Dimethyltryptamine analogues as nitric oxide delivery agents.

Abstract

Provided herein are compounds of formula (I), (II), or pharma- ceutically acceptable salts thereof.Also provided herein are pharmaceutical compositions comprising the compounds of formula (I), (II), or pharma- ceutically acceptable salts thereof, and methods of using, for example, the compounds of formula (I), (II), or pharma- ceutically acceptable salts thereof. [Formula 1] JPEG2024545787000024.jpg47137

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 295,199, filed December 30, 2021, the contents of which are incorporated by reference in their entirety herein. Summary of the Invention

[0002] In embodiments, the present disclosure provides dimethyltryptamine derivatives that release nitric oxide (NO) in vivo.

[0003] In embodiments, the present disclosure provides prodrugs of dimethyltryptamine and derivatives thereof.

[0004] In embodiments, the disclosure provides a compound of Formula (I), Formula (II), or a pharma- ceutically acceptable salt thereof.

[0005] In embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R1, R3, R4, and R5 are independently H, halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m -CH(NH2)CH2ONO2, Each R2 is independently a C1-C6 alkyl; X, Y, and Z are independently absent, H, O, S, NH, and -O-(P=O)OHO-; R7 and R7' are independently H, halogen, or C1-C6 alkyl; m is 2, 3, or 4; each n is independently 1, 2, 3, 4, or 5; A -is a pharma- ceutically acceptable anion; In the formula, at least one of R1, R3, R4, and R5 is -(C=O)(CR7R7') n -ONO2 or -(C=O)(CR7R7') m -CH(NH2)CH2ONO2.

[0006] In embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R3, R 4、 and R5 are independently H, halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m -CH(NH2)CH2ONO2, R1 and R6 are independently H, C1-C6 alkyl, -(C=O)(CH2) l -ONO2, -(C=O)(CH2) m -CH(NH2)CH2ONO2, R2 is H or C1-C6 alkyl; R7 and R7' are independently H, halogen, or C1-C6 alkyl; X, Y, and Z are independently absent, O, S, NH, and -O-(P=O)OHO-; m is 2, 3, or 4; and each n is independently 1, 2, 3, 4, or 5; In the formula, at least one of R1, R3, R4, R5, and R6 is -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m -CH(NH2)CH2ONO2.

[0007] In embodiments, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound of Formula (I), (II) or Table 1) and a pharma- ceutically acceptable excipient.

[0008] In embodiments, the disclosure provides methods of using one or more compounds of the disclosure (eg, a compound of Formula (I), (II), or Table 1), eg, as an NO delivery agent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications are incorporated by reference in their entirety into this disclosure for all purposes in order to more fully describe the state of the art as 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.

[0010] 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.

[0011] The terms "administer", "administering" or "administration" as used herein refer to administering a compound or a pharma- ceutically acceptable salt of the compound, or a composition or formulation comprising a compound or a pharma- ceutically acceptable salt of the compound, to a patient.

[0012] The term "treating" as used herein with respect to a patient or subject refers to improving at least one symptom of a disorder in the patient or subject. In some embodiments, treating can be improving or at least partially reversing a disorder or one or more symptoms of a disorder.

[0013] The term "therapeutically effective" as applied to a dose or amount refers to an amount of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit following administration to a patient or subject in need thereof.

[0014] The term "pharmaceutically acceptable salts" 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, such as 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 pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., acids that form salts containing pharmaceutically 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.

[0015] 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.

[0016] "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 having up to 6 carbon atoms, which is C1-C6 alkyl, and an alkyl group having 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 C12 Including 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.

[0017] 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 an atom that is not hydrogen, including, but not limited to, halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms have been replaced by a higher order 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 have been replaced by -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NRg 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 R h "Substituted" also refers to any of the above groups being substituted with one or more hydrogen atoms. g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R hare 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 substituted with one or more of the above substituents.

[0018] compound In embodiments, the present disclosure provides dimethyltryptamine derivatives that release nitric oxide (NO) in vivo. In embodiments, the present disclosure provides prodrugs of dimethyltryptamine and its derivatives. In embodiments, the present disclosure provides compounds of formula (I) and (II), or pharma- ceutically acceptable salts thereof.

[0019] In embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, R1, R3, R4, and R5 are independently H, halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m -CH(NH2)CH2ONO2, R2 is independently C1-C6 alkyl; X, Y, and Z are independently absent, H, O, S, NH, and -O-(P=O)OHO-; m is 2, 3, or 4; each n is independently 1, 2, 3, 4, or 5; A - is a pharma- ceutically acceptable anion; In the formula, at least one of R1, R3, R4, and R5 is -(C=O)(CR7R7') n -ONO2 or -(C=O)(CR7R7') m -CH(NH2)CH2ONO2.

[0020] In an embodiment of the compound of formula (I), R1 is C1-C6 alkyl. In an embodiment of the compound of formula (I), R1 is methyl, ethyl or propyl. In an embodiment of the compound of formula (I), R1 is methyl. In an embodiment of the compound of formula (I), R1 is H.

[0021] In an embodiment of the compound of formula (I), R1 is C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R1 is H, -(C=O)(CR7R7'). n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R1 is H, C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (I), R1 is H, C1-C6 alkyl, or -(C=O)(CR7R7'). n In an embodiment of the compound of formula (I), R1 is -(C=O)(CR7R7'). n -ONO2, or -(C=O)(CR7R7') mIn an embodiment of the compound of formula (I), R1 is C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (I), R1 is halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m -CH(NH2)CH2ONO2.

