N-substituted tryptamines and n-substituted lysergamides and their use as therapeutic agents

Abstract

Provided are N-substituted tryptamine and N-substituted lysergamide compounds, methods of making the same, and methods of using such compounds, for example, as receptor probes, as modulators of neurotransmission, and as therapeutic agents, for example as CNS agents. Also provided are pharmaceutical compositions comprising the disclosed compounds and methods of their use, such as in the treatment of disorders related to serotonergic neurotransmission, including multidimensional and complex neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD), bipolar disorder, and psychotic disorders like schizophrenia, as well as in the treatment of ion-channel mediated conditions, such as seizure disorders.

Description

[0001] N-SUBSTITUTED TRYPTAMINES AND N-SUBSTITUTED LYSERGAMIDES AND THEIR USE AS THERAPEUTIC AGENTS

[0002] INVENTOR: Nicholas V. Cozzi

[0003] CROSS-REFERENCE

[0004]

[0001] Priority is claimed under PCT Art. 8(1) and Rule 4.10 to U.S. Provisional Appl. Nos. 63 / 614,467 and 63 / 614,490, both filed December 23, 2023, and both fully incorporated herein by reference for all purposes.

[0005] TECHNICAL FIELD

[0006]

[0002] This disclosure relates in some aspects to N-substituted tryptamine and N-substituted lysergamide compounds. In some further aspects, it also relates to methods of synthesizing the compounds, compositions containing the compounds, and methods of using such compounds, including their administration to subjects. In yet further aspects, useful features of the compounds include neuromodulatory and therapeutic activity.

[0007] BACKGROUND OF THE INVENTION

[0008]

[0003] Psychedelic compounds, including tryptamines such as psilocybin and dimethyltryptamine (DMT), and lysergamides such as lysergic acid diethylamide (LSD), show promise as therapeutic candidates for numerous neuropsychiatric disorders (see, e.g., Vollenweider & Preller. Nat Rev Neurosci. 2020;21 (11):611-624; D’Souza et al. Neuropsychopharmacol. 2022; 47(10): 1854-1862; Nichols. ACS Chem Neurosci. 2018;9(10):2331 -2343; Brandt et al. Drug Test Anal. 2020; 12(6):812-826). Many questions persist however concerning the safety and efficacy of psychedelic compounds in the treatment of multidimensional and complex neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD), bipolar disorder, and psychotic disorders like schizophrenia.

[0009]

[0004] Aside from their use for neuropsychiatric disorders, there is increasing interest in the potential application of tryptamines and lysergamides in the treatment of physical and neurological conditions and disorders, especially where such treatment is without subjective or “psychedelic” effects. Among lysergamides, for example, 2-bromo-LSD shows potential to treat cluster headache (Karst et al. Cephalalgia. 2010;30(9): 1140-1144).

[0010]

[0005] Altogether, there are important and ongoing unmet needs for alternative treatments, for both neuropsychiatric disorders and physical and neurological disorders, especially those which minimize side effects, show greater efficacy, increase access, and improve upon existing agents through new therapeutic mechanisms.

[0006] Provided herein are compounds, compositions, methods, uses, and kits to meet this need and others, and having such advantages and improvements as will become readily apparent through the disclosure below.

[0011] INCORPORATION BY REFERENCE

[0012]

[0007] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each was incorporated by reference individually, and as if each is fully set forth herein. However, no such citation should be construed as an admission that a cited reference is from an area that is analogous or directly applicable to the invention, nor should any citation be construed as an admission that a document or underlying information, in any jurisdiction, is prior art or part of the common general knowledge in the art. BRIEF SUMMARY OF THE INVENTION

[0013]

[0008] The following is a simplified summary of some embodiments of the invention in order to provide a basic understanding thereof. It is not an extensive overview of the invention, nor intended to identify key or critical elements of the invention or to delineate its scope. Its purpose is to present some embodiments and aspects of the invention in a simplified form as a prelude to the detailed description that follows.

[0014]

[0009] In some aspects are disclosed compounds of Formula (I):

[0015] D-(CH2)mX(CH2)nPh (I), or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein: m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14;

[0016] X is 0, S, or NH;

[0017] Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and wherein the * indicates the point of connection to — (CH2)mX(CH2)nPh; and wherein:

[0018] Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6- C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or any two of Ra, Rb, R2, R4, R5, R6, and R7are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and the remaining Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alky nyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0019] R' is H, D, PO3H2, or C(O)-C1-C8 alkyl; and

[0020] RNis H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl; or wherein the * indicates the point of connection to — (CH2)mX(CH2)nPh; and wherein:

[0021] RN1is:

[0022] (a) H, deuterium (D), C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0023] (b) taken together with RN2and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0024] RN2, if present, is:

[0025] (a) H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0026] (b) taken together with RN1and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0027] R2, R12, R13, and R14are each independently selected from the group consisting of hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0028] R9is H or D; and

[0029] R6, if present, is hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and

[0030] R' is H, D, PO3H2, or C(O)-C1-C8 alkyl.

[0031]

[0010] In some aspects are provided compounds of Formula (1) wherein m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14;

[0032] X is 0, S, or NH;

[0033] Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6- C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or any two of Ra, Rb, R2, R4, R5, R6, and R7are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and the remaining Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alky nyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0034] R' is H, D, PO3H2, or C(O)-C1-C8 alkyl;

[0035] RNis H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl;

[0036] Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[0037]

[0011] In some embodiments, R4is OR'. In some embodiments, R' is H. In some embodiments, R' is PO3H2. In some embodiments, R' is C(O)-C1-C8 alkyl. In some embodiments, R' is C(O)-CH3. In some embodiments, R5is C1-C8 alkoxy. In some embodiments, R5is methoxy.

[0038]

[0012] In some embodiments, the compound has the structure of any of Formulas (IIA), (IIB), and (IIC), or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein such Formulas are as follows:

[0039]

[0013] In some embodiments, RNis H. In some embodiments, RNis C1-C8 alkyl. In some embodiments, RNis methyl, ethyl, or isopropyl. In some embodiments, RNis C2-C8 alkenyl. In some embodiments, RNis allyl. In some embodiments, RNis C2-C8 alkynyl. In some embodiments, Ph is unsubstituted phenyl. In some embodiments, Ph is phenyl substituted by azido, D, NH2, OAc, or C1-C8 alkoxy. In some embodiments, X is 0.

[0014] In some embodiments, the sum of m + n is from 8 to 12. In embodiments, the sum of m + n is from 9 to 11. In some embodiments, the sum of m + n is 10. In some embodiments, m is 6 and n is 4.

[0040]

[0015] In some embodiments, and:

[0041] RN1is:

[0042] (a) H, deuterium (D), C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0043] (b) taken together with RN2and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0044] RN2is:

[0045] (a) H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2- C8 alkynyl; or

[0046] (b) taken together with RN1and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0047] (c) - (CH2)mX(CH2)nPh;

[0048] R2, R12, R13, and R14are each independently selected from the group consisting of hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0049] R9is H or D; (a) hydrogen, D, halogen, OR1, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0050] (b) - (CH2)mX(CH2)nPh;

[0051] R’ is H, D, PO3H2, or C(O)-C1-C8 alkyl; m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14;

[0052] X is O, S, or NH;

[0053] Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[0054]

[0016] In some embodiments, the compound has the structure of either Formula (IIIA) or Formula (IIIB): or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[0055]

[0017] In some embodiments, Ph is unsubstituted phenyl. In some embodiments, Ph is phenyl substituted by azido, D, NH2, OAc, or C1-C8 alkoxy. In some embodiments, X is 0. In some embodiments, the sum of m + n is from 8 to 12. 1 n some embodiments, the sum of m + n is from 9 to 11 . 1 n some embodiments, the sum of m + n is 10. In some embodiments, m is 6 and n is 4.

[0056]

[0018] In some embodiments, the compound is selected from Table 2, Table 3, Table 4, Table 5, or Table 6, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[0057]

[0019] In some aspects are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, or transdermal administration. In some embodiments, the composition is in unit dosage form. In some embodiments, the unit dosage form is in a total amount of between about 1 and about 500 mg, between about 2.5 and about 250 mg, or between about 5 and about 125 mg. In some embodiments, the composition is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

[0058]

[0020] In some embodiments, a disclosed pharmaceutical composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, such as selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, entactogens, empathogens, entheogens, psychedelics, plasticity-inducing agents, psychoplastogens, neuroplastogens), monoamine oxidase inhibitors, RIMAs, tryptamines, terpenes, phenethylamines, aphrodisiacs, oneirogens, sedatives, stimulants, serotonergic agents, and vitamins, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[0059]

[0021] In some aspects the provided compounds, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, are for use in the treatment of a medical condition. In some further aspects are provided the use of a disclosed compound, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, for the manufacture of a medicament to treat a medical condition. In yet further aspects are provided methods for modulating neurotransmission in a mammal, comprising administering to the mammal a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[0060]

[0022] In still further aspects are provided methods of treating a medical condition in a mammal in need of such treatment, the method comprising administering a disclosed compound, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof. In some embodiments, the medical condition is a disorder linked to dysregulation or inadequate functioning of neurotransmission. In some embodiments, the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission. In some embodiments, the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of serotonergic neurotransmission. In some embodiments, the medical condition is a mental health disorder.

[0061]

[0023] In some embodiments, the mental health disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, a substance-induced psychotic disorder, bipolar disorder, bipolar type I disorder, bipolar type II disorder, cyclothymic disorder, post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, alcohol or drug abuse or dependence disorders, a substance use disorder, substance-induced mood disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, and dissociative disorders.

[0062]

[0024] In some embodiments, the medical condition is a seizure disorder. In some embodiments, the seizure disorder is epilepsy. In some embodiments, the medical condition is a disorder linked to dysregulation or inadequate functioning of a voltage-gated ion channel. In some embodiments, the voltage-gated ion channel is a voltage-gated sodium channel. In some embodiments, the compound inhibits the activity of the voltage-gated sodium channel. In some embodiments, the mammal has a genetic variation associated with drug metabolism, associated with a mental health disorder, or relating to a membrane transporter. In some embodiments, the mammal has altered epigenetic regulation of a gene the expression of which is associated with a mental health condition or with susceptibility to a mental health condition. In some embodiments, the mammal is a human.

[0063]

[0025] In still further aspects are provided methods of reducing the symptoms of a mental health disorder in a human, comprising identifying a human in need of said reducing, and administering to the human a disclosed compound, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof. In still further aspects are provided methods of reducing the symptoms of a mental health disorder in a human, comprising identifying a human in need of said reducing, and administering to the human a disclosed pharmaceutical composition.

[0064]

[0026] In still further aspects are provided methods of improving mental health or functioning in a human, the method comprising identifying a human in need of said improving, and administering to the human a disclosed compound, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof. In still further aspects are provided methods of improving mental health or functioning in a human, the method comprising identifying a human in need of said improving, and administering to the human a disclosed pharmaceutical composition.

[0065]

[0027] The foregoing has outlined broadly and in summary certain pertinent features of the disclosure so that the detailed description that follows may be better understood, and so that the present contribution to the art can be more fully appreciated. Hence, this summary is to be considered as a brief and general synopsis of only some of the objects and embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the claims are lawfully entitled. Additional features of the invention are described hereinafter. It should be appreciated by those in the art that all disclosed specific compositions and methods are only exemplary, and may be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purposes. Such equivalent compositions and methods will be appreciated to be also within the scope and spirit of the invention as set forth in the claims. The headings in this document are utilized only to expedite its review by a reader and must not be construed as limiting the invention in any manner.

[0066] DETAILED DESCRIPTION OF THE INVENTION

[0067]

[0028] While various aspects and embodiments are summarized above, certain exemplary embodiments are described in further detail to enable one of skill in the art to practice the invention, including to make and use the full scope of the invention as is now or will be claimed. Examples are illustrative only, and not to limit the scope of the invention or its applications. Many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention illustrated herein can be made by those in the art without departing from the spirit of the invention, or the scope of the invention as described in the claims. A. General Definitions and Terms

[0068]

[0029] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an active agent” includes reference to a combination of two or more active agents, and reference to “an excipient” includes reference to a combination of two or more excipients. While the term “one or more” may be used, its absence (or its replacement by the singular) does not signify the singular only, but simply underscores the possibility of multiple agents or ingredients in particular embodiments.

[0069]

[0030] The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements). Thus, the term “including” means, and is used interchangeably with, the phrase “including but not limited to.” The term “or” means, and is used interchangeably with, the term “and / or,” unless context clearly indicates otherwise.

[0070]

[0031] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about,” even where not so stated explicitly. In alternative embodiments, such numbers will be understood as not being modified by the term “about.” In some embodiments (equivalently, and as shorthand, “in embodiments”), the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In embodiments, “about” may refer to plus or minus five percent (±5%) of the recited unit of measure. In other embodiments, “about” may refer to plus or minus ten percent (±10%) of the recited unit of measure. Where “about” is used to modify one number in a series or range, it is understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range; thus, the term “about 1 , 2, or 3” is understood to mean “about 1 , about 2, or about 3” and the term “about 1 to 10” means “about 1 to about 10.” The term “substantially,” where it is applied to modify a feature or limitation herein, will be read in the context of the invention and in light of the knowledge in the art to provide the appropriate certainty, e.g., by using a standard that is recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the art.

[0071]

[0032] In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. “In embodiments” may be used equivalently with, and only as shorthand for, “in some embodiments.” “Embodiments” refers to disclosed embodiments and their equivalents.

[0072]

[0033] Terms herein may be referred to by a shorthand, and the shorthand will have the same meaning as the complete term. For example, a “pharmaceutical composition” may be referred to simply as shorthand, unless context clearly indicates otherwise, as a “composition,” and other such shorthand will be readily understood in view of the disclosure. Unless context indicates a distinction relevant to a described or claimed embodiment, "composition" and "formulation" are used interchangeably and equivalently herein.

[0073]

[0034] A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill appears in the first issue of each volume of the Journal of Organic Chemistry, typically presented in the table “Standard List of Abbreviations.” The current list as of the filing date is incorporated by reference as if fully set forth herein.

[0074]

[0035] The nomenclature used and procedures performed herein are generally from fields relating to one or more aspects of the invention, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, and / or medicinal chemistry, and will be well known and commonly employed in such fields.

[0075]

[0036] Unless described otherwise, disclosed techniques and procedures are those that are standard and known in the art, and performed according to conventional methods in the art. If no techniques or procedures are expressly disclosed for any methods or steps herein, it may be inferred that one or more standard techniques or procedures is performed. Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by a person having ordinary skill in the art to which this invention belongs, who as a shorthand may be referred to simply as “one of skill” or “the skilled artisan” and similar terms.

[0076]

[0037] Further definitions to assist a reader in understanding the embodiments are below and throughout; however, such definitions are not intended to limit the scope of the invention, which is properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill in the relevant art) in view of the language used in the claims. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0077]

[0038] “Alkyl” will be understood to include straight-chain or branched radicals having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” can also be used. In some embodiments, an alkyl group comprises from 1-10 carbon atoms, from 1-6 carbon atoms, from 1-4 carbon atoms, or from 1-3 carbon atoms (inclusive). For any alkyl, the alkyl may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH)2, -OC(O)H, -OSO2OH, -OC(O)NH2, or — SONH2.

[0078]

[0039] “Alkanyl” refers to saturated branched, straight-chain, or cyclic alkyl radicals derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Alkanyl groups include methanyl; ethanyl; propanyls such as propan-1 -yl, propan-2-yl (isopropyl), and cyclopropan-1-yl; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1 -yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), and cyclobutan-1-yl; etc.

[0079]

[0040] “Alkenyl” refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Alkenyl groups include ethenyl; propenyls such as prop-1 -en-1-yl, prop-1 -en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1 -en-1-yl, and cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1 -en-2-yl, 2-methyl-prop-1-en- 1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2yl, buta-1 ,3-dien-1-yl, buta-1 ,3-dien-2-yl, cyclobut-1 -en-1 -yl, cyclobut-1 -en-3-yl, and cyclobuta-1 ,3-dien-1 -yl; and the like.

[0080]

[0041] “Alkynyl” refers to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Alkynyl groups include ethynyl; propynyls such as prop-1 -yn-1-yl, and prop-2-yn-1 -yl; butynyls such as but-1 -yn-1-yl, but-1 -yn-3-yl, and but-3-yn-1 -yl; and the like.

[0081]

[0042] “Aryl” refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. Preferably, an aryl group comprises from 6 to 20 or more preferably from 6 to 12 carbon atoms.

[0082]

[0043] “Cycloalkyl” refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Monocyclic cycloalkyl rings include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds. Bicyclic and polycyclic cycloalkyl rings include, e.g., norbornane, bicyclooctane, decahydronaphthalene and adamantane. When cycloalkyl is a monocyclic C3-8 cycloalkyl, exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a monocyclic C3-6 cycloalkyl, exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0083]

[0044] “Cycloalkenyl” refers to a mono- or multi-cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring. However, if there is more than one double bond, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. Cycloalkenyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Representative cycloalkenyl groups include cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1 ,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1 ,3-, 1 ,4- and 1 ,5-isomers), norbornene, and norbornadiene. A cycloalkenyl group may be unsubstituted or substituted.

[0084]

[0045] “Halogen” refers to fluorine, chlorine, bromine, and iodine.

[0085]

[0046] “Heterocycloalkyl” or “heterocyclyl” refers to a cycloalkyl as defined above, having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Heterocycloalkyl includes bicyclic compounds which include a heteroatom. Bicyclic compounds includes spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds The heteroatoms also can be oxidized, such as — S(O)— and — S(O)2— . Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 , or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1 , 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1 ,2-, 1 ,3- and 1 ,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with C1-6 alkyl or oxo (=0), among many others.

[0086]

[0047] “Alkyl-heterocycloalkyl” refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heterocycloalkyl component and to the point of attachment. The alkyl component can include any number of carbons, such as CO-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent. The heterocycloalkyl component is as defined above. Alkyl-heterocycloalkyl groups can be substituted or unsubstituted.

[0048] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, 0 or S. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 , or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1 , 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1 ,2,4- and 1 ,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0087]

[0049] “Alkyl-heteroaryl” refers to a radical having an alkyl component and a heteroaryl component, where the alkyl links the heteroaryl to the point of attachment. The alkyl component is as defined herein, except the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of attachment. The alkyl component can include any number of carbons, such as CO-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component is absent. The heteroaryl component is as defined herein. Alkyl-heteroaryl groups can be substituted or unsubstituted.

[0088]

[0050] “Alkoxy” refers to the formula —OR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n- propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0089]

[0051] “Acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, connected via a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.

[0090]

[0052] “Aryloxy” refers to an aryl moiety, as defined herein, attached to an oxygen atom, wherein the oxygen atom serves as the attaching point to the remainder of the molecule. Aryloxy groups include phenoxy, tolyloxy (including p-tolyloxy, m-toyloxy, and o-tolyloxy), ethylphenyloxy (including p-ethylphenyloxy, m-ethylphenyloxy, and o-ethylphenyloxy), naphthyloxy, and the like. An aryloxy may be substituted or unsubstituted.

[0091]

[0053] “Alkylamino” refers to groups such as N-alkylamino (i.e., R— NHR’) and N,N-dialkylamino (i.e., R— NR’R”), wherein the amino groups are independently substituted with one alkyl radical (i.e., R’) or with two alkyl radicals (i.e., R’ and R”), respectively; and wherein R represents an alkyl as defined herein. Examples of alkylamino radicals include mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N, N-diethylamino, and the like. An alkylamino can be unsubstituted or substituted.

[0092]

[0054] “Alkylthio” or “thioalkyl” refer to the formula —SR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, as defined herein. Wherein R is aryl, the —SR moiety is termed “thioaryl.” Alkylthios and thioalkyls include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, phenylthio, and benzylthio. An alkylthio or thioalkyl may be substituted or unsubstituted.

[0093]

[0055] “Arylamido” refers to an aryl moiety, as defined herein, attached to an amide moiety, wherein the amide moiety serves as the attaching point to the remainder of the molecule. In some embodiments, an arylamido has the formula Ar— C(=O)NH— * or Ar— NH— C(=O)— *, wherein Ar is aryl as defined herein, and * represents the point of connection to the remainder of the molecule. An arylamido can be substituted or unsubstituted.

