Novel prodrugs and conjugates of dimethyltryptamine

Abstract

Provided herein is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R8, R9, X, Y, Z, W, and m are as defined herein. Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. [Formula 1] TIFF2024522174000115.tif2135

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 208,874, filed June 9, 2021, and U.S. Provisional Patent Application No. 63 / 229,879, filed August 5, 2021, which are incorporated by reference herein in their entireties. [Background technology]

[0002] N,N-Dimethyltryptamine (DMT), a naturally occurring compound found in many plant species and botanical preparations (such as the hallucinogenic infusion known as ayahuasca), is classified as a classical serotonergic hallucinogen that induces strong alterations of perception, emotion, and cognition in humans. At high doses, DMT has a rapid onset, strong hallucinogenic effects, and a relatively short duration of action, with an estimated half-life of less than 15 minutes. Like other hallucinogens in the tryptamine family, DMT binds to serotonin receptors to produce euphoric and hallucinogenic effects. Unfortunately, DMT is metabolically unstable and is readily converted by monoamine oxidase (MAO) to indole acetic acid and N-oxidized metabolites, resulting in poor oral bioavailability.

[0003] Serotonergic hallucinogens have also demonstrated promising antidepressant, anti-anxiety, and anti-addiction properties.

[0004] There remains a need for improved prodrugs of tryptamine, such as N,N-dimethyltryptamine (DMT). Summary of the Invention

[0005] In one embodiment, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R1 and R2 are independently hydrogen, alkyl, cycloalkyl, or R1 and R2 together with the atoms to which they are attached form a heterocycle; X, Y, and Z are independently hydrogen, halogen, -O-, -S-, -NR A -OR-(P=O)-OR A (-OR') and R A is hydrogen or alkyl, R', R3, R4, R5, and R6 are independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and R7 and R8 are independently hydrogen or alkyl; R9 is hydrogen, alkyl, or halogen, preferably bromo; L and M are independently alkyl or aryl; W is oxygen, sulfur, or NR6; n is an integer from 2 to 7; m is an integer from 1 to 4; At least one of R', R3, R4, R5, and R6 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0006] In some embodiments, the compound of formula (I) is a compound of formula (IV): [ka] In the formula, R 10 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and A is a pharma- ceutically acceptable anion; R1, R2, R3, R4, R5, R8, R9, X, Y, Z, W, and m are defined herein.

[0007] In some embodiments, the compound of formula (I) is a compound of the formula: [ka] R1, R 10 , R3, R4, R5, R8, R9, X, Y, Z, W, and m are defined herein.

[0008] In some embodiments, the present disclosure provides a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, R1 and R2 are independently hydrogen, alkyl, cycloalkyl, or R1 and R2 together with the atoms to which they are attached form a heterocycle; X, Y, and Z are independently hydrogen, halogen, -O-, -S-, -NR A -OR-(P=O)-OR A (-OR') and R A is hydrogen or alkyl, R', R3, R4, and R5 are independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and R7 and R8 are independently hydrogen or alkyl; R9 is hydrogen, alkyl, or halogen; L and M are independently alkyl or aryl; n is an integer from 2 to 7; m is an integer from 1 to 4; At least one of R', R3, R4, and R5 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0009] In some embodiments, the compound of formula (V) is a compound of the formula: [ka] In the formula, R 10 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n(NH)(C=NH)-NH2, - (C=O)(CH2) n (NH)(C=NH)-NH2 or [ka] and A is a pharma- ceutically acceptable anion; R1, R2, R3, R4, R5, R8, R9, X, Y, Z, and m are defined herein.

[0010] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0011] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (II) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows a PK study of N-phosphonooxymethyl prodrug 6-1-2 (VLS-02-23-0) and metabolite (VLS-02-023-10) following intravenous (1 mg / kg) and oral administration (30 mg / kg) to male CD1 mice (in plasma). [Diagram 2] FIG. 2 shows a PK study of N-phosphonooxymethyl prodrug 6-1-2 (VLS-02-23-0) and metabolite (VLS-02-023-10) following intravenous (1 mg / kg) and oral administration (30 mg / kg) to male CD1 mice (intracerebral). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art known to those skilled in the art as of the date of this disclosure. In the event of a conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure shall control.

[0014] definition For convenience, certain terms used in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0015] The term "about" immediately preceding a numerical value means a range (e.g., plus or minus 10% of the value). For example, unless otherwise indicated by the context of this disclosure or inconsistent with such an interpretation, "about 50" can mean 45 to 55, and "about 25,000" can mean 22,500 to 27,500. For example, in a list of numerical values ​​such as "about 49, about 50, about 55, ...", "about 50" means a range extending less than half the interval between the preceding value and the following value, e.g., from more than 49.5 to less than 50.5. Furthermore, the phrase "less than about (value)" or "more than about (value)" should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" when preceding a series of numerical values ​​or a range of values ​​(e.g., about 10, 20, 30", or "about 10 to 30") refers to all values ​​in the series, or to the end points of the range, respectively.

[0016] As used herein, the terms "administer," "administering," or "administration" refer to administering a compound or a pharma- ceutically acceptable salt of a compound, or a composition or formulation containing a compound or a pharma- ceutically acceptable salt of a compound, to a patient.

[0017] The term "pharmaceutical acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include salts obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.). The acids that can be used to prepare pharmaceutical acceptable acid addition salts of such basic compounds are non-toxic acid addition salts, i.e., acids that form salts containing pharmaceutical acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, acetate, tartrate, oleate, fumarate, formate, benzoate, glutamate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate. Base addition salts include, but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine dicyclohexylamine, etc. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc. Examples of ammonium salts and alkylated ammonium salts include ammonium salts, methylammonium salts, dimethylammonium salts, trimethylammonium salts, ethylammonium salts, hydroxyethylammonium salts, diethylammonium salts, butylammonium salts, tetramethylammonium salts, etc. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, and the like.Those skilled in the art will further recognize that acid addition salts can be prepared by reacting the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0018] The term "treating" as used herein with respect to a patient refers to improving at least one symptom of the patient's disorder. In some embodiments, treating can improve or at least partially ameliorate the disorder or one or more symptoms of the disorder.

[0019] The term "preventing" as used herein with respect to a patient or subject refers to preventing the onset of a disease where the disease has not yet occurred, preventing a disease or disorder from occurring in a subject or patient who is susceptible to the disorder or disease but has not yet been diagnosed with the disorder or disease, and / or preventing further onset of the disease / disorder if already present.

[0020] The term "therapeutically effective" as applied to a dose or amount refers to that amount of a compound or pharmaceutical preparation that is sufficient to result in a desired clinical benefit following administration to a patient in need thereof.

[0021] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" means C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C5 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0022] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms and attached to the remainder of the molecule by a single bond. Alkyl containing any number of carbon atoms from one to twelve is included. Alkyl containing up to twelve carbon atoms is C1-C 12 Alkyl, alkyl containing up to 10 carbon atoms is C1-C 10 An alkyl group is one in which an alkyl group containing up to 6 carbon atoms is C1-C6 alkyl, and an alkyl group containing up to 5 carbon atoms is C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties listed above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 Alkyl includes all of the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9, and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, except C 11 and C 12 Includes alkyl. C1~C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0023] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6-18 carbon atoms, and at least one aromatic ring, attached to the remainder of the molecule by a single bond. For purposes of this disclosure, aryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. Aryl includes, but is not limited to, aryls derived from acentrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise stated in the specification, "aryl" may be optionally substituted.

[0024] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon, consisting only of carbon and hydrogen atoms, which may include fused, bridged, or spirocyclic ring systems having from 3 to 20 carbon atoms (e.g., having from 3 to 10 carbon atoms), and which is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated in the specification, cycloalkyl groups can be optionally substituted.

[0025] "Heterocyclyl", "heterocycle", or "heterocycle" refers to a stable saturated, unsaturated, or aromatic 3-20 membered ring consisting of 2-19 carbon atoms and 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, attached to the remainder of the molecule by a single bond. Heterocyclyl or heterocycle includes heteroaryl, heterocyclylalkyl, heterocyclylalkenyl, and heterocyclylalkynyl. Unless otherwise stated in the specification, a heterocyclyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused, bridged, or spirocyclic ring systems, the nitrogen, carbon, or sulfur atoms in a heterocyclyl may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclyl may be partially or fully saturated. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, heterocyclyl groups may be optionally substituted.

[0026] "Heteroaryl" refers to a 5-20 membered ring system containing a hydrogen atom, 1-19 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, at least one aromatic ring, and attached to the remainder of the molecule by a single bond. For purposes of this disclosure, a heteroaryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused or bridged ring systems, in which the nitrogen, carbon, or sulfur atoms in the heteroaryl may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthanyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, in ... Examples of phenyl include, but are not limited to, phenyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0027] The term "substituted," as used herein, means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclyl, and / or heteroaryl) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, including, but not limited to, a halogen atom, such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl, alkoxy, and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms of various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., a double bond or a triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" means that one or more hydrogen atoms are replaced by -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , ‐SO2R g , ‐OSO2R g , ‐SO2OR g , =NSO2R g , and -SO2NR g Rh "Substituted" also refers to any of the above groups being replaced with one or more hydrogen atoms by -C(=O)R. g , -C(=O)ORg, -C(=O)NR g R h , ‐CH2SO2R g , -CH2SO2NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.