[0022] In an embodiment of the compound of formula (I), R1 is -(C=O)(CR7R7') n In an embodiment of the compound of formula (I), R1 is -(C=O)(CR7R7'). m In an embodiment of the compound of formula (I), R1 is -(C=O)(CH2) n In an embodiment of the compound of formula (I), R1 is -(C=O)(CH2). m In an embodiment of the compound of formula (I), R1 is -(C=O)(CH2)3-ONO2. In an embodiment of the compound of formula (I), R1 is -(C=O)(CH2)2-CH(NH2)CH2ONO2.

[0023] In an embodiment of the compound of formula (I), R3 is H. In an embodiment of the compound of formula (I), R3 is halogen. In an embodiment of the compound of formula (I), R3 is C1-C6 alkyl.

[0024] In an embodiment of the compound of formula (I), R3 is H, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R3 is H, halogen, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') mIn an embodiment of the compound of formula (I), R3 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (I), R3 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). n -ONO2. In an embodiment of the compound of formula (I), R3 is H, halogen, or C1-C6 alkyl. In an embodiment of the compound of formula (I), R3 is H, or halogen. In an embodiment of the compound of formula (I), R3 is H, or C1-C6 alkyl. In an embodiment of the compound of formula (I), R3 is halogen, or C1-C6 alkyl.

[0025] In an embodiment of the compound of formula (I), R3 is -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R3 is -(C=O)(CR7R7'). n In an embodiment of the compound of formula (I), R3 is -(C=O)(CR7R7'). m -CH(NH2)CH2ONO2.

[0026] In an embodiment of the compound of formula (I), R4 is H, halogen, or C1-C6 alkyl. In an embodiment of the compound of formula (I), R4 is H, or halogen. In an embodiment of the compound of formula (I), R4 is H, or C1-C6 alkyl. In an embodiment of the compound of formula (I), R4 is halogen, or C1-C6 alkyl.

[0027] In an embodiment of the compound of formula (I), R4 is halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R4 is H, C1-C6 alkyl, -(C=O)(CR7R7')n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R4 is H, halogen, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R4 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (I), R4 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). n -ONO2.

[0028] In an embodiment of the compound of formula (I), R4 is -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R4 is -(C=O)(CR7R7'). n In an embodiment of the compound of formula (I), R4 is -(C=O)(CR7R7'). m -CH(NH2)CH2ONO2.

[0029] In an embodiment of the compound of formula (I), R5 is H. In an embodiment of the compound of formula (I), R5 is halogen. In an embodiment of the compound of formula (I), R5 is C1-C6 alkyl. In an embodiment of the compound of formula (I), R5 is H, halogen, or C1-C6 alkyl. In an embodiment of the compound of formula (I), R5 is H, or halogen. In an embodiment of the compound of formula (I), R5 is H, or C1-C6 alkyl. In an embodiment of the compound of formula (I), R5 is halogen, or C1-C6 alkyl.

[0030] In an embodiment of the compound of formula (I), R5 is halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7')m In an embodiment of the compound of formula (I), R5 is H, C1-C6 alkyl, -(C=O)(CR7R7'). n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R5 is H, halogen, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R5 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (I), R5 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). n -ONO2.

[0031] In an embodiment of the compound of formula (I), R5 is -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (I), R5 is -(C=O)(CR7R7'). n In an embodiment of the compound of formula (I), R5 is -(C=O)(CR7R7'). m -CH(NH2)CH2ONO2.

[0032] In an embodiment of a compound of formula (I), R7 and R7' are independently H, or C1-C6 alkyl. In an embodiment of a compound of formula (I), R7 and R7' are independently H, or C1-C3 alkyl. In an embodiment of a compound of formula (I), R7 and R7' are independently H, or halogen alkyl. In an embodiment of a compound of formula (I), R7 and R7' are independently halogen, or C1-C6 alkyl. In an embodiment of a compound of formula (I), R7 and R7' are independently halogen, or C1-C3 alkyl.

[0033] In an embodiment of the compound of formula (I), X is O, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (I), X is absent, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (I), X is absent, O, S, or -O-(P=O)OHO-. In an embodiment of the compound of formula (I), X is absent, O, S, or NH. In an embodiment of the compound of formula (I), X is O, or -O-(P=O)OHO-.

[0034] In an embodiment of the compound of formula (I), X is absent. In an embodiment of the compound of formula (I), X is O. In an embodiment of the compound of formula (I), X is S. In an embodiment of the compound of formula (I), X is NH. In an embodiment of the compound of formula (I), X is -O-(P=O)OHO-.

[0035] In an embodiment of the compound of formula (I), Y is O, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (I), Y is absent, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (I), Y is absent, O, S, or -O-(P=O)OHO-. In an embodiment of the compound of formula (I), Y is absent, O, S, or NH. In an embodiment of the compound of formula (I), Y is O, or -O-(P=O)OHO-.

[0036] In an embodiment of the compound of formula (I), Y is absent. In an embodiment of the compound of formula (I), Y is O. In an embodiment of the compound of formula (I), Y is S. In an embodiment of the compound of formula (I), Y is NH. In an embodiment of the compound of formula (I), Y is -O-(P=O)OHO-.