[0094]

[0056] “Alkylamido” refers to an alkyl moiety, as defined herein, attached to an amide moiety, wherein the amide moiety serves as the attaching point to the remainder of the molecule. In some embodiments, an alkylamido has the formula Ak— C(=O)NH— * or Ak— NH— C(=O)— *, wherein Ak is alkyl as defined herein, and * represents the point of connection to the remainder of the molecule. An alkylamido can be substituted or unsubstituted.

[0095]

[0057] “Haloalkyl” will be understood to include any alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen (e.g., a fluorine, a chlorine, a bromine, or an iodine). Where an alkyl radical is substituted by more than one halogen, it may be referred to using a prefix corresponding to the number of halogen substitutions, e.g., di haloalkyl refers to an alkyl substituted by two halo groups, which may or may not be the same halogen. Haloalkyl groups include difluoromethyl (— CHF2), bromofluoromethyl (— CHBrF), trifluoromethyl (— CF3), and 2-fluoroethyl (— CH2CH2F). Additional examples of haloalkyl groups include — CHF2, -CH2F, -CH2CF3, - CH2CHF2, - CH2CH2F, -CH(CH3)(CF3), -CH(CH3)(CHF2), and -CH(CH3)(CH2F).

[0096]

[0058] “Hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Hydroxyalkyl groups include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2- dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0097]

[0059] “Haloalkoxy” refers to an — O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). The halogens may be the same or different in each instance. Such groups include chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1- chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0098]

[0060] “Sulfenyl” refers to an —SR group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A sulfenyl may be substituted or unsubstituted.

[0099]

[0061] “Sulfinyl” refers to an — S(=O)— R group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted. “Sulfonyl” refers to an — SO2R group in which R can be the same as defined with respect to sulfenyl. “Alkylsulfonyl” specifically refers to an — SO2R group in which R is alkyl, as defined herein. A sulfonyl (or alkylsulfonyl) may be substituted or unsubstituted.

[0100]

[0062] “Carboxy” refers to a — RC(=O)O— group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A carboxy may be substituted or unsubstituted.

[0063] “Ester” and “C-carboxy” refer to a — C(=O)OR group in which R can be the same as defined with respect to O-carboxy. “Alkyl ester” refers to a — C(=O)OR group in which R is alkyl, as defined herein. Ester and C- carboxy groups may be substituted or unsubstituted.

[0101]

[0064] “Thiocarbonyl” refers to a — C(=S)R group in which R can be the same as defined with respect to 0- carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0102]

[0065] “Trihalomethanesulfonyl” refers to an X3CSO2— group wherein each X is a halogen.

[0103]

[0066] “Trihalomethanesulfonamido” refers to an X3CS(O)2N(RA)— group wherein each X is a halogen, and RA is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein.

[0104]

[0067] “S-sulfonamido” refers to a — S02N(RARB) group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An S-sulfonamido may be substituted or unsubstituted. “N-sulfonamido” refers to a RS02N(RA)— group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-sulfonamido may be substituted or unsubstituted.

[0105]

[0068] “Carbamoyl” includes O-carbamoyl and N-carbamoyl groups. “O-carbamoyl” refers to a — 0C(=0)N(RARB) group in which RA and Rs can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carbamoyl may be substituted or unsubstituted. “N- carbamoyl” refers to an R0C(=0)N(RA)— group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-carbamoyl may be substituted or unsubstituted.

[0106]

[0069] “O-thiocarbamyl” refers to a — OC(=S)— N(RARB) group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An 0- thiocarbamyl may be substituted or unsubstituted. “N-thiocarbamyl” refers to an R0C(=S)N(RA)— group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-thiocarbamyl may be substituted or unsubstituted.

[0107]

[0070] “C-amido” group refers to a — C(=0)N(RARB) group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A C-amido may be substituted or unsubstituted. “N-amido” refers to a RC(=0)N(RA)— group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-amido may be substituted or unsubstituted.

[0108]

[0071] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted, or substituted by one or more of the substituents listed for that group. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. When there are more than one substituents, the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. If no substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, 0- carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group, a di-substituted amino group, and a tri-substituted amino group.

[0109]

[0072] All groups defined above, even where not stated, can be substituted or unsubstituted.

[0110]

[0073] Still additional definitions and abbreviations are provided elsewhere herein.

[0111] B. Compounds

[0112]

[0074] Psychedelics are a unique class of psychoactive drugs defined by their ability to alter thought, feeling, and perception (Masters and Houston, The Varieties of Psychedelic Experience., Dell Publishing Co., Inc., 1966; Nichols. Pharmacol Rev. 2016;68(2):264-355). Major chemotypes of the psychedelic class include phenylalkylamines, tryptamines, and lysergamides (Nichols. Pharmacol Rev. 2016;68(2):264-355). The typical psychoactive effects on consciousness of psychedelic tryptamines such as psilocin are primarily mediated via activation of the 5-HT2A subtype of serotonin (5-HT) receptors (Glennon et al. Life Sci. 1984;35(25):2505-2511 ; Titeler et al. Psychopharmacology (Berl). 1988;94(2): 213-216; Vollenweider et al. Neuroreport. 1998; 9(17): 3897-3902). It is believed that activation of the 5-HT2A receptor is also important for the psychoactivity of lysergamides such as lysergic acid diethylamide (LSD), and phenethylamines such as 2-(4-bromo-2,5- dimethoxyphenyl) ethanamine (2C-B) (Shulgin and Carter. Psychopharmacol Common 1. 1975;93-98).

[0113]

[0075] The 5-HT2A receptor, like the 02 adrenergic receptor, belongs to the superfamily of G protein-coupled receptors containing seven transmembrane domains (TMDs). Addition of a phenethyloxyhexyl side-chain to the 02 agonist salbutamol resulted in salmeterol, a 02 agonist with improved potency and duration of action in the treatment of bronchoconstriction associated with asthma and chronic obstructive pulmonary disease (COPD) (Johnson. Med Res Rev. 1995;15(3):225-257). The extended linear dimension of the salmeterol molecule (25 A) compared to the salbutamol molecule (11 A) allows the side-chain of salmeterol to bind to an accessory binding region within the 02 receptor, distinct from the agonist binding domain, termed the exosite (Johnson. Med Res Rev. 1995; 15(3):225-257; Masureel et al. Nat Chem Biol. 2018;14(11 ):1059-1066).

[0114]

[0076] Evidence from site-directed mutagenesis, chimeric P1 / P2 receptors, photoaffinity labelling, x-ray diffraction crystallography, and computer modeling of the 02 receptor localizes the exosite within TMDs 4, 6, and 7 and extracellular loops (ECL) 2 and 3 of the 02 receptor. (Green et al. J Biol Chem. 1996; 271 (39):24029-24035; Isogaya et al. Mol Pharmacol. 1998; 54(4):616-622; Johnson. Med Res Rev. 1995; 15(3):225-257; Masureel et al. Nat Chem Biol 2018;14(11):1059-1066; Rong et al. Biochemistry. 1999;38(35):11278-11286). The X-ray crystal structure of salmeterol bound to the 02 receptor shows that the aryloxyalkyl tail occupies a cleft formed by residues from extracellular loop ECL2, ECL3, and the extracellular ends of TMD6 and TMD7 (Masureel et al. Nat Chem Biol. 2018; 14(11 ): 1059-1066).

[0115]

[0077] Following an amino acid sequence alignment between the human 02 receptor and the human 5-HT2A receptor using the UniProt Align alignment routine (https: / / www.uniprot.org / ), it was observed that the amino acid sequences in three TMDs of the 5 HT2A receptor show high sequence homology (70-94%) with the three TMDs comprising the 02 receptor exosite, while ECL 2 and 3 exhibited lower homology (<50% conserved). Based on these sequence homologies, it was hypothesized that the 5-HT2A receptor, like the 02 receptor, contains an exosite that might engage an extended N-linked side-chain of a modified 5-HT2A agonist.

[0116]

[0078] Also in view of this discovery is Applicant’s International Patent Appl. No. PCT / US2023 / 026258, filed June 26, 2023 and published as W02024 / 006226, and its U.S. Provisional Appl. No. 63 / 355,632, filed June 26, 2022, as well as Denomme et al. Mol Pharmacol. 2024; 106(2):92-106, all fully incorporated by reference herein.

[0117]

[0079] Provided are compounds comprising a 5-HT2A-binding (e.g., 5-HT2A agonist) fragment; connected to a linker (e.g., an alkylene linker, wherein one or more methylene units is optionally replaced by a heteroatom such as O, S, or NH); connected to a 5-HT2A exosite-binding fragment (e.g., an optionally substituted phenyl ring).

[0118]

[0080] In some embodiments, the compounds are substituted tryptamines. In some embodiments, the 5-HT2A- binding fragment is a tryptamine. In embodiments, the compounds are substituted tryptamines bearing an N- linked side chain. In embodiments, the substituted tryptamine is a tryptamine having one of its amine substituents replaced by an N-linked side chain, wherein the tryptamine is any of (where “-T” in any compound name means “tryptamine”): O-phosphoryl-4-hydroxy-N,N-dimethyl-T (psilocybin), 6-allyl-N,N-diethyl-norlysergamide (AL- LAD), N,N-dibutyl-T (DBT), N,N-diethyl-T (DET), N,N-diisopropyl-T (DiPT), 5-methoxy-a-methyl-T (a,O-DMS), N, N-dimethyl-T (DMT), 2,a-dimethyl-T (2,a-DMT), a, N-dimethyl-T (a,N-DMT), N, N-dipropyl-T (DPT), N-ethyl-N- isopropyl-T (EiPT), a-ethyl-T (AET), 6,N,N-triethylnor-lysergamide (ETH-LAD), 3,4-dihydro-7-methoxy-1- methylcarboline (Harmaline), 7-methoxy-1 -methylcarboline (Harmine), N,N-dibutyl-4-hydroxy— T (4-HO-DBT), N,N-diethyl-4-hydroxy-T (4-HO-DET), N,N-diisopropyl-4-hydroxy-T (4-HO-DiPT), 4-hydroxy-N,N,N-trimethyl-T (4-HO-TMT), N,N-dimethyl-4-hydroxy-T (4-HO-DMT), N,N-dimethyl-5-hydroxy-T (5-HO-DMT, bufotenine), N,N- dipropyl-4-hydroxy-T (4-HO-DPT), N-ethyl-4-hydroxy-N-methyl-T (4-HO-MET), 4-hydroxy-N-isopropyl-N-methyl- T (4-HO-MiPT), 4-hydroxy-N-methyl-N-propyl--T (4-HO-MPT), 4-hydroxy-N,N-tetramethylene-T (4-HO-pyr-T), 12-methoxyibogamine (Ibogaine), N-butyl-N-methyl-T (MBT), N,N-diisopropyl-4,5-methylenedioxy-T (4,5-MDO- DiPT), N,N-diisopropyl-5,6-methylenedioxy-T (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxy-T (4,5-MDO- DMT), N,N-dimethyl-5,6-methylenedioxy-T (5,6-MDO-DMT), N-isopropyl-N-methyl-5,6-methylenedioxy-T (5,6- MDO-MiPT), N,N-diethyl-2-methyl-T (2-Me-DET), 2,N,N-trimethyl-T (2-Me-DMT), N-acetyl-5-methoxy-T (melatonin), N,N-diethyl-5-methoxy-T (5-MeO-DET), N,N-diisopropyl-5-methoxy--T (5-MeO-DiPT), N,N,diallyl-5- methoxy-T (5-MeO-DALT), 5-methoxy-N, N-dimethyl-T (5-MeO-DMT), N-isopropyl-4-methoxy-N-methyl-T (4- MeO-MiPT), N-isopropyl-5-methoxy-N-methyl-T (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyl-T (5,6- MeO-MiPT), 5-methoxy-N-methyl--T (5-MeO-NMT), 5-methoxy-N,N-tetramethylene-T (5-MeO-pyr-T), 6- methoxy-1 -methyl- 1 ,2,3,4-tetrahydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl-T (5-MeO-TMT), N,N- dimethyl-5-methylthio-T (5-MeS-DMT), N-isopropyl-N-methyl-T (MiPT), a-methyl-T (a-MT), N-ethyl-T (NET), N- methyl-T (NMT), 6-propylnorlysergamide (PRO-LAD), N,N-tetra-methylene-T (pyr-T), -T (T), 7-methoxy-1- methyl-1 ,2,3,4-tetrahydrocarboline (THH), and a,N-dimethyl-5-methoxy-T (a,N,O-TMS).

[0119]

[0081] In some embodiments, the compounds are substituted lysergamides. In some embodiments, the 5-HT2A- binding fragment is a lysergamide. In some embodiments, the compounds are substituted lysergamides bearing an N-linked side chain. In some embodiments, the substituted lysergamide is a lysergamide having one of its amide substituents, or the N(6)-substituent (represented in formulae herein as N6) replaced by an N-linked side chain, wherein the lysergamide is any of lysergic acid diethylamide (i.e. , LSD, LSD-25, LAD, Delysid), 6-ethyl-6- nor-LSD (ETH-LAD), 6-propynyl-6-nor-LSD (PARGY-LAD), 6-allyl-6-nor-LSD (AL-LAD), 6-propyl-6-nor-LSD (PRO-LAD), 6-isopropyl-6-nor-LSD (IP-LAD), 6-cylopropyl-6-nor-LSD (CIP-LAD), 6-butyl-6-nor-LSD (BU-LAD), 6-(2-fluoroethyl)-6-nor-LSD (FLUOROETH-LAD), 1-acetyl-LSD (i.e., ALD, ALD-52, N-acetyl-LSD), 1-propionyl- LSD (1 P-LSD), 1-butyryl-LSD (1 B-LSD), 1-valeryl-LSD (1V-LSD), 1-(cyclopropyl-methanoyl)-LSD (1cP-LSD), 1- (1,2-dimethylcyclobutane-1-carbonyl)-LSD (1 D-LSD), 1-propionyl-6-allyl-6-nor-LSD (1 P-AL-LAD), 1- (cyclopropyl-methanoyl)-6-allyl-6-nor-LSD (1cP-AL-LAD), 1 -propionyl-6-ethyl-6-nor-LSD (1 P-ETH-LAD), lysergic acid 2,4-dimethylazetidide (i.e., LA-SS-Az, LSZ), lysergic acid piperidide (LSD-Pip), and lysergic acid methylisopropyl amide (MIPLA).

[0120]

[0082] In the context of the disclosed substituted tryptamine and lysergamide compounds, the term “side chain” refers to an optionally substituted alkyl chain (e.g., optionally substituted n-decyl). In some embodiments, one or more methylene units of the alkyl chain may be replaced by a heteroatom (e.g., an oxygen; thereby introducing an ether linkage into the side chain). In some embodiments, the alkyl chain is substituted. For example, in some embodiments, the side chain is aryl-substituted (e.g., substituted by an optionally substituted phenyl ring).

[0121]

[0083] The term “unsubstituted tryptamine” (e.g., “corresponding unsubstituted tryptamine”) refers to a tryptamine lacking an N-linked side chain, even if the tryptamine has other substituents (e.g., a 4-OH-tryptamine may be referred to as an “unsubstituted” tryptamine if it lacks a side chain). Substituted tryptamines of the disclosure (e.g., containing an N-linked side chain) are also referred to herein as “the compound” or “the compounds” of the disclosure; it will be understood that the terms “the compound” and “the substituted tryptamine” both equivalently refer to the N-linked substituted tryptamine compounds of the disclosure.

[0122]

[0084] The term “unsubstituted lysergamide” (e.g., “corresponding unsubstituted lysergamide”) refers to a lysergamide lacking an N-linked side chain, even if the lysergamide has other substituents (e.g., a 2-Br- lysergamide may be referred to as an “unsubstituted” lysergamide if it lacks a side chain). Substituted lysergamides of the disclosure (e.g., containing an N-linked side chain) also may be referred to as “the compound” or “the compounds” of the disclosure; thus, terms such as “the compound” and “the substituted lysergamide” both equivalently refer to a N-linked substituted lysergamide compound of the disclosure.

[0085] In some embodiments, the side chain has the structure of:

[0123] -(CH2)mX(CH2)nPh wherein X is a methylene (CH2) or a heteroatom linker (e.g., 0, S, NH, etc.); Ph is an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and m and n are each independently an integer from 1 to 20.

[0124]

[0086] In embodiments, X is CH2. In embodiments, X is 0. In embodiments, X is S. In embodiments, X is NH.

[0125]

[0087] In some embodiments, the side chain is an aralkyloxyalkyl (e.g., a side chain having the formula of — (CH2)mO(CH2)nPh), and the disclosed compound is N-aralkyloxyalkyl-substituted tryptamine.

[0126]

[0088] In some embodiments, Ph is an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. In embodiments, Ph is an optionally substituted 3-membered, 4-membered, 5-membered, 6-membered, 7- membered, 8-membered, 9-membered or 10-membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. In embodiments, Ph is an optionally substituted aryl. In embodiments, Ph is an optionally substituted phenyl. In embodiments, Ph is an unsubstituted phenyl. In embodiments, Ph is a phenyl substituted by halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0127]

[0089] In some embodiments, m is an integer from 1 to 20. In embodiments, m is 1. In embodiments, m is 2.

[0128] In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6. In embodiments, m is 7. In embodiments, m is 8. In embodiments, m is 9. In embodiments, m is 10. In embodiments, m is 11. In embodiments, m is 12. In embodiments, m is 13. In embodiments, m is 14. In embodiments, m is 15. In embodiments, m is 16. In embodiments, m is 17. In embodiments, m is 18. In embodiments, m is 19. In embodiments, m is 20. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. In embodiments, n is 11. In embodiments, n is 12. In embodiments, n is 13. In embodiments, n is 14. In embodiments, n is 15. In embodiments, n is 16. In embodiments, n is 17. In embodiments, n is 18. In embodiments, n is 19. In embodiments, n is 20. In embodiments, the sum of m + n is from 4 to 16. In embodiments, the sum of m + n is from 6 to 14. In embodiments, the sum of m + n is from 7 to 13. In embodiments, the sum of m + n is from 8 to

[0129] 12. In embodiments, the sum of m + n is from 9 to 11. In embodiments, the sum of m + n is 6. In embodiments, the sum of m + n is 7. In embodiments, the sum of m + n is 8. In embodiments, the sum of m + n is 9. In embodiments, the sum of m + n is 10. In embodiments, the sum of m + n is 11. In embodiments, the sum of m + n is 12. In embodiments, the sum of m + n is 13. In embodiments, the sum of m + n is 14. In embodiments, m and n are selected from the following pair series: 1 and 9, 2 and 8, 3 and 7, 4 and 6, 5 and 5, 6 and 4, 7 and 3, 8 and 2, 9 and 1. In embodiments, the side chain has a structure selected from Table 1 (wherein * indicates the point of connection between the N-linked side chain and the remainder of the compound).

[0130] Table 1. Exemplary Side Chain Structures

[0131]

[0132]

[0133]

[0134]

[0090] In some embodiments, the compound has the structure of Formula (I):

[0135] D-(CH2)mX(CH2)nPh (I), or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein: m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14;

[0136] X is 0, S, or NH;

[0137] Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and wherein the * indicates the point of connection to — (CH2)mX(CH2)nPh; and wherein:

[0138] Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6- C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or any two of Ra, Rb, R2, R4, R5, R6, and R7are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and the remaining Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2- C8 alkenyl, or C2-C8 alky nyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3- C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0139] R' is H, D, PO3H2, or C(O)-C1-C8 alkyl; and

[0140] RNis H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 wherein the * indicates the point of connection to — (CH2)mX(CH2)nPh; and wherein:

[0141] RN1is:

[0142] (a) H, deuterium (D), C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0143] (b) taken together with RN2and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0144] RN2, if present, is:

[0145] (a) H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0146] (b) taken together with RN1and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0147] R2, R12, R13, and R14are each independently selected from the group consisting of hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0148] R9is H or D; and

[0149] R6, if present, is hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and R' is H, D, PO3H2, or C(O)-C1-C8 alkyl.

