with the compounds of the disclosure include monoamine oxidase inhibitors, antioxidants, pH buffers, excipients, binders, flavorings, thickeners, or combinations thereof. As used herein, the term "monoamine oxidase inhibitor" (MAOI) refers to a compound that blocks the actions of monoamine oxidase enzymes. For example, in some embodiments, a MAOI inhibits the activity of one or both monoamine oxidase A and monoamine oxidase B. In some embodiments, a MAOI is a reversible inhibitors of monoamine oxidase A. In some embodiments, a MAOI is a drug chosen from isocarboxazid, phenelzine, or tranylcypromine.

[0246] Kits

[0247] For use in the methods described herein, kits and articles of manufacture are also provided, which include a compound or pharmaceutical composition described herein (e.g., a compound of structure (I), (II), or (III); or a pharmaceutical composition comprising a compound of structure (I), (II), or (III)). In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

[0248] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Patent Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and anypackaging material suitable for a selected formulation and intended mode of administration and treatment. For example, in some embodiments the container(s) includes a compound of structure (I), (II), or (III), optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0249] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenserdevice which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. Or, the pack ordispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulatedin a compatible pharmaceutical carrierare prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0250] Although the disclosure herein refers to certain illustrated embodiments, it is to be understood that these embodiments are presented by way of example and not by way of limitation.ExamplesExample 1 - reaction schemes

[0251] The cyclic carbamate compounds described herein can be synthesized by a variety of methods. One approach is illustrated in Scheme 1 , which involves reaction of a 4-hydroxy-tryptamine comprising R (see, e.g., Sherwood, infra) with triphosgene (bis(trichloromethyl) carbonate), Hunig’s base (A / ,A / -diisopropylethylamine), and pyridine in dichloromethane to produce a cyclic carbamate comprising R.

[0252] Scheme 1

[0253] The open-chain A / ,O-acyl carbamates described herein can be synthesized by a variety of methods. One approach is illustrated in Scheme 2, which involves reaction of a 4-hydroxy-tryptamine comprising R (see, e.g., Sherwood, infra).

[0254] Scheme 2DIPEATFA ACN, 0 °C, 10 minsDCM rt, 2.5 hrs 2. DIPEA, KI, R2COOH60 °C, 5 hrsExample 2 - cyclic carbamates

[0255] During the development of embodiments of the technology described herein, cyclic carbamates were synthesized and characterized. Reactions were performed using commercially obtained reagents and solvents. Unless otherwise stated, all commercially obtained reagents and solvents were used as received. A number of 4- hydroxy-tryptamines (4-HO-NXT) were synthesized as described in Sherwood (2024) “Psychedelic-like Activity of Norpsilocin Analogues” ACS Chemical Neuroscience 15: 315-27, which is incorporated herein by reference. In particular, 4-hydroxy-A / - ethyltryptamine, 4-hydroxy-A / -propyltryptamine, 4-hydroxy- / V-isopropyltryptamine, 4- hydroxy-AZ-allyltryptamine, and 4-hydroxy-N-benzyltryptamine were synthesized (see FIG. 2) using the Speeter-Anthony method from 4-acetoxyindole (1 ) via a divergent acyl chloride intermediate (2). Reaction of the acyl chloride intermediate (2) with appropriately substituted primary amines comprising group X provided the similarly substituted ketoamides (3X) comprising group X, which were then reduced with lithiumaluminum hydride to produce the target 4-HO-NXT compounds comprising group X.FIG. 2.

