WO2025137730A1

WO2025137730A1 - N-substituted tryptamines and n-substituted lysergamides and their use as therapeutic agents

Info

Publication number: WO2025137730A1
Application number: PCT/US2024/061815
Authority: WO
Inventors: Nicholas V. Cozzi
Original assignee: Alexander Shulgin Research Institute Inc
Current assignee: Alexander Shulgin Research Institute Inc
Priority date: 2023-12-22
Filing date: 2024-12-23
Publication date: 2025-06-26
Anticipated expiration: 2026-06-22

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

N-SUBSTITUTED TRYPTAMINES AND N-SUBSTITUTED LYSERGAMIDES AND THEIR USE AS THERAPEUTIC AGENTS

INVENTOR: Nicholas V. Cozzi

CROSS-REFERENCE

[01 ] 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.

TECHNICAL FIELD

[02] 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.

BACKGROUND OF THE INVENTION

[03] 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.

[04] 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).

[05] 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. [06] 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.

INCORPORATION BY REFERENCE

[07] 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

[08] 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.

[09] In some aspects are disclosed compounds 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; and

wherein the * indicates the point of connection to — (CH₂)_mX(CH₂)_nPh; and wherein:

R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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;

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

R^N is 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:

R^N1 is:

(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 R^N2 and 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;

R^N2, 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 R^N1 and 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 R¹⁴ are 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;

R⁹ is H or D; and

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.

[10] 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;

X is 0, S, or NH;

R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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;

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

R^N is 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.

[1 1 ] In some embodiments, R⁴ is 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, R⁵ is C1-C8 alkoxy. In some embodiments, R⁵ is methoxy.

[12] 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:

[13] In some embodiments, R^N is H. In some embodiments, R^N is C1-C8 alkyl. In some embodiments, R^N is methyl, ethyl, or isopropyl. In some embodiments, R^N is C2-C8 alkenyl. In some embodiments, R^N is allyl. In some embodiments, R^N is 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. [14] 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.

[15] In some embodiments,

and:

R^N1 is:

R^N2 is:

(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 R^N1 and 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;

R⁹ is 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

(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 O, S, or NH;

[16] 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.

[17] 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.

[18] 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.

[19] 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.

[20] 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.

[21 ] 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.

[22] 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.

[23] 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.

[24] 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.

[25] 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.

[26] 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.

[27] 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.

DETAILED DESCRIPTION OF THE INVENTION

[28] 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

[29] 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.

[30] 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.

[31 ] 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.

[32] 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.

[33] 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.

[34] 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.

[35] 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.

[36] 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.

[37] 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.

[38] “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.

[39] “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.

[40] “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.

[41 ] “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.

[42] “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.

[43] “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.

[44] “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.

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

[46] “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.

[47] “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. [48] “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.

[49] “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.

[50] “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.

[51 ] “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.

[52] “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.

[53] “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.

[54] “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.

[55] “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.

[56] “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.

[57] “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).

[58] “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.

[59] “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.

[60] “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.

[61 ] “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.

[62] “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. [63] “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.

[64] “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.

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

[66] “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.

[67] “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.

[68] “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.

[69] “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.

[70] “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.

[71 ] “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.

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

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

B. Compounds

[74] 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).

[75] 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).

[76] 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).

[77] 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.

[78] 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.

[79] 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).

[80] 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).

[81 ] 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).

[82] 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).

[83] 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.

[84] 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. [85] In some embodiments, the side chain has the structure of:

-(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.

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

[87] 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.

[88] 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.

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

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).

Table 1. Exemplary Side Chain Structures

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

X is 0, S, or NH;

R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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;

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

R^N is H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8

R^N1 is:

R^N2, if present, is:

R⁹ is H or D; and

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.

[91 ] 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, R^a, R^b, R², R⁴, R⁵, R⁶, R⁷, R', and R^N of Formula (II) or any subformula thereof may be combined with every description, variation, embodiment or aspect of m, n X, Ph, R^a, R^b, R², R⁴, R⁵, R⁶, R⁷, R', and R^N in 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, R^N1, R^N2, 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, R^a, R^b, R², R⁴, R⁵, R⁶, R⁷, R', and R^N in 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. [92] 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;

R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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;

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

R^N is 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.

[93] 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.

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.

[94] 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.

[95] In some embodiments of Formula (II), R², R⁴, R⁵, R⁶, and R⁷ are 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.

[96] In some embodiments, any two of R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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.

[97] In some embodiments, R^a and R^N are 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, R^a and R^b are 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, R^a and R² are 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.

[98] In some embodiments, R^b and R⁴ are 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, R^b and R^N are 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.

[99] In some embodiments, R⁴ and R⁵ are 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.

[100] In some embodiments, R⁵ and R⁶ are 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. [101] In some embodiments, R⁶ and R⁷ are 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.

[102] In some embodiments of Formula (II), R² is 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, R² is hydrogen. In embodiments, R² is D. In embodiments, R² is D. In embodiments, R² is halogen. In embodiments, R² is F. In embodiments, R² is Cl. In embodiments, R² is Br. In embodiments, R² is I. In embodiments, R² is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R² is OH. In embodiments, R² is OPO3H2. In embodiments, R² is 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, R² is substituted C(O)-C1-C8 alkyl. In embodiments, R² is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)- CH3. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkyl. In embodiments, R² is substituted C1-C8 alkyl. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkoxy. In embodiments, R² is methoxy. In embodiments, R² is substituted C1-C8 alkoxy. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkenyl. In embodiments, R² is substituted C1-C8 alkenyl. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkynyl. In embodiments, R² is substituted C1-C8 alkynyl. In embodiments, R² is 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, R² is unsubstituted C3-C8 cycloalkyl. In embodiments, R² is substituted C3-C8 cycloalkyl. In embodiments, R² is 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, R² is unsubstituted C3-C8 cycloalkenyl. In embodiments, R² is substituted C3-C8 cycloalkenyl. In embodiments, R² is 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, R² is substituted C3-C8 heterocycloalkyl. In embodiments, R² is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R² is 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, R² is substituted C3-C8 heterocycloalkenyl. In embodiments, R² is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R² is 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, R² is unsubstituted C6-C10 aryl. In embodiments, R² is substituted C6-C10 aryl. In embodiments, R² is 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, R² is unsubstituted 6-10 membered heteroaryl. In embodiments, R² is substituted 6-10 membered heteroaryl.

[103] In some embodiments of Formula (II), R⁴ is 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, R⁴ is hydrogen. In embodiments, R⁴ is D. In embodiments, R⁴ is halogen. In embodiments, R⁴ is F. In embodiments, R⁴ is Cl. In embodiments, R⁴ is Br. In embodiments, R⁴ is I. In embodiments, R⁴ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R⁴ is OH. In embodiments, R⁴ is OPO3H2. In embodiments, R⁴ is 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, R⁴ is substituted C(O)-C1- C8 alkyl. In embodiments, R⁴ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R⁴ is 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, R⁴ is unsubstituted C1-C8 alkyl. In embodiments, R⁴ is substituted C1-C8 alkyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C1-C8 alkoxy. In embodiments, R⁴ is methoxy. In embodiments, R⁴ is substituted C1-C8 alkoxy. In embodiments, R⁴ is 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, R⁴ is unsubstituted C1-C8 alkenyl. In embodiments, R⁴ is substituted C1-C8 alkenyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C1-C8 alkynyl. In embodiments, R⁴ is substituted C1-C8 alkynyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C3-C8 cycloalkyl. In embodiments, R⁴ is substituted C3-C8 cycloalkyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R⁴ is substituted C3-C8 cycloalkenyl. In embodiments, R⁴ is 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, R⁴ is substituted C3-C8 heterocycloalkyl. In embodiments, R⁴ is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R⁴ is 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, R⁴ is substituted C3-C8 heterocycloalkenyl. In embodiments, R⁴ is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C6-C10 aryl. In embodiments, R⁴ is substituted C6-C10 aryl. In embodiments, R⁴ is 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, R⁴ is unsubstituted 6-10 membered heteroaryl. In embodiments, R⁴ is substituted 6-10 membered heteroaryl.

[104] In some embodiments of Formula (II), R⁵ is 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, R⁵ is hydrogen. In embodiments, R⁵ is D. In embodiments, R⁵ is halogen. In embodiments, R⁵ is F. In embodiments, R⁵ is Cl. In embodiments, R⁵ is Br. In embodiments, R⁵ is I. In embodiments, R⁵ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R⁵ is OH. In embodiments, R⁵ is OPO3H2. In embodiments, R⁵ is 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, R⁵ is substituted C(O)-C1- C8 alkyl. In embodiments, R⁵ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R⁵ is 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, R⁵ is unsubstituted C1-C8 alkyl. In embodiments, R⁵ is substituted C1-C8 alkyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C1-C8 alkoxy. In embodiments, R⁵ is methoxy. In embodiments, R⁵ is substituted C1-C8 alkoxy. In embodiments, R⁵ is 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, R⁵ is unsubstituted C1-C8 alkenyl. In embodiments, R⁵ is substituted C1-C8 alkenyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C1-C8 alkynyl. In embodiments, R⁵ is substituted C1-C8 alkynyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C3-C8 cycloalkyl. In embodiments, R⁵ is substituted C3-C8 cycloalkyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R⁵ is substituted C3-C8 cycloalkenyl. In embodiments, R⁵ is 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, R⁵ is substituted C3-C8 heterocycloalkyl. In embodiments, R⁵ is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R⁵ is 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, R⁵ is substituted C3-C8 heterocycloalkenyl. In embodiments, R⁵ is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C6-C10 aryl. In embodiments, R⁵ is substituted C6-C10 aryl. In embodiments, R⁵ is 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, R⁵ is unsubstituted 6-10 membered heteroaryl. In embodiments, R⁵ is substituted 6-10 membered heteroaryl.