[0150]

[0091] In the descriptions herein, it is understood that every description, variation, embodiment or aspect of a moiety may be combined with every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment or aspect provided herein with respect to m, n, X, Ph, Ra, Rb, R2, R4, R5, R6, R7, R', and RNof Formula (II) or any subformula thereof may be combined with every description, variation, embodiment or aspect of m, n X, Ph, Ra, Rb, R2, R4, R5, R6, R7, R', and RNin Formula (I); the same as if each and every combination were specifically and individually listed for Formula (I). Likewise, every description, variation, embodiment or aspect provided herein with respect to m, n, X, Ph, RN1, RN2, R2, R6, R9, R12, R13, R14, and R' of Formula (III) or any subformula thereof may be combined with every description, variation, embodiment or aspect of m, n X, Ph, Ra, Rb, R2, R4, R5, R6, R7, R', and RNin Formula (I); the same as if each and every combination were specifically and individually listed for Formula (I). It is also understood that all descriptions, variations, embodiments or aspects of Formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments or aspects of Formula (I), where applicable, apply equally to any of Formula (II), Formula (III), and any subformula thereof, are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae.

[0092] In some embodiments, the compound has the structure of Formula (II): wherein: m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14; X is 0, S, or NH;

[0151] Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6- C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or any two of Ra, Rb, R2, R4, R5, R6, and R7are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and the remaining Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2- C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3- C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0152] R' is H, D, PO3H2, or C(O)-C1-C8 alkyl;

[0153] RNis H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl; Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[0154]

[0093] In some embodiments of Formula (II), m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3.

[0155] In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6. In embodiments, m is 7. In embodiments, m is 8. In embodiments, m is 9. In embodiments, m is 10. In embodiments, m is 11. In embodiments, m is 12. In embodiments, m is 13. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. In embodiments, n is 11. In embodiments, n is 12. In embodiments, n is 13. In embodiments, the sum of m + n is from 6 to 14. In embodiments, the sum of m + n is from 7 to 13. In embodiments, the sum of m + n is from 8 to 12. In embodiments, the sum of m + n is from 9 to 11 . In embodiments, the sum of m + n is 6. In embodiments, the sum of m + n is 7. In embodiments, the sum of m + n is 8. In embodiments, the sum of m + n is 9. In embodiments, the sum of m + n is 10. In embodiments, the sum of m + n is 11. In embodiments, the sum of m + n is 12. In embodiments, the sum of m + n is 13. In embodiments, the sum of m + n is 14.

[0156]

[0094] In some embodiments of Formula (II), X is 0, S, or NH. In embodiments, X is 0. In embodiments, X is S. In embodiments, X is NH.

[0157]

[0095] In some embodiments of Formula (II), R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl.

[0158]

[0096] In some embodiments, any two of Ra, Rb, R2, R4, R5, R6, and R7are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and the remaining Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0159]

[0097] In some embodiments, Raand RNare taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In some embodiments, Raand Rbare taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In some embodiments, Raand R2are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0160]

[0098] In some embodiments, Rband R4are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In some embodiments, Rband RNare taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0161]

[0099] In some embodiments, R4and R5are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0162]

[0100] In some embodiments, R5and R6are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0101] In some embodiments, R6and R7are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0163]

[0102] In some embodiments of Formula (II), R2is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R2is hydrogen. In embodiments, R2is D. In embodiments, R2is D. In embodiments, R2is halogen. In embodiments, R2is F. In embodiments, R2is Cl. In embodiments, R2is Br. In embodiments, R2is I. In embodiments, R2is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R2is OH. In embodiments, R2is OPO3H2. In embodiments, R2is C(O)-C1 -C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is substituted C(O)-C1-C8 alkyl. In embodiments, R2is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)- CH3. In embodiments, R2is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkyl. In embodiments, R2is substituted C1-C8 alkyl. In embodiments, R2is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkoxy. In embodiments, R2is methoxy. In embodiments, R2is substituted C1-C8 alkoxy. In embodiments, R2is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkenyl. In embodiments, R2is substituted C1-C8 alkenyl. In embodiments, R2is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkynyl. In embodiments, R2is substituted C1-C8 alkynyl. In embodiments, R2is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C3-C8 cycloalkyl. In embodiments, R2is substituted C3-C8 cycloalkyl. In embodiments, R2is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C3-C8 cycloalkenyl. In embodiments, R2is substituted C3-C8 cycloalkenyl. In embodiments, R2is C3-C8 heterocycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is substituted C3-C8 heterocycloalkyl. In embodiments, R2is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R2is C3-C8 heterocycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is substituted C3-C8 heterocycloalkenyl. In embodiments, R2is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R2is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C6-C10 aryl. In embodiments, R2is substituted C6-C10 aryl. In embodiments, R2is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted 6-10 membered heteroaryl. In embodiments, R2is substituted 6-10 membered heteroaryl.

[0164]

[0103] In some embodiments of Formula (II), R4is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R4is hydrogen. In embodiments, R4is D. In embodiments, R4is halogen. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R4is OH. In embodiments, R4is OPO3H2. In embodiments, R4is C(O)- C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is substituted C(O)-C1- C8 alkyl. In embodiments, R4is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R4is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C1-C8 alkyl. In embodiments, R4is substituted C1-C8 alkyl. In embodiments, R4is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C1-C8 alkoxy. In embodiments, R4is methoxy. In embodiments, R4is substituted C1-C8 alkoxy. In embodiments, R4is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C1-C8 alkenyl. In embodiments, R4is substituted C1-C8 alkenyl. In embodiments, R4is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C1-C8 alkynyl. In embodiments, R4is substituted C1-C8 alkynyl. In embodiments, R4is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C3-C8 cycloalkyl. In embodiments, R4is substituted C3-C8 cycloalkyl. In embodiments, R4is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C3-C8 cycloalkenyl. In embodiments, R4is substituted C3-C8 cycloalkenyl. In embodiments, R4is C3-C8 heterocycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is substituted C3-C8 heterocycloalkyl. In embodiments, R4is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R4is C3-C8 heterocycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is substituted C3-C8 heterocycloalkenyl. In embodiments, R4is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R4is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C6-C10 aryl. In embodiments, R4is substituted C6-C10 aryl. In embodiments, R4is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted 6-10 membered heteroaryl. In embodiments, R4is substituted 6-10 membered heteroaryl.

[0165]

[0104] In some embodiments of Formula (II), R5is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R5is hydrogen. In embodiments, R5is D. In embodiments, R5is halogen. In embodiments, R5is F. In embodiments, R5is Cl. In embodiments, R5is Br. In embodiments, R5is I. In embodiments, R5is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R5is OH. In embodiments, R5is OPO3H2. In embodiments, R5is C(O)- C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is substituted C(O)-C1- C8 alkyl. In embodiments, R5is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R5is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C1-C8 alkyl. In embodiments, R5is substituted C1-C8 alkyl. In embodiments, R5is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C1-C8 alkoxy. In embodiments, R5is methoxy. In embodiments, R5is substituted C1-C8 alkoxy. In embodiments, R5is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C1-C8 alkenyl. In embodiments, R5is substituted C1-C8 alkenyl. In embodiments, R5is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C1-C8 alkynyl. In embodiments, R5is substituted C1-C8 alkynyl. In embodiments, R5is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C3-C8 cycloalkyl. In embodiments, R5is substituted C3-C8 cycloalkyl. In embodiments, R5is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C3-C8 cycloalkenyl. In embodiments, R5is substituted C3-C8 cycloalkenyl. In embodiments, R5is C3-C8 heterocycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is substituted C3-C8 heterocycloalkyl. In embodiments, R5is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R5is C3-C8 heterocycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is substituted C3-C8 heterocycloalkenyl. In embodiments, R5is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R5is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C6-C10 aryl. In embodiments, R5is substituted C6-C10 aryl. In embodiments, R5is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted 6-10 membered heteroaryl. In embodiments, R5is substituted 6-10 membered heteroaryl.

[0166]

[0105] In some embodiments of Formula (II), R6is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R6is hydrogen. In embodiments, R6is D. In embodiments, R6is halogen. In embodiments, R6is F. In embodiments, R6is Cl. In embodiments, R6is Br. In embodiments, R6is I. In embodiments, R6is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R6is OH. In embodiments, R6is OPO3H2. In embodiments, R6is C(O)- C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is substituted C(O)-C1- C8 alkyl. In embodiments, R6is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R6is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkyl. In embodiments, R6is substituted C1-C8 alkyl. In embodiments, R6is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkoxy. In embodiments, R6is methoxy. In embodiments, R6is substituted C1-C8 alkoxy. In embodiments, R6is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkenyl. In embodiments, R6is substituted C1-C8 alkenyl. In embodiments, R6is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkynyl. In embodiments, R6is substituted C1-C8 alkynyl. In embodiments, R6is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C3-C8 cycloalkyl. In embodiments, R6is substituted C3-C8 cycloalkyl. In embodiments, R6is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C3-C8 cycloalkenyl. In embodiments, R6is substituted C3-C8 cycloalkenyl. In embodiments, R6is C3-C8 heterocycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is substituted C3-C8 heterocycloalkyl. In embodiments, R6is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R6is C3-C8 heterocycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is substituted C3-C8 heterocycloalkenyl. In embodiments, R6is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R6is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C6-C10 aryl. In embodiments, R6is substituted C6-C10 aryl. In embodiments, R6is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted 6-10 membered heteroaryl. In embodiments, R6is substituted 6-10 membered heteroaryl.

[0167]

[0106] In some embodiments of Formula (II), R7is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R7is hydrogen. In embodiments, R7is D. In embodiments, R7is halogen. In embodiments, R7is F. In embodiments, R7is Cl. In embodiments, R7is Br. In embodiments, R7is I. In embodiments, R7is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R7is OH. In embodiments, R7is OPO3H2. In embodiments, R7is C(O)- C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is substituted C(O)-C1- C8 alkyl. In embodiments, R7is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R7is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is unsubstituted C1-C8 alkyl. In embodiments, R7is substituted C1-C8 alkyl. In embodiments, R7is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is unsubstituted C1-C8 alkoxy. In embodiments, R7is methoxy. In embodiments, R7is substituted C1-C8 alkoxy. In embodiments, R7is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is unsubstituted C1-C8 alkenyl. In embodiments, R7is substituted C1-C8 alkenyl. In embodiments, R7is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is unsubstituted C1-C8 alkynyl. In embodiments, R7is substituted C1-C8 alkynyl. In embodiments, R7is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is unsubstituted C3-C8 cycloalkyl. In embodiments, R7is substituted C3-C8 cycloalkyl. In embodiments, R7is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is unsubstituted C3-C8 cycloalkenyl. In embodiments, R7is substituted C3-C8 cycloalkenyl. In embodiments, R7is C3-C8 heterocycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is substituted C3-C8 heterocycloalkyl. In embodiments, R7is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R7is C3-C8 heterocycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is substituted C3-C8 heterocycloalkenyl. In embodiments, R7is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R7is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is unsubstituted C6-C10 aryl. In embodiments, R7is substituted C6-C10 aryl. In embodiments, R7is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R7is unsubstituted 6-10 membered heteroaryl. In embodiments, R7is substituted 6-10 membered heteroaryl.

[0168]

[0107] In some embodiments of Formula (II), RNH, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl. In embodiments, RNis H. In embodiments, RNis D. In embodiments, RNis C1-C8 alkyl. In embodiments, RNis methyl. In embodiments, RNis ethyl. In embodiments, RNis n-propyl. In embodiments, RNis isopropyl. In embodiments, RNis butyl. In embodiments, RNis n-butyl. In embodiments, RNis sec-butyl. In embodiments, RNis iso-butyl. In embodiments, RNis isobutyl. In embodiments, RNis tertbutyl. In embodiments, RNis C3-C8 cycloalkyl. In embodiments, RNis cyclopropyl. In embodiments, RNis cyclobutyl. In embodiments, RNis cyclopentyl. In embodiments, RNis C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, RNis CH2- cyclopropyl. In embodiments, RNis C2-C8 alkenyl. In embodiments, RNis allyl. In embodiments, RNis C2-C8 alkynyl. In embodiments, RNis C2-C8 alkynyl.

[0169]

[0108] In some embodiments of Formula (II), Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0170]

[0109] In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.

[0171]

[0110] In embodiments, Ph is phenyl substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, Ph is phenyl substituted by halogen. In embodiments, Ph is phenyl substituted by D. In embodiments, Ph is phenyl substituted by F, Cl, Br or I. In embodiments, Ph is phenyl substituted by azido. In embodiments, Ph is phenyl substituted by alkyl. In embodiments, Ph is phenyl substituted by alkyl ester. In embodiments, Ph is phenyl substituted by hydroxy. In embodiments, Ph is phenyl substituted by alkoxy. In embodiments, Ph is phenyl substituted by methoxy. In embodiments, Ph is phenyl substituted by carboxy. In embodiments, Ph is phenyl substituted by formyl. In embodiments, Ph is phenyl substituted by aryl. In embodiments, Ph is phenyl substituted by heterocyclyl. In embodiments, Ph is phenyl substituted by amino. In embodiments, Ph is phenyl substituted by alkylamino. In embodiments, Ph is phenyl substituted by arylamido. In embodiments, Ph is phenyl substituted by alkylamido. In embodiments, Ph is phenyl substituted by thiol. In embodiments, Ph is phenyl substituted by thioalkyl. In embodiments, Ph is phenyl substituted by thioaryl. In embodiments, Ph is phenyl substituted by alkylsulfonyl. In embodiments, Ph is phenyl substituted by alkylcarbamoyl. In embodiments, Ph is phenyl substituted by arylcarbamoyl. In embodiments, Ph is phenyl substituted by nitro. In embodiments, Ph is phenyl substituted by cyano. In embodiments, Ph is phenyl substituted by nitrate.

[0172]

[0111] In some embodiments, the compound has the structure of Formula (IIA):

[0173]

[0112] In some embodiments of Formula (IIA), m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6. In embodiments, m is 7. In embodiments, m is 8. In embodiments, m is 9. In embodiments, m is 10. In embodiments, m is 11. In embodiments, m is 12. In embodiments, m is 13. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. In embodiments, n is 11. In embodiments, n is 12. In embodiments, n is 13. In embodiments, the sum of m + n is from 6 to 14. In embodiments, the sum of m + n is from 7 to 13. In embodiments, the sum of m + n is from 8 to 12. In embodiments, the sum of m + n is from 9 to 11 . In embodiments, the sum of m + n is 6. In embodiments, the sum of m + n is 7. In embodiments, the sum of m + n is 8. In embodiments, the sum of m + n is 9. In embodiments, the sum of m + n is 10. In embodiments, the sum of m + n is 11. In embodiments, the sum of m + n is 12. In embodiments, the sum of m + n is 13. In embodiments, the sum of m + n is 14.

[0174]

[0113] In some embodiments of Formula (I I A), X is 0, S, or NH. In embodiments, X is 0. In embodiments, X is S. In embodiments, X is NH.

[0175]

[0114] In some embodiments of Formula (IIA), RNH, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl. In embodiments, RNis H. In embodiments, RNis C1-C8 alkyl. In embodiments, RNis methyl. In embodiments, RNis ethyl. In embodiments, RNis n-propyl. In embodiments, RNis isopropyl. In embodiments, RNis butyl. In embodiments, RNis n-butyl. In embodiments, RNis sec-butyl. In embodiments, RNis iso-butyl. In embodiments, RNis isobutyl. In embodiments, RNis tert-butyl. In embodiments, RNis C3-C8 cycloalkyl. In embodiments, RNis cyclopropyl. In embodiments, RNis cyclobutyl. In embodiments, RNis cyclopentyl. In embodiments, RNis C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, RNis CH2- cyclopropyl. In embodiments, RNis C2-C8 alkenyl. In embodiments, RNis allyl. In embodiments, RNis C2-C8 alkynyl. In embodiments, RNis C2-C8 alkynyl.

[0176]

[0115] In some embodiments of Formula (IIA), Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0177]

[0116] In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.

[0178]

[0117] In embodiments, Ph is phenyl substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, Ph is phenyl substituted by halogen. In embodiments, Ph is phenyl substituted by D. In embodiments, Ph is phenyl substituted by F, Cl, Br or I. In embodiments, Ph is phenyl substituted by azido. In embodiments, Ph is phenyl substituted by alkyl. In embodiments, Ph is phenyl substituted by alkyl ester. In embodiments, Ph is phenyl substituted by hydroxy. In embodiments, Ph is phenyl substituted by alkoxy. In embodiments, Ph is phenyl substituted by methoxy. In embodiments, Ph is phenyl substituted by carboxy. In embodiments, Ph is phenyl substituted by formyl. In embodiments, Ph is phenyl substituted by aryl. In embodiments, Ph is phenyl substituted by heterocyclyl. In embodiments, Ph is phenyl substituted by amino. In embodiments, Ph is phenyl substituted by alkylamino. In embodiments, Ph is phenyl substituted by arylamido. In embodiments, Ph is phenyl substituted by alkylamido. In embodiments, Ph is phenyl substituted by thiol. In embodiments, Ph is phenyl substituted by thioalkyl. In embodiments, Ph is phenyl substituted by thioaryl. In embodiments, Ph is phenyl substituted by alkylsulfonyl. In embodiments, Ph is phenyl substituted by alkylcarbamoyl. In embodiments, Ph is phenyl substituted by arylcarbamoyl. In embodiments, Ph is phenyl substituted by nitro. In embodiments, Ph is phenyl substituted by cyano. In embodiments, Ph is phenyl substituted by nitrate.

[0118] In some embodiments, the compound is selected from Table 2:

[0179] Table 2. Exemplary Compounds of Formula (HA)

[0180]

[0119] In some embodiments, the compound has the structure of Formula (IIB):

[0181]

[0120] In some embodiments of Formula (IIB), m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6. In embodiments, m is 7. In embodiments, m is 8. In embodiments, m is 9. In embodiments, m is 10. In embodiments, m is 11. In embodiments, m is 12. In embodiments, m is 13. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. In embodiments, n is 11. In embodiments, n is 12. In embodiments, n is 13. In embodiments, the sum of m + n is from 6 to 14. In embodiments, the sum of m + n is from 7 to 13. In embodiments, the sum of m + n is from 8 to 12. In embodiments, the sum of m + n is from 9 to 11 . In embodiments, the sum of m + n is 6. In embodiments, the sum of m + n is 7. In embodiments, the sum of m + n is 8. In embodiments, the sum of m + n is 9. In embodiments, the sum of m + n is 10. In embodiments, the sum of m + n is 11. In embodiments, the sum of m + n is 12. In embodiments, the sum of m + n is 13. In embodiments, the sum of m + n is 14.

[0121] In some embodiments of Formula (I IB), X is 0, S, or NH. In embodiments, X is 0. In embodiments, X is S. In embodiments, X is NH.

[0182]

[0122] In some embodiments of Formula (II B), R4is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R4is hydrogen. In embodiments, R4is D. In embodiments, R4is halogen. In embodiments, R4is F. In embodiments, R4is Cl. In embodiments, R4is Br. In embodiments, R4is I. In embodiments, R4is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R4is OH. In embodiments, R4is OPO3H2. In embodiments, R4is C(0)- C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is substituted C(O)-C1- C8 alkyl. In embodiments, R4is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R4is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C1-C8 alkyl. In embodiments, R4is substituted C1-C8 alkyl. In embodiments, R4is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C1-C8 alkoxy. In embodiments, R4is methoxy. In embodiments, R4is substituted C1-C8 alkoxy. In embodiments, R4is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C1-C8 alkenyl. In embodiments, R4is substituted C1-C8 alkenyl. In embodiments, R4is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C1-C8 alkynyl. In embodiments, R4is substituted C1-C8 alkynyl. In embodiments, R4is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C3-C8 cycloalkyl. In embodiments, R4is substituted C3-C8 cycloalkyl. In embodiments, R4is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C3-C8 cycloalkenyl. In embodiments, R4is substituted C3-C8 cycloalkenyl. In embodiments, R4is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted C6-C10 aryl. In embodiments, R4is substituted C6-C10 aryl. In embodiments, R4is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R4is unsubstituted 6-10 membered heteroaryl. In embodiments, R4is substituted 6-10 membered heteroaryl.