[0256] The 4-hydroxy-tryptamine compounds comprising group X (4-HO-NXT) were used in a reaction according to Scheme 1 to produce cyclic carbamates. Note that the X group of each 4-hydroxy-tryptamine is represented as an R group in Scheme 1 . Each cyclic carbamate compound was synthesized according to Scheme 1 using a 5 mmol solution of a 4-hydroxy-tryptamine compound comprising R (see, e.g., Sherwood, infra) in 50 mL anhydrous dichloromethane (DCM) cooled over an ice bath. Next, 8 equivalents of Hunig’s base (N,N-diisopropylethylamine) and 6 equivalents of pyridine were added. A solution of 0.45 equivalents of triphosgene (bis(trichloromethyl) carbonate) in 10 mL anhydrous DCM was then added dropwise over 30 minutes. The reaction was monitored for completion by ultra-performance liquid chromatography- high-resolution mass spectrometry (UPLC-HRMS). Crude reaction mixtures were purified by automated flash-column chromatography (FCC) and eluted with a gradient of 15 to 35% ethyl acetate in hexanes. Isolated products were characterized by UPLC- HRMS and nuclear magnetic resonance (NMR).

[0257] 3-Ethyl-3.4.5.7-tetrahydro-2H-[1.3]oxazocino[6.7.8-cd]indol-2-one

[0258] HRMS (ESI) m / z [M + Na]+calcd for Ci3Hi4N2NaO2+ 253.0947, found 253.0948.1H NMR (400 MHz, ACETONITRILE-d3) 6 = 9.54 - 9.28 (m, 1 H), 7.26 (dd, J = 0.8, 8.2 Hz, 1 H), 7.13 - 7.10 (m, 1 H), 7.06 (t, J = 7.9 Hz, 1 H), 6.84 (dd, J = 0.9, 7.5 Hz, 1 H), 3.98 (br s, 2H), 3.34 (d, J = 7.1 Hz, 2H), 3.19 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, ACETONITRILE-da) 5 = 156.56, 149.17, 139.84, 125.49, 122.81 , 120.95, 113.03, 111 .71 , 110.13, 47.87, 43.22, 27.71 , 13.70.

[0259] 3-Propyl-3.4.5.7-tetrahydro-2H-[1 .3]oxazocino[6.7.8-cd]indol-2-one

[0260] HRMS (ESI) m / z [M + Na]+calcd for Ci4Hi6N2NaO2+ 267.1104, found 267.1113.1H NMR (400 MHz, ACETONITRILE-d3 ) 5 = 9.42 (br s, 1 H), 7.25 (dd, J = 0.8, 8.1 Hz, 1 H), 7.11 - 7.10 (m, 1 H), 7.06 (t, J = 7.9 Hz, 1 H), 6.84 (dd, J = 0.8, 7.5 Hz, 1 H), 3.98 (br s, 2H), 3.26 (br t, J = 7.3 Hz, 2H), 3.18 (t, J = 5.6 Hz, 2H), 1 .63 (sxt, J = 7 A Hz, 2H), 0.90 (t, J = 7 A Hz, 3H).13C NMR (101 MHz, ACETONITRILE-d3) 6 = 156.68, 148.86, 139.51 , 125.19, 122.50, 120.68, 112.70, 111 .40, 109.82, 49.53, 47.88, 27.29, 21 .89, 11 .55.

[0261] 3-Allyl-3.4.5.7-tetrahvdro-2H-[1 .3]oxazocino[6.7.8-cd]indol-2-one

[0262] HRMS (ESI) m / z [M + Na]+calcd for C14H14N2NaO2+ 265.0947, found 265.0948.1H NMR (400 MHz, ACETONITRILE-d3) 6 = 9.46 (br s, 1 H), 7.29 (dd, J = 0.8, 8.2 Hz, 1 H), 7.17 - 7.13 (m, 1 H), 7.09 (t, J = 7.9 Hz, 1 H), 6.89 (dd, J = 0.8, 7.6 Hz, 1 H), 5.89 (tdd, J = 5.7, 10.3, 17.2 Hz, 1 H), 5.34 - 5.16 (m, 2H), 4.14 - 3.99 (m, 1 H), 3.97 (br d, J = 5.5 Hz, 3H), 3.21 (t, J = 5.6 Hz, 2H).13C NMR (101 MHz, ACETONITRILE-d3) 5 = 156.09, 148.30, 139.05, 133.83, 124.76, 122.02, 120.16, 117.12, 112.23, 110.85, 109.45, 49.73, 47.13, 26.66.