[0028] compound The present disclosure provides compounds that are prodrugs of tryptamine and relates to scaffolds, such as N,N-dimethyltryptamine (DMT), as well as pharmaceutical compositions thereof.

[0029] DMT is metabolically unstable and easily converted by monoamine oxidase (MAO) to indole acetic acid and N-oxidized metabolites, resulting in reduced oral bioavailability. In some embodiments, the compounds of the present disclosure allow for controlled release of DMT. The advantages of the compounds of the present disclosure may include increased metabolic stability, increased absorption, reduced maximum plasma concentration of parent drug DMT over time, and reduced dosing frequency. In some embodiments, the compounds of the present disclosure prevent or inhibit N-oxidation to promote increased oral bioavailability and exposure.

[0030] In some embodiments, the compounds of the present disclosure include an enacarbyl moiety. Without being bound by theory, such compounds may increase bioavailability by active transport of the prodrug in the small intestine by high-capacity nutrient transporters, including, for example, monocarboxylate transporter-1 (MCT-1). DMT-enacarbyl prodrugs may also reduce the potential for abuse by preventing absorption by nasal inhalation or insufflation.

[0031] In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R1 and R2 are independently hydrogen, alkyl, cycloalkyl, or R1 and R2 together with the atoms to which they are attached form a heterocycle; X, Y, and Z are independently hydrogen, halogen, -O-, -S-, -NR A -OR-(P=O)-OR A (-OR') and R A is hydrogen or alkyl, R', R3, R4, R5, and R6 are independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2)n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and R7 and R8 are independently hydrogen or alkyl; R9 is hydrogen, alkyl, or halogen; L and M are independently alkyl or aryl; W is oxygen, sulfur, or NR6; n is an integer from 2 to 7; m is an integer from 1 to 4; At least one of R', R3, R4, R5, and R6 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0032] In some embodiments, the present specification provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, R1 and R2 are independently hydrogen, alkyl, cycloalkyl, or R1 and R2 together with the atoms to which they are attached form a heterocycle; X, Y, and Z are independently hydrogen, halogen, -O-, -S-, -NR A -OR-(P=O)-OR A (-OR') and R Ais hydrogen or alkyl, R', R3, R4, R5, and R6 are independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7, -(C=O)(CH2) n (NH2), -(C)CH(NH2)(CH3), -(C=O)CH(NH2), (CH2) n (NH)(C=NH), or -(C=O)(CH2) n (NH)(C=NH)-NH2, R7 and R8 are independently hydrogen or alkyl; R9 is hydrogen, alkyl, or halogen; L and M are independently alkyl or aryl; W is oxygen, sulfur, or NR6; n is an integer from 2 to 7; m is an integer from 1 to 4; At least one of R', R3, R4, R5 and R6 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0033] In some embodiments, R9 is halogen. In some embodiments, R9 is bromo.

[0034] In some embodiments, the present specification provides a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, R1 and R2 are independently hydrogen, alkyl, cycloalkyl, or R1 and R2 together with the atoms to which they are attached form a heterocycle; X, Y and Z are independently hydrogen, halogen, -O-, -S-, -NR A -, -O(P=O)-OR A (-OR'), or -(P=O)-OR A (-OR') and R A is hydrogen or alkyl, R', R3, R4, and R5 are independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and R7 and R8 are independently hydrogen or alkyl; R9 is hydrogen, alkyl, or halogen; L and M are independently alkyl or aryl; n is an integer from 2 to 7; m is an integer from 1 to 4; At least one of R', R3, R4, and R5 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] A compound.

[0035] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R1 and R2 are independently hydrogen, alkyl, or cycloalkyl, or R1 and R2 together with the atom to which they are attached form a heterocycle.

[0036] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R 1 and R 2 are independently hydrogen, alkyl, or cycloalkyl.

[0037] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R 1 and R 2 together with the atoms to which they are attached form a heterocycle.

[0038] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R1 and R2 are independently halogen or C1-C6 alkyl.

[0039] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R1 and R2 are independently C1-C6 alkyl.

[0040] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R1 and R2 are independently methyl, ethyl, propyl, and isopropyl.

[0041] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R1 and R2 are methyl.

[0042] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), X, Y, and Z are independently hydrogen, halogen, -O-, -S-, -NR A -, -O(P=O)-OR A (-OR'), or -(P=O)-OR A (-OR').

[0043] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), X, Y and Z are H.

[0044] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), two of X, Y, and Z are hydrogen.

[0045] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), two of X, Y, and Z are hydrogen, and the non-hydrogen X, Y, or Z is -O-, -S-, -NR A -, -O(P=O)-OR A (-OR'), or -(P=O)-OR A (-OR') and R A is hydrogen or alkyl.

[0046] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), X and Y are hydrogen and Z is -O-, -S-, -NR A -, -O(P=O)-OR A (-OR'), or -(P=O)-OR A (-OR') and R A is hydrogen or alkyl.

[0047] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), X and Z are hydrogen and Y is -O-, -S-, -NR A -, -O(P=O)-OR A (-OR'), or -(P=O)-OR A (-OR') and R A is hydrogen or alkyl.

[0048] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), Y and Z are hydrogen and X is -O-, -S-, -NR A -, -O(P=O)-OR A (-OR'), or -(P=O)-OR A (-OR') and R Ais hydrogen or alkyl.

[0049] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), at least one of X, Y, or Z is -O(P=O)-OR A (-OR').

[0050] In some embodiments of the compound of Formula (I), Formula (II), or Formula (III), X is -O(P=O)-OR A (-OR') and R3 is absent.

[0051] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), Y is -O(P=O)-OR A (-OR') and R4 is absent.

[0052] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), Z is -O(P=O)-OR A (-OR') and R5 is absent.

[0053] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R' is halogen or alkyl.

[0054] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R A is hydrogen or alkyl.

[0055] In some embodiments of the compounds of Formula (I) or Formula (II), R', R3, R4, R5, and R6 are independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and At least one of R', R3, R4, R5, and R6 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0056] In some embodiments of the compound of Formula (III), R', R3, R4, and R5 are independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and At least one of R', R3, R4, and R5 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0057] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R' is absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2 or [ka] It is.

[0058] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R' is hydrogen or alkyl.

[0059] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R3 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0060] In some embodiments of the compound of Formula (I), Formula (II), or Formula (III), R4 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0061] In some embodiments of the compound of Formula (I), Formula (II), or Formula (III), R5 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0062] In some embodiments of the compound of Formula (I), R6 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0063] In some embodiments of the compounds of formula (I), X, Y, and Z are H, W is NR6, and R6 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0064] In some embodiments of the compound of Formula (I), at least one of R', R3, R4, R5, and R6 is -(C=O)(CH2). n (NH2) and n is 3.

[0065] In some embodiments of the compound of Formula (I), at least one of R', R3, R4, R5, and R6 is -(C=O)CH(NH2)(CH2). n (NH2) and n is 4.

[0066] In some embodiments of the compound of Formula (I), at least one of R', R3, R4, R5, and R6 is -(C=O)(CH2). n (NH)(C=NH)-NH2, where n is 3.

[0067] In some embodiments of the compound of Formula (I), at least one of R', R3, R4, R5, and R6 is -(C=O)CH(NH)(CH2). n (C=NH)-NH2, where n is 2.

[0068] In some embodiments of the compounds of Formula (I), at least one of R', R3, R4, R5, and R6 is [ka] It is.

[0069] In some embodiments of the compound of Formula (III), at least one of R', R3, R4, and R5 is -(C=O)(CH2) n (NH2) and n is 3.

[0070] In some embodiments of the compound of Formula (III), at least one of R', R3, R4, and R5 is -(C=O)CH(NH2)(CH2). n (NH2) and n is 4.

[0071] In some embodiments of the compound of Formula (III), at least one of R', R3, R4, and R5 is -(C=O)(CH2) n (NH)(C=NH)-NH2, where n is 3.

[0072] In some embodiments of formula (III), at least one of R', R3, R4, and R5 is -(C=O)CH(NH2)(CH2). n (NH)(C=NH)-NH2, where n is 2.

[0073] In some embodiments of the compound of Formula (III), at least one of R', R3, R4, and R5 is [ka] It is.

[0074] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), L and M are independently alkyl or aryl.

[0075] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), L is alkyl and M is alkyl or aryl.

[0076] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), L is methyl or isopropyl and M is alkyl or aryl.

[0077] In some embodiments of the compounds of Formula (I) or Formula (II), W is oxygen, sulfur, or NR6.

[0078] In some embodiments of the compounds of Formula (I) or Formula (II), W is NR6, where R6 is hydrogen or alkyl.

[0079] In some embodiments of the compounds of Formula (I) or Formula (II), R7, R8, and R9 are independently hydrogen or alkyl.

[0080] In some embodiments of the compound of Formula (III), R8 and R9 are independently hydrogen or alkyl.

[0081] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R8 is hydrogen.

[0082] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R8 is alkyl.

[0083] In some embodiments of the compound of Formula (I), Formula (II), or Formula (III), R8 is C1-C6 alkyl.