[105] In some embodiments of Formula (II), R⁶ is 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, R⁶ is hydrogen. In embodiments, R⁶ is D. In embodiments, R⁶ is halogen. In embodiments, R⁶ is F. In embodiments, R⁶ is Cl. In embodiments, R⁶ is Br. In embodiments, R⁶ is I. In embodiments, R⁶ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R⁶ is OH. In embodiments, R⁶ is OPO3H2. In embodiments, R⁶ is 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, R⁶ is substituted C(O)-C1- C8 alkyl. In embodiments, R⁶ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkyl. In embodiments, R⁶ is substituted C1-C8 alkyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkoxy. In embodiments, R⁶ is methoxy. In embodiments, R⁶ is substituted C1-C8 alkoxy. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkenyl. In embodiments, R⁶ is substituted C1-C8 alkenyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkynyl. In embodiments, R⁶ is substituted C1-C8 alkynyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C3-C8 cycloalkyl. In embodiments, R⁶ is substituted C3-C8 cycloalkyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R⁶ is substituted C3-C8 cycloalkenyl. In embodiments, R⁶ is 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, R⁶ is substituted C3-C8 heterocycloalkyl. In embodiments, R⁶ is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R⁶ is 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, R⁶ is substituted C3-C8 heterocycloalkenyl. In embodiments, R⁶ is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C6-C10 aryl. In embodiments, R⁶ is substituted C6-C10 aryl. In embodiments, R⁶ is 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, R⁶ is unsubstituted 6-10 membered heteroaryl. In embodiments, R⁶ is substituted 6-10 membered heteroaryl.

[106] In some embodiments of Formula (II), R⁷ is 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, R⁷ is hydrogen. In embodiments, R⁷ is D. In embodiments, R⁷ is halogen. In embodiments, R⁷ is F. In embodiments, R⁷ is Cl. In embodiments, R⁷ is Br. In embodiments, R⁷ is I. In embodiments, R⁷ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R⁷ is OH. In embodiments, R⁷ is OPO3H2. In embodiments, R⁷ is 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, R⁷ is substituted C(O)-C1- C8 alkyl. In embodiments, R⁷ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R⁷ is 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, R⁷ is unsubstituted C1-C8 alkyl. In embodiments, R⁷ is substituted C1-C8 alkyl. In embodiments, R⁷ is 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, R⁷ is unsubstituted C1-C8 alkoxy. In embodiments, R⁷ is methoxy. In embodiments, R⁷ is substituted C1-C8 alkoxy. In embodiments, R⁷ is 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, R⁷ is unsubstituted C1-C8 alkenyl. In embodiments, R⁷ is substituted C1-C8 alkenyl. In embodiments, R⁷ is 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, R⁷ is unsubstituted C1-C8 alkynyl. In embodiments, R⁷ is substituted C1-C8 alkynyl. In embodiments, R⁷ is 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, R⁷ is unsubstituted C3-C8 cycloalkyl. In embodiments, R⁷ is substituted C3-C8 cycloalkyl. In embodiments, R⁷ is 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, R⁷ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R⁷ is substituted C3-C8 cycloalkenyl. In embodiments, R⁷ is 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, R⁷ is substituted C3-C8 heterocycloalkyl. In embodiments, R⁷ is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R⁷ is 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, R⁷ is substituted C3-C8 heterocycloalkenyl. In embodiments, R⁷ is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R⁷ is 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, R⁷ is unsubstituted C6-C10 aryl. In embodiments, R⁷ is substituted C6-C10 aryl. In embodiments, R⁷ is 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, R⁷ is unsubstituted 6-10 membered heteroaryl. In embodiments, R⁷ is substituted 6-10 membered heteroaryl.

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

[108] 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.

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

[1 10] 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.

[1 1 1] In some embodiments, the compound has the structure of Formula (IIA):

[1 12] 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.

[1 13] 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.

[1 14] In some embodiments of Formula (IIA), R^N H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl. In embodiments, R^N is H. In embodiments, R^N is C1-C8 alkyl. In embodiments, R^N is methyl. In embodiments, R^N is ethyl. In embodiments, R^N is n-propyl. In embodiments, R^N is isopropyl. In embodiments, R^N is butyl. In embodiments, R^N is n-butyl. In embodiments, R^N is sec-butyl. In embodiments, R^N is iso-butyl. In embodiments, R^N is isobutyl. In embodiments, R^N is tert-butyl. In embodiments, R^N is C3-C8 cycloalkyl. In embodiments, R^N is cyclopropyl. In embodiments, R^N is cyclobutyl. In embodiments, R^N is cyclopentyl. In embodiments, R^N is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, R^N is CH2- cyclopropyl. In embodiments, R^N is C2-C8 alkenyl. In embodiments, R^N is allyl. In embodiments, R^N is C2-C8 alkynyl. In embodiments, R^N is C2-C8 alkynyl.

[1 15] 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.

[1 16] In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.

[1 17] 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. [1 18] In some embodiments, the compound is selected from Table 2:

Table 2. Exemplary Compounds of Formula (HA)

[1 19] In some embodiments, the compound has the structure of Formula (IIB):

[120] 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. [121] 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.

[122] In some embodiments of Formula (II B), R⁴ is 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, R⁴ is hydrogen. In embodiments, R⁴ is D. In embodiments, R⁴ is halogen. In embodiments, R⁴ is F. In embodiments, R⁴ is Cl. In embodiments, R⁴ is Br. In embodiments, R⁴ is I. In embodiments, R⁴ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R⁴ is OH. In embodiments, R⁴ is OPO3H2. In embodiments, R⁴ is 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, R⁴ is substituted C(O)-C1- C8 alkyl. In embodiments, R⁴ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R⁴ is 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, R⁴ is unsubstituted C1-C8 alkyl. In embodiments, R⁴ is substituted C1-C8 alkyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C1-C8 alkoxy. In embodiments, R⁴ is methoxy. In embodiments, R⁴ is substituted C1-C8 alkoxy. In embodiments, R⁴ is 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, R⁴ is unsubstituted C1-C8 alkenyl. In embodiments, R⁴ is substituted C1-C8 alkenyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C1-C8 alkynyl. In embodiments, R⁴ is substituted C1-C8 alkynyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C3-C8 cycloalkyl. In embodiments, R⁴ is substituted C3-C8 cycloalkyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R⁴ is substituted C3-C8 cycloalkenyl. In embodiments, R⁴ is 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, R⁴ is unsubstituted C6-C10 aryl. In embodiments, R⁴ is substituted C6-C10 aryl. In embodiments, R⁴ is 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, R⁴ is unsubstituted 6-10 membered heteroaryl. In embodiments, R⁴ is substituted 6-10 membered heteroaryl.

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

[124] 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.

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

[126] 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.

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

Table 3. Exemplary Compounds of Formula (IIB)

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

[129] 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.

[130] 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.

[131] In some embodiments of Formula (IIC), R⁵ is 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, R⁵ is hydrogen. In embodiments, R⁵ is D. In embodiments, R⁵ is halogen. In embodiments, R⁵ is F. In embodiments, R⁵ is Cl. In embodiments, R⁵ is Br. In embodiments, R⁵ is I. In embodiments, R⁵ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R⁵ is OH. In embodiments, R⁵ is OPO3H2. In embodiments, R⁵ is 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, R⁵ is substituted C(O)-C1- C8 alkyl. In embodiments, R⁵ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R⁵ is 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, R⁵ is unsubstituted C1-C8 alkyl. In embodiments, R⁵ is substituted C1-C8 alkyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C1-C8 alkoxy. In embodiments, R⁵ is methoxy. In embodiments, R⁵ is substituted C1-C8 alkoxy. In embodiments, R⁵ is 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, R⁵ is unsubstituted C1-C8 alkenyl. In embodiments, R⁵ is substituted C1-C8 alkenyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C1-C8 alkynyl. In embodiments, R⁵ is substituted C1-C8 alkynyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C3-C8 cycloalkyl. In embodiments, R⁵ is substituted C3- C8 cycloalkyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R⁵ is substituted C3-C8 cycloalkenyl. In embodiments, R⁵ is 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, R⁵ is unsubstituted C6-C10 aryl. In embodiments, R⁵ is substituted C6-C10 aryl. In embodiments, R⁵ is 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, R⁵ is unsubstituted 6-10 membered heteroaryl. In embodiments, R⁵ is substituted 6-10 membered heteroaryl. [132] In some embodiments of Formula (IIC), R^N H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl. In embodiments, R^N is H. In embodiments, R^N is D. In embodiments, R^N is C1-C8 alkyl. In embodiments, R^N is methyl. In embodiments, R^N is ethyl. In embodiments, R^N is n-propyl. In embodiments, R^N is isopropyl. In embodiments, R^N is butyl. In embodiments, R^N is n-butyl. In embodiments, R^N is sec-butyl. In embodiments, R^N is iso-butyl. In embodiments, R^N is isobutyl. In embodiments, R^N is tertbutyl. In embodiments, R^N is C3-C8 cycloalkyl. In embodiments, R^N is cyclopropyl. In embodiments, R^N is cyclobutyl. In embodiments, R^N is cyclopentyl. In embodiments, R^N is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, R^N is CH2- cyclopropyl. In embodiments, R^N is C2-C8 alkenyl. In embodiments, R^N is allyl. In embodiments, R^N is C2-C8 alkynyl. In embodiments, R^N is C2-C8 alkynyl.