[0263] 3-Benzyl-3.4.5.7-tetrahydro-2H-[1 .3]oxazocino[6.7.8-cd]indol-2-one

[0264] HRMS (ESI) m / z [M + Na]+calcd for C18H16N2NaO2+ 315.1104, found 315.1105.1H NMR (400 MHz, ACETONITRILE-d3) 5 = 9.43 (br s, 1 H), 7.45 - 7.24 (m, 6H), 7.16 - 6.98 (m, 2H), 6.95 - 6.82 (m, 1 H), 4.54 (s, 2H), 4.19 - 3.82 (m, 2H), 3.13 (t, J = 5.6 Hz, 2H).13C NMR (101 MHz, ACETONITRILE-d3) 6 = 156.77, 148.30, 139.05, 138.16, 129.18 (s, 2C), 128.26 (s, 2C), 128.07, 124.77, 122.05, 120.21 , 112.24, 110.83, 109.51 , 50.64, 47.24, 26.52.

[0265] 3-lsopropyl-3.4.5.7-tetrahydro-2H-[1.3]oxazocino[6.7.8-cd]indol-2-one

[0266] HRMS (ESI) m / z [M + Na]+calcd for Ci4Hi6N2NaO2+ 267.1104, found 267.1113.1H NMR (400 MHz, ACETONITRILE-d3) 6 = 9.42 (br d, J = 1 .8 Hz, 1 H), 7.28 (dd, J = 0.8, 8.2 Hz, 1 H), 7.15 - 7.11 (m, 1 H), 7.09 (t, J = 7.9 Hz, 1 H), 6.87 (dd, J = 0.9, 7.5 Hz, 1 H), 4.16 - 4.06 (m, 1 H), 4.06 - 3.93 (m, 2H), 3.26 - 3.14 (m, 2H), 1.25 (d, J = 6.9 Hz, 6H).13C NMR (101 MHz, ACETON ITRILE-da) 5 = 155.27, 148.24, 138.93, 124.65, 122.01 , 120.34, 112.22, 110.76, 109.30, 49.96, 43.86, 28.66, 20.21 .

[0267] Example 3 - Open-chain / V,O-acyl carbamates

[0268] Duringthe development of embodiments of the technology described herein, open-chain N,O-acyl carbamates were synthesized and characterized. Reactions were performed using commercially obtained reagents and solvents according to Scheme 2. Commercially available alpha-chloro chloroformates include a-chloro chloroformates comprising an R' that is methyl, ethyl, propyl, isopropyl, butyl, or aryl. Commercially available anhydrides include anhydrides comprising an R" that is methyl, ethyl, propyl,isopropyl, butyl (e.g., (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, cyclohexyl, aryl, heteroaryl, or benzyl.

[0269] The following steps were performed to synthesize the N-ethyl open chain N,O- acyl carbamate according to Scheme 2.