[0183]

[0123] In some embodiments of Formula (I IB), RNH, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl. In embodiments, RNis H. In embodiments, RNis D. In embodiments, RNis C1-C8 alkyl. In embodiments, RNis methyl. In embodiments, RNis ethyl. In embodiments, RNis n-propyl. In embodiments, RNis isopropyl. In embodiments, RNis butyl. In embodiments, RNis n-butyl. In embodiments, RNis sec-butyl. In embodiments, RNis iso-butyl. In embodiments, RNis isobutyl. In embodiments, RNis tertbutyl. In embodiments, RNis C3-C8 cycloalkyl. In embodiments, RNis cyclopropyl. In embodiments, RNis cyclobutyl. In embodiments, RNis cyclopentyl. In embodiments, RNis C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, RNis CH2- cyclopropyl. In embodiments, RNis C2-C8 alkenyl. In embodiments, RNis allyl. In embodiments, RNis C2-C8 alkynyl. In embodiments, RNis C2-C8 alkynyl.

[0184]

[0124] In some embodiments of Formula (II B), Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0185]

[0125] In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.

[0186]

[0126] In embodiments, Ph is phenyl substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, Ph is phenyl substituted by halogen. In embodiments, Ph is phenyl substituted by D. In embodiments, Ph is phenyl substituted by F, Cl, Br or I. In embodiments, Ph is phenyl substituted by azido. In embodiments, Ph is phenyl substituted by alkyl. In embodiments, Ph is phenyl substituted by alkyl ester. In embodiments, Ph is phenyl substituted by hydroxy. In embodiments, Ph is phenyl substituted by alkoxy. In embodiments, Ph is phenyl substituted by methoxy. In embodiments, Ph is phenyl substituted by carboxy. In embodiments, Ph is phenyl substituted by formyl. In embodiments, Ph is phenyl substituted by aryl. In embodiments, Ph is phenyl substituted by heterocyclyl. In embodiments, Ph is phenyl substituted by amino. In embodiments, Ph is phenyl substituted by alkylamino. In embodiments, Ph is phenyl substituted by arylamido. In embodiments, Ph is phenyl substituted by alkylamido. In embodiments, Ph is phenyl substituted by thiol. In embodiments, Ph is phenyl substituted by thioalkyl. In embodiments, Ph is phenyl substituted by thioaryl. In embodiments, Ph is phenyl substituted by alkylsulfonyl. In embodiments, Ph is phenyl substituted by alkylcarbamoyl. In embodiments, Ph is phenyl substituted by arylcarbamoyl. In embodiments, Ph is phenyl substituted by nitro. In embodiments, Ph is phenyl substituted by cyano. In embodiments, Ph is phenyl substituted by nitrate.

[0187]

[0127] In embodiments, the compound is selected from Table 3:

[0188] Table 3. Exemplary Compounds of Formula (IIB)

[0189]

[0128] In some embodiments, the compound has the structure of Formula (IIC):

[0190]

[0129] In some embodiments of Formula (IIC), m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6. In embodiments, m is 7. In embodiments, m is 8. In embodiments, m is 9. In embodiments, m is 10. In embodiments, m is 11. In embodiments, m is 12. In embodiments, m is 13. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. In embodiments, n is 11. In embodiments, n is 12. In embodiments, n is 13. In embodiments, the sum of m + n is from 6 to 14. In embodiments, the sum of m + n is from 7 to 13. In embodiments, the sum of m + n is from 8 to 12. In embodiments, the sum of m + n is from 9 to 11 . In embodiments, the sum of m + n is 6. In embodiments, the sum of m + n is 7. In embodiments, the sum of m + n is 8. In embodiments, the sum of m + n is 9. In embodiments, the sum of m + n is 10. In embodiments, the sum of m + n is 11. In embodiments, the sum of m + n is 12. In embodiments, the sum of m + n is 13. In embodiments, the sum of m + n is 14.

[0191]

[0130] In some embodiments of Formula (IIC), X is 0, S, or NH. In embodiments, X is O. In embodiments, X is S. In embodiments, X is NH.

[0192]

[0131] In some embodiments of Formula (IIC), R5is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R5is hydrogen. In embodiments, R5is D. In embodiments, R5is halogen. In embodiments, R5is F. In embodiments, R5is Cl. In embodiments, R5is Br. In embodiments, R5is I. In embodiments, R5is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R5is OH. In embodiments, R5is OPO3H2. In embodiments, R5is C(O)- C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is substituted C(O)-C1- C8 alkyl. In embodiments, R5is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R5is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C1-C8 alkyl. In embodiments, R5is substituted C1-C8 alkyl. In embodiments, R5is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C1-C8 alkoxy. In embodiments, R5is methoxy. In embodiments, R5is substituted C1-C8 alkoxy. In embodiments, R5is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C1-C8 alkenyl. In embodiments, R5is substituted C1-C8 alkenyl. In embodiments, R5is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C1-C8 alkynyl. In embodiments, R5is substituted C1-C8 alkynyl. In embodiments, R5is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C3-C8 cycloalkyl. In embodiments, R5is substituted C3- C8 cycloalkyl. In embodiments, R5is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C3-C8 cycloalkenyl. In embodiments, R5is substituted C3-C8 cycloalkenyl. In embodiments, R5is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted C6-C10 aryl. In embodiments, R5is substituted C6-C10 aryl. In embodiments, R5is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R5is unsubstituted 6-10 membered heteroaryl. In embodiments, R5is substituted 6-10 membered heteroaryl.

[0132] In some embodiments of Formula (IIC), RNH, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl. In embodiments, RNis H. In embodiments, RNis D. In embodiments, RNis C1-C8 alkyl. In embodiments, RNis methyl. In embodiments, RNis ethyl. In embodiments, RNis n-propyl. In embodiments, RNis isopropyl. In embodiments, RNis butyl. In embodiments, RNis n-butyl. In embodiments, RNis sec-butyl. In embodiments, RNis iso-butyl. In embodiments, RNis isobutyl. In embodiments, RNis tertbutyl. In embodiments, RNis C3-C8 cycloalkyl. In embodiments, RNis cyclopropyl. In embodiments, RNis cyclobutyl. In embodiments, RNis cyclopentyl. In embodiments, RNis C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, RNis CH2- cyclopropyl. In embodiments, RNis C2-C8 alkenyl. In embodiments, RNis allyl. In embodiments, RNis C2-C8 alkynyl. In embodiments, RNis C2-C8 alkynyl.

[0193]

[0133] In some embodiments of Formula (IIC), Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0194]

[0134] In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.

[0195]

[0135] In embodiments, Ph is phenyl substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, Ph is phenyl substituted by halogen. In embodiments, Ph is phenyl substituted by D. In embodiments, Ph is phenyl substituted by F, Cl, Br or I. In embodiments, Ph is phenyl substituted by azido. In embodiments, Ph is phenyl substituted by alkyl. In embodiments, Ph is phenyl substituted by alkyl ester. In embodiments, Ph is phenyl substituted by hydroxy. In embodiments, Ph is phenyl substituted by alkoxy. In embodiments, Ph is phenyl substituted by methoxy. In embodiments, Ph is phenyl substituted by carboxy. In embodiments, Ph is phenyl substituted by formyl. In embodiments, Ph is phenyl substituted by aryl. In embodiments, Ph is phenyl substituted by heterocyclyl. In embodiments, Ph is phenyl substituted by amino. In embodiments, Ph is phenyl substituted by alkylamino. In embodiments, Ph is phenyl substituted by arylamido. In embodiments, Ph is phenyl substituted by alkylamido. In embodiments, Ph is phenyl substituted by thiol. In embodiments, Ph is phenyl substituted by thioalkyl. In embodiments, Ph is phenyl substituted by thioaryl. In embodiments, Ph is phenyl substituted by alkylsulfonyl. In embodiments, Ph is phenyl substituted by alkylcarbamoyl. In embodiments, Ph is phenyl substituted by arylcarbamoyl. In embodiments, Ph is phenyl substituted by nitro. In embodiments, Ph is phenyl substituted by cyano. In embodiments, Ph is phenyl substituted by nitrate.

[0196]

[0136] In some embodiments, the compound is selected from Table 4: Table 4. Exemplary Compounds of Formula (IIC)

[0197]

[0137] In some embodiments, the compound has the structure of Formula (III): wherein:

[0198] RN1is:

[0199] (a) H, deuterium (D), C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0200] (b) taken together with RN2and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0201] RN2is:

[0202] (a) H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2- C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0203] (b) taken together with RN1and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0204] (c) (CH2)mX(CH2)nPh;

[0205] R2, R12, R13, and R14are each independently selected from the group consisting of hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

[0206] R9is H or D; R6is:

[0207] (a) hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or

[0208] (b) (CH2)mX(CH2)nPh;

[0209] R' is H, D, PO3H2, or C(O)-C1-C8 alkyl; m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14; X is 0, S, or NH;

[0210] Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein one of RN2and R6is (CH2)mX(CH2)nPh; or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[0211]

[0138] In some embodiments of Formula (III), RN1is H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3- C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, RN1is H. In embodiments, RN1is D. In embodiments, RN1is C1-C8 alkyl. In embodiments, RN1is methyl. In embodiments, RN1is ethyl. In embodiments, RN1is n-propyl. In embodiments, RN1is isopropyl. In embodiments, RN1is butyl. In embodiments, RN1is n-butyl. In embodiments, RN1is sec-butyl. In embodiments, RN1is iso-butyl. In embodiments, RN1is isobutyl. In embodiments, RN1is tert-butyl. In embodiments, RN1is C3-C8 cycloalkyl. In embodiments, RN1is cyclopropyl. In embodiments, RN1is cyclobutyl. In embodiments, RN1is cyclopentyl. In embodiments, RN1is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, RN1is CH2— cyclopropyl. In embodiments, RNis C2-C8 alkenyl. In embodiments, RN1is allyl. In embodiments, RN1is C2-C8 alkynyl. In embodiments, RN1is C2-C8 alkynyl.

[0212]

[0139] In some embodiments of Formula (III), RN2is H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3- C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, RN2is H. In embodiments, RN2is D. In embodiments, RN2is C1-C8 alkyl. In embodiments, RN2is methyl. In embodiments, RN2is ethyl. In embodiments, RN2is n-propyl. In embodiments, RN2is isopropyl. In embodiments, RN2is butyl. In embodiments, RN2is n-butyl. In embodiments, RN2is sec-butyl. In embodiments, RN2is iso-butyl. In embodiments, RN2is isobutyl. In embodiments, RN2is tert-butyl. In embodiments, RN2is C3-C8 cycloalkyl. In embodiments, RN2is cyclopropyl. In embodiments, RN2is cyclobutyl. In embodiments, RN2is cyclopentyl. In embodiments, RN2is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, RN2is CH2- cyclopropyl. In embodiments, RN2is C2-C8 alkenyl. In embodiments, RN2is allyl. In embodiments, RN2is C2-C8 alkynyl. In embodiments, RN2is C2-C8 alkynyl.

[0213]

[0140] In some embodiments of Formula (III), RN1and RN2are taken together with the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, RN1and RN2are taken together with the nitrogen to which they are attached to form an azetidnyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, RN1and RN2are taken together with the nitrogen to which they are attached to for an dimethylazetidnyl. In embodiments, RN1and RN2are taken together with the nitrogen to which they are attached to form a 2,4-dimethylazetidnyl. In embodiments, RN1and RN2are taken together with the nitrogen to which they are attached to form a pyrrolidinyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, RN1and RN2are taken together with the nitrogen to which they are attached to form a piperidinyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate

[0214]

[0141] In some embodiments of Formula (III), RN2is (CH2)mX(CH2)nPh, wherein m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14; X is 0, S, or NH; and Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0215]

[0142] In some embodiments of Formula (III), e.g., wherein RN2or R6is (CH2)mX(CH2)nPh, m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6. In embodiments, m is 7. In embodiments, m is 8. In embodiments, m is 9. In embodiments, m is 10. In embodiments, m is 11. In embodiments, m is 12. In embodiments, m is 13. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. In embodiments, n is 11. In embodiments, n is 12. In embodiments, n is 13. In embodiments, the sum of m + n is from 6 to 14. In embodiments, the sum of m + n is from 7 to 13. In embodiments, the sum of m + n is from 8 to 12. In embodiments, the sum of m + n is from 9 to 11. In embodiments, the sum of m + n is 6. In embodiments, the sum of m + n is 7. In embodiments, the sum of m + n is 8. In embodiments, the sum of m + n is 9. In embodiments, the sum of m + n is 10. In embodiments, the sum of m + n is 11. In embodiments, the sum of m + n is 12. In embodiments, the sum of m + n is 13. In embodiments, the sum of m + n is 14.

[0216]

[0143] In some embodiments of Formula (III), e.g., wherein RN2or R6is (CH2)mX(CH2)nPh, X is 0, S, or NH. In embodiments, X is 0. In embodiments, X is S. In embodiments, X is NH.

[0217]

[0144] In some embodiments of Formula (III), e.g., wherein RN2or R6is (CH2)mX(CH2)nPh, Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0218]

[0145] In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.

[0219]

[0146] In embodiments, Ph is phenyl substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, Ph is phenyl substituted by halogen. In embodiments, Ph is phenyl substituted by D. In embodiments, Ph is phenyl substituted by F, Cl, Br or I. In embodiments, Ph is phenyl substituted by azido. In embodiments, Ph is phenyl substituted by alkyl. In embodiments, Ph is phenyl substituted by alkyl ester. In embodiments, Ph is phenyl substituted by hydroxy. In embodiments, Ph is phenyl substituted by alkoxy. In embodiments, Ph is phenyl substituted by methoxy. In embodiments, Ph is phenyl substituted by carboxy. In embodiments, Ph is phenyl substituted by formyl. In embodiments, Ph is phenyl substituted by aryl. In embodiments, Ph is phenyl substituted by heterocyclyl. In embodiments, Ph is phenyl substituted by amino. In embodiments, Ph is phenyl substituted by alkylamino. In embodiments, Ph is phenyl substituted by arylamido. In embodiments, Ph is phenyl substituted by alkylamido. In embodiments, Ph is phenyl substituted by thiol. In embodiments, Ph is phenyl substituted by thioalkyl. In embodiments, Ph is phenyl substituted by thioaryl. In embodiments, Ph is phenyl substituted by alkylsulfonyl. In embodiments, Ph is phenyl substituted by alkylcarbamoyl. In embodiments, Ph is phenyl substituted by arylcarbamoyl. In embodiments, Ph is phenyl substituted by nitro. In embodiments, Ph is phenyl substituted by cyano. In embodiments, Ph is phenyl substituted by nitrate.

[0220]

[0147] In some embodiments of Formula (III), R2, R12, R13, and R14are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl.

[0221]

[0148] In some embodiments of Formula (III), R2is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R2is hydrogen. In embodiments, R2is D. In embodiments, R2is D. In embodiments, R2is halogen. In embodiments, R2is F. In embodiments, R2is Cl. In embodiments, R2is Br. In embodiments, R2is I. In embodiments, R2is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R2is OH. In embodiments, R2is OPO3H2. In embodiments, R2is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is substituted C(O)-C1-C8 alkyl. In embodiments, R2is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R2is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkyl. In embodiments, R2is substituted C1- C8 alkyl. In embodiments, R2is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkoxy. In embodiments, R2is methoxy. In embodiments, R2is substituted C1-C8 alkoxy. In embodiments, R2is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkenyl. In embodiments, R2is substituted C1-C8 alkenyl. In embodiments, R2is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkynyl. In embodiments, R2is substituted C1-C8 alkynyl. In embodiments, R2is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C3-C8 cycloalkyl. In embodiments, R2is substituted C3-C8 cycloalkyl. In embodiments, R2is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C3-C8 cycloalkenyl. In embodiments, R2is substituted C3-C8 cycloalkenyl. In embodiments, R2is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C6-C10 aryl. In embodiments, R2is substituted C6-C10 aryl. In embodiments, R2is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted 6-10 membered heteroaryl. In embodiments, R2is substituted 6-10 membered heteroaryl.

[0222]

[0149] In some embodiments of Formula (III), R12is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R12is hydrogen. In embodiments, R12is D. In embodiments, R12is halogen. In embodiments, R12is F. In embodiments, R12is Cl. In embodiments, R12is Br. In embodiments, R4is I. In embodiments, R4is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R12is OH. In embodiments, R12is OPO3H2. In embodiments, R12is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is substituted C(O)-C1-C8 alkyl. In embodiments, R12is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R12is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkyl. In embodiments, R12is substituted C1- C8 alkyl. In embodiments, R12is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkoxy. In embodiments, R12is methoxy. In embodiments, R12is substituted C1-C8 alkoxy. In embodiments, R12is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkenyl. In embodiments, R12is substituted C1-C8 alkenyl. In embodiments, R12is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkynyl. In embodiments, R12is substituted C1-C8 alkynyl. In embodiments, R12is C3- C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C3- C8 cycloalkyl. In embodiments, R12is substituted C3-C8 cycloalkyl. In embodiments, R12is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C3-C8 cycloalkenyl. In embodiments, R12is substituted C3-C8 cycloalkenyl. In embodiments, R12is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C6-C10 aryl. In embodiments, R12is substituted C6-C10 aryl. In embodiments, R12is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted 6-10 membered heteroaryl. In embodiments, R12is substituted 6-10 membered heteroaryl.

[0223]

[0150] In some embodiments of Formula (III), R13is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R13is hydrogen. In embodiments, R13is D. In embodiments, R13is halogen. In embodiments, R13is F. In embodiments, R13is Cl. In embodiments, R13is Br. In embodiments, R13is I. In embodiments, R13is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R13is OH. In embodiments, R13is OPO3H2. In embodiments, R13is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is substituted C(O)-C1-C8 alkyl. In embodiments, R13is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R13is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkyl. In embodiments, R13is substituted C1- C8 alkyl. In embodiments, R13is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkoxy. In embodiments, R13is methoxy. In embodiments, R13is substituted C1-C8 alkoxy. In embodiments, R13is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkenyl. In embodiments, R13is substituted C1-C8 alkenyl. In embodiments, R13is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkynyl. In embodiments, R13is substituted C1-C8 alkynyl. In embodiments, R13is C3- C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C3- C8 cycloalkyl. In embodiments, R13is substituted C3-C8 cycloalkyl. In embodiments, R13is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C3-C8 cycloalkenyl. In embodiments, R13is substituted C3-C8 cycloalkenyl. In embodiments, R13is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C6-C10 aryl. In embodiments, R13is substituted C6-C10 aryl. In embodiments, R13is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted 6-10 membered heteroaryl. In embodiments, R13is substituted 6-10 membered heteroaryl.

[0224]

[0151] In some embodiments of Formula (III), R14is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R14is hydrogen. In embodiments, R14is D. In embodiments, R14is halogen. In embodiments, R14is F. In embodiments, R14is Cl. In embodiments, R14is Br. In embodiments, R14is I. In embodiments, R14is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R14is OH. In embodiments, R14is OPO3H2. In embodiments, R14is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is substituted C(O)-C1-C8 alkyl. In embodiments, R14is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R14is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkyl. In embodiments, R14is substituted C1- C8 alkyl. In embodiments, R14is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkoxy. In embodiments, R14is methoxy. In embodiments, R14is substituted C1-C8 alkoxy. In embodiments, R14is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkenyl. In embodiments, R14is substituted C1-C8 alkenyl. In embodiments, R14is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkynyl. In embodiments, R14is substituted C1-C8 alkynyl. In embodiments, R14is C3- C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C3- C8 cycloalkyl. In embodiments, R14is substituted C3-C8 cycloalkyl. In embodiments, R14is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C3-C8 cycloalkenyl. In embodiments, R14is substituted C3-C8 cycloalkenyl. In embodiments, R14is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C6-C10 aryl. In embodiments, R14is substituted C6-C10 aryl. In embodiments, R14is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted 6-10 membered heteroaryl. In embodiments, R14is substituted 6-10 membered heteroaryl.