[0084] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R9 is hydrogen, halogen, or alkyl.

[0085] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R9 is hydrogen.

[0086] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), R9 is alkyl.

[0087] In some embodiments of the compound of Formula (I), Formula (II), or Formula (III), R9 is C1-C6 alkyl.

[0088] In some embodiments of the compounds of formula (I), formula (II), or formula (III), R9 is halogen. In some embodiments, R9 is -F, -Cl, -Br, or -I. In some embodiments, R9 is -Cl, -Br, or -I. In some embodiments, R9 is -Cl or -Br. In some embodiments, R9 is -F. In some embodiments, R9 is -Cl. In some embodiments, R9 is -Br. In some embodiments, R9 is -I.

[0089] In some embodiments of the compounds of Formula (I) or Formula (II), R7 and R8 are independently hydrogen or C1-C8 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, thiol, and halogen.

[0090] In some embodiments of the compound of Formula (III), R8 is hydrogen or C1-C8 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, thiol, and halogen.

[0091] In some embodiments of the compound of Formula (I), Formula (II), or Formula (III), R9 is hydrogen, halogen, or C1-C8 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, thiol, and halogen.

[0092] In some embodiments of the compound of Formula (I) or Formula (II), R7, R8, and R9 are independently hydrogen or C1-C8 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, thiol, and halogen.

[0093] In some embodiments of the compound of Formula (III), R8 and R9 are independently hydrogen or C1-C8 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, thiol, and halogen.

[0094] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), n is an integer from 2 to 7 (i.e., 2, 3, 4, 5, 6, or 7). In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7.

[0095] In some embodiments of the compounds of Formula (I), Formula (II), or Formula (III), n is an integer from 1 to 4 (i.e., 1, 2, 3, or 4). In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0096] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IV): [ka] In the formula, R 10 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and A is a pharma- ceutically acceptable anion; R1, R2, R3, R4, R5, R8, R9, X, Y, Z, W, and m are defined herein.

[0097] In some embodiments, the compound of formula (I) is a compound of formula (V): [ka] In the formula, R 10 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and A is a pharma- ceutically acceptable anion; R1, R2, R3, R4, R5, R8, R9, X, Y, Z, and m are defined herein.

[0098] In some embodiments, the disclosure provides a compound of formula (VI): [ka]

[0099] wherein R1, R2, R3, R4, and R5 are as defined herein; X is carbon or nitrogen; W is carbon, oxygen, or nitrogen; Z is hydrogen, deuterium, or oxygen.

[0100] In some embodiments, the compound of formula (VII) is: [ka]

[0101] In some embodiments, the compound of Formula (VI) or Formula (VII) is: [ka]

[0102] In some embodiments, the disclosure provides a compound of formula (VIII): [ka] wherein R1, R2, R3, R4, R5, and R9 are as defined herein; R11 and R12 are independently a pharma- ceutically acceptable salt, hydrogen, deuterium, alkyl, substituted alkyl, cycloalkyl, or R11 and R12 together with the atom to which they are attached form an alkyl, cycloalkyl, heterocycle, ether, hemiaminal ketal, and amino acid.

[0103] In some embodiments of the compounds of Formula (VIII), R11 and R12 together with the atoms to which they are attached form a heterocycle.

[0104] In some embodiments of the compound of Formula (VIII), the pharma- ceutically acceptable salt is Na + , K + , or NH4 + It is.

[0105] In some embodiments, the present specification provides a compound of formula (IX): [ka] or a pharma- ceutically acceptable salt thereof is provided, During the ceremony, R1 and R2 are each independently hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and X, Y, and Z each independently represent hydrogen, halogen, -O-, -S-, -NR A -OR(P=O)-OR A (-OR'), where R' and R A is hydrogen or alkyl, R3, R4, R5, and R6 are each independently absent, hydrogen, or alkyl; R7 and R8 are each independently hydrogen or alkyl; R9 is hydrogen, alkyl, or halogen; L and M are each independently alkyl or aryl; W is oxygen, sulfur, or NR6; n is an integer from 2 to 7; m is an integer from 1 to 4; At least one of R1 and R2 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0106] In some embodiments of the compound of Formula (IX), X, Y, and Z are each independently hydrogen, halogen, —O—, —S—, —NR A -OR(P=O)-OR A (-OR').

[0107] In some embodiments of the compounds of Formula (IX), X, Y, and Z are hydrogen.

[0108] In some embodiments of the compound of Formula (IX), two of X, Y, and Z are hydrogen.

[0109] In some embodiments of the compound of Formula (IX), two of X, Y, and Z are hydrogen and the non-hydrogen X, Y, or Z is -O-, -S-, -NR A -OR(P=O)-OR A (-OR') and R A is hydrogen or alkyl.

[0110] In some embodiments of the compound of Formula (IX), X and Y are hydrogen and Z is -O-, -S-, -NR A -OR(P=O)-OR A (-OR') and R A is hydrogen or alkyl.

[0111] In some embodiments of the compound of Formula (IX), X and Z are hydrogen and Y is -O-, -S-, -NR A -OR(P=O)-OR A (-OR') and R A is hydrogen or alkyl.

[0112] In some embodiments of the compound of Formula (IX), Y and Z are hydrogen and X is -O-, -S-, -NR A -OR(P=O)-OR A (-OR') and R A is hydrogen or alkyl.

[0113] In some embodiments of the compound of Formula (IX), at least one of X, Y, or Z is -O(P=O)-OR A (-OR').

[0114] In some embodiments of the compound of Formula (IX), X is -O(P=O)-OR A (-OR') and R3 is absent.

[0115] In some embodiments of the compound of Formula (IX), Y is -O(P=O)-OR A (-OR') and R4 is absent.

[0116] In some embodiments of the compound of Formula (IX), Z is -O(P=O)-OR A (-OR') and R5 is absent.

[0117] In some embodiments of the compound of Formula (IX), R' is hydrogen or alkyl.

[0118] In some embodiments of the compound of Formula (IX), R A is hydrogen or alkyl.

[0119] In some embodiments of the compound of Formula (IX), R1 and R2 are each independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2 or [ka] and At least one of R1 and R2 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2 or [ka] It is.

[0120] In some embodiments of the compound of formula (IX), R1 is absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0121] In some embodiments of the compound of Formula (IX), R 1 is hydrogen or alkyl.

[0122] In some embodiments of the compound of formula (IX), R2 is absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0123] In some embodiments of the compound of Formula (IX), R2 is hydrogen or alkyl.

[0124] In some embodiments of the compound of Formula (IX), at least one of R1 and R2 is -(C=O)(CH2). n (NH2) and n is 3.

[0125] In some embodiments of the compound of Formula (IX), at least one of R1 and R2 is -(C=O)CH(NH2)(CH2). n (NH2) and n is 4.

[0126] In some embodiments of the compound of Formula (IX), at least one of R1 and R2 is -(C=O)(CH2). n (NH)(C=NH)-NH2, where n is 3.

[0127] In some embodiments of the compound of Formula (IX), at least one of R1 and R2 is -(C=O)CH(NH)(CH2). n (C=NH)-NH2, where n is 2.

[0128] In some embodiments of the compound of Formula (IX), at least one of R1 and R2 is -(C=O)-alkyl.

[0129] In some embodiments of the compound of Formula (IX), at least one of R1 and R2 is [ka] It is.

[0130] In some embodiments of the compound of Formula (IX), at least one of R1 and R2 is -(C=O)CH(NH2)(CH2). n (NH)(C=NH)-NH2, where n is 4.

[0131] In some embodiments of the compound of Formula (IX), at least one of R1 and R2 is -(C=O)CH(NH2)(CH2). n (NH)(C=NH)-NH2, where n is 3.

[0132] In some embodiments of the compound of Formula (IX), L and M are each independently alkyl or aryl.

[0133] In some embodiments of the compound of Formula (IX), L is alkyl and M is alkyl or aryl.

[0134] In some embodiments of the compound of Formula (IX), L is methyl or isopropyl and M is alkyl or aryl.

[0135] In some embodiments, R3 is hydrogen.

[0136] In some embodiments, R3 is alkyl.

[0137] In some embodiments, R3 is C1-C6 alkyl.

[0138] In some embodiments, R3 is absent.

[0139] In some embodiments, R4 is hydrogen.

[0140] In some embodiments, R4 is alkyl.

[0141] In some embodiments, R4 is C1-C6 alkyl.

[0142] In some embodiments, R4 is absent.

[0143] In some embodiments, R5 is hydrogen.

[0144] In some embodiments, R5 is alkyl.

[0145] In some embodiments, R5 is C1-C6 alkyl.

[0146] In some embodiments, R5 is absent.

[0147] In some embodiments of the compound of Formula (IX), W is oxygen, sulfur, or NR6.

[0148] In some embodiments of the compound of Formula (IX), W is NR6, where R6 is hydrogen or alkyl.

[0149] In some embodiments of the compound of Formula (IX), R7, R8, and R9 are each independently hydrogen or alkyl.

[0150] In some embodiments of the compound of Formula (IX), R8 is hydrogen.

[0151] In some embodiments of the compound of Formula (IX), R8 is alkyl.

[0152] In some embodiments of the compound of Formula (IX), R8 is C1-C6 alkyl.