[133] 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.

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

[135] 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.

[136] In some embodiments, the compound is selected from Table 4:

Table 4. Exemplary Compounds of Formula (IIC)

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

wherein:

R^N1 is:

R^N2 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

(c) (CH₂)mX(CH₂)nPh;

R⁹ is H or D; R⁶ is:

(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; wherein one of R^N2 and R⁶ is (CH₂)_mX(CH₂)_nPh; or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof.

[138] In some embodiments of Formula (III), R^N1 is 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, R^N1 is H. In embodiments, R^N1 is D. In embodiments, R^N1 is C1-C8 alkyl. In embodiments, R^N1 is methyl. In embodiments, R^N1 is ethyl. In embodiments, R^N1 is n-propyl. In embodiments, R^N1 is isopropyl. In embodiments, R^N1 is butyl. In embodiments, R^N1 is n-butyl. In embodiments, R^N1 is sec-butyl. In embodiments, R^N1 is iso-butyl. In embodiments, R^N1 is isobutyl. In embodiments, R^N1 is tert-butyl. In embodiments, R^N1 is C3-C8 cycloalkyl. In embodiments, R^N1 is cyclopropyl. In embodiments, R^N1 is cyclobutyl. In embodiments, R^N1 is cyclopentyl. In embodiments, R^N1 is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, R^N1 is CH₂— cyclopropyl. In embodiments, R^N is C2-C8 alkenyl. In embodiments, R^N1 is allyl. In embodiments, R^N1 is C2-C8 alkynyl. In embodiments, R^N1 is C2-C8 alkynyl.

[139] In some embodiments of Formula (III), R^N2 is 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, R^N2 is H. In embodiments, R^N2 is D. In embodiments, R^N2 is C1-C8 alkyl. In embodiments, R^N2 is methyl. In embodiments, R^N2 is ethyl. In embodiments, R^N2 is n-propyl. In embodiments, R^N2 is isopropyl. In embodiments, R^N2 is butyl. In embodiments, R^N2 is n-butyl. In embodiments, R^N2 is sec-butyl. In embodiments, R^N2 is iso-butyl. In embodiments, R^N2 is isobutyl. In embodiments, R^N2 is tert-butyl. In embodiments, R^N2 is C3-C8 cycloalkyl. In embodiments, R^N2 is cyclopropyl. In embodiments, R^N2 is cyclobutyl. In embodiments, R^N2 is cyclopentyl. In embodiments, R^N2 is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, R^N2 is CH2- cyclopropyl. In embodiments, R^N2 is C2-C8 alkenyl. In embodiments, R^N2 is allyl. In embodiments, R^N2 is C2-C8 alkynyl. In embodiments, R^N2 is C2-C8 alkynyl.

[140] In some embodiments of Formula (III), R^N1 and R^N2 are 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, R^N1 and R^N2 are 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, R^N1 and R^N2 are taken together with the nitrogen to which they are attached to for an dimethylazetidnyl. In embodiments, R^N1 and R^N2 are taken together with the nitrogen to which they are attached to form a 2,4-dimethylazetidnyl. In embodiments, R^N1 and R^N2 are 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, R^N1 and R^N2 are 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

[141] In some embodiments of Formula (III), R^N2 is (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.

[142] In some embodiments of Formula (III), e.g., wherein R^N2 or R⁶ is (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.

[143] In some embodiments of Formula (III), e.g., wherein R^N2 or R⁶ is (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.

[144] In some embodiments of Formula (III), e.g., wherein R^N2 or R⁶ is (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.

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

[146] 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.

[147] In some embodiments of Formula (III), R², R¹², R¹³, and R¹⁴ are 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.

[148] In some embodiments of Formula (III), R² is 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, R² is hydrogen. In embodiments, R² is D. In embodiments, R² is D. In embodiments, R² is halogen. In embodiments, R² is F. In embodiments, R² is Cl. In embodiments, R² is Br. In embodiments, R² is I. In embodiments, R² is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R² is OH. In embodiments, R² is OPO3H2. In embodiments, R² is 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, R² is substituted C(O)-C1-C8 alkyl. In embodiments, R² is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkyl. In embodiments, R² is substituted C1- C8 alkyl. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkoxy. In embodiments, R² is methoxy. In embodiments, R² is substituted C1-C8 alkoxy. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkenyl. In embodiments, R² is substituted C1-C8 alkenyl. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkynyl. In embodiments, R² is substituted C1-C8 alkynyl. In embodiments, R² is 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, R² is unsubstituted C3-C8 cycloalkyl. In embodiments, R² is substituted C3-C8 cycloalkyl. In embodiments, R² is 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, R² is unsubstituted C3-C8 cycloalkenyl. In embodiments, R² is substituted C3-C8 cycloalkenyl. In embodiments, R² is 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, R² is unsubstituted C6-C10 aryl. In embodiments, R² is substituted C6-C10 aryl. In embodiments, R² is 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, R² is unsubstituted 6-10 membered heteroaryl. In embodiments, R² is substituted 6-10 membered heteroaryl.

[149] In some embodiments of Formula (III), R¹² is 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, R¹² is hydrogen. In embodiments, R¹² is D. In embodiments, R¹² is halogen. In embodiments, R¹² is F. In embodiments, R¹² is Cl. In embodiments, R¹² is Br. In embodiments, R⁴ is I. In embodiments, R⁴ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R¹² is OH. In embodiments, R¹² is OPO3H2. In embodiments, R¹² is 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, R¹² is substituted C(O)-C1-C8 alkyl. In embodiments, R¹² is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkyl. In embodiments, R¹² is substituted C1- C8 alkyl. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkoxy. In embodiments, R¹² is methoxy. In embodiments, R¹² is substituted C1-C8 alkoxy. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkenyl. In embodiments, R¹² is substituted C1-C8 alkenyl. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkynyl. In embodiments, R¹² is substituted C1-C8 alkynyl. In embodiments, R¹² is 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, R¹² is unsubstituted C3- C8 cycloalkyl. In embodiments, R¹² is substituted C3-C8 cycloalkyl. In embodiments, R¹² is 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, R¹² is unsubstituted C3-C8 cycloalkenyl. In embodiments, R¹² is substituted C3-C8 cycloalkenyl. In embodiments, R¹² is 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, R¹² is unsubstituted C6-C10 aryl. In embodiments, R¹² is substituted C6-C10 aryl. In embodiments, R¹² is 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, R¹² is unsubstituted 6-10 membered heteroaryl. In embodiments, R¹² is substituted 6-10 membered heteroaryl.

[150] In some embodiments of Formula (III), R¹³ is 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, R¹³ is hydrogen. In embodiments, R¹³ is D. In embodiments, R¹³ is halogen. In embodiments, R¹³ is F. In embodiments, R¹³ is Cl. In embodiments, R¹³ is Br. In embodiments, R¹³ is I. In embodiments, R¹³ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R¹³ is OH. In embodiments, R¹³ is OPO3H2. In embodiments, R¹³ is 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, R¹³ is substituted C(O)-C1-C8 alkyl. In embodiments, R¹³ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkyl. In embodiments, R¹³ is substituted C1- C8 alkyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkoxy. In embodiments, R¹³ is methoxy. In embodiments, R¹³ is substituted C1-C8 alkoxy. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkenyl. In embodiments, R¹³ is substituted C1-C8 alkenyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkynyl. In embodiments, R¹³ is substituted C1-C8 alkynyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C3- C8 cycloalkyl. In embodiments, R¹³ is substituted C3-C8 cycloalkyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R¹³ is substituted C3-C8 cycloalkenyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C6-C10 aryl. In embodiments, R¹³ is substituted C6-C10 aryl. In embodiments, R¹³ is 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, R¹³ is unsubstituted 6-10 membered heteroaryl. In embodiments, R¹³ is substituted 6-10 membered heteroaryl.