[0225]

[0152] In some embodiments of Formula (III), R6is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R6is hydrogen. In embodiments, R6is D. In embodiments, R6is D. In embodiments, R6is halogen. In embodiments, R6is F. In embodiments, R6is Cl. In embodiments, R6is Br. In embodiments, R6is I. In embodiments, R6is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R6is OH. In embodiments, R6is OPO3H2. In embodiments, R6is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is substituted C(O)-C1-C8 alkyl. In embodiments, R6is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R6is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkyl. In embodiments, R6is substituted C1- C8 alkyl. In embodiments, R6is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkoxy. In embodiments, R6is methoxy. In embodiments, R6is substituted C1-C8 alkoxy. In embodiments, R6is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkenyl. In embodiments, R6is substituted C1-C8 alkenyl. In embodiments, R6is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkynyl. In embodiments, R6is substituted C1-C8 alkynyl. In embodiments, R6is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C3-C8 cycloalkyl. In embodiments, R6is substituted C3-C8 cycloalkyl. In embodiments, R6is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C3-C8 cycloalkenyl. In embodiments, R6is substituted C3-C8 cycloalkenyl. In embodiments, R6is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C6-C10 aryl. In embodiments, R6is substituted C6-C10 aryl. In embodiments, R6is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted 6-10 membered heteroaryl. In embodiments, R6is substituted 6-10 membered heteroaryl.

[0226]

[0153] In some embodiments of Formula (III), R6is (CH2)mX(CH2)nPh, wherein m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14; X is 0, S, or NH; and Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0227]

[0154] In some embodiments of Formula (III), R9is H or D. In embodiments, R9is H. In embodiments, R9is D.

[0228]

[0155] In some embodiments, the compound has the structure of Formula (IIIA):

[0229]

[0156] In some embodiments of Formula (IIIA), RN1is H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, RN1is H. In embodiments, RN1is D. In embodiments, RN1is C1-C8 alkyl. In embodiments, RN1is methyl. In embodiments, RN1is ethyl. In embodiments, RN1is n-propyl. In embodiments, RN1is isopropyl. In embodiments, RN1is butyl. In embodiments, RN1is n-butyl. In embodiments, RN1is sec-butyl. In embodiments, RN1is iso-butyl. In embodiments, RN1is isobutyl. In embodiments, RN1is tert-butyl. In embodiments, RN1is C3- C8 cycloalkyl. In embodiments, RN1is cyclopropyl. In embodiments, RN1is cyclobutyl. In embodiments, RN1is cyclopentyl. In embodiments, RN1is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, RN1is CH2- cyclopropyl. In embodiments, RNis C2-C8 alkenyl. In embodiments, RN1is allyl. In embodiments, RN1is C2-C8 alkynyl. In embodiments, RN1is C2-C8 alkynyl.

[0157] In some embodiments of Formula (I II A), R2, R12, R13, and R14are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl.

[0230]

[0158] In some embodiments of Formula (IIIA), R2is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R2is hydrogen. In embodiments, R2is D. In embodiments, R2is D. In embodiments, R2is halogen. In embodiments, R2is F. In embodiments, R2is Cl. In embodiments, R2is Br. In embodiments, R2is I. In embodiments, R2is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R2is OH. In embodiments, R2is OPO3H2. In embodiments, R2is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is substituted C(O)-C1-C8 alkyl. In embodiments, R2is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R2is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkyl. In embodiments, R2is substituted C1- C8 alkyl. In embodiments, R2is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkoxy. In embodiments, R2is methoxy. In embodiments, R2is substituted C1-C8 alkoxy. In embodiments, R2is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkenyl. In embodiments, R2is substituted C1-C8 alkenyl. In embodiments, R2is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkynyl. In embodiments, R2is substituted C1-C8 alkynyl. In embodiments, R2is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C3-C8 cycloalkyl. In embodiments, R2is substituted C3-C8 cycloalkyl. In embodiments, R2is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C3-C8 cycloalkenyl. In embodiments, R2is substituted C3-C8 cycloalkenyl. In embodiments, R2is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C6-C10 aryl. In embodiments, R2is substituted C6-C10 aryl. In embodiments, R2is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted 6-10 membered heteroaryl. In embodiments, R2is substituted 6-10 membered heteroaryl.

[0231]

[0159] In some embodiments of Formula (IIIA), R6is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R6is hydrogen. In embodiments, R6is D. In embodiments, R6is D. In embodiments, R6is halogen. In embodiments, R6is F. In embodiments, R6is Cl. In embodiments, R6is Br. In embodiments, R6is I. In embodiments, R6is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R6is OH. In embodiments, R6is OPO3H2. In embodiments, R6is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is substituted C(O)-C1-C8 alkyl. In embodiments, R6is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R6is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkyl. In embodiments, R6is substituted C1- C8 alkyl. In embodiments, R6is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkoxy. In embodiments, R6is methoxy. In embodiments, R6is substituted C1-C8 alkoxy. In embodiments, R6is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkenyl. In embodiments, R6is substituted C1-C8 alkenyl. In embodiments, R6is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C1-C8 alkynyl. In embodiments, R6is substituted C1-C8 alkynyl. In embodiments, R6is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C3-C8 cycloalkyl. In embodiments, R6is substituted C3-C8 cycloalkyl. In embodiments, R6is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C3-C8 cycloalkenyl. In embodiments, R6is substituted C3-C8 cycloalkenyl. In embodiments, R6is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted C6-C10 aryl. In embodiments, R6is substituted C6-C10 aryl. In embodiments, R6is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R6is unsubstituted 6-10 membered heteroaryl. In embodiments, R6is substituted 6-10 membered heteroaryl.

[0232]

[0160] In some embodiments of Formula (IIIA), R12is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R12is hydrogen. In embodiments, R12is D. In embodiments, R12is halogen. In embodiments, R12is F. In embodiments, R12is Cl. In embodiments, R12is Br. In embodiments, R4is I. In embodiments, R4is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R12is OH. In embodiments, R12is OPO3H2. In embodiments, R12is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is substituted C(O)-C1-C8 alkyl. In embodiments, R12is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R12is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkyl. In embodiments, R12is substituted C1- C8 alkyl. In embodiments, R12is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkoxy. In embodiments, R12is methoxy. In embodiments, R12is substituted C1-C8 alkoxy. In embodiments, R12is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkenyl. In embodiments, R12is substituted C1-C8 alkenyl. In embodiments, R12is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkynyl. In embodiments, R12is substituted C1-C8 alkynyl. In embodiments, R12is C3- C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C3- C8 cycloalkyl. In embodiments, R12is substituted C3-C8 cycloalkyl. In embodiments, R12is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C3-C8 cycloalkenyl. In embodiments, R12is substituted C3-C8 cycloalkenyl. In embodiments, R12is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C6-C10 aryl. In embodiments, R12is substituted C6-C10 aryl. In embodiments, R12is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted 6-10 membered heteroaryl. In embodiments, R12is substituted 6-10 membered heteroaryl.

[0233]

[0161] In some embodiments of Formula (IIIA), R13is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R13is hydrogen. In embodiments, R13is D. In embodiments, R13is halogen. In embodiments, R13is F. In embodiments, R13is Cl. In embodiments, R13is Br. In embodiments, R13is I. In embodiments, R13is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R13is OH. In embodiments, R13is OPO3H2. In embodiments, R13is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is substituted C(O)-C1-C8 alkyl. In embodiments, R13is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R13is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkyl. In embodiments, R13is substituted C1- C8 alkyl. In embodiments, R13is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkoxy. In embodiments, R13is methoxy. In embodiments, R13is substituted C1-C8 alkoxy. In embodiments, R13is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkenyl. In embodiments, R13is substituted C1-C8 alkenyl. In embodiments, R13is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkynyl. In embodiments, R13is substituted C1-C8 alkynyl. In embodiments, R13is C3- C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C3- C8 cycloalkyl. In embodiments, R13is substituted C3-C8 cycloalkyl. In embodiments, R13is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C3-C8 cycloalkenyl. In embodiments, R13is substituted C3-C8 cycloalkenyl. In embodiments, R13is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C6-C10 aryl. In embodiments, R13is substituted C6-C10 aryl. In embodiments, R13is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted 6-10 membered heteroaryl. In embodiments, R13is substituted 6-10 membered heteroaryl.

[0234]

[0162] In some embodiments of Formula (IIIA), R14is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R14is hydrogen. In embodiments, R14is D. In embodiments, R14is halogen. In embodiments, R14is F. In embodiments, R14is Cl. In embodiments, R14is Br. In embodiments, R14is I. In embodiments, R14is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R14is OH. In embodiments, R14is OPO3H2. In embodiments, R14is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is substituted C(O)-C1-C8 alkyl. In embodiments, R14is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R14is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkyl. In embodiments, R14is substituted C1- C8 alkyl. In embodiments, R14is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkoxy. In embodiments, R14is methoxy. In embodiments, R14is substituted C1-C8 alkoxy. In embodiments, R14is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkenyl. In embodiments, R14is substituted C1-C8 alkenyl. In embodiments, R14is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkynyl. In embodiments, R14is substituted C1-C8 alkynyl. In embodiments, R14is C3- C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C3- C8 cycloalkyl. In embodiments, R14is substituted C3-C8 cycloalkyl. In embodiments, R14is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C3-C8 cycloalkenyl. In embodiments, R14is substituted C3-C8 cycloalkenyl. In embodiments, R14is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C6-C10 aryl. In embodiments, R14is substituted C6-C10 aryl. In embodiments, R14is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted 6-10 membered heteroaryl. In embodiments, R14is substituted 6-10 membered heteroaryl.

[0235]

[0163] In some embodiments of Formula (IIIA), m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6. In embodiments, m is 7. In embodiments, m is 8. In embodiments, m is 9. In embodiments, m is 10. In embodiments, m is 11. In embodiments, m is 12. In embodiments, m is 13. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. In embodiments, n is 11. In embodiments, n is 12. In embodiments, n is 13. In embodiments, the sum of m + n is from 6 to 14. In embodiments, the sum of m + n is from 7 to 13. In embodiments, the sum of m + n is from 8 to 12. In embodiments, the sum of m + n is from 9 to 11 . In embodiments, the sum of m + n is 6. In embodiments, the sum of m + n is 7. In embodiments, the sum of m + n is 8. In embodiments, the sum of m + n is 9. In embodiments, the sum of m + n is 10. In embodiments, the sum of m + n is 11. In embodiments, the sum of m + n is 12. In embodiments, the sum of m + n is 13. In embodiments, the sum of m + n is 14.

[0236]

[0164] In some embodiments of Formula (IIIA), X is O, S, or NH. In embodiments, X is O. In embodiments, X is S. In embodiments, X is NH.

[0237]

[0165] In some embodiments of Formula (IIIA), Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0238]

[0166] In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.

[0167] In embodiments, Ph is phenyl substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, Ph is phenyl substituted by halogen. In embodiments, Ph is phenyl substituted by D. In embodiments, Ph is phenyl substituted by F, Cl, Br or I. In embodiments, Ph is phenyl substituted by azido. In embodiments, Ph is phenyl substituted by alkyl. In embodiments, Ph is phenyl substituted by alkyl ester. In embodiments, Ph is phenyl substituted by hydroxy. In embodiments, Ph is phenyl substituted by alkoxy. In embodiments, Ph is phenyl substituted by methoxy. In embodiments, Ph is phenyl substituted by carboxy. In embodiments, Ph is phenyl substituted by formyl. In embodiments, Ph is phenyl substituted by aryl. In embodiments, Ph is phenyl substituted by heterocyclyl. In embodiments, Ph is phenyl substituted by amino. In embodiments, Ph is phenyl substituted by alkylamino. In embodiments, Ph is phenyl substituted by arylamido. In embodiments, Ph is phenyl substituted by alkylamido. In embodiments, Ph is phenyl substituted by thiol. In embodiments, Ph is phenyl substituted by thioalkyl. In embodiments, Ph is phenyl substituted by thioaryl. In embodiments, Ph is phenyl substituted by alkylsulfonyl. In embodiments, Ph is phenyl substituted by alkylcarbamoyl. In embodiments, Ph is phenyl substituted by arylcarbamoyl. In embodiments, Ph is phenyl substituted by nitro. In embodiments, Ph is phenyl substituted by cyano. In embodiments, Ph is phenyl substituted by nitrate.

[0239]

[0168] In embodiments of Formula (I HA), R9is H or D. In embodiments, R9is H. In embodiments, R9is D.

[0240]

[0169] In some embodiments, the compound is selected from Table 5:

[0241] Table 5. Exemplary Compounds of Formula (IIIA)

[0242]

[0170] In some embodiments, the compound has the structure of Formula (I IIB):

[0243] C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, RN1is H. In embodiments, RN1is D. In embodiments, RN1is C1-C8 alkyl. In embodiments, RN1is methyl. In embodiments, RN1is ethyl. In embodiments, RN1is n-propyl. In embodiments, RN1is isopropyl. In embodiments, RN1is butyl. In embodiments, RN1is n-butyl. In embodiments, RN1is sec-butyl. In embodiments, RN1is iso-butyl. In embodiments, RN1is isobutyl. In embodiments, RN1is tert-butyl. In embodiments, RN1is C3- C8 cycloalkyl. In embodiments, RN1is cyclopropyl. In embodiments, RN1is cyclobutyl. In embodiments, RN1is cyclopentyl. In embodiments, RN1is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, RN1is CH2- cyclopropyl. In embodiments, RNis C2-C8 alkenyl. In embodiments, RN1is allyl. In embodiments, RN1is C2-C8 alkynyl. In embodiments, RN1is C2-C8 alkynyl.

[0244]

[0172] In some embodiments of Formula (II IB), RN2is (CH2)mX(CH2)nPh, wherein m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14; X is 0, S, or NH; and Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0245]

[0173] In some embodiments of Formula (IIIB), m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5. In embodiments, m is 6. In embodiments, m is 7. In embodiments, m is 8. In embodiments, m is 9. In embodiments, m is 10. In embodiments, m is 11. In embodiments, m is 12. In embodiments, m is 13. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10. In embodiments, n is 11. In embodiments, n is 12. In embodiments, n is 13. In embodiments, the sum of m + n is from 6 to 14. In embodiments, the sum of m + n is from 7 to 13. In embodiments, the sum of m + n is from 8 to 12. In embodiments, the sum of m + n is from 9 to 11 . In embodiments, the sum of m + n is 6. In embodiments, the sum of m + n is 7. In embodiments, the sum of m + n is 8. In embodiments, the sum of m + n is 9. In embodiments, the sum of m + n is 10. In embodiments, the sum of m + n is 11. In embodiments, the sum of m + n is 12. In embodiments, the sum of m + n is 13. In embodiments, the sum of m + n is 14.

[0246]

[0174] In some embodiments of Formula (IIIB), X is 0, S, or NH. In embodiments, X is 0. In embodiments, X is S. In embodiments, X is NH.

[0247]

[0175] In some embodiments of Formula (IIIB), Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0248]

[0176] In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.

[0249]

[0177] In embodiments, Ph is phenyl substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, Ph is phenyl substituted by halogen. In embodiments, Ph is phenyl substituted by D. In embodiments, Ph is phenyl substituted by F, Cl, Br or I. In embodiments, Ph is phenyl substituted by azido. In embodiments, Ph is phenyl substituted by alkyl. In embodiments, Ph is phenyl substituted by alkyl ester. In embodiments, Ph is phenyl substituted by hydroxy. In embodiments, Ph is phenyl substituted by alkoxy. In embodiments, Ph is phenyl substituted by methoxy. In embodiments, Ph is phenyl substituted by carboxy. In embodiments, Ph is phenyl substituted by formyl. In embodiments, Ph is phenyl substituted by aryl. In embodiments, Ph is phenyl substituted by heterocyclyl. In embodiments, Ph is phenyl substituted by amino. In embodiments, Ph is phenyl substituted by alkylamino. In embodiments, Ph is phenyl substituted by arylamido. In embodiments, Ph is phenyl substituted by alkylamido. In embodiments, Ph is phenyl substituted by thiol. In embodiments, Ph is phenyl substituted by thioalkyl. In embodiments, Ph is phenyl substituted by thioaryl. In embodiments, Ph is phenyl substituted by alkylsulfonyl. In embodiments, Ph is phenyl substituted by alkylcarbamoyl. In embodiments, Ph is phenyl substituted by arylcarbamoyl. In embodiments, Ph is phenyl substituted by nitro. In embodiments, Ph is phenyl substituted by cyano. In embodiments, Ph is phenyl substituted by nitrate.

[0250]

[0178] In some embodiments of Formula (IIIB), R2, R12, R13, and R14are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)-C1-C8 alkyl.

[0251]

[0179] In some embodiments of Formula (II IB), R2is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R2is hydrogen. In embodiments, R2is D. In embodiments, R2is D. In embodiments, R2is halogen. In embodiments, R2is F. In embodiments, R2is Cl. In embodiments, R2is Br. In embodiments, R2is I. In embodiments, R2is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R2is OH. In embodiments, R2is OPO3H2. In embodiments, R2is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is substituted C(O)-C1-C8 alkyl. In embodiments, R2is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R2is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkyl. In embodiments, R2is substituted C1- C8 alkyl. In embodiments, R2is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkoxy. In embodiments, R2is methoxy. In embodiments, R2is substituted C1-C8 alkoxy. In embodiments, R2is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkenyl. In embodiments, R2is substituted C1-C8 alkenyl. In embodiments, R2is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C1-C8 alkynyl. In embodiments, R2is substituted C1-C8 alkynyl. In embodiments, R2is C3-C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C3-C8 cycloalkyl. In embodiments, R2is substituted C3-C8 cycloalkyl. In embodiments, R2is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C3-C8 cycloalkenyl. In embodiments, R2is substituted C3-C8 cycloalkenyl. In embodiments, R2is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted C6-C10 aryl. In embodiments, R2is substituted C6-C10 aryl. In embodiments, R2is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R2is unsubstituted 6-10 membered heteroaryl. In embodiments, R2is substituted 6-10 membered heteroaryl.

[0252]

[0180] In some embodiments of Formula (IIIB), R12is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R12is hydrogen. In embodiments, R12is D. In embodiments, R12is halogen. In embodiments, R12is F. In embodiments, R12is Cl. In embodiments, R12is Br. In embodiments, R4is I. In embodiments, R4is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R12is OH. In embodiments, R12is OPO3H2. In embodiments, R12is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is substituted C(O)-C1-C8 alkyl. In embodiments, R12is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R12is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkyl. In embodiments, R12is substituted C1- C8 alkyl. In embodiments, R12is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkoxy. In embodiments, R12is methoxy. In embodiments, R12is substituted C1-C8 alkoxy. In embodiments, R12is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkenyl. In embodiments, R12is substituted C1-C8 alkenyl. In embodiments, R12is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C1-C8 alkynyl. In embodiments, R12is substituted C1-C8 alkynyl. In embodiments, R12is C3- C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C3- C8 cycloalkyl. In embodiments, R12is substituted C3-C8 cycloalkyl. In embodiments, R12is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C3-C8 cycloalkenyl. In embodiments, R12is substituted C3-C8 cycloalkenyl. In embodiments, R12is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted C6-C10 aryl. In embodiments, R12is substituted C6-C10 aryl. In embodiments, R12is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R12is unsubstituted 6-10 membered heteroaryl. In embodiments, R12is substituted 6-10 membered heteroaryl.

[0253]

[0181] In some embodiments of Formula (IIIB), R13is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R13is hydrogen. In embodiments, R13is D. In embodiments, R13is halogen. In embodiments, R13is F. In embodiments, R13is Cl. In embodiments, R13is Br. In embodiments, R13is I. In embodiments, R13is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R13is OH. In embodiments, R13is OPO3H2. In embodiments, R13is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is substituted C(O)-C1-C8 alkyl. In embodiments, R13is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R13is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkyl. In embodiments, R13is substituted C1- C8 alkyl. In embodiments, R13is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkoxy. In embodiments, R13is methoxy. In embodiments, R13is substituted C1-C8 alkoxy. In embodiments, R13is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkenyl. In embodiments, R13is substituted C1-C8 alkenyl. In embodiments, R13is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C1-C8 alkynyl. In embodiments, R13is substituted C1-C8 alkynyl. In embodiments, R13is C3- C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C3- C8 cycloalkyl. In embodiments, R13is substituted C3-C8 cycloalkyl. In embodiments, R13is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C3-C8 cycloalkenyl. In embodiments, R13is substituted C3-C8 cycloalkenyl. In embodiments, R13is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted C6-C10 aryl. In embodiments, R13is substituted C6-C10 aryl. In embodiments, R13is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R13is unsubstituted 6-10 membered heteroaryl. In embodiments, R13is substituted 6-10 membered heteroaryl.