[0153] In some embodiments of the compound of Formula (IX), R9 is hydrogen, halogen, or alkyl.

[0154] In some embodiments of the compound of Formula (IX), R9 is hydrogen.

[0155] In some embodiments of the compound of Formula (IX), R9 is alkyl.

[0156] In some embodiments of the compound of Formula (IX), R9 is C1-C6 alkyl.

[0157] In some embodiments of the compound of formula (IX), R9 is halogen. In some embodiments, R9 is -F, -Cl, -Br, or -I. In some embodiments, R9 is -Cl, -Br, or -I. In some embodiments, R9 is -Cl or -Br. In some embodiments, R9 is -F. In some embodiments, R9 is -Cl. In some embodiments, R9 is -Br. In some embodiments, R9 is -I.

[0158] In some embodiments of the compound of Formula (IX), R7 and R8 are each independently hydrogen or C1-C8 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, thiol, and halogen.

[0159] In some embodiments of the compound of Formula (IX), R9 is hydrogen, halogen, or C1-C8 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, thiol, and halogen.

[0160] In some embodiments of the compound of Formula (IX), R7, R8, and R9 are each independently hydrogen or C1-C8 alkyl optionally substituted with 1-3 groups independently selected from hydroxyl, thiol, and halogen.

[0161] In some embodiments of the compound of Formula (IX), n is an integer from 2 to 7 (i.e., 2, 3, 4, 5, 6, or 7). In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7.

[0162] In some embodiments of the compound of Formula (IX), m is an integer from 1 to 4 (i.e., 1, 2, 3, or 4). In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0163] In some embodiments, provided herein is a compound of formula (X): [ka] During the ceremony, R1 and R2 together with the atoms to which they are attached form a heterocycle; X and Y each independently represent hydrogen, halogen, -O-, -S-, -NR A -OR(P=O)-OR A (-OR') and R A is hydrogen or alkyl, R', R3, and R4 are each independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH)(C=NH)-NH2, -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] and At least one of R', R3, and R4 is -(C=O)-alkyl, -(C=O)CHR7(NH2), -(C=O)(CH2) n (NH2), -(C=O)CH(NH2)(CH2) n (NH2), -(C=O)(CH2) n (NH)(C=NH)-NH2, or [ka] It is.

[0164] In some embodiments, provided herein is one or more compounds selected from Table 1.

[0165] In some embodiments, provided herein is one or more pharma- ceutically acceptable salts of a compound selected from Table 1. [Table 1-1] [Table 1-2] [Table 1-3]

[0166] In some embodiments, provided herein is one or more compounds selected from Table 2.

[0167] In some embodiments, provided herein is one or more pharma- ceutically acceptable salts of a compound selected from Table 2. [Table 2-1] [Table 2-2] [Table 2-3]

[0168] In some embodiments of the compounds of Table 2, X and Y are hydrogen and R3 and R4 are absent.

[0169] In some embodiments of the compounds of Table 2, X is hydrogen, R3 is absent, Y is O, and R4 is hydrogen.

[0170] In some embodiments of the compounds of Table 2, X is hydrogen, R3 is absent, Y is O, and R4 is Me.

[0171] In some embodiments of the compounds of Table 2, X is hydrogen, R3 is absent, Y is O, and R4 is Ac.

[0172] In some embodiments of the compounds of Table 2, X is O, R3 is hydrogen, Y is hydrogen, and R4 is absent.

[0173] In some embodiments of the compounds of Table 2, X is O, R3 is Me, Y is hydrogen, and R4 is absent.

[0174] In some embodiments of the compounds of Table 2, X is O, R3 is Ac, Y is hydrogen, and R4 is absent. In some embodiments, provided herein is one or more compounds selected from Table 3.

[0175] In some embodiments, provided herein is one or more pharma- ceutically acceptable salts of a compound selected from Table 3. [Table 3] wherein X, Y, R3, and R4 have the definitions provided herein.

[0176] In some embodiments of the compounds of Table 3, R3 is absent, X is hydrogen, R4 is absent, and Y is hydrogen.

[0177] In some embodiments of the compounds of Table 3, R3 is absent, X is hydrogen, R4 is hydrogen, and Y is -O-.

[0178] In some embodiments of the compounds of Table 3, R3 is absent, X is hydrogen, R4 is alkyl, and Y is -O-.

[0179] In some embodiments of the compounds of Table 3, R3 is hydrogen, X is -O-, R4 is absent, and Y is hydrogen.

[0180] In some embodiments of the compounds of Table 3, R3 is alkyl, X is -O-, R4 is absent hydrogen, and Y is hydrogen.

[0181] In some embodiments of the compounds of Table 3, R3 is absent, X is hydrogen, R4 is absent, and Y is -O(P=O)(OR A )(OR'), and R A is hydrogen or alkyl, and R' is hydrogen or alkyl.

[0182] In some embodiments of the compounds of Table 3, R3 is absent, X is hydrogen, R4 is absent, and Y is -O(P=O)(OH)(OH).

[0183] In some embodiments of the compounds of Table 3, R3 is absent and X is -O(P=O)(OR A )(OR'), and R A is hydrogen or alkyl, R' is hydrogen or alkyl, R4 is absent, and Y is hydrogen.

[0184] In some embodiments of the compounds of Table 3, R3 is absent, X is -O(P=O)(OH)(OH), R4 is absent, and Y is hydrogen.

[0185] In some embodiments, provided herein is one or more compounds selected from Table 4.

[0186] In some embodiments, provided herein is one or more pharma- ceutically acceptable salts of a compound selected from Table 4. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0187] composition In some embodiments of the present disclosure, the pharmaceutical compositions comprise a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formulas (I)-(X) or a compound of Tables 1-4) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0188] Pharmaceutically acceptable excipients and adjuvants are added to compositions or formulations for various purposes. In some embodiments, pharmaceutical compositions comprising one or more compounds disclosed herein, or pharma- ceutically acceptable salts thereof, further comprise a pharma- ceutically acceptable carrier. In some embodiments, the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable excipient, binder, and / or diluent. In some embodiments, suitable pharma- ceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents, and sterile aqueous or organic solutions. In some embodiments, suitable pharma- ceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0189] For the purpose of this disclosure, the compounds of this disclosure can be formulated for administration by various means, including oral, parenteral, by inhalation spray, topical, or rectal, in a formulation containing pharmaceutically acceptable carriers, adjuvants, and vehicles.As used herein, the term parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, and intraarterial injection using various injection techniques.As used herein, intraarterial and intravenous injection include administration through catheter.

[0190] method In one aspect, the disclosure provides a method of treating or preventing a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formulas (I)-(X) or a compound of Tables 1-4), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0191] In some embodiments, the neurological disorder is a mood disorder. In some embodiments, the mood disorder is clinical depression, postpartum depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, major depressive disorder, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic symptoms, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), or women's health disorders or conditions. In some embodiments, the mood disorder is depression. In some embodiments, the mood disorder is treatment-resistant depression or major depressive disorder. In some embodiments, the mood disorder is major depressive disorder, hi some embodiments, the mood disorder is treatment-resistant depression.

[0192] In some embodiments, the disclosure provides a method of treating or preventing PTSD, a mood disorder, a generalized anxiety disorder, an addictive disorder, and / or a drug dependency in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formulas (I)-(X) or a compound of Tables 1-4), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0193] In some embodiments, the disclosure provides a method of treating or preventing PTSD in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formulas (I)-(X) or a compound of Tables 1-4), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.

[0194] In some embodiments, the method includes treating PTSD through induction and maintenance therapy by administering a compound disclosed herein, its pharma- ceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the compounds disclosed herein have an improved safety profile when compared to treatment with entactogenic, oneirophrenic, or psychedelic compounds (e.g., dimethyltryptamine or related compounds, psilocybin, or MDMA) alone, and are used in induction and maintenance therapy to treat PTSD.

[0195] In some embodiments, the disclosure provides a method of treating or preventing a behavioral or mood disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I)-(X) or a compound of Tables 1-4), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the behavioral or mood disorder comprises anxiety, such as social anxiety in an autistic subject (e.g., an autistic adult), and anxiety associated with a life-threatening illness. In some embodiments, the behavioral or mood disorder comprises stress (e.g., as measured by the effect on amygdala response). In some embodiments, the anxiety disorder is panic disorder, obsessive-compulsive disorder, and / or generalized anxiety disorder. In some embodiments, the subject suffers from lack of motivation, attention, memory recall accuracy, response speed, perseveration, and / or cognitive engagement. Further examples include depression (e.g., MDD or TRD), attention disorders, disorders of executive function and / or cognitive engagement, obsessive-compulsive disorder, bipolar disorder, panic disorder, phobias, schizophrenia, psychopathy, antisocial personality disorder, and / or neurocognitive disorders.

[0196] In some embodiments, the disclosure provides a method of treating or preventing an addictive disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I)-(X) or a compound of Tables 1-4), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the addictive disorder is alcohol abuse, drug abuse, smoking, obesity, or a mixture thereof. In some embodiments, the disorder is an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, etc.) or an auditory disorder.