[0037] In an embodiment of the compound of formula (I), Z is O, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (I), Z is absent, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (I), Z is absent, O, S, or -O-(P=O)OHO-. In an embodiment of the compound of formula (I), Z is absent, O, S, or NH. In an embodiment of the compound of formula (I), Z is O, or -O-(P=O)OHO-.

[0038] In an embodiment of the compound of formula (I), Z is absent. In an embodiment of the compound of formula (I), Z is O. In an embodiment of the compound of formula (I), Z is S. In an embodiment of the compound of formula (I), Z is NH. In an embodiment of the compound of formula (I), Z is -O-(P=O)OHO-.

[0039] In an embodiment of the compound of formula (I), n is 1. In an embodiment of the compound of formula (I), n is 2. In an embodiment of the compound of formula (I), n is 3. In an embodiment of the compound of formula (I), n is 4. In an embodiment of the compound of formula (I), n is 5.

[0040] In an embodiment of the compound of formula (I), m is 2. In an embodiment of the compound of formula (I), m is 3. In an embodiment of the compound of formula (I), m is 4. In an embodiment of the compound of formula (I), m is 5.

[0041] In an embodiment of a compound of formula (I), R3 is H and X is absent. In an embodiment of a compound of formula (I), R3 is halogen and X is absent. In an embodiment of a compound of formula (I), R3 is H and X is O. In an embodiment of a compound of formula (I), R3 is C1-C6 alkyl and X is O. In an embodiment of a compound of formula (I), R3 is Cl, F, Br, or I and X is absent. In an embodiment of a compound of formula (I), R3 is F and X is absent.

[0042] In an embodiment of a compound of formula (I), R4 is H and Y is absent. In an embodiment of a compound of formula (I), R4 is halogen and Y is absent. In an embodiment of a compound of formula (I), R4 is H and Y is O. In an embodiment of a compound of formula (I), R4 is C1-C6 alkyl and Y is O. In an embodiment of a compound of formula (I), R4 is Cl, F, Br, or I and Y is absent. In an embodiment of a compound of formula (I), R4 is F and Y is absent.

[0043] In an embodiment of a compound of formula (I), R5 is H and Z is absent. In an embodiment of a compound of formula (I), R5 is halogen and Z is absent. In an embodiment of a compound of formula (I), R5 is H and Z is O. In an embodiment of a compound of formula (I), R5 is C1-C6 alkyl and Z is O. In an embodiment of a compound of formula (I), R5 is Cl, F, Br, or I and Z is absent. In an embodiment of a compound of formula (II), R5 is F and Z is absent.

[0044] Formula (II): In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, R3, R 4、 and R5 are independently H, halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m -CH(NH2)CH2ONO2, R1 and R6 are independently H, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m -CH(NH2)CH2ONO2, R2 is H or C1-C6 alkyl; and R7 and R7' are independently H, halogen, or C1-C6 alkyl; X, Y, and Z are independently absent, O, S, NH, and -O-(P=O)OHO-; m is 2, 3, or 4; and each n is independently 1, 2, 3, 4, or 5; In the formula, at least one of R1, R3, R4, R5, and R6 is -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m -CH(NH2)CH2ONO2.

[0045] In an embodiment of the compound of formula (II), R1 is C1-C6 alkyl. In an embodiment of the compound of formula (II), R1 is methyl, ethyl or propyl. In an embodiment of the compound of formula (II), R1 is methyl. In an embodiment of the compound of formula (II), R1 is H.

[0046] In an embodiment of the compound of formula (II), R1 is -(C=O)(CR7R7') n -ONO2.

[0047] In an embodiment of the compound of formula (II), R1 is -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R is -(C=O)(CH) n In an embodiment of the compound of formula (II), R1 is -(C=O)(CH2). m In an embodiment of the compound of formula (II), R1 is -(C=O)(CH2)3-ONO2. In an embodiment of the compound of formula (II), R1 is -(C=O)(CH2)2-CH(NH2)CH2ONO2.

[0048] In an embodiment of the compound of formula (II), R1 is C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7')m In an embodiment of the compound of formula (II), R1 is H, -(C=O)(CR7R7'). n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R1 is H, C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (II), R1 is H, C1-C6 alkyl, or -(C=O)(CR7R7'). n In an embodiment of the compound of formula (II), R1 is -(C=O)(CR7R7'). n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R1 is C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (II), R1 is C1-C6 alkyl or -(C=O)(, halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m -CH(NH2)CH2ONO2.

[0049] In an embodiment of the compound of formula (II), R3 is H, halogen, or C1-C6 alkyl. In an embodiment of the compound of formula (II), R3 is H, or halogen. In an embodiment of the compound of formula (II), R3 is H, or C1-C6 alkyl. In an embodiment of the compound of formula (II), R3 is halogen, or C1-C6 alkyl. In an embodiment of the compound of formula (II), R3 is H. In an embodiment of the compound of formula (II), R3 is halogen. In an embodiment of the compound of formula (II), R3 is C1-C6 alkyl.

[0050] In an embodiment of the compound of formula (II), R3 is H, C1-C6 alkyl, -(C=O)(CR7R7') n-ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R3 is H, halogen, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m -CH(NH2)CH2ONO2.