[0254]

[0182] In some embodiments of Formula (IIIB), R14is hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1- C8 alkoxy, C1 -C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; wherein R' is H, PO3H2, or C(O)- C1-C8 alkyl. In embodiments, R14is hydrogen. In embodiments, R14is D. In embodiments, R14is halogen. In embodiments, R14is F. In embodiments, R14is Cl. In embodiments, R14is Br. In embodiments, R14is I. In embodiments, R14is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R14is OH. In embodiments, R14is OPO3H2. In embodiments, R14is C(O)-C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is substituted C(O)-C1-C8 alkyl. In embodiments, R14is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R14is C1-C8 alkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkyl. In embodiments, R14is substituted C1- C8 alkyl. In embodiments, R14is C1-C8 alkoxy optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkoxy. In embodiments, R14is methoxy. In embodiments, R14is substituted C1-C8 alkoxy. In embodiments, R14is C1-C8 alkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkenyl. In embodiments, R14is substituted C1-C8 alkenyl. In embodiments, R14is C1-C8 alkynyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C1-C8 alkynyl. In embodiments, R14is substituted C1-C8 alkynyl. In embodiments, R14is C3- C8 cycloalkyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C3- C8 cycloalkyl. In embodiments, R14is substituted C3-C8 cycloalkyl. In embodiments, R14is C3-C8 cycloalkenyl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C3-C8 cycloalkenyl. In embodiments, R14is substituted C3-C8 cycloalkenyl. In embodiments, R14is C6-C10 aryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted C6-C10 aryl. In embodiments, R14 is substituted C6-C10 aryl. In embodiments, R14is 6-10 membered heteroaryl optionally substituted at one or more positions by a halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. In embodiments, R14is unsubstituted 6-10 membered heteroaryl. In embodiments, R14is substituted 6-10 membered heteroaryl.

[0255]

[0183] In some embodiments of Formula (IIIB), R6is (CH2)mX(CH2)nPh, wherein m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14; X is 0, S, or NH; and Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0256]

[0184] In embodiments of Formula (IIIB), R9is H or D. In embodiments, R9is H. In embodiments, R9is D.

[0257]

[0185] In some embodiments, the compound is selected from Table 6:

[0258] Table 6. Exemplary Compounds of Formula (IIIB)

[0259]

[0260]

[0186] For any of the exemplary species provided above (e.g., in Tables 2-6) that contain a side chain having the structure of — (CH2)eO(CH2)4Ph, also provided is the corresponding compound wherein the side chain is replaced by any of the other disclosed side chains, as provided in, e.g., Table 1; or any side chain within the scope of the general formula — (CH2)mX(CH2)nPh, as defined in embodiments herein.

[0261]

[0187] In embodiments, additional N-substituted tryptamine compounds of this disclosure include the substituted tryptamines disclosed as “additional active compounds” herein, disclosed in TiHKAL, or disclosed as a substituted tryptamine in any of PCT Pub. Nos. WO2023212811 ; WO2021173989; W02022051670; WO2022061242; WO2023141225; WO2022153268; WO2023077125; WO2022081549; WO2023183613; WO2023201421; WO2022183287; WO2023173196; W02022000091; WO2022225884; WO2022173584; WO2023108167; WO2023108174; WO2023081892; WO2023173197; WO2021236759; WO2023177294; WO2022140844; WO2023205768; WO2023278403; WO2022170442; WO2022183288; WO2023023287; WO2023186867; WO2023173197; WO2023201293; WO2023034645; WO2023173229; WO2022232233; WO2023019367; WO2023108260; WO2022256554; WO2023186963; WO2023150547; W02023200671; WO2023173227; WO2023173227; W02023064840; W02023217800; WO2023218423; WO2023225043; WO2023225679; and WO2023225678; as well as U.S. Appl. Nos. US18218216; US18353492; US18297370; US17863427; US18123812; US17906212; US18024545; US17998870; US18079617; US17388257; US17192863; US18203823; US17364047; US17720229; US16827072; US17977398; US18051449;

[0262] US17833341; US17679439; US17903080; US17893113; US17866477; US18001191; US17942706;

[0263] US17995516; US18350103; US17987208; US18180685; US17885978; US17801552; US18172691 ;

[0264] US18247057; US18051228; and US18248577; each of which is hereby incorporated by reference as if fully set forth herein, wherein the amine nitrogen of any such disclosed substituted tryptamine compound is substituted with — (CH2)mX(CH2)nPh as defined herein, and all other substituents are as otherwise defined therein for such disclosed substituted tryptamine compound, and including the derivatives of all of the substituted tryptamine compounds disclosed in each reference. In some other embodiments, the N-substituted tryptamine compounds of this disclosure expressly exclude all such substituted tryptamine compounds as so defined.

[0265]

[0188] In some embodiments, additional N-substituted lysergamide compounds of this disclosure include those in the paragraphs that follow. Further embodiments include the derivatives of any or all of the compounds disclosed in these paragraphs. All of the references cited in these paragraphs are hereby incorporated by reference as if fully disclosed herein. In some other embodiments, the N-substituted lysergamide compounds of this disclosure expressly exclude any or all such compounds as so defined, in any one or more such paragraphs.

[0266]

[0189] In some embodiments, additional N-substituted lysergamide compounds (“N-substituted lysergamides” as shorthand) include the compounds of Formula (I) disclosed in US2023 / 0116703, wherein any of R1 , R2, or R3 is — (CH2)mX(CH2)nPh as defined herein, with all other substituents as otherwise defined therein.

[0267]

[0190] In some embodiments, additional N-substituted lysergamides include the compounds of Formula (I) disclosed in US2023 / 0088860 or US2023 / 0167112, wherein either of the D-ring (6-position) N or the amine N is substituted with — (CH2)mX(CH2)nPh as defined herein, with all other substituents as otherwise defined therein.

[0268]

[0191] In some embodiments, additional N-substituted lysergamides include the compounds of Formula (I) disclosed in US2023 / 0286975, wherein either of the D-ring (6-position) nitrogen or the amine nitrogen is substituted with — (CH2)mX(CH2)nPh as defined herein, with all other substituents as otherwise defined therein.

[0269]

[0192] In some embodiments, additional N-substituted lysergamides include the compounds of Formula (I) disclosed in WO2023 / 115006, wherein either of the D-ring (6-position) nitrogen or the amine nitrogen is substituted with — (CH2)mX(CH2)nPh as defined herein, with all other substituents as otherwise defined therein.

[0270]

[0193] In some embodiments, additional N-substituted lysergamides comprise the compounds of Formula I disclosed in US2023 / 0219955 or US2023 / 0357243, wherein any of R5, R1 , or R2 is — (CH2)mX(CH2)nPh as defined herein, with all other substituents as otherwise defined therein.

[0271]

[0194] In some embodiments, additional N-substituted lysergamides comprise the compounds of Formula (I) disclosed in WO2023 / 073423, wherein any of R4, R6, or R7 is — (CH2)mX(CH2)nPh as defined herein, with all other substituents as otherwise defined therein.

[0272]

[0195] In embodiments, additional N-substituted lysergamides comprise the compounds of Formula I disclosed in WO2023 / 115060 or US2020 / 0030309, wherein either of the D-ring (6-position) nitrogen or the amine nitrogen is substituted with — (CH2)mX(CH2)nPh as defined herein, with all other substituents as otherwise defined therein.

[0196] Disclosed compounds, including when used in disclosed compositions, will be understood to encompass the pharmaceutically acceptable salts of such compounds. “Pharmaceutically acceptable salt” herein refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, such as may be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of a compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. A variety of counterions may be pharmaceutically acceptable, as known to one of skill. In specific applications, the selection of an anion or cation to prepare a salt may result in increased or decreased solubility of the salt. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy- 2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d- aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, I- aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc and the like (see e.g. Berge et al. J Pharm Sci. 1997;66:1-19).

[0273]

[0197] Certain compounds disclosed herein contain one or more ionizable groups (groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)). All possible ionic forms of such molecules and salts thereof are included in the present disclosure.

[0274]

[0198] A compound described herein can exist in solid or liquid form. In the solid state, the compound may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline or non-crystalline compounds. Solvates may involve non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice (“hydrates”). Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.

[0275]

[0199] The skilled artisan will appreciate that certain disclosed compounds can exist in crystalline form, including the various solvates thereof, and may exhibit polymorphism. The disclosure of a compound herein includes such polymorphs. In some embodiments, a polymorph of a disclosed compound has at least one different physical property, such as related to shape, density, hardness, deformability, stability, and dissolution. In some embodiments, a polymorph of a disclosed compound exhibits one or more of, compared to another form, such as a prior art form, different melting points, IR spectra, and X-ray powder diffraction patterns. Those of skill will appreciate that different polymorphs may be produced, for example, by changing the reaction conditions or reagents used in making the compound, and one may vary the temperature, pressure, or solvent.

[0276]

[0200] Disclosed compounds may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The disclosure includes all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard tests described herein and other tests well known in the art. Examples of methods that can be used to obtain optical isomers of the compounds according to the present disclosure include selective crystallization, enzymatic resolution, asymmetric synthesis (including asymmetric chemical synthesis and asymmetric enzymatic synthesis), kinetic resolution, and chiral chromatography (including chiral liquid chromatography, gas chromatography, and high-performance liquid chromatography).

[0277]

[0201] Where disclosed compounds contain olefinic double bonds or other centers of geometric asymmetry, both E and Z geometric isomers are included unless indicated otherwise. Tautomeric forms also are included.

[0278]

[0202] Also provided are compounds with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., isotopically enriched analogs of disclosed compounds. Isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, such as2H,3H,11C,13C,14C,15N,170,18O, and36CI respectively. In embodiments, isotopically labeled compounds can be used in metabolic studies (with14C), reaction kinetic studies (with, e.g.,2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In some embodiments, an18F-labeled compound is used for PET or SPECT studies. In some embodiments, substitution with heavier isotopes such as deuterium, i.e.,2H, provide certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the disclosure generally can be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0279]

[0203] Also provided are prodrugs of disclosed compounds, such as undergo a chemical or a metabolic conversion to become the biologically active compound. A prodrug can be converted ex vivo to the active compound by chemical transformative processes. In vivo, a prodrug can be converted to the active compound by the action of a metabolic process, an enzymatic process, or a degradative process to remove the prodrug moiety and form the active compound. In some embodiments, a prodrug includes compounds with biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. In some embodiments, a prodrug includes compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. In some embodiments, functional groups include esters, carbonates, carbamates, amides, phosphates, and sulfonamides, including attached to the active compound via a linker that is designed to be cleaved under specific physiological conditions, such as enzymatic hydrolysis or pH-dependent cleavage. As will be appreciated by those of skill, the choice of functional group may depend on factors such as stability, ease of synthesis, enzymatic activity, and desired rate of prodrug conversion.

[0280]

[0204] Disclosed compounds may be provided as isolated or purified compounds. The terms “isolated,” “purified,” or “substantially pure,” as used herein, refer to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced. An “isolated,” “purified,” or “substantially pure” preparation of a compound can refer to a preparation having a chromatographic purity (of the desired compound) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, and most preferably greater than 99.9%, as determined by area normalization of an HPLC profile or other similar detection method. In some embodiments, a substantially pure compound of the disclosure is substantially free of any other active compounds which are not intended to be administered to a subject. In this context, “substantially free” can be taken to mean that no active compound(s) other than the active compound intended to be administered to a subject are detectable by HPLC or other similar detection method, or are below a desired threshold of detection such as defined above.

[0281] C. Methods of Preparing Disclosed Compounds

[0282]

[0205] Tryptamine-containing disclosed compounds can be prepared by chemical synthesis according to the general reaction sequence shown below.

[0206] Briefly, a suitable tryptamine precursor is reacted with a side chain precursor (e.g., Br(CH2)mX(CH2)nPh as shown above) to produce the compound (e.g., of Formula (I)) by nucleophilic substitution of the leaving group (in this exemplary case, bromide) by the tryptamine amine.

[0283]

[0207] An alternative reaction sequence is provided below:

[0284]

[0208] In a first reaction step, an amine precursor (RN-NH2) is alkylated with a side chain precursor (e.g., as shown above, Br(CH2)mX(CH2)nPh). The resulting (secondary amine) intermediate is reacted with a tryptamine precursor containing a suitable leaving group (here, e.g., bromide) to produce the compound of Formula (I).

[0285]

[0209] This reaction sequence can be used in the synthesis of, e.g., a substituted tryptamine having an N- methyltryptamine component:

[0286]

[0210] In these exemplary reactions, potassium iodide is used to accelerate the nucleophilic substitution reaction. Addition of an inorganic iodide salt (e.g., potassium iodide, sodium iodide) to improve the efficiency of nucleophilic substitution reactions is a well-known technique. However, potassium iodide is not necessary for the reaction to proceed. One of skill can determine whether potassium iodide should be added and, if so, how much should be used. Likewise, triethylamine is used as an exemplary base. However, as will be appreciated by one of skill, other bases may be used. For example, diisopropylethylamine (DIPEA) and pyridine are common organic bases. Likewise, although acetonitrile is depicted as an exemplary solvent, substitution of acetonitrile for another suitable solvent can be performed according to the general knowledge in the art.

[0287]

[0211] Certain lysergamide-containing compounds of the disclosure, wherein RN2is (CH2)mX(CH2)nPh, can be synthesized from a suitable lysergic acid precursor as follows:

[0288]

[0212] In a first reaction step, an amine precursor (RN-NH2) is alkylated with a side chain precursor (e.g., as shown above, Br(CH2)mX(CH2)nPh). The resulting (secondary amine) intermediate is then reacted with a lysergic acid precursor to produce the compound of Formula (II). The synthesis of lysergic acid precursors is known to those of skill in the art. For example, lysergic acid can be obtained by hydrolysis of naturally occurring lysergamides, or produced synthetically (see, e.g., Jastrz^bski et al. Molecules. 2022;27(21):7322). Substituted lysergic acid precursors can also be obtained by chemical synthesis, as disclosed in, e.g., Knight et al. J Org Chem. 2023;88(4):2158-2165 and Hoffman and Nichols. J Med Chem 1985;28:1252-1255.

[0289]

[0213] In exemplary reactions, potassium iodide is used to accelerate the nucleophilic substitution reaction. Addition of an inorganic iodide salt (e.g., potassium iodide, sodium iodide) to improve the efficiency of nucleophilic substitution reactions is a well-known technique. However, potassium iodide is not necessary for the reaction to proceed. The person of skill in the art can determine whether potassium iodide should be added, and if so, how much should be used. Likewise, triethylamine is used as an exemplary base. However, as will be appreciated by the person of skill, other bases may be used. For example, diisopropylethylamine (DIPEA) and pyridine are common organic bases. Likewise, although acetonitrile is depicted as an exemplary solvent, substitution of acetonitrile for another suitable solvent can be performed according to the knowledge of a person of ordinary skill.

[0290]

[0214] In another exemplary reaction sequence, other lysergamide-containing compounds of the disclosure can be prepared by dealkylation (e.g., demethylation) of a lysergamide precursor wherein R6is alkyl (e.g., methyl), followed by N(6) alkylation with a suitable side chain precursor:

[0291]

[0292]

[0215] As another more specific example, the scheme below shows an exemplary reaction sequence in which lysergamide-containing compounds of the disclosure are prepared from LSD as a precursor:

[0293]

[0216] During the synthesis of disclosed compounds, it may be necessary to protect the indole nitrogen of the tryptamine or lysergic acid precursor with a suitable protecting group prior to reacting the tryptamine precursor with the side chain precursor. Suitable protecting groups are known to one of skill (e.g., t-butyloxycarbonyl (Boc) or triisopropylsilyl (TIPS)), as are the reaction conditions for conducting protection and deprotection reactions.

[0294]

[0217] The synthesis of any other necessary starting materials or reagents will be readily apparent to one of skill in view of this disclosure and general references well known in the art, such as Green et al., “Protective Groups in Organic Chemistry,” (Wiley, 2nd ed. 1991); Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wiley and Sons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al, “Reagents for Organic Synthesis,” Volumes 1- 17, Wiley Interscience; Trost et al., “Comprehensive Oraanic Synthesis,” Pergamon Press, 1991 ; “Theilheimer’s Synthetic Methods of Organic Chemistry,” Vols. 1-45, Karger, 1991 ; March, “Advanced Organic Chemistry,” Wiley Interscience, 1991 ; Larock “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons, 1995; Glennon et al. J Med Chem. 1986;29(2): 194-199; Nichols et al. JMed Chem. 1991;34(1):276-281 ; Kedrowski et al. OrganicLett. 2007;9(17): 3205-3207; Heravi and Zadsirjan. Current Organic Synthesis. 2016;13(6):780-833; Keri et al. European J Med Chem. 2017;138:1002-1033; Perez-Silanes et al. J Heterocyclic Chem. 2001 ;38(5):1025-1030; and EP1937626 (US8648214); which describes synthesis of salmeterol and analogs thereof. All of the foregoing, hereby fully incorporated by reference, in combination with the disclosure, may be used to prepare disclosed compounds.

[0295] D. Pharmaceutical Compositions

[0296]

[0218] In some aspects, provided herein are compositions, such as pharmaceutical compositions, comprising a disclosed compound, such as a compound of any disclosed Formulae or subformulae thereof. “Pharmaceutical compositions” are compositions comprising disclosed compound(s) together with a pharmaceutically acceptable carrier, diluent, or excipient, and which in some embodiments may be provided in a specific concentration and / or amount (for example, as a unit dosage form). Some embodiments will not have a single carrier, diluent, or excipient alone, but will include multiple carriers, diluents, and / or excipients. Compositions can be prepared by standard pharmaceutical formulation techniques as disclosed in, e.g., Remington: The Science & Practice of Pharmacy (2020) 23th ed., Academic Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, N.J.; Pharm. Principles of Solid Dosage Forms (1993), Technomic Pub. Co., Inc., Lancaster, Pa.; and Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, Md.; & Poznansky et al. Drug Delivery Systems (1980), R.L. Juliano, ed., Oxford, N.Y., pp. 253-315).

[0297]

[0219] “Pharmaceutically acceptable” used in connection with an excipient, carrier, diluent, or other ingredient means the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with cells of humans and animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk / benefit ratio.

[0298]

[0220] In some embodiments, disclosed pharmaceutical compositions can be administered by a variety of routes including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal. In some embodiments, the compounds employed in the methods of this invention are effective as oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal compositions. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise a disclosed compound (see, e.g., Remington, 2020).

[0299]

[0221] Disclosed compositions may be formulated or otherwise provided in a unit dosage form, such as where each dosage contains a therapeutically effective amount of a disclosed compound, for example in any dose amount disclosed below. A “unit dosage form” may refer to a physically discrete unit suited as unitary dosages for a subject, each unit containing a predetermined quantity of disclosed compound(s) calculated to produce the desired therapeutic effect(s), together with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms may provide ease of administration and uniformity of dosage. Unit dosage forms may comprise a single or individual dose or unit, a sub-dose, or an appropriate fraction of the pharmaceutical composition administered.

[0300]

[0222] Unit dosage forms include capsules, troches, cachets, lozenges, and tablets.

[0301]

[0223] Unit dosage forms include ampules and vials, which may comprise a composition in a freeze-dried or lyophilized state, and to which a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo, or which may comprise liquid compositions disposed therein.

[0302]

[0224] Unit dosage forms also may be prepared for transdermal administration, such as “patches” that contact the epidermis (including the mucosa) of a subject for an extended or for a brief period of time.

[0303]

[0225] In embodiments, disclosed compositions are prepared as a (equivalently to “formulated” as a) pharmaceutically acceptable oral dosage form. Oral dosage forms include oral liquid dosage forms (such as tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like) and oral solid dosage forms.

[0304]

[0226] In embodiments, disclosed compositions are prepared as an oral solid dosage form. Oral solid dosage forms may include lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combinations thereof. Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations. Accordingly, in some embodiments, the disclosed oral solid dosage forms may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-melt tablet. Additionally, pharmaceutical formulations may be administered as a single capsule or in multiple capsule dosage form. In embodiments, the pharmaceutical formulation is administered in two, three, four, or more capsules or tablets.