[0197] In some embodiments, the disclosure provides a method of treating or preventing an impulse disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formulas (I)-(X) or a compound of Tables 1-4), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject. In some embodiments, the impulse disorder is Attention Deficit Hyperactivity Disorder (ADHD), Attention Deficit Disorder (ADD), Tourette's Syndrome, Autism, or a combination thereof.

[0198] In some embodiments, the disclosure provides a method of treating or preventing obsessive-compulsive disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formulas (I)-(X) or a compound of Tables 1-4), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the obsessive-compulsive disorder is obsessive-compulsive disorder (OCD), gambling, aberrant sexual behavior, or a combination thereof.

[0199] In some embodiments, the disclosure provides a method of treating or preventing a personality disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formulas (I)-(X) or a compound of Tables 1-4), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the personality disorder is conduct disorder, antisocial personality, aggressive behavior toward a subject, or a combination thereof. EXAMPLES

[0200] The compounds of the present disclosure can be synthesized using the exemplary methods below or other methods known to those of skill in the art.

[0201] General reaction conditions are provided and reaction products can be purified by known methods, including silica gel chromatography using a variety of organic solvents, such as hexane, dichloromethane, ethyl acetate, methanol, or preparative reverse-phase high pressure liquid chromatography.

[0202] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one of ordinary skill in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley & Sons, 2006, and Jerry March, Advanced Organic Chemistry, 4 th edition, John Wiley & Sons, publisher, New York, 1992, which are incorporated herein by reference in their entireties.

[0203] Scheme 1: Representative synthesis of compounds of the present disclosure [ka] As shown in Scheme 1, 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine can be coupled with a carboxylic acid of formula (A), where PG1 is a protecting group (e.g., using TFA) under amide coupling conditions (e.g., in the presence of 1,1'-carbonyldiimidazole (CDI), dimethylaminopyridine (DMAP), and a strong base such as sodium hydride), followed by deprotection of the protecting group PG1 (e.g., using TFA) to provide a compound of formula (Ia).

[0204] Scheme 2: Representative synthesis of compounds of the present disclosure [ka] As shown in Scheme 2, 2-(1H-indol-3-yl)-N-methylethan-1-amine can be reacted with a carboxylic acid of formula (A) under amide coupling conditions (e.g., in the presence of a base such as CDI, DMAP, and a tertiary amine base such as triethylamine), where PG1 is a protecting group (such as Boc), followed by deprotection of the protecting group PG1 (e.g., using TFA) to provide a compound of formula (Ib).

[0205] Scheme 3: Representative synthesis of compounds of the present disclosure [ka] As shown in Scheme 3, 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol can be converted to 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl dihydrogen phosphate in the presence of POCl3. 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl dihydrogen phosphate can be reacted with a carboxylic acid of formula (B) in the presence of CDI and a tertiary amine such as triethylamine to form a compound of formula (Ic). The compound of formula (Ic) can be deprotected, for example with TFA, to provide a compound of formula (Id).

[0206] 1. Synthesis of 1-2 [ka] To a solution of tryptophol (6 g, 37.27 mmol, 1.0 equiv.) in dimethyl sulfoxide (60 mL) was added 2-iodoxybenzoic acid (12.5 g, 44.72 mmol, 1.2 equiv.) under nitrogen atmosphere at 40° C. The mixture was stirred at 40° C. for 2 h. The reaction solution was diluted with 200 mL of dichloromethane and washed with 2×200 mL of saturated sodium bicarbonate solution and 2×200 mL of saturated aqueous sodium chloride solution, respectively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied to a silica gel column with petroleum ether / ethyl acetate (3:1). 4 g (67%) of 1-2 was obtained as a yellow oil.

[0207] 2. 1-2-1 Synthesis [ka] To a solution of 1-2 (100 mg, 0.63 mmol, 1.00 equiv) and 1-isopropylpiperazine (241.5 mg, 1.89 mmol, 3.00 equiv) in dichloromethane (1 mL) was added triethylamine (190.9 mg, 1.89 mmol, 3.00 equiv) and a solution of SnCl4 in dichloromethane (1N, 0.32 mL, 0.5 equiv) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h under nitrogen atmosphere. Sodium cyanoborohydride (58.6 mg, 0.95 mmol, 1.50 equiv) was then added in portions. The mixture was stirred at 25 °C for 2 h. The reaction was diluted with 20 mL of dichloromethane. The organic layer was washed with 2 × 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified twice by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 50% B, 50% B in 9 min; Wavelength: 254 nm; 4.6 mg (3%) of 1-2-1 was obtained as a brown solid. MS m / z [M+H] + (ESI): 272.25. 1 H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.51-7.49 (m, 1H), 7.34-7.32 (m, 1H), 7.14-6.97 (m, 3H), 2.83 (s, 2H), 2.58-2.46 (m, 11H), 0.97 (s, 6H).

[0208] 3. 1-2-2 Synthesis [ka] Compound 1-2-2 was prepared from 100 mg of 1-2 and 189 mg of 1-methylpiperazine in a similar manner as described for 1-2-1. 5.1 mg (3%) of 1-2-2 was obtained as a brown oil. MS m / z [M+H] + (ESI): 244.10. 1 H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 2.85-2.79 (m, 2H), 2.58-2.53 (m, 2H), 2.47-2.33 (m, 8H), 2.15 (s, 3H).

[0209] 4. 1-2-3 Synthesis [ka] Compound 1-2-3 was prepared from 100 mg of 1-2 and 164.4 mg of morpholine in a similar manner as described for 1-2-1. 25.5 mg (17%) of 1-2-3 was obtained as a brown solid. MS m / z [M+H] + (ESI): 231.05. 1 H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.07-6.94 (m, 2H), 3.60 (t, J = 4.2 Hz, 4H), 2.84 (t, J = 7.8 Hz, 2H), 2.54 (t, J = 7.8 Hz, 2H), 2.47-2.45 (m, 4H).

[0210] 1-2-4 synthesis [ka] Compound 1-2-4 was prepared from 100 mg of 1-2 and 168.2 mg of piperidine in a similar manner as described for 1-2-1. 3.4 mg (2%) of 1-2-4 was obtained as a brown solid. MS m / z [M+H] + (ESI): 229.20. 1 H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.49 (d, J = 5.1 Hz, 1H), 7.32 (d, J = 6.0 Hz, 1H), 7.12 (s, 1H), 7.04-6.95 (m, 2H), 2.82 (s, 2H), 2.55 (s, 2H), 2.42 (s, 4H), 1.51-1.40 (m, 6H).

[0211] 1-2-5 Synthesis [ka] Compound 1-2-5 was prepared from 100 mg of 1-2 and 190.9 mg of 4-hydroxypiperidine in a similar manner as described for 1-2-1. 18.9 mg (12%) of 1-2-5 was obtained as a brown solid. MS m / z [M+H] + (ESI): 245.10. 1 H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.13-6.93 (m, 3H), 4.53 (s, 1H), 3.49-3.38 (m, 1H), 2.87-2.73 (m, 4H), 2.59-2.52 (m, 2H), 2.12-2.01 (m, 2H), 1.75-1.70 (m, 2H), 1.45-1.33 (m, 2H).

[0212] 7. 1-2-6 Synthesis [ka] To a solution of methyl 4-piperidineacetate (296.7 mg, 1.89 mmol, 3.00 equiv) and acetic acid (0.1 mL) in methanol (1 mL) was added sodium cyanoborohydride (58.6 mg, 0.95 mmol, 1.50 equiv) at 0 °C. Then 1-2 (100 mg, 0.63 mmol, 1.00 equiv) was added dropwise to the mixture at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction was diluted with 20 mL of dichloromethane. The organic layer was washed with 2 × 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 58% B in 9 min, 58% B, Wavelength: 254 nm. 27.1 mg (14%) of 1-2-6 was obtained as a brown solid. MS m / z [M+H] + (ESI): 301.05. 1 H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 7.07-7.02 (m, 1H), 6.97-6.93 (m, 1H), 3.59 (s, 3H), 2.96-2.92 (m, 2H), 2.84-2.79 (m, 2H), 2.57-2.51 (m, 2H), 2.24 (d, J = 6.6 Hz, 2H), 1.98-1.89 (m, 2H), 1.72-1.60 (m, 3H), 1.29-1.13 (m, 2H).

[0213] 8. 1-2-7 Synthesis [ka] Compound 1-2-7 was prepared from 100 mg of 1-2 and 270.2 mg of piperidin-4-ylacetic acid in a similar manner as described for 1-2-1. 7.8 mg (4%) of 1-2-7 was obtained as a white solid. MS m / z [M+H] + (ESI): 287.10. 1 H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.13-6.95 (m, 3H), 3.02-2.89 (m, 2H), 2.88-2.74 (m, 2H), 2.57-2.53 (m, 2H), 2.11 (s, 2H), 1.99-1.90 (m, 2H), 1.67-1.63 (m, 3H), 1.26-1.12 (m, 2H).