[151] In some embodiments of Formula (III), R¹⁴ is 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, R¹⁴ is hydrogen. In embodiments, R¹⁴ is D. In embodiments, R¹⁴ is halogen. In embodiments, R¹⁴ is F. In embodiments, R¹⁴ is Cl. In embodiments, R¹⁴ is Br. In embodiments, R¹⁴ is I. In embodiments, R¹⁴ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R¹⁴ is OH. In embodiments, R¹⁴ is OPO3H2. In embodiments, R¹⁴ is 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, R¹⁴ is substituted C(O)-C1-C8 alkyl. In embodiments, R¹⁴ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkyl. In embodiments, R¹⁴ is substituted C1- C8 alkyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkoxy. In embodiments, R¹⁴ is methoxy. In embodiments, R¹⁴ is substituted C1-C8 alkoxy. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkenyl. In embodiments, R¹⁴ is substituted C1-C8 alkenyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkynyl. In embodiments, R¹⁴ is substituted C1-C8 alkynyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C3- C8 cycloalkyl. In embodiments, R¹⁴ is substituted C3-C8 cycloalkyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R¹⁴ is substituted C3-C8 cycloalkenyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C6-C10 aryl. In embodiments, R¹⁴ is substituted C6-C10 aryl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted 6-10 membered heteroaryl. In embodiments, R¹⁴ is substituted 6-10 membered heteroaryl.

[152] In some embodiments of Formula (III), R⁶ is 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, R⁶ is hydrogen. In embodiments, R⁶ is D. In embodiments, R⁶ is D. In embodiments, R⁶ is halogen. In embodiments, R⁶ is F. In embodiments, R⁶ is Cl. In embodiments, R⁶ is Br. In embodiments, R⁶ is I. In embodiments, R⁶ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R⁶ is OH. In embodiments, R⁶ is OPO3H2. In embodiments, R⁶ is 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, R⁶ is substituted C(O)-C1-C8 alkyl. In embodiments, R⁶ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkyl. In embodiments, R⁶ is substituted C1- C8 alkyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkoxy. In embodiments, R⁶ is methoxy. In embodiments, R⁶ is substituted C1-C8 alkoxy. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkenyl. In embodiments, R⁶ is substituted C1-C8 alkenyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkynyl. In embodiments, R⁶ is substituted C1-C8 alkynyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C3-C8 cycloalkyl. In embodiments, R⁶ is substituted C3-C8 cycloalkyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R⁶ is substituted C3-C8 cycloalkenyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C6-C10 aryl. In embodiments, R⁶ is substituted C6-C10 aryl. In embodiments, R⁶ is 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, R⁶ is unsubstituted 6-10 membered heteroaryl. In embodiments, R⁶ is substituted 6-10 membered heteroaryl.

[153] In some embodiments of Formula (III), R⁶ is (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.

[154] In some embodiments of Formula (III), R⁹ is H or D. In embodiments, R⁹ is H. In embodiments, R⁹ is D.

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

[156] In some embodiments of Formula (IIIA), R^N1 is 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, R^N1 is H. In embodiments, R^N1 is D. In embodiments, R^N1 is C1-C8 alkyl. In embodiments, R^N1 is methyl. In embodiments, R^N1 is ethyl. In embodiments, R^N1 is n-propyl. In embodiments, R^N1 is isopropyl. In embodiments, R^N1 is butyl. In embodiments, R^N1 is n-butyl. In embodiments, R^N1 is sec-butyl. In embodiments, R^N1 is iso-butyl. In embodiments, R^N1 is isobutyl. In embodiments, R^N1 is tert-butyl. In embodiments, R^N1 is C3- C8 cycloalkyl. In embodiments, R^N1 is cyclopropyl. In embodiments, R^N1 is cyclobutyl. In embodiments, R^N1 is cyclopentyl. In embodiments, R^N1 is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, R^N1 is CH2- cyclopropyl. In embodiments, R^N is C2-C8 alkenyl. In embodiments, R^N1 is allyl. In embodiments, R^N1 is C2-C8 alkynyl. In embodiments, R^N1 is C2-C8 alkynyl. [157] In some embodiments of Formula (I II A), R², R¹², R¹³, and R¹⁴ are 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.

[158] In some embodiments of Formula (IIIA), R² is 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, R² is hydrogen. In embodiments, R² is D. In embodiments, R² is D. In embodiments, R² is halogen. In embodiments, R² is F. In embodiments, R² is Cl. In embodiments, R² is Br. In embodiments, R² is I. In embodiments, R² is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R² is OH. In embodiments, R² is OPO3H2. In embodiments, R² is 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, R² is substituted C(O)-C1-C8 alkyl. In embodiments, R² is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkyl. In embodiments, R² is substituted C1- C8 alkyl. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkoxy. In embodiments, R² is methoxy. In embodiments, R² is substituted C1-C8 alkoxy. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkenyl. In embodiments, R² is substituted C1-C8 alkenyl. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkynyl. In embodiments, R² is substituted C1-C8 alkynyl. In embodiments, R² is 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, R² is unsubstituted C3-C8 cycloalkyl. In embodiments, R² is substituted C3-C8 cycloalkyl. In embodiments, R² is 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, R² is unsubstituted C3-C8 cycloalkenyl. In embodiments, R² is substituted C3-C8 cycloalkenyl. In embodiments, R² is 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, R² is unsubstituted C6-C10 aryl. In embodiments, R² is substituted C6-C10 aryl. In embodiments, R² is 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, R² is unsubstituted 6-10 membered heteroaryl. In embodiments, R² is substituted 6-10 membered heteroaryl.

[159] In some embodiments of Formula (IIIA), R⁶ is 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, R⁶ is hydrogen. In embodiments, R⁶ is D. In embodiments, R⁶ is D. In embodiments, R⁶ is halogen. In embodiments, R⁶ is F. In embodiments, R⁶ is Cl. In embodiments, R⁶ is Br. In embodiments, R⁶ is I. In embodiments, R⁶ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R⁶ is OH. In embodiments, R⁶ is OPO3H2. In embodiments, R⁶ is 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, R⁶ is substituted C(O)-C1-C8 alkyl. In embodiments, R⁶ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkyl. In embodiments, R⁶ is substituted C1- C8 alkyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkoxy. In embodiments, R⁶ is methoxy. In embodiments, R⁶ is substituted C1-C8 alkoxy. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkenyl. In embodiments, R⁶ is substituted C1-C8 alkenyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C1-C8 alkynyl. In embodiments, R⁶ is substituted C1-C8 alkynyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C3-C8 cycloalkyl. In embodiments, R⁶ is substituted C3-C8 cycloalkyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R⁶ is substituted C3-C8 cycloalkenyl. In embodiments, R⁶ is 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, R⁶ is unsubstituted C6-C10 aryl. In embodiments, R⁶ is substituted C6-C10 aryl. In embodiments, R⁶ is 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, R⁶ is unsubstituted 6-10 membered heteroaryl. In embodiments, R⁶ is substituted 6-10 membered heteroaryl.

[160] In some embodiments of Formula (IIIA), R¹² is 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, R¹² is hydrogen. In embodiments, R¹² is D. In embodiments, R¹² is halogen. In embodiments, R¹² is F. In embodiments, R¹² is Cl. In embodiments, R¹² is Br. In embodiments, R⁴ is I. In embodiments, R⁴ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R¹² is OH. In embodiments, R¹² is OPO3H2. In embodiments, R¹² is 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, R¹² is substituted C(O)-C1-C8 alkyl. In embodiments, R¹² is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkyl. In embodiments, R¹² is substituted C1- C8 alkyl. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkoxy. In embodiments, R¹² is methoxy. In embodiments, R¹² is substituted C1-C8 alkoxy. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkenyl. In embodiments, R¹² is substituted C1-C8 alkenyl. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkynyl. In embodiments, R¹² is substituted C1-C8 alkynyl. In embodiments, R¹² is 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, R¹² is unsubstituted C3- C8 cycloalkyl. In embodiments, R¹² is substituted C3-C8 cycloalkyl. In embodiments, R¹² is 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, R¹² is unsubstituted C3-C8 cycloalkenyl. In embodiments, R¹² is substituted C3-C8 cycloalkenyl. In embodiments, R¹² is 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, R¹² is unsubstituted C6-C10 aryl. In embodiments, R¹² is substituted C6-C10 aryl. In embodiments, R¹² is 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, R¹² is unsubstituted 6-10 membered heteroaryl. In embodiments, R¹² is substituted 6-10 membered heteroaryl.