[0305]

[0227] Oral solid dosage forms may comprise pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosityincreasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof. Oral solid dosage forms also can comprise one or more pharmaceutically acceptable additives such as a compatible carrier, complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination, as well as supplementary active compound(s).

[0306]

[0228] Supplementary active compounds include preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents. Preservatives can be used to inhibit microbial growth or increase stability of the active ingredient thereby prolonging the shelf life of the formulation. Suitable preservatives are known in the art and include EDTA, EGTA, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate. Antioxidants include vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and compounds such as alpha lipoic acid.

[0307]

[0229] In embodiments, a disclosed composition is formulated as an oral liquid dosage form. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like. Oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill for the preparation of liquid dosage forms, and with solvents, diluents, carriers, excipients, and the like chosen as appropriate to the solubility and other properties of the active agents and other ingredients. Solvents may be, for example, water, glycerin, simple syrup, alcohol, medium chain triglycerides (MOT), and combinations thereof.

[0308]

[0230] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may comprise an inactive diluent, such as water.

[0309]

[0231] Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as an oil, water, an alcohol, and combinations thereof, and pharmaceutically suitable surfactants, suspending agents, and / or emulsifying agents, may be added for oral or parenteral administration. Liquid dosage forms may comprise additives, such as one or more (a) disintegrating agents, (b) dispersing agents, (c) wetting agents, (d) preservatives, (e) viscosity enhancing agents, (f) sweetening agents, or (g) flavoring agents.

[0310]

[0232] Liquid dosage forms for oral administration include aqueous suspensions such as pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, and syrups, which may be prepared according to, e.g., Singh et al., Encyclopedia Pharm Tech., 2nd Ed., 754-57 (2002). Suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil, as well as carrier oils such as MCT and long chain triglyceride (LCT) oils. Suspensions also may contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspensions may include alcohols (e.g., ethanol, isopropyl, hexadecyl), glycerol, and propylene glycol. Ethers, such as polyethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspensions. Suspensions therefore include aqueous liquids, non-aqueous liquids, oil-in-water liquid emulsions, and water-in-oil emulsions.

[0311]

[0233] In some embodiments, a formulation comprises a disclosed compound and at least one dispersing agent or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained. The aqueous dispersion can comprise amorphous and non-amorphous particles consisting of multiple effective particle sizes such that a drug is absorbed in a controlled manner over time.

[0312]

[0234] Liquid formulations also may be prepared as single dose or multi-dose beverages.

[0313]

[0235] Disclosed compositions may be prepared for intramuscular (IM), subcutaneous (SC), intraperitoneal (IP), or intravenous (IV) injection. Such formulations include sterile aqueous or non-aqueous solutions, dispersions, suspensions, and emulsions, as well as liposomes and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0236] Disclosed compositions may be prepared as a topical dosage form (“topical”). Topicals include trans- mucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. Such formulations may comprise penetrants and carriers. Penetrants include, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Carriers include, for transdermal administration, Vaseline®, lanolin, PEG, alcohols, transdermal enhancers, and combinations thereof.

[0314] E. Pharmaceutical Combinations

[0315]

[0237] Disclosed compositions are not limited to combinations of a single compound, or (when formulated as a pharmaceutical composition) limited to a single carrier, diluent, and / or excipient alone, but include combinations of multiple compounds (including additional active compounds), and / or multiple carriers, diluents, and / or excipients. Compositions thus may comprise a disclosed compound together with one or more other active agents, including other disclosed compounds, in combination, together with one or more pharmaceutically- acceptable carriers, diluents, and / or excipients, and additionally with one or more other active compounds.

[0316]

[0238] In some embodiments, a formulation is prepared so as to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf-life, decrease an unwanted effect or property, alter a property in a desirable way (such as pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide synergistic effects.

[0317]

[0239] “Therapeutic effects,” for example that may be increased or added in embodiments, include anti-oxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, aphrodisiac, bronchodilator, nootropic, neuro- protective, entactogenic, empathogenic, entheogenic, psychedelic, oneirogenic, sedative, and stimulant effects.

[0318]

[0240] “Synergistic effects” include increases in potency, bioactivity, bioaccessibility, bioavailability, therapeutic effect, and the like, that are greater than the additive contributions of the components acting alone. Numerous methods known to those of skill can be used to determine whether there is synergy as to a particular effect, such that an effect is greater than the sum of the effects of the individual components alone, producing “1 +1 > 2.”

[0319]

[0241] Suitable methods include isobologram (or contour) analysis (Huang. Front Pharmacol. 2019;10:1222); the equation of Loewe additivity (Loewe and Muischnek. Arch Exp Pathol Pharmacol. 1926;114:313-326); the Sigmoid-Emax equation (Holford and Scheiner. Clin Pharmacokinet. 1981 ;6:429-453); and the median-effect equation (Chou and Talalay. Adv Enzyme Regul. 1984;22:27-55). These and other equations may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of a drug combination, such as the a concentration-effect curve or a combination-index curve.

[0320]

[0242] In some embodiments, a disclosed composition comprises an additional active compound. The additional active compound may be selected from any of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, entactogens, empathogens, entheogens, psychedelics, plasticityinducing agents (e.g., psychoplastogens and neuroplastogens), monoamine oxidase inhibitors (e.g., RIMAs), tryptamines, terpenes, phenethylamines, aphrodisiacs, oneirogens, sedatives, stimulants, serotonergic agents, and vitamins. In embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, increase plasticity (e.g., neuroplasticity), or alter pharmacokinetics or pharmacodynamics. “Therapeutic effects” include those listed above, and such others as will be appreciated by those of skill.

[0321]

[0243] In embodiments, an additional active compound is a serotonin receptor antagonist. In embodiments, the serotonin receptor antagonist is a 5-HT2A antagonist. In embodiments, the serotonin receptor antagonist is a 5- HT2B antagonist. In embodiments, the serotonin receptor antagonist is peripherally-restricted antagonist.

[0322]

[0244] In embodiments, an additional active compound is a tryptamine.

[0323]

[0245] A tryptamine will have the general structure below, wherein RN1, RN2, Ra, RP, R2, R4, R5, R6, and R7are as disclosed herein and as generally understood in the art:

[0324]

[0246] In some embodiments, RN1, RN2, Ra, RP, R2, R4, R5, R6, and R7are each independently hydrogen, deuterium, halogen (F, Cl, Br, or I), OH, phosphoryloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Additionally, any two of RN1, RN2, Ra, RP, R2, R4, R5, R6, and R7and the intervening atoms can be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In embodiments, the tryptamine is a quaternary salt, in which an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0325]

[0247] In some embodiments, the additional active compound is a tryptamine selected from the group consisting of psilocybin, psilocin, psilacetin, DBT, DET, DiPT, a,O-DMS, DMT, 2,a-DMT, a,N-DMT, DPT, EiPT, AET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-TMT, 4-HO-DMT, 5-HO-DMT (i.e., bufotenine), 4-HO-DPT, 4- HO-MET, 4-HO-MiPT, 4-HO-MPT, 4-HO-pyr-T, ibogaine, MBT, 4,5-MDO-DiPT, 5,6-MDO-DiPT, 4,5-MDO-DMT, 5,6-MDO-DMT, 5,6-MDO-MiPT, 2-Me-DET, 5-Br-DMT, 5-CI-DMT, 5-F-DMT, 4,5-MDO-DMT, 4,5-MDO-DiPT, 2- Me-DMT, melatonin, 5-MeO-DET, 5-MeO-DiPT, 5-MeO-DALT, 5-MeO-DMT, 4-MeO-MiPT, 5-MeO-MiPT, 5,6- MeO-MiPT, 5-MeO-NMT, 5-MeO-pyr-T, 5-MeO-TMT. 5-MeS-DMT, MiPT, a-MT (i.e., AMT), NET, NMT, pyr-T, tryptamine, or a,N,O-TMS, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof. In some embodiments, an additional tryptamine will be a “complex tryptamine” or other indolamine and including such examples as iboga alkaloids such as ibogaine, betacarbolines, and their analogs, metabolites, and derivatives.

[0326]

[0248] In some embodiments, the additional active compound is a phenethylamine.

[0327]

[0249] A phenethylamine will have the general structure below, wherein RN1, RN2, Ra, RP, and each of R2-R6are as disclosed herein and generally understood in the art:

[0328]

[0250] In embodiments, the phenethylamine is any of mescaline, a-ethylmescaline, escaline, symbescaline, metaescaline, allylescaline, methallyl-escaline, asymbescaline, cyclopropylmescaline, phenescaline, 4- desoxymescaline, isomescaline, proscaline, metaproscaline, isoproscaline, thiomescaline, thioescaline, thioproscaline, thiobuscaline, a thiomescaline analog (e.g., 3-TM, 4-TM), buscaline, a thioisomescaline (e.g., 2- TIM, 3-TIM, 4-TIM), Aleph (i.e., DOT), a thiometa-escaline (e.g., 3-TME, 4-TME, 5-TME), a thiotrisescaline (e.g., 3-T-TRIS, 4-T-TRIS), a thiosymbescaline (e.g., 3-TSB, 4-TSB), Aleph-2, Aleph-4, Aleph-6, Aleph-7, Ariadne, Beatrice (i.e., MDO-D, MDOM), BIS-TOM, BOB, BOD, BOH, BOHD, BOM, 4-Br-3,5-DMA, 2-Br-4,5-MDA, MDEA, 3C-BZ, a 2C-X compound (e.g., 2C-B, 2C-B-AN, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-B-FLY-NBOMe, 2C-B-FLY- NB2EtO5CI, 2C-Bn, 2C-Bu, 2C-B-5-HEMIFLY, 20-0, 2C-C-3, 2C-CN, 2C-CP, 2C-D, 2C-E, 2C-EF, 2C-F, 2C-G, 2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, 2C-G-N, 2C-H, 2C-I, 2CB-lnd, 2C-iP, 2C-N, 2C-NH2, 20- PYR, 2C-PIP, 20-0, 2C-O-4, 2C-M0M, 2C-P, 2C-Ph, 2C-Se, 2C-T, 2C-T-2, 2C-T-3, 2C-T-4, 2C-T-5, 2C-T-6, 2C-T-7, 2C-T-8, 2C-T-9, 2C-T-10, 2C-T-11 , 2C-T-12, 2C-T-13, 2C-T-14, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-18, 2C-T-19, 2C-T-21 , 2C-T-21.5, 2C-T-22, 2C-T-23, 2C-T-24, 2C-T-25, 2C-T-27, 2C-T-28, 2C-T-30, 2C-T-31 , 20- T-32, 2C-T-33, 2C-DFM, 2C-TFM, 2C-TFE, 2C-YN, 2C-V, 2C-AL, CPM, psi-2C-T-4, 2C-Se), 3C-BZ, 3C-E, 4-D, beta-D, 2,4-DMA, 2,5-DMA, 3,4-DMA, DMCPA, DME, DMMDA, DMMDA-2, DMPEA, DOAM, DOB, DOBU, DOC, DOEF, DOET, DOI, DOM (i.e., STP), psi-DOM, DON, DOPR, EEE, EEM, EME, EMM, ETHYL-J, ETHYL-K, F- 2, F-22, FLEA, GANESHA, a GANESHA analog (e.g., G-3, G-4, G-5, G-N), HOT-2, HOT-7, HOT-17, IDNNA, IRIS, BDB, LOPHOPHINE, 4-MA (i.e., PMA), MADAM-6, MDA, MDMA, MDAL, MDBU, MDBZ, MDCPM, MDDM, MDE, MDHOET, MDIP, MDMC, MDMEO, MDMEOET, MDMP, MDOH, MDPEA, MDPH, MDPL, MDPR, MEDA, MEE, MEM, MEPEA, META-DOB, META-DOT, METHYL-DMA, METHYL-DOB, METHYL-J (i.e., MBDB), METHYL-K, METHYL-MA (i.e., PMMA), METHYL-MMDA-2, MMDA, MMDA-2, MMDA-3a, MMDA-3b, MME, MPM, ORTHO-DOT, PEA, PROPYNYL, tetramethoxy- amphetamine, 3-TASB, 4-TASB, 5-TASB, 3-TE, 4-TE, TMA, TMA-2, TMA-3, TMA-4, TMA-5, TMA-6, 2T-MMDA-3a, 4T-MMDA-2, TMPEA, 2-TOET, 5-TOET, 2-TOM, 5-TOM, TOMSO, 4-MTA, MDAI, 5-methyl-MDA, 5-APB. 6-APB, and DiFMDA, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof. As known in the art, the systematic naming of phenethylamines, such as herein, uses prefixes and suffixes to indicate substitutions on the phenyl ring and / or side chain of the phenethylamine core structure. For example, MDBZ stands for methylenedioxybenzyl-amphetamine (i.e., 3,4-methylenedioxy-N-benzylamphetamine) (see also, e.g., PiHKAL).

[0329]

[0251] In some embodiments, the additional active compound is an ergoline. In embodiments, the additional active compound is an ergot alkaloid. In embodiments, the additional active compound is a lysergamide.

[0330]

[0252] A lysergamide will have the general structure below, wherein RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are as disclosed herein and as generally understood in the art:

[0331]

[0253] In some embodiments, RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are each independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. Additionally, any two of RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14and the intervening atoms can be taken together to form an optionally substituted optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl. In embodiments, the lysergamide is a quaternary salt, in which an additional R6Ais connected to the nitrogen to which R6is bound; wherein R6Ais optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.

[0332]

[0254] In embodiments, the lysergamide is any of LSD, ETH-LAD, PARGY-LAD, AL-LAD, PRO-LAD, IP-LAD, CIP-LAD, BU-LAD, FLUOROETH-LAD, ALD, 1 P-LSD, 1 B-LSD, 1V-LSD, 1cP-LSD, 1 D-LSD, 1 P-AL-LAD, 1cP- AL-LAD, 1 P-ETH-LAD, LSZ, LSD-Pip, and MIPLA, including salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, and combinations thereof.

[0333]

[0255] Other tryptamines, phenethylamines, and lysergamides, including those useful as additional active compounds, will be as generally known in the art (see, e.g., Shulgin & Shulgin, PiHKAL: A Chemical Love Story, Transf. Press (1991); Shulgin AT, The Shulgin Index Vol.1 : Psychedelic Phenethylamines & Related Compounds, Transf. Press (2011); Shulgin & Shulgin, TiHKAL: The Continuation, Transform Press (1997) (“TiHKAL”); Grob & Grigsby, Handbook Medical Hallucinogens, 2021; Luethi & Liechti, Arch. Toxicol., 2020; 94, 1085-1133; Nichols, Pharm Revs., 2016; 68(2), 264-355; Glennon, Pharmacol Biochem Behav., 1999; 64, 251- 256; each of which is fully incorporated by reference herein).

[0334] F. Dose and Dosage

[0335]

[0256] In some embodiments, pharmaceutical compositions comprise an effective amount, such as a therapeutically effective amount, of a disclosed compound, such as for administration to a subject. Administration of a disclosed composition in a “therapeutically effective amount,” or an “effective amount” to a subject means administration of an amount of the composition sufficient to achieve a desired effect. When an “effective amount” means an amount effective to treat a disorder or its symptoms in a subject, a “therapeutic effect” should be understood to mean the responses(s) in the subject after treatment that are judged to be desirable and beneficial. Such responses may differ, but will be readily understood by those of skill, in view of the disclosure and the general knowledge of the art (e.g., by reference to symptoms listed in the DSM-5 for the relevant disorder).

[0336]

[0257] In some embodiments, a composition comprises a disclosed compound in an amount so that a single dose is (in a mg dose amount calculated based on the kg weight of the patient), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1.4 mg / kg, at least 1.5 mg / kg, at least 1.6 mg / kg, at least 1.7 mg / kg, at least 1.8 mg / kg, at least 1.9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, including amounts within these ranges.

[0337]

[0258] In some embodiments, a composition comprises a disclosed compound in an amount so that a single dose is (in a mg [milligram] dose amount calculated based on the kg [kilogram] weight of the patient) between about 0.01 mg / kg and 0.1 mg / kg, such as about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg about 0.08 mg / kg about 0.09 mg / kg, and about 0.1 mg / kg, including ranges between these values. In some embodiments, a single dose is between about 0.1 mg / kg and 1.0 mg / kg, such as about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg about 0.8 mg / kg about 0.9 mg / kg, and about 1.0 mg / kg, including ranges between these values.

[0338]

[0259] In some embodiments, a composition comprises a disclosed compound in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, including amounts within these ranges.

[0339]

[0260] In some embodiments, a composition comprises a disclosed compound in an amount so that a single dose is (whether or not such dose is present in a unit dosage form) between about 0.1 mg and 1.0 mg, such as about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, and about 1.0 mg, including ranges between these values. In embodiments, a single dose is between about 1 mg and 10 mg, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg, including ranges between these values. In some embodiments, a single dose is between about 10 mg and 100 mg.

[0340]

[0261] In some embodiments, a composition comprises a disclosed compound in an amount so that a single dose is (in a pg [microgram] dosage amount calculated based on the kg weight of the patient), e.g., 0.25 pg / kg or less (including a dose of 0.10 pg / kg or less, 0.05 pg / kg or less, and 0.01 pg / kg or less), at least 0.50 pg / kg, at least 0.55 pg / kg, at least 0.60 pg / kg, at least 0.65 pg / kg, at least 0.70 pg / kg, at least 0.75 pg / kg, at least 0.80 pg / kg, at least 0.85 pg / kg, at least 0.90 pg / kg, at least 0.95 pg / kg, at least 1 .0 pg / kg, at least 1.1 pg / kg, at least 1 .2 pg / kg, at least 1 .3 pg / kg, at least 1 .4 pg / kg, at least 1 .5 pg / kg, at least 1 .6 pg / kg, at least 1.7 pg / kg, at least 1 .8 pg / kg, at least 1 .9 pg / kg, at least 2.0 pg / kg, at least 2.1 pg / kg, at least 2.2 pg / kg, at least 2.3 pg / kg, at least 2.4 pg / kg, at least 2.5 pg / kg, at least 2.6 pg / kg, at least 2.7 pg / kg, at least 2.8 pg / kg, at least 2.9 pg / kg, or at least 3.0 pg / kg, including ranges between these values.

[0341]

[0262] In some embodiments, a composition comprises a disclosed compound in an amount so that a single dose is (in a pg dosage amount calculated based on the kg weight of the patient) between about 0.01 pg / kg and 0.1 pg / kg, such as about 0.01 pg / kg, about 0.02 pg / kg, about 0.03 pg / kg, about 0.04 pg / kg, about 0.05 pg / kg, about 0.06 pg / kg, about 0.07 pg / kg about 0.08 pg / kg about 0.09 pg / kg, and about 0.1 pg / kg, including ranges between these values. In some embodiments, a single dose is between about 0.1 pg / kg and 3.0 pg / kg, such as about 0.1 pg / kg, about 0.2 pg / kg, about 0.3 pg / kg, about 0.4 pg / kg, about 0.5 pg / kg, about 0.6 pg / kg, about 0.7 pg / kg about 0.8 pg / kg about 0.9 pg / kg, about 1 .0 pg / kg, about 1.2 pg / kg, about 1 .4 pg / kg, about 1 .6 pg / kg, about 1.8 pg / kg, about 2.0 pg / kg, about 2.2 pg / kg, about 2.4 pg / kg, about 2.6 pg / kg, about 2.8 pg / kg, about 3.0 pg / kg, including ranges between these values.

[0342]

[0263] In embodiments, a composition comprises a disclosed compound in an amount so that a single dose is (whether or not the dose is present in a unit dosage form), e.g., 25 pg or less (including a dose of 10 pg or less, 5 pg or less, 2.5 pg or less, and 1 pg or less), at least 25 pg, at least 30 pg, at least 35 pg, at least 40 pg, at least 45 pg, at least 50 pg, at least 55 pg, at least 60 pg, at least 65 pg, at least 70 pg, at least 75 pg, at least 80 pg, at least 85 pg, at least 90 pg, at least 95 pg, at least 100 pg, at least 105 pg, at least 110 pg, at least 115 pg, at least 120 pg, at least 125 pg, at least 130 pg, at least 135 pg, at least 140 pg, at least 145 pg, at least 150 pg, at least 155 pg, at least 160 pg, at least 165 pg, at least 170 pg, at least 175 pg, at least 180 pg, at least 185 pg, at least 190 pg, at least 195 pg, at least 200 pg, at least 225 pg, at least 250 pg, at least 275 pg, at least 300 pg, at least 400 pg, at least 500 pg, or at least 1000 pg, including ranges between these values.