[0214] 9. 1-2-8 Synthesis [ka] Compound 1-2-8 was prepared from 100 mg of 1-2 and 270.2 mg of methyl isonipecotate in a similar manner as described for 1-2-7. 26.1 mg (14%) of 1-2-8 was obtained as a brown solid. MS m / z [M+H] + (ESI): 287.05. 1 H NMR (300 MHz, DMSO-d6) δ10.76 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.34-7.29 (m, 1H), 7.13 (d, J = 2.1 Hz, 1H), 7.07-7.02 (m, 1H), 6.98-6.93 (m, 1H), 3.60 (s, 3H), 2.94-2.89 (m, 2H), 2.85-2.80 (m, 2H), 2.58-2.53 (m, 2H), 2.38-2.26 (m, 1H), 2.09-1.99 (m, 2H), 1.86-1.77 (m, 2H), 1.64-1.51 (m, 2H).

[0215] 10. 1-2-9 Synthesis [ka] Compound 1-2-9 was prepared from 100 mg of 1-2 and 243.8 mg of isonipecotic acid in a similar manner as described for 1-2-1. 4.3 mg (2%) of 1-2-9 was obtained as a white solid. MS m / z [M+H] + (ESI): 273.10. 1 H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.13 (s, 1H), 7.09-6.90 (m, 2H), 2.95-2.78 (m, 4H), 2.58-2.53 (m, 2H), 2.22-1.96 (m, 3H), 1.82-1.77 (m, 2H), 1.61-1.48 (m, 2H).

[0216] 11. 1-2-10 Synthesis [ka] Compound 1-2-10 was prepared from 100 mg of 1-2 and 134.2 mg of pyrrolidine in a similar manner as described for 1-2-1. 8.0 mg (6%) of 1-2-10 was obtained as a brown solid. MS m / z [M+H] + (ESI): 215.10. 1 H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.07-7.02 (m, 1H), 6.98-6.93 (m, 1H), 2.87-2.82 (m, 2H), 2.69-2.64 (m, 2H), 2.59-2.50 (m, 4H), 1.75-1.64 (m, 4H).

[0217] 12. 1-2-11 Synthesis [ka] Compound 1-2-11 was prepared from 100 mg of 1-2 and 164.4 mg of 3-pyrrolidinol in a similar manner as described for 1-2-1. 5.5 mg (4%) of 1-2-11 (racemate) was obtained as a white solid. MS m / z [M+H] + (ESI): 231.05. 1 H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 7.07-7.02 (m, 1H), 6.98-6.93 (m, 1H), 4.67 (s, 1H), 4.19 (s, 1H), 2.84-2.73 (m, 3H), 2.67-2.58 (m, 3H), 2.45-2.34 (m, 2H), 2.01-1.95 (m, 1H), 1.56-1.51 (m, 1H).

[0218] 13. 1-2-12 Synthesis [ka] Compound 1-2-12 was prepared from 100 mg of 1-2 and 243.8 mg of methyl 3-pyrrolidinecarboxylate in a similar manner as described for 1-2-6. 34.1 mg (20%) of 1-2-12 was obtained as a brown solid. MS m / z [M+H] + (ESI): 273.05. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 7.07-7.02 (m, 1H), 6.98-6.93 (m, 1H), 3.62 (s, 3H), 3.08-2.98 (m, 1H), 2.86-2.79 (m, 3H), 2.72-2.53 (m, 5H), 2.04-1.91 (m, 2H).

[0219] 14. 1-2-13 Synthesis [ka] Compound 1-2-13 was prepared from 100 mg of 1-2 and 217.3 mg of methyl 3-pyrrolidinecarboxylate in a similar manner as described for 1-2-1. 24.0 mg (15%) of 1-2-13 was obtained as a white solid. MS m / z [M+H] + (ESI): 259.05. 1 H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.50 (d, J = 6.9 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.14 (s, 1H), 7.08-6.93 (m, 2H), 2.84-2.55 (m, 9H), 1.95 (s, 2H).

[0220] 15. Synthesis of 1-2-14 [ka] Compound 1-2-14 was prepared from 100 mg of 1-2 and 228.7 mg of N-ethylaniline in a similar manner as described for 1-2-1. 6.3 mg (4%) of 1-2-14 was obtained as a white solid. MS m / z [M+H] + (ESI): 265.10. 1H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.55 (d, J = 6.6 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.22-7.15 (m, 3H), 7.11-6.96 (m, 2H), 6.72 (d, J = 6.9 Hz, 2H), 6.60-6.54 (m, 1H), 3.55-3.49 (m, 2H), 3.41-3.35 (m, 2H), 2.95-2.90 (m, 2H), 1.11-1.06 (m, 3H).

[0221] 16. 2-1-2 synthesis

change

[0222] To a solution of 2-1-1 (120 mg, 0.29 mmol, 1.0 equiv) in dichloromethane (1.2 mL) in an inert atmosphere of argon, trifluoroacetic acid (0.6 mL) was added slowly at room temperature. The resulting solution was stirred at room temperature for 1 h. The resulting solution was concentrated under reduced pressure. The crude product was purified by Flash with the following conditions: Column: C18 silica gel, Mobile phase: water and methanol (20% methanol to 100% in 15 min, hold at 100% for 5 min), Detector: 220 nm. Fractions were concentrated under reduced pressure. 28.3 mg (27.6% yield) of 2-1-2 was obtained as a white solid. MS m / z [M+H] +(ESI): 299.05. 1 H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.26 (s, 1H), 7.11-6.98 (m, 2H), 4.89 (d, J = 8.7 Hz, 2H), 3.51-3.45 (m, 2H), 3.18-3.13 (m, 2H), 3.07 (s, 6H). 31 P NMR (121MHz, DMSO-d6) δ-1.88.

[0223] 19. Synthesis of 3-1-4 [ka] To a 250 mL flask in an ice bath, 12.83 g (0.11 mol, 1.1 eq.) of thionyl chloride was added, followed by 8.91 g (0.10 mol, 1 eq.) of N,N-dimethylethanolamine, which was added dropwise under stirring over 0.5 h. The resulting mixture was stirred at 50° C. for 1 h. Then, 150 mL of ethanol was added and heated to reflux for 0.5 h. After cooling to room temperature, 3-1-1 (6 g, 42%) was collected by filtration as a pale yellow solid.

[0224] 21. 3-1-2 Synthesis A solution of 3-1-1 (6 g, 41.9 mmol, 1 equiv.) in N,N-dimethylformamide (60 mL) was treated with KOH (11.75 g, 209.5 mmol, 5 equiv.) at 25° C. for 1 h. 7-Methoxy-1H-indole (6.17 g, 41.9 mmol, 1 equiv.) was added to the mixture at 25° C. The resulting mixture was stirred at 50° C. for 16 h. The reaction was diluted with dichloromethane (200 mL) and washed with water (3×200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Flash with the following conditions: Column: C18 silica gel, Mobile phase: water (0.05% NH4HCO3) and acetonitrile (10% acetonitrile to 100% in 20 min, hold at 100% for 5 min), Detector: 220 nm. The fractions were concentrated under reduced pressure to give 3-1-2 (5 g, 54%) as a white solid. MS m / z [M+H] + (ESI): 219.14.

[0225] 22. 3-1-3 Synthesis To a solution of 3-1-2 (600 mg, 2.75 mmol, 1 equiv) in dichloromethane (20 mL) was added aluminum chloride (1.83 g, 13.75 mmol, 5 equiv) in portions at 0° C. The mixture was stirred at 25° C. overnight. The reaction was quenched with methanol (20 mL), filtered, and concentrated under reduced pressure. The crude product was purified by flash with the following conditions: Column: C18 silica gel, Mobile phase: Water (0.1% NH 3. HO) and methanol (10% methanol to 100% in 20 min, hold at 100% for 5 min), detector: 220 nm. The fractions were concentrated under reduced pressure. This gave 3-1-3 (415 mg, 73%) as a brown oil. MS m / z [M+H] + (ESI): 205.13.

[0226] 23. Synthesis of 3-1-4 To a solution of 3-1-3 (100 mg, 0.49 mmol, 1 equiv.) in dichloromethane (1 mL) was added pentanoic acid (75 mg, 0.74 mmol, 1.5 equiv.), 4-dimethylaminopyridine (17.9 mg, 0.15 mmol, 0.3 equiv.), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (141.2 mg, 0.74 mmol, 1.5 equiv.) at 25°C. The mixture was stirred at 25°C for 2 h, then diluted with 20 mL of dichloromethane and washed with 2 x 10 mL of saturated sodium bicarbonate solution and 2 x 10 mL of saturated aqueous sodium chloride solution, respectively. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by Flash under the following conditions: Column: C18 silica gel, Mobile phase: water (0.05% NH4HCO3) and acetonitrile (20% acetonitrile to 100% in 20 min, hold at 100% for 5 min), Detector: 220 nm. The fractions were concentrated under reduced pressure. This gave 3-1-4 (22.6 mg, 16%) as a brown oil. MS m / z [M+H] + (ESI): 289.25. 1 H NMR (300 MHz, methanol-d4) δ 7.42-7.38 (m, 1H), 7.16 (s, 1H), 7.01-6.94 (m, 1H), 6.82-6.78 (m, 1H), 6.48-6.44 (m, 1H), 4.33-4.26 (m, 2H), 2.75-2.60 (m, 4H), 2.23 (s, 6H), 1.81-1.69 (m, 2H), 1.53-1.43 (m, 2H), 1.03-0.96 (m, 3H).