[161] In some embodiments of Formula (IIIA), R¹³ is 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, R¹³ is hydrogen. In embodiments, R¹³ is D. In embodiments, R¹³ is halogen. In embodiments, R¹³ is F. In embodiments, R¹³ is Cl. In embodiments, R¹³ is Br. In embodiments, R¹³ is I. In embodiments, R¹³ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R¹³ is OH. In embodiments, R¹³ is OPO3H2. In embodiments, R¹³ is 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, R¹³ is substituted C(O)-C1-C8 alkyl. In embodiments, R¹³ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkyl. In embodiments, R¹³ is substituted C1- C8 alkyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkoxy. In embodiments, R¹³ is methoxy. In embodiments, R¹³ is substituted C1-C8 alkoxy. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkenyl. In embodiments, R¹³ is substituted C1-C8 alkenyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkynyl. In embodiments, R¹³ is substituted C1-C8 alkynyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C3- C8 cycloalkyl. In embodiments, R¹³ is substituted C3-C8 cycloalkyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R¹³ is substituted C3-C8 cycloalkenyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C6-C10 aryl. In embodiments, R¹³ is substituted C6-C10 aryl. In embodiments, R¹³ is 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, R¹³ is unsubstituted 6-10 membered heteroaryl. In embodiments, R¹³ is substituted 6-10 membered heteroaryl.

[162] In some embodiments of Formula (IIIA), R¹⁴ is 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, R¹⁴ is hydrogen. In embodiments, R¹⁴ is D. In embodiments, R¹⁴ is halogen. In embodiments, R¹⁴ is F. In embodiments, R¹⁴ is Cl. In embodiments, R¹⁴ is Br. In embodiments, R¹⁴ is I. In embodiments, R¹⁴ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R¹⁴ is OH. In embodiments, R¹⁴ is OPO3H2. In embodiments, R¹⁴ is 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, R¹⁴ is substituted C(O)-C1-C8 alkyl. In embodiments, R¹⁴ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkyl. In embodiments, R¹⁴ is substituted C1- C8 alkyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkoxy. In embodiments, R¹⁴ is methoxy. In embodiments, R¹⁴ is substituted C1-C8 alkoxy. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkenyl. In embodiments, R¹⁴ is substituted C1-C8 alkenyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkynyl. In embodiments, R¹⁴ is substituted C1-C8 alkynyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C3- C8 cycloalkyl. In embodiments, R¹⁴ is substituted C3-C8 cycloalkyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R¹⁴ is substituted C3-C8 cycloalkenyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C6-C10 aryl. In embodiments, R¹⁴ is substituted C6-C10 aryl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted 6-10 membered heteroaryl. In embodiments, R¹⁴ is substituted 6-10 membered heteroaryl.

[163] 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.

[164] 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.

[165] 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.

[166] In embodiments, Ph is phenyl. In embodiments, Ph is unsubstituted phenyl. [167] 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.

[168] In embodiments of Formula (I HA), R⁹ is H or D. In embodiments, R⁹ is H. In embodiments, R⁹ is D.

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

Table 5. Exemplary Compounds of Formula (IIIA)

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

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, R^N1 is H. In embodiments, R^N1 is D. In embodiments, R^N1 is C1-C8 alkyl. In embodiments, R^N1 is methyl. In embodiments, R^N1 is ethyl. In embodiments, R^N1 is n-propyl. In embodiments, R^N1 is isopropyl. In embodiments, R^N1 is butyl. In embodiments, R^N1 is n-butyl. In embodiments, R^N1 is sec-butyl. In embodiments, R^N1 is iso-butyl. In embodiments, R^N1 is isobutyl. In embodiments, R^N1 is tert-butyl. In embodiments, R^N1 is C3- C8 cycloalkyl. In embodiments, R^N1 is cyclopropyl. In embodiments, R^N1 is cyclobutyl. In embodiments, R^N1 is cyclopentyl. In embodiments, R^N1 is C1-C8 alkylene— C3-C8 cycloalkyl. In embodiments, R^N1 is CH2- cyclopropyl. In embodiments, R^N is C2-C8 alkenyl. In embodiments, R^N1 is allyl. In embodiments, R^N1 is C2-C8 alkynyl. In embodiments, R^N1 is C2-C8 alkynyl.

[172] In some embodiments of Formula (II IB), R^N2 is (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.

[173] 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.

[174] 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.

[175] 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.

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

[177] 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.

[178] In some embodiments of Formula (IIIB), R², R¹², R¹³, and R¹⁴ are 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.

[179] In some embodiments of Formula (II IB), R² is 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, R² is hydrogen. In embodiments, R² is D. In embodiments, R² is D. In embodiments, R² is halogen. In embodiments, R² is F. In embodiments, R² is Cl. In embodiments, R² is Br. In embodiments, R² is I. In embodiments, R² is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R² is OH. In embodiments, R² is OPO3H2. In embodiments, R² is 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, R² is substituted C(O)-C1-C8 alkyl. In embodiments, R² is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkyl. In embodiments, R² is substituted C1- C8 alkyl. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkoxy. In embodiments, R² is methoxy. In embodiments, R² is substituted C1-C8 alkoxy. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkenyl. In embodiments, R² is substituted C1-C8 alkenyl. In embodiments, R² is 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, R² is unsubstituted C1-C8 alkynyl. In embodiments, R² is substituted C1-C8 alkynyl. In embodiments, R² is 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, R² is unsubstituted C3-C8 cycloalkyl. In embodiments, R² is substituted C3-C8 cycloalkyl. In embodiments, R² is 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, R² is unsubstituted C3-C8 cycloalkenyl. In embodiments, R² is substituted C3-C8 cycloalkenyl. In embodiments, R² is 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, R² is unsubstituted C6-C10 aryl. In embodiments, R² is substituted C6-C10 aryl. In embodiments, R² is 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, R² is unsubstituted 6-10 membered heteroaryl. In embodiments, R² is substituted 6-10 membered heteroaryl.

[180] In some embodiments of Formula (IIIB), R¹² is 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, R¹² is hydrogen. In embodiments, R¹² is D. In embodiments, R¹² is halogen. In embodiments, R¹² is F. In embodiments, R¹² is Cl. In embodiments, R¹² is Br. In embodiments, R⁴ is I. In embodiments, R⁴ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R¹² is OH. In embodiments, R¹² is OPO3H2. In embodiments, R¹² is 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, R¹² is substituted C(O)-C1-C8 alkyl. In embodiments, R¹² is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkyl. In embodiments, R¹² is substituted C1- C8 alkyl. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkoxy. In embodiments, R¹² is methoxy. In embodiments, R¹² is substituted C1-C8 alkoxy. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkenyl. In embodiments, R¹² is substituted C1-C8 alkenyl. In embodiments, R¹² is 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, R¹² is unsubstituted C1-C8 alkynyl. In embodiments, R¹² is substituted C1-C8 alkynyl. In embodiments, R¹² is 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, R¹² is unsubstituted C3- C8 cycloalkyl. In embodiments, R¹² is substituted C3-C8 cycloalkyl. In embodiments, R¹² is 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, R¹² is unsubstituted C3-C8 cycloalkenyl. In embodiments, R¹² is substituted C3-C8 cycloalkenyl. In embodiments, R¹² is 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, R¹² is unsubstituted C6-C10 aryl. In embodiments, R¹² is substituted C6-C10 aryl. In embodiments, R¹² is 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, R¹² is unsubstituted 6-10 membered heteroaryl. In embodiments, R¹² is substituted 6-10 membered heteroaryl.

[181] In some embodiments of Formula (IIIB), R¹³ is 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, R¹³ is hydrogen. In embodiments, R¹³ is D. In embodiments, R¹³ is halogen. In embodiments, R¹³ is F. In embodiments, R¹³ is Cl. In embodiments, R¹³ is Br. In embodiments, R¹³ is I. In embodiments, R¹³ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R¹³ is OH. In embodiments, R¹³ is OPO3H2. In embodiments, R¹³ is 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, R¹³ is substituted C(O)-C1-C8 alkyl. In embodiments, R¹³ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkyl. In embodiments, R¹³ is substituted C1- C8 alkyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkoxy. In embodiments, R¹³ is methoxy. In embodiments, R¹³ is substituted C1-C8 alkoxy. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkenyl. In embodiments, R¹³ is substituted C1-C8 alkenyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C1-C8 alkynyl. In embodiments, R¹³ is substituted C1-C8 alkynyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C3- C8 cycloalkyl. In embodiments, R¹³ is substituted C3-C8 cycloalkyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R¹³ is substituted C3-C8 cycloalkenyl. In embodiments, R¹³ is 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, R¹³ is unsubstituted C6-C10 aryl. In embodiments, R¹³ is substituted C6-C10 aryl. In embodiments, R¹³ is 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, R¹³ is unsubstituted 6-10 membered heteroaryl. In embodiments, R¹³ is substituted 6-10 membered heteroaryl.