[0270] First, tert-Butyl Ethyl(2-(4-hydroxy-1 H-indol-3-yl)ethyl)carbamate was synthesized as follows. To a solution of 4-HO-A / -ethyl tryptamine (745.0 mg, 3.647 mmol) in methanol (35 mL), sodium bicarbonate (1 .2 g, 4 eq) was added in a single portion, followed by di-tert-butyl dicarbonate (1 .0g, 1 .3 eq). The reaction was stirred at room temperature for 90 minutes, at which point UPLC-MS indicated the reaction was complete. The reaction was then concentrated, the residue taken up in 30 mL EtOAc, washed twice with 15 mL 1 M HCl, then brine, then the organic layer was dried with sodium sulfate and concentrated. The residue was dried under vacuum overnight to produce a black waxy solid that was triturated in heptanes and filtered to give 1 .04g gray-purple solid, 93.7% yield. Next, 1-Acetyl-3-(2-((tert- butoxycarbonyl)(ethyl)amino)ethyl)-1 H-indol-4-yl Acetate was synthesized - to a solution of tert-butyl ethyl(2-(4-hydroxy-1 H-indol-3-yl)ethyl)carbamate (710.0 mg, 2.333 mmol) in anhydrous THF (30.00 mL), a 1 M solution of lithium bis(trimethylsilyl)amide in methyl tert-butyl ether (5.8 mL, 2.5 eq) was added dropwise at RT. A solution of acetic anhydride (595.3 mg, 2.5 eq) in 2 mL THF was then added dropwise. After 20 minutes, LCMS indicated the reaction was complete, and the reaction was quenched by addition of 1 mL MeOH, and the crude reaction mixture was dry-loaded onto silica for flashcolumn chromatography elutingwith a gradient of 20-50% ethyl acetate / hexanes. The combined fractions were concentrated and dried to 320 mg orange solid, 35.3% yield. In the next step, 2-(4-Acetoxy-1 -acetyl-1 H-indol-3-yl)-N-ethylethan-1-aminium 2,2,2- T rifluoroacetate was synthesized as follows: to a solution of 1 -acetyl-3-(2-((tert- butoxycarbonyl)(ethyl)amino)ethyl)-1 H-indol-4-yl acetate (313.0 mg, 805.7 pmol) in 8mL DCM, 2 mL trifluoroacetic acid (TFA) was added at RT, and the reaction was monitored by UPLC-MS. After 2 hours, another 1 mLTFA was added, and the reaction was stirred for another 30 minutes. The solution was then concentrated to a brown oil that was triturated in MTBE to produce a pale red-orange solid that was dried under vacuum overnight to give 344 mg faint red solid as the TFA salt that was used in the next step without further purification. In the last step, 1 -(((2-(4-Acetoxy-1 -acetyl-1 H-indol-3- yl)ethyl)(ethyl)carbamoyl)oxy)ethyl Acetate was synthesized: to a solution of methyl 2,2,2-trifluoroacetate, 2-(4-acetoxy-1 -acetyl-1 H-indol-3-yl)-N-ethylethan-1 -aminium salt (191 .0 mg, 457.6 pmol) in 9 mL anhydrous ACN, DIPEA (177 mg, 3 eq)was added and the reaction was cooled over an ice bath. A solution of 1 -chloroethyl carbonochloridate (78.50 mg, 1 .2 Eq) in 1 mL ACN was added over 1 minute. After 10 minutes, TLC in 100% EtOAc indicated starting material had been consumed. The reaction was brought to RT and additional DIPEA (296 mg, 5 eq) was added, followed by AcOH (110 mg, 4 eq) and solid potassium iodide (15 mg, 0.2 eq). The reaction was moved to a sand bath and stirred at 60 °C for 5 hours. The crude reaction mixture was dry-loaded onto silica for flash column chromatography eluting with a gradient of 20- 40% EtOAc / hexanes which afforded 64 mg of a colorless oil, 33.4% yield.

[0271] Example 4- Biological assaysThe compounds described herein are tested using known biological assays including, e.g., incubating a compound described herein with human liver and / or intestinal microsomes and / or testing a compound described herein using a head-twitch response in mice. In addition, compounds described herein are tested for plasma stability and / or Caco-2 permeability. In some embodiments, compounds described herein are tested using an off-target GPCR screen and / or to assay hERG inhibition.

[0272] All publications and patents mentioned in the above specification are herein incorporated by reference in their entirety for all purposes. Various modifications and variations of the described compositions, methods, and uses of the technology will be apparent to those skilled in the art without departing from the scope and spirit of the technology as described. Although the technology has been described in connection with specific exemplary embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, variousmodifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the following claims.