[0051] In an embodiment of the compound of formula (II), R3 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R3 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). n In an embodiment of the compound of formula (II), R3 is -(C=O)(CR7R7'). n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R3 is -(C=O)(CR7R7'). n In an embodiment of the compound of formula (II), R3 is -(C=O)(CR7R7'). m -CH(NH2)CH2ONO2.

[0052] In an embodiment of the compound of formula (II), R4 is H, halogen, or C1-C6 alkyl. In an embodiment of the compound of formula (II), R4 is H, or halogen. In an embodiment of the compound of formula (II), R4 is H, or C1-C6 alkyl. In an embodiment of the compound of formula (II), R4 is halogen, or C1-C6 alkyl.

[0053] In an embodiment of the compound of formula (II), R4 is halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R4 is H, C1-C6 alkyl, -(C=O)(CR7R7') n-ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R4 is H, halogen, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R4 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (II), R4 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). n In an embodiment of the compound of formula (II), R4 is -(C=O)(CR7R7'). n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R4 is -(C=O)(CR7R7'). n In an embodiment of the compound of formula (II), R4 is -(C=O)(CR7R7'). m -CH(NH2)CH2ONO2.

[0054] In an embodiment of the compound of formula (II), R5 is H, halogen, or C1-C6 alkyl. In an embodiment of the compound of formula (II), R5 is H, or halogen. In an embodiment of the compound of formula (II), R5 is H, or C1-C6 alkyl. In an embodiment of the compound of formula (II), R5 is halogen, or C1-C6 alkyl. In an embodiment of the compound of formula (II), R5 is H. In an embodiment of the compound of formula (II), R5 is halogen. In an embodiment of the compound of formula (II), R5 is C1-C6 alkyl.

[0055] In an embodiment of the compound of formula (II), R5 is halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') mIn an embodiment of the compound of formula (II), R5 is H, C1-C6 alkyl, -(C=O)(CR7R7'). n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R5 is H, halogen, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R5 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (II), R5 is H, halogen, C1-C6 alkyl, or -(C=O)(CR7R7'). n In an embodiment of the compound of formula (II), R5 is -(C=O)(CR7R7'). n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R5 is -(C=O)(CR7R7'). n In an embodiment of the compound of formula (II), R5 is -(C=O)(CR7R7'). m -CH(NH2)CH2ONO2.

[0056] In an embodiment of the compound of formula (II), R6 is H, or C1-C6 alkyl. In an embodiment of the compound of formula (II), R6 is C1-C6 alkyl. In an embodiment of the compound of formula (II), R6 is methyl, ethyl, or propyl. In an embodiment of the compound of formula (II), R6 is methyl. In an embodiment of the compound of formula (II), R6 is H. In an embodiment of the compound of formula (II), R6 is -(C=O)(CR7R7') n -ONO2.

[0057] In an embodiment of the compound of formula (II), R6 is -(C=O)(CR7R7') mIn an embodiment of the compound of formula (II), R6 is -(C=O)(CH2) n In an embodiment of the compound of formula (II), R6 is -(C=O)(CH2). m In an embodiment of the compound of formula (II), R6 is -(C=O)(CH2)3-ONO2. In an embodiment of the compound of formula (II), R6 is -(C=O)(CH2)2-CH(NH2)CH2ONO2. In an embodiment of the compound of formula (II), R6 is C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R6 is H, -(C=O)(CR7R7'). n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R6 is H, C1-C6 alkyl, or -(C=O)(CR7R7'). m In an embodiment of the compound of formula (II), R6 is H, C1-C6 alkyl, or -(C=O)(CR7R7'). n In an embodiment of the compound of formula (II), R6 is -(C=O)(CR7R7'). n -ONO2, or -(C=O)(CR7R7') m In an embodiment of the compound of formula (II), R6 is C1-C6 alkyl, or -(C=O)(CR7R7'). m -CH(NH2)CH2ONO2.

[0058] In an embodiment of the compound of formula (II), R6 is C1-C6 alkyl, or -(C=O)(CR7R7') n In an embodiment of the compound of formula (II), R6 is H or -(C=O)(CR7R7'). n In an embodiment of the compound of formula (II), R6 is H or -(C=O)(CR7R7').m -CH(NH2)CH2ONO2.

[0059] In an embodiment of a compound of formula (II), R7 and R7' are independently H, or C1-C6 alkyl. In an embodiment of a compound of formula (II), R7 and R7' are independently H, or C1-C3 alkyl. In an embodiment of a compound of formula (II), R7 and R7' are independently H, or halogen alkyl. In an embodiment of a compound of formula (II), R7 and R7' are independently halogen, or C1-C6 alkyl. In an embodiment of a compound of formula (II), R7 and R7' are independently halogen, or C1-C3 alkyl.

[0060] In an embodiment of the compound of formula (II), X is O, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (II), X is absent, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (II), X is absent, O, S, or -O-(P=O)OHO-. In an embodiment of the compound of formula (II), X is absent, O, S, or NH. In an embodiment of the compound of formula (II), X is absent. In an embodiment of the compound of formula (II), X is O. In an embodiment of the compound of formula (II), X is S. In an embodiment of the compound of formula (II), X is NH. In an embodiment of the compound of formula (II), X is -O-(P=O)OHO-. In an embodiment of the compound of formula (II), X is O, or -O-(P=O)OHO-.