[0227] 24. Combination of 4-1-2, 4-1-3, and 4-1-4 To a solution of tryptamine (400 mg, 2.5 mmol, 1.0 equiv) in 3 mL of methanol was added sodium cyanoborohydride (393.8 mg, 6.26 mmol, 2.50 equiv), acetic acid (0.3 mL), and formaldehyde (507.6 mg, 6.26 mol, 2.5 equiv, 37% aqueous solution) in methanol (4 mL) at 0 °C. The mixture was stirred overnight at 25 °C and then concentrated under vacuum. The resulting solution was diluted with 20 mL of saturated sodium bicarbonate and extracted with 3 × 20 mL of ethyl acetate. The combined organic layers were washed with 2 × 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The resulting mixture was dissolved in 3 mL of dichloromethane, then 483.5 mg of triethylamine was added and 1-chloroethyl carbonochloridate (340 mg, 2.39 mmol, 1.5 equiv) was added dropwise at 0 °C. The mixture was stirred at 25° C. for 2 h. The reaction was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium chloride solution (2×20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 300 mg (crude) of 4-1-1 (intermediate) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0228] 25. Synthesis of 4-1-2 (racemic form) To a solution of 4-1-1 (300 mg, 1.02 mmol, 1.0 equiv) and triethylamine (2.06 g, 20.40 mmol, 20 equiv) in dimethylformamide (6 mL) was added isobutyric acid (449 mg, 5.10 mmol, 5 equiv) at 25 °C. The mixture was stirred at 60 °C for 16 h. The reaction was diluted with 50 mL of dichloromethane and washed with 1 x 50 mL of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified twice by Prep-HPLC with the following conditions: Column: X Select CSH Fluoro Phenyl, 30×150 mm, 5 μm; Mobile phase A: Water (0.05% HCl), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 58% B in 8 min, 58% B, Wavelength: 254 nm, to give 9.0 mg of 4-1-2 as a light brown solid. The other batches were combined to give 26 mg of 4-1-2. MS m / z [M+H] + (ESI): 347.25. 1 H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J = 8.1 Hz, 1H), 7.75-7.67 (m, 2H), 7.44-7.32 (m, 2H), 7.02-6.97 (m, 1H), 3.40-3.35 (m, 2H), 3.12 -3.07 (m, 2H), 2.84 (s, 6H), 2.66-2.56 (m, 1H), 1.65 (d, J = 5.4 Hz, 3H), 1.11 (d, J = 7.2 Hz, 6H).

[0229] 26. Synthesis of 4-1-3 (racemic form) Compound 4-1-3 was prepared from 300 mg of 4-1-1 and 306 mg of acetic acid in a similar manner as described for 4-1-2. 5.0 mg of 4-1-3 was obtained as a light brown solid. Other batches were combined to give 40 mg of 4-1-3. MS m / z [M+H] + (ESI): 319.10. 1H NMR (400 MHz, DMSO-d6) δ10.16 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.6Hz, 1H), 7.65 (s, 1H), 7.43-7.32 (m, 2H), 7.01-6.97 (m, 1H), 3.39-3.33 (m, 2H), 3.15-3.11 (m, 2H), 2.83 (s, 6H), 2.10 (s, 3H), 1.63 (d, J = 5.6 Hz, 3H).

[0230] 27. Synthesis of 4-1-4 (racemic form) Compound 4-1-4 was prepared from 300 mg of 4-1-1 and 520 mg of pivalic acid in a similar manner as described for 4-1-2. The crude product (300 mg) was purified by Prep-HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3.H2O), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 48% B to 78% B in 9 min, 78% B, wavelength: 254 nm). 5 mg of 4-1-4 was obtained as an oil. MS m / z [M+H]+ (ESI): 361.25. 1 H NMR (300 MHz, DMSO-d6) δ 8.03 (d, J = 8.1 Hz, 1H), 7.65-7.62 (m, 1H), 7.51 (s, 1H), 7.39-7.26 (m, 2H), 6.98-6.93 (m, 1H), 2.83-2.78 (m, 2H), 2.57-2.54 (m, 2H), 2.20 (s, 6H), 1.64 (d, J = 5.4 Hz, 3H), 1.17 (s, 9H).

[0231] 28. Synthesis of 5-1-4 [ka]

[0232] To a stirred solution of 4-methoxy-1H-indole (1.0 g, 6.80 mmol, 1.0 equiv) in diethyl ether (20.0 mL) was added oxalyl chloride (0.9 g, 6.80 mmol, 1.0 equiv) dropwise under nitrogen at 0° C. The resulting mixture was stirred at room temperature for an additional 3 h. The resulting mixture 5-1-1 was used directly in the next step without further purification.

[0233] To a stirred solution of dimethylamine hydrochloride (1.7 g, 21.04 mmol, 5.0 equiv.) and triethylamine (3.4 g, 33.66 mmol, 8.0 equiv.) in tetrahydrofuran (10.0 mL) was added 5-1-1 (crude, obtained in the last step) dropwise at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for another 0.5 h. The reaction was quenched by adding water (50 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude was purified by Flash with the following conditions: Column: C18 silica gel, Mobile phase: water (0.05% NH4HCO3) and acetonitrile (10% acetonitrile to 100% in 15 min, hold at 100% for 5 min), Detector: 254 nm. Obtained 600 mg (58% yield) of 5-1-2 as a yellow solid. MS m / z [M+H] + (ESI): 247.10

[0234] To a stirred solution of 5-1-2 (600.0 mg, 2.44 mmol, 1.0 equiv) in tetrahydrofuran (10.0 mL) was added lithium aluminum hydride (184.9 mg, 4.87 mmol, 2.0 equiv) in portions at 0° C. The resulting mixture was stirred at 70° C. for 1.5 days. The reaction was quenched by adding water (20.0 mL) at 0° C. The aqueous layer was extracted with ethyl acetate (3×30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude was purified by Flash with the following conditions: Column: C18 silica gel, Mobile phase: Water (0.1% NH3.H2O+10 mmol / L NH4HCO3) and acetonitrile (10% acetonitrile to 100% in 15 min, hold at 100% for 5 min), Detector: 254 nm. Obtained 350 mg (66% yield) of 5-1-3 as a yellow solid. MS m / z [M+H] + (ESI): 219.15.

[0235] To a stirred solution of 5-1-3 (80.0 mg, 0.37 mmol, 1.0 equiv) in dichloromethane (1.0 mL) was added tribromoborane (459.0 mg, 1.83 mmol, 5.0 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 9 h. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (30.0 mL) and 50 mg of KHCO3 and 15.0 mL of methanol were added. After stirring for 30 min, the resulting mixture was concentrated under reduced pressure. The resulting mixture was dissolved in N,N-dimethylformamide (1.0 mL) and entanoic acid (30.0 mg, 0.15 mmol, 1.0 equiv), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (56.3 mg, 0.29 mmol, 2.0 equiv) and 4-dimethylaminopyridine (9.0 mg, 0.07 mmol, 0.5 equiv) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate (3 x 10 mL) and washed with water (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash under the following conditions: Column: C18 silica gel, Mobile phase: water (0.05% NH4HCO3) and acetonitrile (10% acetonitrile to 100% in 20 min, hold at 100% for 5 min), Detector: 254 nm. This gave 5-1-5 (20.0 mg, 47%) as a colorless oil. MS m / z [M+H] + (ESI): 289.25. 1 H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.06-7.01 (m, 1H), 6.66-6.63 (m, 1H), 2.78-2.65 (m, 4H), 2.47-2.43 (m, 2H), 2.20 (s, 6H), 1.73-1.63 (m, 2H), 1.48-1.35 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[0236] Improved prodrugs of tryptamine, such as N,N-dimethyltryptamine (DMT). Prodrugs 3-1-4, 4-1-2, and 4-1-4 should be stable in formulation and should release the parent compound in vivo. [ka]

[0237] Preliminary studies have demonstrated the stability of the prodrugs (Tables 5-9). Although solution stability has been demonstrated for the prodrugs, plasma stability data clearly demonstrated immediate release of the parent drug in mouse plasma. The following prodrugs were tested:

[0238] Stability of prodrugs 3-1-4, 4-1-2, and 4-1-4 in PBS pH 6.5 with and without pepsin [Table 5] [Table 6] [Table 7] [Table 8]

[0239] Stability results of prodrugs 3-1-4, 4-1-2, and 4-1-4 in mouse plasma [Table 9]

[0240] N-Phosphonooxymethyl Prodrug 6-1-2 (PH-VLS-02-23-0) [ka]

[0241] The N-phosphonooxymethyl prodrug compounds were prepared using the method described by Gunda I. George (Journal of Medicinal Chemistry, 1999, Vol. 42, 3095).

[0242] Example of a prodrug strategy: [ka] 6-1-2 was synthesized as a novel prodrug strategy to improve the water solubility of tertiary amine-containing drugs. The tertiary amine DMT was converted to the highly polar N-phosphonooxymethyl prodrug 6-1-3 in a two-step reaction.