[182] In some embodiments of Formula (IIIB), R¹⁴ is 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, R¹⁴ is hydrogen. In embodiments, R¹⁴ is D. In embodiments, R¹⁴ is halogen. In embodiments, R¹⁴ is F. In embodiments, R¹⁴ is Cl. In embodiments, R¹⁴ is Br. In embodiments, R¹⁴ is I. In embodiments, R¹⁴ is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R¹⁴ is OH. In embodiments, R¹⁴ is OPO3H2. In embodiments, R¹⁴ is 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, R¹⁴ is substituted C(O)-C1-C8 alkyl. In embodiments, R¹⁴ is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkyl. In embodiments, R¹⁴ is substituted C1- C8 alkyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkoxy. In embodiments, R¹⁴ is methoxy. In embodiments, R¹⁴ is substituted C1-C8 alkoxy. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkenyl. In embodiments, R¹⁴ is substituted C1-C8 alkenyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C1-C8 alkynyl. In embodiments, R¹⁴ is substituted C1-C8 alkynyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C3- C8 cycloalkyl. In embodiments, R¹⁴ is substituted C3-C8 cycloalkyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C3-C8 cycloalkenyl. In embodiments, R¹⁴ is substituted C3-C8 cycloalkenyl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted C6-C10 aryl. In embodiments, R¹⁴ is substituted C6-C10 aryl. In embodiments, R¹⁴ is 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, R¹⁴ is unsubstituted 6-10 membered heteroaryl. In embodiments, R¹⁴ is substituted 6-10 membered heteroaryl.

[183] In some embodiments of Formula (IIIB), R⁶ is (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.

[184] In embodiments of Formula (IIIB), R⁹ is H or D. In embodiments, R⁹ is H. In embodiments, R⁹ is D.

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

Table 6. Exemplary Compounds of Formula (IIIB)

[186] 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.

[187] 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;

US17833341; US17679439; US17903080; US17893113; US17866477; US18001191; US17942706;

US17995516; US18350103; US17987208; US18180685; US17885978; US17801552; US18172691 ;

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.

[188] 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.

[189] 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.

[190] 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.

[191] 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.

[192] 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.

[193] 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.

[194] 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.

[195] 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. [196] 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).

[197] 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.

[198] 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.

[199] 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.

[200] 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).

[201] 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.

[202] 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 as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸O, and ³⁶CI respectively. In embodiments, isotopically labeled compounds can be used in metabolic studies (with ¹⁴C), reaction kinetic studies (with, e.g., ²H or ³H), 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, an ¹⁸F-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.

[203] 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.

[204] 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.

C. Methods of Preparing Disclosed Compounds

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

[206] 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.

[207] An alternative reaction sequence is provided below:

[208] In a first reaction step, an amine precursor (R^N-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).

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

[210] 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.

[21 1] Certain lysergamide-containing compounds of the disclosure, wherein R^N2 is (CH2)_mX(CH2)_nPh, can be synthesized from a suitable lysergic acid precursor as follows:

[212] In a first reaction step, an amine precursor (R^N-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.

[213] 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.

[214] 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 R⁶ is alkyl (e.g., methyl), followed by N(6) alkylation with a suitable side chain precursor:

[215] 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:

[216] 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.

[217] 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.

D. Pharmaceutical Compositions

[218] 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).

[219] “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.

[220] 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).

[221] 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.

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

[223] 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.

[224] 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.

[225] 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.

[226] 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.

[227] 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).

[228] 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.

[229] 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.

[230] 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.

[231] 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.

[232] 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.

[233] 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.

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

[235] 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. [236] 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.

E. Pharmaceutical Combinations

[237] 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.

[238] 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.

[239] “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.

[240] “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.”

[241] 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.

[242] 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.

[243] 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.

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

[245] A tryptamine will have the general structure below, wherein R^N1, R^N2, R^a, RP, R², R⁴, R⁵, R⁶, and R⁷ are as disclosed herein and as generally understood in the art:

[246] In some embodiments, R^N1, R^N2, R^a, RP, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^N1, R^N2, R^a, RP, R², R⁴, R⁵, R⁶, and R⁷ and 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 R^N3 is connected to the nitrogen to which R^N1 and R^N2 are bound; wherein R^N3 is 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.

[247] 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.

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

[249] A phenethylamine will have the general structure below, wherein R^N1, R^N2, R^a, RP, and each of R²-R⁶ are as disclosed herein and generally understood in the art:

[250] 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).

[251] 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.

[252] A lysergamide will have the general structure below, wherein R^N1, R^N2, R¹, R², R⁴, R⁶, R⁷, R⁸, R⁹, R¹², R¹³, and R¹⁴ are as disclosed herein and as generally understood in the art:

[253] In some embodiments, R^N1, R^N2, R¹, R², R⁴, R⁶, R⁷, R⁸, R⁹, R¹², R¹³, and R¹⁴ are 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 R^N1, R^N2, R¹, R², R⁴, R⁶, R⁷, R⁸, R⁹, R¹², R¹³, and R¹⁴ and 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 R^6A is connected to the nitrogen to which R⁶ is bound; wherein R^6A is 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.

[254] 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.

[255] 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).

F. Dose and Dosage

[256] 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).

[257] 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.

[258] 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.

[259] 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.

[260] 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.

[261] 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.

[262] 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.

[263] 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.

[264] 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.

[265] 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.

[266] 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.

[267] 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.

[268] 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.

[269] 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.

F. Pharmaceutical Kits

[270] 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.

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

[272] 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.

[273] 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).

[274] 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.

G. Methods of Use

[275] 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).

[276] In some embodiments, disclosed compounds are used to modulate neurotransmission. [277] In some embodiments, disclosed compounds are used to treat a condition, e.g., a disease or a disorder.

[278] 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.

[279] 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.

[280] 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.

[281] 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.

[282] 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.

[283] 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.

[284] 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

[285] 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.

[286] 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.

[287] 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.

[288] 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.

[289] 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.

[290] 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.

Table 7. Exemplary Receptor Sequences

b. Serotonin Receptor Ligands

[291] 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.”

[292] 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.

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

[294] 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 disclosed compound binds to a 5-HT2 receptor at one or more sites, such as an orthosteric site and an extended binding site. In embodiments, a disclosed compound binds to one or more 5-HT2 receptor subtypes, such as 5- HT2A, 5-HT2B, and 5-HT2C receptors, at one or more sites, such as an orthosteric site and an extended binding site. In embodiments, a disclosed compound binds to a 5-HT4 receptor at one or more sites, such as an orthosteric site and an extended binding site. In embodiments, a disclosed compound binds to a 5-HTs receptor at one or more sites, such as an orthosteric site and an extended binding site. In embodiments, a disclosed compound binds to a 5-HTe receptor at one or more sites, such as an orthosteric site and an extended binding site. In embodiments, a disclosed compound binds to a 5-HT? receptor at one or more sites, such as an orthosteric site and an extended binding site. In embodiments, the receptor is of mammalian origin. In embodiments, the receptor is of human origin. In embodiments, the receptor is recombinant.

[295] As determined in complex with the antagonist zotepine, the extended binding site spans transmembrane domains (TMDs) 4 and 5, and is surrounded by hydrophobic residues on TMD3, TMD4, TMD5, and extracellular loop (ECL) 2. A glycine residue at position 5.42x43 at the entrance of the side-extended cavity is essential for formation of the exosite. This glycine positioning is conserved only in the 5-HT2 family of receptors (Kimura et al., Nat Struct Mol Biol., 2019;26(2):121 -128). An extended binding site has also been described for 5-HTIB and 5-HT2B receptors (McCorvy & Roth, Pharmacol The , 2015;150:129-142).

[296] Methods for determining binding to a 5-HT receptor are available to one of skill in the art, including, e.g., in vitro and in silico computational methods. For example, Kimura et al., describes constructing a 5-HT2A , crystallizing the receptor with an inverse agonist and an antagonist, and determining the binding using microcrystallography and molecular docking software Glide (Schrodinger) (Kimura et al., Nat Struct Mol Biol., 2019;26: 121-128). Wacker et al. describes resolving the structure of LSD bound to an engineered 5-HT2B receptor using X-ray crystallography. Given the homology between 5-HT2A and 5-HT2B receptors, the 5-HT2B receptor was used as a model system for 5-HT2A receptor (Wacker et al., Cell. 2017; 168(3): 377— 389.e12). X-ray crystallography has also been used to determine the structure of 5-HT2A complexed with LSD and inverse agonist methiothepin, whereas cryo-electron microscopy of prototypical hallucinogen 25CN-NBOH in complex with an engineered Gaq heterotrimer has been used to determine the active state of 5-HT2A (Kim et al., Cell. 2020 Sep 17; 182(6): 1574- 1588.e19). Homology modeling based on the P(2)-adrenergic receptor and the G protein-bound opsin crystal structures have also been used to model the 5-HT2A (Isberg et al., J Chem Inf Model. 2011 ;51 (2) : 315-25).