[0061] In an embodiment of the compound of formula (II), Y is O, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (II), Y is absent, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (II), Y is absent, O, S, or -O-(P=O)OHO-. In an embodiment of the compound of formula (II), Y is absent, O, S, or NH. In an embodiment of the compound of formula (II), Y is absent. In an embodiment of the compound of formula (II), Y is O. In an embodiment of the compound of formula (II), Y is S. In an embodiment of the compound of formula (II), Y is NH. In an embodiment of the compound of formula (II), Y is -O-(P=O)OHO-. In an embodiment of the compound of formula (II), Y is O, or -O-(P=O)OHO-.

[0062] In an embodiment of the compound of formula (II), Z is O, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (II), Z is absent, S, NH, and -O-(P=O)OHO-. In an embodiment of the compound of formula (II), Z is absent, O, S, or -O-(P=O)OHO-. In an embodiment of the compound of formula (II), Z is absent, O, S, or NH. In an embodiment of the compound of formula (II), Z is absent. In an embodiment of the compound of formula (II), Z is O. In an embodiment of the compound of formula (II), Z is S. In an embodiment of the compound of formula (II), Z is NH. In an embodiment of the compound of formula (II), Z is -O-(P=O)OHO-. In an embodiment of the compound of formula (II), Z is O, or -O-(P=O)OHO-.

[0063] In an embodiment of the compound of formula (II), n is 1. In an embodiment of the compound of formula (II), n is 2. In an embodiment of the compound of formula (II), n is 3. In an embodiment of the compound of formula (II), n is 4. In an embodiment of the compound of formula (II), n is 5.

[0064] In an embodiment of the compound of formula (II), m is 2. In an embodiment of the compound of formula (II), m is 3. In an embodiment of the compound of formula (II), m is 4. In an embodiment of the compound of formula (II), m is 5.

[0065] In an embodiment of a compound of formula (II), R3 is H and X is absent. In an embodiment of a compound of formula (II), R3 is halogen and X is absent. In an embodiment of a compound of formula (II), R3 is H and X is O. In an embodiment of a compound of formula (II), R3 is C1-C6 alkyl and X is O. In an embodiment of a compound of formula (II), R3 is Cl, F, Br, or I and X is absent. In an embodiment of a compound of formula (II), R3 is F and X is absent.

[0066] In an embodiment of a compound of formula (II), R4 is H and Y is absent. In an embodiment of a compound of formula (II), R4 is halogen and Y is absent. In an embodiment of a compound of formula (II), R4 is H and Y is O. In an embodiment of a compound of formula (II), R4 is C1-C6 alkyl and Y is O. In an embodiment of a compound of formula (II), R4 is Cl, F, Br, or I and Y is absent. In an embodiment of a compound of formula (II), R4 is F and Y is absent.

[0067] In an embodiment of a compound of formula (II), R5 is H and Z is absent. In an embodiment of a compound of formula (II), R5 is halogen and Z is absent. In an embodiment of a compound of formula (II), R5 is H and Z is O. In an embodiment of a compound of formula (II), R5 is C1-C6 alkyl and Z is O. In an embodiment of a compound of formula (II), R5 is Cl, F, Br, or I and Z is absent. In an embodiment of a compound of formula (II), R5 is F and Z is absent. [Table 1-1] [Table 1-2] [Table 1-3]

[0068] composition In embodiments, the disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the disclosure (e.g., a compound of Formula (I), (II) or Table 1), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0069] 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.

[0070] 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, as 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 injection and intravenous injection include administration through catheter.

[0071] Treatment method In one aspect, the disclosure provides a method of treating a disease or 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), (II) or Table 1), or a pharma- ceutically acceptable salt thereof.

[0072] In an embodiment, the disease or disorder is a mental health disease or disorder. In an embodiment, the mental health disease or disorder is selected from the group consisting of major depressive disorder, treatment-resistant depression, substance use disorder, and eating disorder. In an embodiment, the eating disorder includes diseases such as anorexia nervosa, bulimia nervosa, and other disorders related to eating (e.g., binge eating).

[0073] In an embodiment, the mental health disease or disorder is an eating disorder.

[0074] In embodiments, the mental health disease or disorder is selected from the group consisting of obsessive-compulsive disorder, anxiety disorder, stress disorder, and rumination.

[0075] In embodiments, the mental health disease or disorder is a mood disorder, hi embodiments, mood disorders include depressive disorders, such as major depressive disorder or treatment-resistant depression. In an embodiment, the mental health disorder is a substance abuse disorder. In an embodiment, the substance use-related disorder is a disorder of maladaptive patterns of substance use, including criteria such as recurrent substance use-related problems, tolerance to the substance, withdrawal symptoms upon cessation, inability to reduce or control substance use, and abandonment of important social, occupational, or recreational activities due to substance use. For example, see the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In an embodiment, the substance use-related disorder is a disorder resulting from the use of alcohol, caffeine, cannabis, hallucinogens (such as phencyclidine or similarly acting arylcyclohexylamines, and other hallucinogens such as LSD), inhalants, opioids, sedatives, hypnotics, or anxiolytics, stimulants (including amphetamine-type substances, cocaine, and other stimulants), tobacco, and other substances.

[0076] In embodiments, administration of a compound of the present disclosure (e.g., a compound of Formula (I), (II), or Table 1) or a pharma- ceutically acceptable salt thereof releases nitric oxide (NO) (e.g., a compound of the present disclosure is a NO delivery agent). In embodiments, a compound of the present disclosure is useful for releasing NO in vivo.