Claims

CLAIMSWE CLAIM:

1. A compound of formula (I):wherein: each of R1, R2, and R3is independently selected from hydrogen, substituted or unsubstituted straight chain or branched Ci-C6alkyl, substituted or unsubstituted straight chain or branched C2-C6alkenyl, -(CH2)n-Ar, or-(CH2)m- heteroaryl, wherein each of n and m is independently an integer selected from 0, 1 , 2, 3, and 4;Ar is substituted or unsubstituted aryl; andR4is H or COR2; and X = O or S.

2. The compound of claim 1 , wherein the straight chain or branched Ci-C6alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, and sec-hexyl.

3. The compound of claim 1 or claim 2, wherein the straight chain or branched C2- C6alkenyl is selected from vinyl (CH2=CH-), allyl (CH2=CHCH2-), 1 -butenyl (CH2=CH-CH2CH2-), 2-butenyl (CH3-CH=CH-CH2-), 3-butenyl (CH3CH2- CH=CH-), 1 -pentenyl (CH2=CH-CH2CH2CH2-), 2-pentenyl (CH3-CH=CH- CH2CH2-), 3-pentenyl (CH3CH2-CH=CH-CH2-), 4-pentenyl (CH3CH2CH2- CH=CH-), 1 -hexenyl (CH2=CH-CH2CH2CH2CH2-), 2-hexenyl (CH3-CH=CH- CH2CH2CH2-), 3-hexenyl (CH3CH2-CH=CH-CH2CH2-), 4-hexenyl (CH3CH2CH2- CH=CH-CH2), 5-hexenyl (CH3CH2CH2CH2CH=CH-), and structural isomers thereof.

4. The compound of claim 1 , wherein for-(CH2)n-Ar, n is 1 and Ar is phenyl.

5. The compound of claim 1 , wherein the heteroaryl can be substituted or unsubstituted and is selected from 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6- quinolyL6. The compound of claim 1 or claim 2, wherein the compound of formula (I) is selected from:

7. A compound of formula (II):wherein:R1is selected from hydrogen, substituted or unsubstituted straight chain or branched Ci-Ce alkyl, substituted or unsubstituted straight chain or branched C2-C6 alkenyl, -(CH2)n-Ar, or-(CH2)m-heteroaryl, wherein each of n and m is independently an integer selected from 0, 1 , 2, 3, and 4;Ar is substituted or unsubstituted aryl; andX = O or S.

8. The compound of claim 7, wherein the straight chain or branched Ci-C6alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, and sec-hexyl.

9. The compound of claim 7 or claim 8, wherein the straight chain or branched C2- C6alkenyl is selected from vinyl (CH2=CH-), allyl (CH2=CHCH2-), 1 -butenyl (CH2=CH-CH2CH2-), 2-butenyl (CH3-CH=CH-CH2-)> 3-butenyl (CH3CH2- CH=CH-), 1 -pentenyl (CH2=CH-CH2CH2CH2-), 2-pentenyl (CH3-CH=CH- CH2CH2-), 3-pentenyl (CH3CH2-CH=CH-CH2-), 4-pentenyl (CH3CH2CH2- CH=CH-), 1 -hexenyl (CH2=CH-CH2CH2CH2CHH» 2-hexenyl (CH3-CH=CH- CH2CH2CH2-), 3-hexenyl (CH3CH2-CH=CH-CH2CH2-), 4-hexenyl (CH3CH2CH2- CH=CH-CH2), 5-hexenyl (CH3CH2CH2CH2CH=CH-), and structural isomers thereof.

10. The compound of claim 7 , wherein for-(CH2)n-Ar, n is 1 and Ar is phenyl.11 . The compound of claim 7, wherein the heteroaryl can be substituted or unsubstituted and is selected from 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6- quinolyl.

12. The compound of claim 7, wherein the compound of formula (II) is selected from:

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