[0243] The prodrug 6-1-2 releases the parent DMT in vivo via a two-step bioreversion process. The rate-limiting first step is via an enzymatic process, where the bioreversion of the prodrug involves phosphatase-catalyzed dephosphorylation resulting in a hydroxymethyl quaternary ammonium intermediate and inorganic phosphate. The second step involves chemical conversion of the hydroxymethyl quaternary ammonium intermediate to DMT and formaldehyde at physiological pH. [ka]

[0244] The chemical stability of the prodrug 6-1-2 (VLS-02-23) was evaluated and the results are listed in Tables 10-11. PK studies of the prodrug 6-1-2 and metabolite (VLS-02-23-10) in mice were also performed and both plasma and brain exposure were analyzed as shown in Figures 1-2, respectively.

[0245] Chemical stability of N-phosphonooxymethyl prodrug 6-1-2 (VLS-02-23) [Table 10]

[0246] Plasma stability of N-phosphonooxymethyl prodrug 6-1-2 (VLS-02-23) [Table 11]

Claims

1. A compound of formula (I), 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein In the formula,[[]] R １ and R ２ are independently hydrogen, alkyl, cycloalkyl, or R １ and R ２ together with the atoms to which they are attached form a heterocyclic ring, X, Y, and Z are independently hydrogen, halogen, -O-, -S-, -NR Ａ -, or -(P=O)-OR Ａ (-OR'), where R Ａ is hydrogen or alkyl, R', R ３ , R ４ , R ５ , and R ６ are independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR ７ , -(C=O)(CH ２ ) ｎ (NH ２ ), -(C)CH(NH ２ )(CH ３ ), -(C=O)CH(NH ２ ), (CH ２ ) ｎ (NH)(C=NH), or -(C=O)(CH ２ ) ｎ (NH)(C=NH)-NH ２ is, R ７ and R ８ are independently hydrogen or alkyl, R ９ is hydrogen, alkyl, or halogen, L and M are independently alkyl or aryl, W is oxygen, sulfur, or NR ６ is, n is an integer from 2 to 7, m is an integer from 1 to 4, R', R ３ , R ４ , and R ５ and R ６ at least one of which is -(C=O)-alkyl, -(C=O)CHR ７ (NH ２ ), -(C=O)(CH ２ ) ｎ (NH ２ ), -(C=O)CH(NH ２ )(CH ２ ) ｎ (NH ２ ), -(C=O)(CH ２ ) ｎ (NH)(C=NH)-NH ２ , or 【Chemical Formula 2】 is a compound.

2. X, Y, and Z are hydrogen, W is NR ６ , and R ６ is -(C=O)-alkyl or -(C=O)(CH ２ ) ｎ (NH ２ ), the compound according to claim 1.

3. Two of X, Y, and Z are hydrogen, the compound according to claim 1.

4. The non-hydrogen X, Y, or Z is -O-, -S-, -NR Ａ -, or -(P=O)-OR Ａ (-OR'), and R Ａ is hydrogen or alkyl, the compound according to claim 3.

5. X and Y are hydrogen, Z is -O-, -S-, -NR Ａ (-), or -(P=O)-OR Ａ (-OR'), and R Ａ is hydrogen or alkyl, the compound according to claim 1.

6. X and Z are hydrogen, Y is -O-, -S-, -NR Ａ— or —(P=O)—OR Ａ (—OR’) and R Ａ is hydrogen or alkyl, the compound according to claim 1.

7. Y and Z are hydrogen, X is —O—, —S—, —NR Ａ — or —(P=O)—OR Ａ (—OR’) and R Ａ is hydrogen or alkyl, the compound according to claim 1.

8. A salt of formula (IV), 【Chemical formula 3】 In the formula, R １０ is —(C=O)—alkyl, —(C=O)CHR ７ (NH ２ )—(C=O)(CH ２ ) ｎ (NH ２ )—(C=O)CH(NH ２ )(CH ２ ) ｎ (NH ２ )—(C=O)(CH ２ ) ｎ (NH)(C=NH)—NH ２ or 【Chemical formula 4】 and A is a pharmaceutically acceptable anion, the compound according to claim 1.

9. A compound of formula (III), 【Chemical formula 5】 or a pharmaceutically acceptable salt thereof, In the formula, R １ and R ２ are independently hydrogen, alkyl, cycloalkyl, or R １ and R ２ together with the atoms to which they are attached form a heterocyclic ring, X, Y, and Z are independently hydrogen, halogen, —O—, —S—, —NR Ａ—OR—(P=O)—OR Ａ (—OR'), where R Ａ is hydrogen or alkyl, R', R ３ , R ４ , and R ５ are each independently absent, hydrogen, alkyl, —(C=O)—alkyl, —(C=O)CHR ７ (NH ２ ), —(C=O)(CH ２ ) ｎ (NH ２ ), —(C=O)CH(NH ２ )(CH ２ ) ｎ (NH ２ ), —(C=O)CH(NH ２ )(CH ２ ) ｎ (NH)(C=NH)—NH ２ , —(C=O)(CH ２ ) ｎ (NH)(C=NH)—NH ２ , or [Chemical Formula 6] and R ７ and R ８ are each independently hydrogen or alkyl, R ９ is hydrogen, alkyl, or halogen, L and M are each independently alkyl or aryl, n is an integer from 2 to 7, m is an integer from 1 to 4, R', R ３ , R ４ , and R ５ at least one of which is —(C=O)—alkyl, —(C=O)CHR ７ (NH ２ ), —(C=O)(CH ２ ) ｎ (NH ２ ), —(C=O)CH(NH ２ )(CH ２ ) ｎ (NH ２ ), —(C=O)(CH ２ ) ｎ (NH)(C=NH)-NH ２ or 【Chemical Formula 7】 is a compound.

10. The compound according to claim 9, wherein two of X, Y, and Z are hydrogen.

11. The X, Y, or Z that is not hydrogen is -O-, -S-, -NR Ａ -, or -(P=O)-OR Ａ (-OR'), where R Ａ is hydrogen or alkyl, is the compound according to claim 10.

12. X and Y are hydrogen, and Z is -O-, -S-, -NR Ａ -, or -(P=O)-OR Ａ (-OR'), where R Ａ is hydrogen or alkyl, is the compound according to claim 9.

13. X and Z are hydrogen, and Y is -O-, -S-, -NR Ａ -, or -(P=O)-OR Ａ (-OR'), where R Ａ is hydrogen or alkyl, is the compound according to claim 9.

14. Y and Z are hydrogen, and X is -O-, -S-, -NR Ａ -, or -(P=O)-OR Ａ (-OR'), where R Ａ is hydrogen or alkyl, is the compound according to claim 9.

15. R', R ３ 、R ４ 、and R ５ at least one of which is 【Chemical Formula 8】 is the compound according to claim 9.

16. It is a salt form of formula (V), 【Chemical Formula 9】 In the formula, R １０ is -(C=O)-alkyl, -(C=O)CHR ７ (NH ２ ), -(C=O)(CH ２ ), ｎ (NH ２ ), -(C=O)CH(NH ２ )(CH ２ ), ｎ (NH ２ ), -(C=O)CH(NH ２ )(CH ２ ), ｎ (NH)(C=NH)-NH ２ , -(C=O)(CH ２ ), ｎ (NH)(C=NH)-NH ２ , or 【Chemical Formula 10】 and A is a pharmaceutically acceptable anion, the compound according to claim 9.

17. The compound according to claim 16, wherein L is methyl or isopropyl and M is alkyl or aryl.

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

19. A compound of the following formula. 【Chemical Formula 12】

20. A compound of formula (VI), 【Chemical Formula 15】 R １ and R ２ are independently hydrogen, alkyl, cycloalkyl, or R １ and R ２ together with the atoms to which they are attached form a heterocyclic ring, R ３ , R ４ , R ５ , and R ６ is independently absent, hydrogen, alkyl, -(C=O)-alkyl, -(C=O)CHR ７ , -(C=O)(CH ２ ) ｎ (NH ２ ), -(C)CH(NH ２ )(CH ３ ), -(C=O)CH(NH ２ ), (CH ２ ) ｎ (NH)(C=NH), or -(C=O)(CH ２ ) ｎ (NH)(C=NH)-NH ２ and X is carbon or nitrogen, W is carbon, oxygen, or nitrogen, Z is hydrogen, deuterium, or oxygen, a compound.

21. The compound according to claim 20, having the following chemical formula. 【Chemical Formula 16】

22. A compound selected from the following formulas. 【Chemical Formula 17】

23. The phosphonooxymethyl prodrug according to claim 1 of formula (VIII), 【Chemical Formula 18】 wherein, R １１ and R １２ are pharmaceutically acceptable salts and are independently H, D, Na+, K+, NH4+, or R11 and R12 are independently pharmaceutically acceptable salts, hydrogen, deuterium, alkyl, substituted alkyl, cycloalkyl, or R11 and R12, together with the atoms to which they are attached, form alkyl, cycloalkyl, heterocycle, and are ether, hemiaminalketal, and amino acid, and the pharmaceutically acceptable salts are Na+, K+, NH4+, a phosphonooxymethyl prodrug.

24. A pharmaceutical composition comprising the compound according to any one of claims 19 to 23 and a pharmaceutically acceptable excipient.

25. An oral dosage form comprising the pharmaceutical composition according to claim 18.

26. An oral dosage form comprising the pharmaceutical composition according to claim 24.

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