[0077] Numbered embodiments In addition to the above disclosure, the following examples, and the appended claims, the present disclosure describes the following numbered embodiments: 1. A compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R3, R 4、 and R5 are independently H, halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m -CH(NH2)CH2ONO2, R1 and R6 are independently H, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m -CH(NH2)CH2ONO2, R2 is H or C1-C6 alkyl; and R7 and R7' are independently H, halogen, or C1-C6 alkyl; X, Y, and Z are independently absent, O, S, NH, or -O-(P=O)OHO-; m is 2, 3, or 4; and each n is independently 1, 2, 3, 4, or 5; In the formula, at least one of R1, R3, R4, R5, and R6 is -(C=O)(CR7R7') n -ONO2, -(C=O)(CR7R7') m The compound is -CH(NH2)CH2ONO2. 2. The compound of embodiment 1, wherein R1 is C1-C6 alkyl. 3. The compound of embodiment 1, wherein R1 is methyl. 4. The compound of embodiment 1, wherein R1 is H. 5. The compound according to any one of embodiments 1-4, wherein R2 is C1-C6 alkyl. 6. The compound according to any one of embodiments 1-4, wherein R2 is methyl. 7. The compound according to any one of embodiments 1-4, wherein R2 is H. 8. The compound according to any one of embodiments 1-7, wherein R3 is H and X is absent. 9. The compound according to any one of embodiments 1-7, wherein R3 is halogen and X is absent. 10. A compound according to any one of embodiments 1-7, wherein R3 is H and X is O. 11. A compound according to any one of embodiments 1-7, wherein R3 is C1-C6 alkyl and X is O. 12. A compound according to any one of the preceding embodiments, wherein R4 is H and Y is absent. 13. A compound according to any one of the preceding embodiments, wherein R4 is H and Y is O. 14. A compound according to any one of the preceding embodiments, wherein R4 is halogen and Y is absent. 15. A compound according to any one of embodiments 1-11, wherein R4 is C1-C6 alkyl and Y is O. 16. A compound according to any one of the preceding embodiments, wherein R5 is H and Z is absent. 17. A compound according to any one of the preceding embodiments, wherein R5 is H and Z is O. 18. A compound according to any one of the preceding embodiments, wherein R5 is halogen and Z is absent. 19. A compound according to any one of the preceding embodiments, wherein R5 is C1-C6 alkyl and Z is absent. 20. A compound according to any one of the preceding embodiments, wherein R5 is C1-C6 alkyl and Z is O. 21. R6 is -(C=O)(CR7R7') n The compound of any one of embodiments 1-20, wherein: 22. R6 is -(C=O)(CR7R7') m The compound according to any one of embodiments 1 to 20, wherein the compound is -CH(NH2)CH2ONO2. 23. R6 is -(C=O)(CH2) n The compound of any one of embodiments 1-20, wherein: 24. R6 is -(C=O)(CH2) m The compound according to any one of embodiments 1 to 20, wherein the compound is -CH(NH2)CH2ONO2. 25. A compound according to any one of embodiments 1-20, wherein R6 is -(C=O)(CH2)3-ONO2. 26. The compound of any one of embodiments 1-25, having the following chemical formula: [ka] [ka] [ka] 27. The compound of embodiment 26, having the following chemical formula: [ka] 28. The compound of embodiment 26, having the following chemical formula: [ka] 29. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 28 and a pharma- ceutically acceptable excipient. 30. A method for treating a mental health disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-28 or a pharmaceutical composition according to embodiment 29. 31. A compound of formula (I), [ka] or a pharma- ceutically acceptable salt thereof, wherein: R1, R3, R4, and R5 are independently H, halogen, C1-C6 alkyl, -(C=O)(CR7R7') n -ONO2, or -(C=O)(CR7R7') m -CH(NH2)CH2ONO2, R2 is a C1-C6 alkyl; X, Y, and Z are independently absent, H, O, S, NH, and -O-(P=O)OHO-; m is 2, 3, or 4; each n is independently 1, 2, 3, 4, or 5; A - is a pharma- ceutically acceptable anion; In the formula, at least one of R1, R3, R4, and R5 is -(C=O)(CR7R7') n -ONO2 or -(C=O)(CR7R7') m The compound is -CH(NH2)CH2ONO2. 32. R1 is -(C=O)(CR7R7') n -ONO2. 33. R1 is -(C=O)(CR7R7') m The compound of embodiment 31, wherein the compound is -CH(NH2)CH2ONO2. 34. R1 is -(C=O)(CH2) n -ONO2. 35. R1 is -(C=O)(CH2) m The compound of embodiment 31, wherein the compound is -CH(NH2)CH2ONO2. 36. The compound according to embodiment 31, wherein R1 is -(C=O)(CH2)3-ONO2. 37. The compound according to embodiment 31, wherein R1 is -(C=O)(CH2)2-CH(NH2)CH2ONO2. 38. The compound according to any one of embodiments 31-37, wherein R2 is C1-C3 alkyl. 39. A compound according to any one of embodiments 31-38, wherein R3 is H and X is absent. 40. A compound according to any one of embodiments 31-38, wherein R3 is halogen and X is absent. 41. A compound according to any one of embodiments 31-38, wherein R3 is H and X is O. 42. The compound according to any one of embodiments 31-38, wherein R3 is C1-C6 alkyl and X is O. 43. A compound according to any one of embodiments 31-42, wherein R4 is H and Y is absent. 44. A compound according to any one of embodiments 31-42, wherein R4 is H and Y is O. 45. A compound according to any one of embodiments 31-42, wherein R4 is halogen and Y is absent. 46. ​​A compound according to any one of embodiments 31-42, wherein R4 is C1-C6 alkyl and Y is O. 47. A compound according to any one of embodiments 31-46, wherein R5 is H and Z is absent. 48. A compound according to any one of embodiments 31-46, wherein R5 is H and Z is O. 49. A compound according to any one of embodiments 31-46, wherein R5 is halogen and Z is absent. 50. A compound according to any one of embodiments 31-46, wherein R5 is C1-C6 alkyl and Z is O. 51. A pharmaceutical composition comprising a compound according to any one of embodiments 31 to 50 and a pharma- ceutically acceptable excipient. 52. A method for treating a mental health disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 31-50 or a pharmaceutical composition according to embodiment 51. EXAMPLES