[297] Additionally, similar strategies that were used to elucidate the ADRB2 exosite may be applied to a 5-HT receptor, such as docking and mutagenic studies. For example, site-directed mutagenesis and evaluation of salmeterol-promoted cAMP accumulation, led to identification of amino acids in TMD4 (residues 149-174) as contributing to the 02 receptor exosite (Green et al., J Biol Chem. 1996;271 (39):24029-35). Direct photoaffinity labeling of the salmeterol binding site in the human [32 receptor using [¹²⁵l]iodoazidosalmeterol as well as x-ray diffraction analysis of salmeterol bound to ADRB2 revealed that TMD6 and TMD7 also contribute to the exosite (Masureel et al., Nat Chem Biol. 2018;14(11):1059-1066; Rong et al., Biochem., 1999;38(35):11278-11286). In the [¹²⁵l]iodoazidosalmeterol photolabeling study, the radioiodinated phenyl azide moiety of the photoaffinity probe, corresponding to the terminal phenyl ring in salmeterol, was specifically attached to tryptophan 313 in TMD7 (Rong et al., Biochem., 1999; 38(35) : 11278-11286). A third study, employing chimeric |31/|32 receptors and alanine-substituted [32 receptor mutants, also identified TMD7 as part of the exosite. The study identified tyrosine 308 and tyrosine 316 in TMD7 as sites of interaction with methylene groups near the protonated amine of salmeterol and the side-chain ether oxygen, respectively (Isogaya et al., Mol Pharmacol. 1998;54: 616-622).

[298] Both the 5-HT2AR and ADRB2 receptors adopt various conformations in response to different ligands. This movement and consequential remodeling of the surrounding membrane influences known pharmacological activity of the ligands, such as full, partial or inverse activators of the receptor. For example, Shan et al. showed distinct 5-HT2AR conformation in response to partial agonist LSD and inverse agonist ketanserin (Shan et al., PLoS Comput Biol. 2012;8(4): e1002473). Relating to ADRB2 ligand studies, the majority or receptor residues showed distinct patterns of reactivity, even between functionally similar ligands, and few receptor residues had reactivity patterns consistent with classical agonism (Kahsai et al., Nat Chem Biol. 2011 ;7(10): 692— 700). Various conformational states of 5-HT receptors may result in distinct pharmacological outcomes, including those related to hallucinogenesis (see, e.g., Weinsten, AAPS J. 7: E871-884). As such, in one aspect, the provided 5-HT receptor ligands may be useful to elucidate the structural basis and mechanisms for different states of 5-HT receptor activation, e.g., 5-HT2AR, 5-HT2BR, and 5-HT2cR.

[299] In some embodiments, a disclosed compound has increased binding affinity for a 5-HT receptor, relative to a comparator. In embodiments, a disclosed compound has decreased binding affinity for a 5-HT receptor, relative to a comparator. In embodiments, a disclosed compound has both increased binding affinity for a 5-HT receptor subtype and decreased binding affinity for another serotonin receptor subtype. In embodiments, the receptor is a 5-HT2A receptor. In embodiments, the receptor is a 5-HT2B receptor. In embodiments, the receptor is a 5-HT2C receptor. In embodiments, the comparator is the corresponding tryptamine lacking an N-linked side chain. In other embodiments, the comparator is serotonin. In embodiments, the comparator is the corresponding lysergamide lacking an N-linked side chain. In other embodiments, the comparator is serotonin.

[300] In some embodiments, a disclosed compound has increased selectivity or specificity for a 5-HT receptor relative to a comparator. In embodiments, a disclosed compound has relatively high selectivity at 5-HT2 receptors, e.g., 5-HT2A, 5-HT2B, and 5-HT2C receptors, relative to a comparator. In embodiments, a disclosed compound has fewer off-target effects, including, e.g., adverse effects, relative to a comparator.

[301] Various strategies are available to determine binding affinity and specificity, as will be appreciated by those in the art, such as radioligand binding experiments for determining binding affinity between a compound and a receptor. Use of radioligands may aid determination of binding affinity in a number of different experimental contexts, including kinetic experiments, wherein the time course of ligand association and dissociation is determined, competition binding assays, dissociation binding assays, saturation binding assays, and in quantitative autoradiography and image analyses (Maguire et al., Methods Mol Biol. 2012;897:31-77).

[302] Affinity can be evaluated by determining the inhibition constant of a disclosed compound and a receptor, such as a 5-HT2 receptor. An inhibition constant (K) may be described as the concentration at which 50% of a radiolabeled ligand, such as an agonist, is displaced by the test ligand. Accordingly, as presented in the Cheng- Prusoff equation, an observed IC50 can be used to determine Ki, where K,=IC5o/(1 +[R]/Kd), where the IC50 is the concentration of the competitive inhibitor producing a 50% inhibition, R is the concentration of radioligand used in the competition binding assay, and Kd is the equilibrium dissociation constant of the radioligand in the assay.

[303] A competition binding assay, otherwise referred to as a radioligand displacement assay, can be used to determine Ki. Generally, the effect of a test ligand on the interactions between a radiolabeled ligand and a receptor preparation is assessed, e.g., the extent of radiolabeled ligand displacement is evaluated.

[304] In some examples, displaced radioligands are antagonists, for example, [³H]ketanserin for 5-HT2A and [³H]mesulergine for 5-HT2C. In some examples, displaced radioligands are agonists, for example [³H]LSD for 5- HT2B. Consistency of test conditions however is preferred for the purposes of making a comparison, as displacement of antagonists may reflect binding to both active and inactive receptor conformations, and displacement of agonists presumably reflects binding to an active conformation (Toro-Sazo et al., PLoS One, 2019; 14(1 ):e0209804). Binding assays are further described in, e.g., Roth’s National Institutes of Mental Health Psychoactive Drug Screening Program, Assay Protocol Book, Version III, 2018.

[305] In some embodiments, a disclosed compound has a binding affinity for any one or more of 5-HT2A, 5- HT2B, and 5-HT2C, that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In embodiments, a disclosed compound has a binding affinity for any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, that is about 10 pM, 5 pM, 1 pM, 0.5 pM, or 0.1 pM. In embodiments, a disclosed compound has increased binding affinity for any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, relative to a comparator. In embodiments, a disclosed compound has decreased binding affinity for any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, relative to a comparator. In embodiments, the comparator is serotonin. Serotonin exhibits moderate Ki values of 330 nM, 470 nM, and 120 nM at 5-HTIA, 5-HT2A, and 5-HT2C receptors, respectively. In embodiments, the comparator is the corresponding tryptamine lacking an N-linked side chain. In embodiments, the binding affinity of a disclosed compound for any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, is increased by about 2- fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 500-fold, 1000-fold or at least 1000-fold relative to a comparator. In embodiments, the binding affinity of a disclosed compound for any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, is decreased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50- fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 500-fold, 1000-fold or at least 1000-fold relative to a comparator.

[306] In some embodiments, a disclosed compound has increased selectivity for the 5-HT2A receptor over another serotonin receptor (e.g., the 5-HT2B receptor and/or the 5-HT2C receptor) relative to a comparator. In embodiments, a disclosed compound has increased selectivity for the 5-HT2A receptor over the 5-HT2B receptor relative to a comparator. In embodiments, a disclosed compound has increased selectivity for the 5-HT2A receptor over the 5-HT2C receptor relative to a comparator. In embodiments, a disclosed compound has increased selectivity for the 5-HT2A receptor over both the 5-HT2B and 5-HT2C receptors, relative to a comparator.

[307] In some embodiments, selectivity is defined by the ratio of the half-maximal effective concentration (EC50) of a disclosed compound for the 5-HT2A receptor as compared to another receptor (e.g., a serotonin receptor, such as the 5-HT2B receptor, or the 5-HT2C receptor). For example, if a hypothetical compound had a 5-HT2A EC50 of 0.2 pM and a 5-HT2A EC50 of 1 .0 pM, the compound could be said to have a 5-fold selectivity for the 5-HT2A receptor over the 5-HT2B receptor. In embodiments, a disclosed compound has about a 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or at least 200-fold selectivity for a first 5-HT receptor subtype over a second 5-HT receptor subtype. The first 5-HT receptor subtype may be any serotonin receptor subtype. The second 5-HT receptor subtype may be any serotonin receptor subtype. In embodiments, a disclosed compound has about a 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80- fold, 90-fold, 100-fold, 200-fold, or at least 200-fold selectivity for the 5-HT2A receptor over the 5-HT2B receptor. In embodiments, a disclosed compound has about a 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80- fold, 90-fold, 100-fold, 200-fold, or at least 200-fold selectivity for the 5-HT2A receptor over the 5-HT2C receptor. In embodiments, a disclosed compound has about a 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80- fold, 90-fold, 100-fold, 200-fold, or at least 200-fold selectivity for the 5-HTIA receptor over the 5-HT2A receptor. In embodiments, a disclosed compound has about a 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80- fold, 90-fold, 10O-fold, 200-fold, or at least 200-fold selectivity for the 5-HTic receptor over the 5-HT2A receptor. In embodiments, a disclosed compound has about a 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80- fold, 90-fold, 10O-fold, 200-fold, or at least 200-fold selectivity for the 5-HT2C receptor over the 5-HT2A receptor. In embodiments, a disclosed compound has about a 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80- fold, 90-fold, 10O-fold, 200-fold, or at least 200-fold selectivity for the 5-HT2C receptor over the 5-HT2B receptor.