[0343]

[0264] In some embodiments, a composition comprises a disclosed compound in an amount so that a single dose is (whether or not such dose is present in a unit dosage form) between about 0.1 pg and 1 .0 pg, such as about 0.1 pg, about 0.2 pg, about 0.3 pg, about 0.4 pg, about 0.5 pg, about 0.6 pg, about 0.7 pg, about 0.8 pg, about 0.9 pg, and about 1.0 pg, including ranges between these values. In some embodiments, a single dose is between about 1 pg and 10 pg, such as about 1 pg, about 2 pg, about 3 pg, about 4 pg, about 5 pg, about 6 pg, about 7 pg, about 8 pg, about 9 pg, and about 10 pg, including ranges between these values.

[0344]

[0265] In some embodiments, a composition comprises an additional active compound, such as a phenethylamine or tryptamine, in an amount so that a single dose is (in a mg dose amount calculated based on the kg weight of the patient), e.g., 0.25 mg / kg or less (including a dose of 0.10 mg / kg or less, 0.05 mg / kg or less, 0.01 mg / kg or less, and 0.005 mg / kg or less), at least 0.50 mg / kg, at least 0.55 mg / kg, at least 0.60 mg / kg, at least 0.65 mg / kg, at least 0.70 mg / kg, at least 0.75 mg / kg, at least 0.80 mg / kg, at least 0.85 mg / kg, at least 0.90 mg / kg, at least 0.95 mg / kg, at least 1.0 mg / kg, at least 1.1 mg / kg, at least 1.2 mg / kg, at least 1.3 mg / kg, or at least 1 .4 mg / kg, at least 1 .5 mg / kg, at least 1 .6 mg / kg, at least 1 .7 mg / kg, at least 1.8 mg / kg, at least 1 .9 mg / kg, at least 2.0 mg / kg, at least 2.1 mg / kg, at least 2.2 mg / kg, at least 2.3 mg / kg, at least 2.4 mg / kg, at least 2.5 mg / kg, at least 2.6 mg / kg, at least 2.7 mg / kg, at least 2.8 mg / kg, at least 2.9 mg / kg, or at least 3.0 mg / kg, including amounts within these ranges.

[0345]

[0266] In some embodiments, a composition comprises an additional active compound, such as a phenethylamine or tryptamine, in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), e.g., 25 mg or less (including a dose of 10 mg or less, 5 mg or less, 1 mg or less, and 0.5 mg or less), at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185 mg, at least 190 mg, at least 195 mg, at least 200 mg, at least 225 mg, or at least 250 mg, including amounts within these ranges.

[0346]

[0267] Doses and dosages may vary depending upon whether a treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability of or susceptibility of a symptom to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence of other disorders or diseases in the subject, and other factors that will be appreciated by the skilled artisan (e.g., medical or familial history). In embodiments, the dose or dosage administered is determined by a physician or medical professional, in view of this and other relevant information, including for example the disorder treated, the route of administration, the composition administered, the age, weight, and response of the patient, the severity of the patient’s symptoms, and the like.

[0347]

[0268] Dose amount, frequency, and / or duration may be increased or reduced, for example as indicated by the clinical outcome desired, status of the pathology or symptom, any adverse side effects of a treatment, or of concomitant medications. One of skill in view of the disclosure will appreciate the factors that may influence the dose, frequency, and timing required to provide an amount sufficient or effective to provide a therapeutic effect or benefit, including depending on the therapeutic effect desired, as well as to avoid or minimize adverse effects.

[0348]

[0269] Disclosed dose and dosage ranges are not intended to limit the scope of the disclosure. In some instances, doses and dosages below the lower limit of a disclosed range may be more than adequate; in others, doses and dosages above a range may be administered without adverse or harmful unintended effects. In some embodiments, larger doses are divided into smaller doses for administration, either taken together or separately.

[0349] F. Pharmaceutical Kits

[0350]

[0270] In some embodiments, for example where a formulation is prepared in single unit dosage form, such as a capsule, tablet, or lozenge, suggested dosages may be known by reference to the format of the preparation itself. In other embodiments, for example where a formulation is prepared in multiple dosage form, such as a liquid suspension or a topical preparation, suggested dosages may be known by reference to the means of administration or by reference to the packaging and labeling, package inserts, marketing materials, training materials, or other information and knowledge available to those of skill or to the public, including to the subject.

[0351]

[0271] In another aspect is provided pharmaceutical kits (“kits”) comprising a disclosed composition, suggested administration guidelines or prescribing information therefor, and a suitable container.

[0352]

[0272] Multi-dose kits or containers may comprise Individual unit dosage forms. Disclosed compositions also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0353]

[0273] Kits generally comprise suitable packaging. For example, a kit may comprise one or more containers comprising any disclosed composition. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelflife permit. Kits may comprise unit dosage forms or sub-unit doses, and may be bulk packages (e.g., multi-dose packages). Kits may comprise sufficient dosage forms to provide effective treatment of a subject for a course of treatment, such as will be known based, e.g., on the disorder, or for a selected period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may comprise multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0354]

[0274] Information pertaining to dosing and proper administration (if needed) may be printed onto a multi-dose kit directly (e.g., on a blister pack or other interior packaging holding the compositions or formulations of the invention). Kits also may comprise package inserts and / or other printed instructions (e.g., on exterior packaging) for administering the disclosed compositions and for their appropriate therapeutic use.

[0355] G. Methods of Use

[0356]

[0275] In some aspects are provided methods of using the disclosed compounds (reference to “disclosed compounds,” in sections where a shorthand can be relevantly used, and unless context clearly indicates otherwise also will include reference to compositions comprising the disclosed compounds).

[0357]

[0276] In some embodiments, disclosed compounds are used to modulate neurotransmission.

[0277] In some embodiments, disclosed compounds are used to treat a condition, e.g., a disease or a disorder.

[0358]

[0278] In some embodiments, disclosed compounds are used in the manufacture of a medicament, such as for the therapeutic and / or the prophylactic treatment of a condition, such as a disease or a disorder.

[0359]

[0279] In some embodiments, disclosed compounds are administered under direct supervision. For example, in some embodiments, disclosed compounds are administered together with therapy, including psychotherapy, together with “psychological support,” as the term is understood in the art, or together with patient monitoring.

[0360]

[0280] In some embodiments, disclosed compounds are administered to a subject. In some embodiments, disclosed compounds are administered, in a therapeutically effective amount, to a subject having a condition, such as a disease or a disorder. In embodiments, the condition is a mental health disorder. In embodiments, the condition is a neurodegenerative disorder. In embodiments, the condition is inflammation or an inflammatory disorder. In embodiments, the condition is pain or a pain disorder.

[0361]

[0281] In some embodiments, disclosed compounds, and compositions thereof, are administered to a subject using a route of administration that may include orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation, and transdermally. When administered by any such route, the disclosed compounds and compositions thereof are useful, such as to treat a patient in need of such treatment.

[0362]

[0282] In some embodiments, disclosed compounds are administered to a subject that is healthy, for example to improve overall health and wellness, to improve mental functioning, or otherwise for the betterment of the well.

[0363]

[0283] Herein, the terms “subject,” “user,” “patient,” and “individual” may be used interchangeably, and generally refer to any mammal, including murines, simians, mammalian farm animals, mammalian sport animals, and mammalian pets, such as canines and felines, although preferably humans. Such terms include one who has an indication for which a disclosed compound, composition, or method may be useful. In general, all of the disclosed compounds, compositions, and methods should be appreciated to work for all individuals, such as within a class of individuals, although individual variation may be expected, modifications in view of such individual variation, if such modifications are necessary, will be understood by those of ordinary skill in the art.

[0364]

[0284] In some embodiments, disclosed methods can be used to treat multiple subjects at the same time, such as couples, families, and groups. The above terms thus should be understood to include two or more subjects. a. Research Tools

[0365]

[0285] In some embodiments, disclosed compounds are used as research tools, e.g., involved in determining the structure and function of a receptor in vitro, in vivo, or in silico. In embodiments, disclosed compounds are used in receptor, ion channel, enzyme, and transporter binding studies. In embodiments, disclosed compounds are used in mapping, and functional studies.

[0366]

[0286] In some embodiments, disclosed compounds are radiolabeled. In embodiments, radiolabeled compounds are used to identify binding sites. In embodiments, radiolabeled compounds are used to assess receptor binding affinity. In embodiments, radiolabeled compounds are used fortissue imaging. In embodiments, radiolabeled compounds are used for receptor expression mapping. In embodiments, radiolabeled compounds are used to track the metabolic fate of a disclosed compound.

[0367]

[0287] In some embodiments, disclosed compounds are used as research tools for 5-HT2 receptors. In embodiments, disclosed compounds are used as research tools for 5-HT2A receptors. In embodiments, disclosed compounds are used as research tools for 5-HT2B receptors. In embodiments, disclosed compounds are used as research tools for 5-HT2C receptors. In embodiments, the research tool is a receptor probe, which may be used for determining downstream events of receptor-ligand interaction, e.g., calcium regulation, kinase, phosphatase and phospholipase activation, and lipid trafficking. In some embodiments of use as a research tool involving a receptor, the receptor is a recombinant receptor. In other embodiments, it is a wild-type receptor.

[0368]

[0288] In some embodiments, disclosed compounds are used as research tools, such as receptor probes. Disclosed compounds can be used as research tools for 5-HT2 receptors of mammalian origin. In embodiments, disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of human (Homo sapiens) origin. In embodiments, disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of non-human primate origin. Non-limiting examples of non-human primate 5-HT2 receptors include chimpanzee (Pan troglodytes) and Rhesus macaque (Macaca mulatta) 5-HT2 receptors.

[0369]

[0289] In some embodiments, disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of rodent origin. Non-limiting examples of rodent 5-HT2 receptors include those of mouse (M. musculus) and rat (R. norvegicus) origin, including in lab mouse strains such as C57BL / 6 and BALB / c, and in lab rat strains such as Sprague-Dawley and Wistar. In embodiments, disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of zebrafish origin. Non-limiting examples of zebrafish 5-HT2 receptors include those of Danio spp., e.g., Danio rerio origin. In embodiments, disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of nematode origin. In one example, 5-HT2 receptors of C. elegans are probed with a disclosed compound. In embodiments, disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of a dog, chicken, frog, or cow.

[0370]

[0290] Sequences may be retrieved by consulting a nucleotide database, e.g., Genbank, or amino acid database, e.g., UniProtKB, as known to one of skill. As examples, sequences 1-45 in Table 7 are available on UniProtKB (www.uniprot.org) by reference to their accession number below; they are also disclosed in the priority document hereof, incorporated as if fully set forth herein.

[0371] Table 7. Exemplary Receptor Sequences b. Serotonin Receptor Ligands

[0372]

[0291] The 5-HT receptor system comprises 14 distinct receptors, which are grouped into seven receptor families (5-HTi to 5-HT?). With the exception of the 5-HT3 ligand-gated ion channel, all 5-HTR families are G- protein coupled receptors (GPCR) (Gothert. Pharmacol Rep., 2013;65(4):771-86). In a representative example, the 5-HT2A receptor has seven transmembrane helices and intracellular amphipathic helix H8, similar to other GPCRs. The receptor comprises a ligand binding site, termed an orthosteric site, in addition to an accessory site, a side-extended cavity that connects the orthosteric site to the plasma membrane. Herein, the side-extended cavity may be referred to herein as an “extended binding site” or an “exosite.”

[0373]

[0292] In some embodiments, a disclosed compound binds to a serotonin (5-HT) receptor. In embodiments, the 5-HT receptor is a subfamily 1 (5-HTi) receptor. In embodiments, the 5-HT receptor is a subfamily 2 (5-HT2) receptor. In embodiments, the 5-HT2 receptor is a subtype 2A, 2B, or 20 (5-HT2A, 5-HT2B, or 5-HT2c) receptor. In embodiments, the 5-HT receptor is a subfamily 4 (5-HT4) receptor. In embodiments, the receptor is a 5-HT receptor of subfamily 5 (5-HTs) receptor. In embodiments, the receptor is a 5-HT receptor of subfamily 6 (5-HTe) receptor. In embodiments, the 5-HT receptor is a subfamily 7 (5-HT?) receptor.

[0374]

[0293] In some embodiments, the receptor is of mammalian origin. In embodiments, the receptor is of human origin. In embodiments, the receptor is recombinant.

[0375]

[0294] In some embodiments, a disclosed compound binds to a serotonin (5-HT) receptor at more than one site, such as an orthosteric site and an extended binding site. In embodiments, a disclosed compound binds to a 5-HTi receptor at one or more sites, such as an orthosteric site and an extended binding site. In embodiments, a disclose...

Claims

CLAIMSThe invention claimed is:

1. A compound of Formula (I):D-(CH2)mX(CH2)nPh (I), or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein: m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14;X is 0, S, or NH;Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; andwherein the * indicates the point of connection to — (CH2)mX(CH2)nPh; and wherein:Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6- C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or any two of Ra, Rb, R2, R4, R5, R6, and R7are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and the remaining Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 memberedheteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;R' is H, D, PO3H2, or C(O)-C1-C8 alkyl; andRNis H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl; orwherein the * indicates the point of connection to — (CH2)mX(CH2)nPh; and wherein:RN1is:(a) H, deuterium (D), C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or(b) taken together with RN2and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;RN2, if present, is:(a) H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or(b) taken together with RN1and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;R2, R12, R13, and R14are each independently selected from the group consisting of hydrogen, D,halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;R9is H or D; andR6, if present, is hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and R' is H, D, PO3H2, or C(O)-C1-C8 alkyl. The compound of claim 1 , whereinwherein: m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14;X is 0, S, or NH;Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6- C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or any two of Ra, Rb, R2, R4, R5, R6, and R7are taken together to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; and the remaining Ra, Rb, R2, R4, R5, R6, and R7are each independently selected from the group consisting of hydrogen, deuterium (D), OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;R' is H, D, PO3H2, or C(O)-C1-C8 alkyl;RNis H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl;Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R4is OR'.

4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R' is H.

5. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R' is PO3H2.

6. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R' is C(O)-C1-C8 alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R' is C(O)-CH3.

8. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R5is C1-C8 alkoxy.

9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R5is methoxy.

10. The compound of claim 2, having the structure of Formula (IIA):or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.The compound of claim 2, having the structure of Formula (IIB):or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

12. The compound of claim 2, having the structure of Formula (IIC):or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein RNis H.

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein RNis C1-C8 alkyl.

15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein RNis methyl, ethyl, or isopropyl.

16. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein RNis C2-C8 alkenyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein RNis allyl.

18. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein RNis C2-C8 alkynyl.

19. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein Ph is unsubstituted phenyl.

20. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein Ph is phenyl substituted by azido, D, NH2, OAc, or C1-C8 alkoxy.

21. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein X is 0.

22. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein the sum of m + n is from 8 to 12.

23. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopicderivative thereof, wherein the sum of m + n is from 9 to 11 .

24. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein the sum of m + n is 10.

25. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein m is 6 and n is 4.The compound of claim 1 , whereinand wherein:RN1is:(a) H, deuterium (D), C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or(b) taken together with RN2and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;RN2is:(a) H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2- C8 alkynyl; or(b) taken together with RN1and the nitrogen to which they are attached to form a C3-C8 heterocycloalkyl which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or(c) - (CH2)mX(CH2)nPh;R2, R12, R13, and R14are each independently selected from the group consisting of hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionallysubstituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;R9is H or D;R6is:(a) hydrogen, D, halogen, OR', C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C10 aryl, or 6-10 membered heteroaryl, each of which is optionally substituted by halogen, D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or(b) - (CH2)mX(CH2)nPh;R' is H, D, PO3H2, or C(O)-C1-C8 alkyl; m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14;X is 0, S, or NH;Ph is phenyl optionally substituted by halogen, D, azido, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

7. The compound of claim 26, having the structure of Formula (111 A),or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

8. The compound of claim 26, having the structure of Formula (IIIB):or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

29. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein Ph is unsubstituted phenyl.

30. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein Ph is phenyl substituted by azido, D, NH2, OAc, or C1-C8 alkoxy.31 . The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein X is 0.

32. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein the sum of m + n is from 8 to 12.

33. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein the sum of m + n is from 9 to 11 .

34. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein the sum of m + n is 10.

35. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein m is 6 and n is 4.

36. A compound selected from Table 2, Table 3, Table 4, Table 5, or Table 6, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

37. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1, 2, and 26, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

38. The pharmaceutical composition of claim 37, wherein the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, or transdermal administration.

39. The pharmaceutical composition of claim 37, wherein the composition is in unit dosage form.

40. The unit dosage form of claim 39, comprising the compound, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, in a total amount of between about 1 and about 500 mg, between about 2.5 and about 250 mg, or between about 5 and about 125 mg.41 . The pharmaceutical composition of claim 38, wherein the composition is an immediate release, controlled release, sustained release, extended release, or modified release formulation.

42. The pharmaceutical composition of claim 37, further comprising a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

43. The pharmaceutical composition of claim 42, wherein the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators,neuroprotectants, nootropics, entactogens, empathogens, entheogens, psychedelics, plasticity-inducing agents, psychoplastogens, neuroplastogens), monoamine oxidase inhibitors, RIMAs, tryptamines, terpenes, phenethylamines, aphrodisiacs, oneirogens, sedatives, stimulants, serotonergic agents, and vitamins, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

44. A compound of any one of claims 1 -36, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, for use in the treatment of a medical condition.

45. Use of the compound of any one of claims 1 -36, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, for the manufacture of a medicament for the treatment of a medical condition.

46. A method for modulating neurotransmission in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of any one of claims 1 -36, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

47. A method of treating a medical condition in a mammal in need of such treatment, the method comprising administering the compound of any one of claims 1 , 2, and 26, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

48. The method of claim 47, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of neurotransmission.

49. The method of claim 48, wherein the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission.

50. The method of claim 49, wherein the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of serotonergic neurotransmission.51 . The method of claim 47, wherein the medical condition is a mental health disorder.

52. The method of claim 51 , wherein the mental health disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, a substance-induced psychotic disorder, bipolar disorder, bipolar type I disorder, bipolar type II disorder, cyclothymic disorder, post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, alcohol or drug abuse or dependence disorders, a substance use disorder, substance-induced mood disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, and dissociative disorders.

53. The method of claim 47, wherein the medical condition is a seizure disorder.

54. The method of claim 53, wherein the seizure disorder is epilepsy.

55. The method of claim 47, wherein the medical condition is a disorder linked to dysregulation or inadequate functioning of a voltage-gated ion channel.

56. The method of claim 55, wherein the voltage-gated ion channel is a voltage-gated sodium channel.

57. The method of claim 56, wherein the compound inhibits the activity of the voltage-gated sodium channel.

58. The method of any one of claims 46-57, wherein the mammal has a genetic variation associated with drug metabolism, associated with a mental health disorder, or relating to a membrane transporter.

59. The method of any one of claims 46-57, wherein the mammal has altered epigenetic regulation of a gene the expression of which is associated with a mental health condition or with susceptibility to a mental health condition.

60. The method of any one of claims 46-59, wherein the mammal is a human.61 . A method of reducing the symptoms of a mental health disorder in a human, the method comprising identifying a human in need of said reducing, and administering to the human the compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

62. A method of reducing the symptoms of a mental health disorder in a human, the method comprising identifying a human in need of said reducing, and administering to the human the pharmaceutical composition of any one of claims 37-43.

63. A method of improving mental health or functioning in a human, the method comprising identifying a human in need of said improving, and administering to the human the compound of any one of claims 1- 36, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

64. A method of improving mental health or functioning in a human, the method comprising identifying a human in need of said improving, and administering to the human the pharmaceutical composition of any one of claims 37-43.

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