[0078] Example 1: Methods of Preparing Compounds of the Present Disclosure Synthesis of compound 2-1 Prodrug 2-1 was synthesized in three steps from commercially available intermediates 2-1-1 and 2-1-3 and is depicted in Scheme 1.

[0079] [ka]

[0080] Synthesis of intermediate 2-1-1: To a stirred solution of methyl 4-bromobutanoate, 2-1-1 (3 g, 16.5 mmol, 1.0 equiv.) in acetonitrile was added AgNO3 (7.0 g, 41.4 mmol, 2.5 equiv.) in portions at room temperature under argon atmosphere. The resulting mixture was stirred overnight at 80° C. under nitrogen atmosphere. A new pot could be detected by TLC. The resulting mixture was filtered and the filter cake was washed with acetonitrile (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL). The resulting mixture was washed with 2×500 mL of water, and then the resulting mixture was washed with 3×300 mL of brine. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 4-(nitrooxy)butanoate, 2-1-2 (2.3 g, 85.08%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0081] Synthesis of intermediate 2-1-4 and final product 1-(3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-4-(nitrooxy)butanoate (2-1): To a stirred solution of tryptamine (200 mg, 1.2 mmol, 1.0 equiv) and NaBH3CN (235.3 mg, 3.7 mmol, 3.0 equiv), AcOH (0.2 mL) in MeOH was added formaldehyde solution (187.4 mg, 6.24 mmol, 5.0 equiv) dropwise at 0° C. under argon atmosphere. The resulting mixture was stirred overnight at room temperature under argon atmosphere. The desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the intermediate as a yellow solid. To a stirred solution of the intermediate and methyl 4-(nitrooxy)butanoate (610.8 mg, 3.7 mmol, 3.0 equiv.) in THF was added dropwise at 0° C. under argon atmosphere. The resulting mixture was stirred at 0° C. for 1 h under argon atmosphere. The desired product could be detected by LCMS. The reaction was quenched with MeOH at 0° C. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography using a C18 silica gel column, a mobile phase of aqueous MeCN (0.1% FA), a 5% to 80% gradient in 40 min, and a UV detector at 254 nm to give 25 mg of 1-(3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-4-(nitrooxy)butanoate (2-1) as a white solid. LCMS of 2-1: [M+H] + 320.10 HNMR-2-1:(400MHz,DMSO-d6)δ8.07(d,J=8.2Hz,1H),7.62(d,J=7.7Hz,1H),7.52(s,1H),7.36-7.25(m, 2H), 4.79(t,J=6.7Hz,2H),4.47(t,J=6.0Hz,2H),2.80(t,J=7.5Hz,2H),2.57-2.40(m,4H),2.22(s,6H).

Claims

1. A compound of formula (II): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: R ３ , R ４ , and R ５ are independently H, halogen, C １ ~C ６ Alkyl, —(C═O)(CR ７ R ７ ') ｎ -ONO ２ , or -(C=O)(CR ７ R ７ ') ｍ -CH(NH ２ ) CH ２ ONO ２ and R １ , and R ６ are independently H, C １ ~C ６ Alkyl, —(C═O)(CR ７ R ７ ') ｎ -ONO ２ , or -(C=O)(CR ７ R ７ ') ｍ -CH(NH ２ ) CH ２ ONO ２ and R ２ is H or C １ ~C ６ is alkyl, and R ７ and R ７ ' are independently H, halogen, or C １ ~C ６ is alkyl, X, Y, and Z are independently absent, O, S, NH, or —O—(P═O)OHO—; m is 2, 3, or 4; and each n is independently 1, 2, 3, 4, or 5; In the formula, R １ , R ３ , R ４ , R ５ , and R ６ At least one of the groups is -(C=O)(CR ７ R ７ ') ｎ -ONO ２ , or -(C=O)(CR ７ R ７ ') ｍ -CH(NH ２ ) CH ２ ONO ２ A compound.

2. R １ is C １ ~C ６ The compound of claim 1 , wherein the aryl group is alkyl.

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

4. R １ The compound of claim 1 , wherein

5. R ２ is C １ ~C ６ The compound of claim 1 , wherein the aryl group is alkyl.

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

7. R ２ The compound of claim 1 , wherein

8. R ３ 2. The compound of claim 1, wherein: is H and X is absent.

9. R ３ 2. The compound of claim 1, wherein: is a halogen and X is absent.

10. R ３ 2. The compound of claim 1, wherein: is H and X is O.

11. R ３ is C １ ~C ６ 2. The compound of claim 1, wherein X is alkyl and X is O.

12. R ４ 2. The compound of claim 1, wherein: is H and Y is absent.

13. R ４ 2. The compound of claim 1, wherein: is H and Y is O.

14. R ４ 2. The compound of claim 1, wherein: is a halogen and Y is absent.

15. R ４ is C １ ~C ６ 2. The compound of claim 1, wherein Y is alkyl and Y is O.

16. R ５ 2. The compound of claim 1, wherein: is H and Z is absent.

17. R ５ 2. The compound of claim 1, wherein: is H and Z is O.

18. R ５ 2. The compound of claim 1, wherein: is a halogen and Z is absent.

19. R ５ is C １ ~C ６ 2. The compound of claim 1, wherein Z is alkyl and Z is absent.

20. R ５ is C １ ~C ６ 2. The compound of claim 1, wherein Z is alkyl and Z is O.

21. R ６ is -(C=O)(CR ７ R ７ ') ｎ -ONO ２ 2. The compound of claim 1, wherein:

22. R ６ is -(C=O)(CR ７ R ７ ') ｍ -CH(NH ２ ) CH ２ ONO ２ 2. The compound of claim 1, wherein:

23. R ６ is -(C=O)(CH ２ ) ｎ -ONO ２ 2. The compound of claim 1, wherein:

24. R ６ is -(C=O)(CH ２ ) ｍ -CH(NH ２ ) CH ２ ONO ２ 2. The compound of claim 1, wherein:

25. R ６ is -(C=O)(CH ２ ) ３ -ONO ２ 2. The compound of claim 1, wherein:

26. 2. The compound of claim 1 having one of the following chemical formulas: 【Chemistry 2-1】 【Chemistry 2-2】 [Chemistry 2-3]

27. 27. The compound of claim 26 having the following chemical formula: 【Transformation 3】

28. 27. The compound of claim 26 having the following chemical formula: 【Chemistry 4】

29. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

30. A compound of formula (I), 【Transformation 5】 or a pharmaceutically acceptable salt thereof, wherein: R １ , R ３ , R ４ , and R ５ are independently H, halogen, C １ ~C ６ Alkyl, —(C═O)(CR ７ R ７ ') ｎ -ONO ２ , or -(C=O)(CR ７ R ７ ') ｍ -CH(NH ２ ) CH ２ ONO ２ and Each R ２ are independently １ ~C ６ is alkyl, X, Y, and Z are independently absent, H, O, S, NH, and —O—(P═O)OHO—; m is 2, 3, or 4; each n is independently 1, 2, 3, 4, or 5; A － is a pharmaceutically acceptable anion, In the formula, R １ , R ３ , R ４ , and R ５ At least one of the groups is -(C=O)(CR ７ R ７ ') ｎ -ONO ２ or -(C=O)(CR ７ R ７ ') ｍ -CH(NH ２ ) CH ２ ONO ２ A compound.

31. R １ is -(C=O)(CR ７ R ７ ') ｎ -ONO ２ 31. The compound of claim 30, wherein:

32. R １ is -(C=O)(CR ７ R ７ ') ｍ -CH(NH ２ ) CH ２ ONO ２ 31. The compound of claim 30, wherein:

33. R １ is -(C=O)(CH ２ ) ｎ -ONO ２ 31. The compound of claim 30, wherein:

34. R １ is -(C=O)(CH ２ ) ｍ -CH(NH ２ ) CH ２ ONO ２ 31. The compound of claim 30, wherein:

35. R １ is -(C=O)(CH ２ ) ３ -ONO ２ 31. The compound of claim 30, wherein:

36. R １ is -(C=O)(CH ２ ) ２ -CH(NH ２ ) CH ２ ONO ２ 31. The compound of claim 30, wherein:

37. R ２ is C １ ~C ３ 31. The compound of claim 30, which is alkyl.

38. R ３ 31. The compound of claim 30, wherein is H and X is absent.

39. R ３ 31. The compound of claim 30, wherein is a halogen and X is absent.

40. R ３ 31. The compound of claim 30, wherein is H and X is O.

41. R ３ is C １ ~C ６ 31. The compound of claim 30, wherein X is alkyl and X is O.

42. R ４ 31. The compound of claim 30, wherein is H and Y is absent.

43. R ４ 31. The compound of claim 30, wherein is H and Y is O.

44. R ４ 31. The compound of claim 30, wherein is halogen and Y is absent.

45. R ４ is C １ ~C ６ 31. The compound of claim 30, wherein Y is alkyl and Y is O.

46. R ５ 31. The compound of claim 30, wherein is H and Z is absent.

47. R ５ 31. The compound of claim 30, wherein is H and Z is O.

48. R ５ 31. The compound of claim 30, wherein is halogen and Z is absent.

49. R ５ is C １ ~C ６ 31. The compound of claim 30, wherein Z is alkyl and Z is O.

50. 31. A pharmaceutical composition comprising the compound of claim 30 and a pharmaceutically acceptable excipient.

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