[308] In some embodiments, a disclosed compound has an increased association rate at a serotonin receptor, such as a 5-HT2 receptor (e.g., 5-HT2A, 5-HT2B, and 5-HT2c) relative to a comparator. In some embodiments, a disclosed compound has a decreased association rate at a serotonin receptor, such as a 5-HT2 receptor (e.g., 5-HT2A, 5-HT2B, and 5-HT2C), or a 5-HTi receptor (e.g., 5-HTIA and 5-HTIB), relative to a comparator. In embodiments, the comparator is serotonin. In embodiments, the association rate of a disclosed compound at any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, is increased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50- fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or at least 200-fold. In embodiments, the association rate of a disclosed compound at any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, is decreased by about 2-fold, 5-fold, 10- fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or at least 200-fold. c. Modulating Neurotransmission

[309] In some embodiments, disclosed compounds modulate neurotransmission in a subject, such as following administration of an effective amount to the subject. In embodiments, modulating neurotransmission by administering a disclosed compound to a subject also treats a disease or disorder in the subject.

[310] In some embodiments, modulating neurotransmission comprises modulating serotonergic neurotransmission. In some embodiments, disclosed compounds can modulate the activity of 5-HT receptors (5- HTRs). 5-HTRs are G-protein coupled receptors (GPCRs) that act through Gai, Gaq/11 , or Gas pathways and affect various signaling mechanisms throughout the body. Modulation of such receptors produces both distinct and overlapping pharmacological effects (Zi^ba et al., Int J Mol Sc/., 2022;23(1 ): 10).

[31 1] Each of the three 5-HT2 receptor subtypes are G-protein-linked single protein molecules of similar size and homology, comprising between 458-471 amino acids. The pharmacology of three subtypes of the 5-HT2 receptor, 5-HT2A, 5-HT2B, and 5-HT2C, have been characterized, and functional activity, such as agonism and antagonism, may be determined according to certain events in resultant signal transduction cascades (see, e.g., Pithadia & Jain, J Clin Med Res. 2009; 1 (2):72— 80; Raote et al., “Serotonin Receptors in Neurobiology,” Chapter 6, Boca Raton (FL): CRC Press/Taylor & Francis; 2007 (“Raote 2007”)).

[312] 5-HT2A activation leads to activation of GPCR subunit Gaq/11 and effector enzyme phospholipase C (PLC), which promotes release and accumulation of inositol triphosphate (IP3), diacylglycerol (DAG), and PKC (Singh et al., Int’l J Neuropsychopharmacol, 2009;12(5):651— 665). In one example, the released inositol phosphate (IP) can be used as an indicator of 5-HT2 receptor signaling activity (see, e.g., 5-HT2A, 5-HT2B and 5- HT2C Receptors: Inositol monophosphate (IP-1) formation described in Eshleman et al., Biochem Pharmacol, 2018;158: 27-34. Additionally, accumulation of IP3 causes a release of calcium, which may be monitored by loading cells with Ca²⁺ sensitive fluorescent dyes, applying a test ligand, and measuring spectral shifts that result from the dye binding to released Ca²⁺. 5-HT2 receptor functional assay methods are described in, e.g., Klein et al., ACS Pharmacol Transl Sci. 2021 ;4(2):533— 542 (“Klein 2021”). IP3 accumulation itself, e.g., accumulation of total radiolabeled IP, such as inositol mono-phosphate, inositol bis-phosphate, and inositol tris-phosphate, may also be used to measure receptor activation and desensitization, including a temporal aspect. In one example, a decrease in basal levels of IP3 provides a measure of antagonism (Raote 2007).

[313] In some embodiments, disclosed compounds can modulate the activity of a 5-HT receptor, including any of activating, inhibiting, partially activating, and partially inhibiting the activity of the receptor. In embodiments, the disclosed compounds are 5-HT receptor ligands that bind to, activate, block, inhibit, or otherwise influence, e.g., via allosteric modulation, activity at a 5-HT receptor. In embodiments, a disclosed compound is a 5-HT2 receptor ligand, such a ligand for one or more of a 5-HT2A receptor, 5-HT2B receptor, and 5-HT2C receptor.

[314] In some embodiments, a disclosed compound agonizes 5-HT2 receptors. In embodiments, a disclosed compound antagonizes 5-HT2 receptors. In embodiments, a disclosed compound partially agonizes 5-HT2 receptors. In embodiments, a disclosed compound partially antagonizes 5-HT2 receptors (see, e.g., Example 2). In embodiments, the 5-HT2 receptor is a 5-HT2A receptor. In embodiments, the 5-HT2 receptor is a 5-HT2B receptor. In embodiments, the 5-HT2 receptor is a 5-HT2C receptor. In some embodiments, a disclosed compound agonizes 5-HTi receptors. In embodiments, a disclosed compound antagonizes 5-HTi receptors. In embodiments, a disclosed compound partially agonizes 5-HTi receptors. In embodiments, a disclosed compound partially antagonizes 5-HTi receptors (see, e.g., Example 2). In embodiments, the 5-HTi receptor is a 5-HTIA receptor. In embodiments, the 5-HTi receptor is a 5-HTIB receptor.

[315] In some embodiments, a disclosed compound has an in vitro EC50 (agonist mode) for any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In embodiments, a disclosed compound has an in vitro EC50 (agonist mode) for any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, that is about 10 pM, 5 pM, 1 pM, 0.5 pM, or 0.1 pM. In embodiments, a disclosed compound has an in vitro EC50 (antagonist mode) for any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In embodiments, a disclosed compound has an in vitro EC50 (antagonist mode) for any one or more of 5-HT2A, 5-HT2B, and 5- HT2C, that is about 10 pM, 5 pM, 1 pM, 0.5 pM, or 0.1 pM. In some embodiments, a disclosed compound has an in vitro EC50 (agonist mode) for either or both of 5-HTiA and 5-HTIB, that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In embodiments, a disclosed compound has an in vitro EC50 (agonist mode) for either or both of 5-HTIA and 5-HTIB, that is about 10 pM, 5 pM, 1 pM, 0.5 pM, or 0.1 pM. In embodiments, a disclosed compound has an in vitro EC50 (antagonist mode) for either or both of 5-HTIA and 5-HTIB, that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In embodiments, a disclosed compound has an in vitro EC50 (antagonist mode) for either or both of 5-HTIA and 5- HTIB, that is about 10 pM, 5 pM, 1 pM, 0.5 pM, or 0.1 pM.

[316] In some embodiments, modulating neurotransmission comprises modulating voltage-gated ion channel activity. In embodiments, a disclosed compound modulates the activity of one or more of a voltage-gated calcium ion (Ca²⁺) channel, a voltage-gated chloride ion (Cl ) channel, a voltage-gated potassium ion (K⁺) channel, and a voltage-gated sodium ion (Na⁺) channel (VGSC). In some embodiments, a disclosed compound has a binding affinity for VGSC that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In embodiments, a disclosed compound has a binding affinity for VGSC that is about 10 pM, 5 pM, 1 pM, 0.5 pM, or 0.1 pM. In embodiments, a disclosed compound has increased binding affinity for VGSC relative to a comparator. In embodiments, the comparator is serotonin. In embodiments, the binding affinity of a disclosed compound for VGSC is increased by about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 80-fold, 90- fold, 100-fold, 200-fold, 500-fold, 1000-fold or at least 1000-fold relative to a comparator. In some embodiments, a disclosed compound is a VGSC inhibitor. In embodiments, a disclosed compound has an in vitro IC50 for VGSC that is less than 10 pM, less than 5 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In embodiments, a disclosed compound has an in vitro IC50 for VGSC that is about 10 pM, 5 pM, 1 pM, 0.5 pM, or 0.1 pM. b. Treatment

[317] In some embodiments, disclosed compounds are used to treat a medical condition, such as a disease or disorder. In embodiments, disclosed compounds are used in the manufacture of a medicament to treat a condition, such as a disease or disorder. Also provided are methods of administering disclosed compounds to a subject having a condition, such as a disease or disorder, thereby treating said condition.

[318] In some embodiments, disclosed compounds and compositions thereof are used to treat serotonin- mediated disorders. In embodiments, disclosed compounds, when administered to a subject in an effective amount, provide beneficial therapeutic effects for the treatment of a serotonin-mediated disorder. Serotonin- mediated disorders include mental health disorders, neurodegenerative diseases and disorders, pain, pain syndromes, and pain disorders, headaches, such as migraines, and inflammation and inflammatory disorders.

[319] In some embodiments, disclosed compounds and compositions thereof are administered to a subject by one or more routes of administration, including oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes, and when administered by one or more of such routes, are useful in methods of treating the subject, who is in need of such treatment.

[320] In some embodiments, disclosed methods of treating or preventing a condition in a mammal comprise administering to the mammal a therapeutically effective amount of a disclosed compound or composition thereof.

[321] In some embodiments, “treating” or “treatment” refers to treating a disease or disorder in a mammal, and preferably in a human, and includes causing a desired biological or pharmacological effect, such as: (a) preventing a disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with it; (b) inhibiting a disorder, i.e. arresting its development; (c) relieving a disorder, i.e., causing regression thereof; (d) protecting from or relieving a symptom or pathology caused by or related to a disorder; (e) reducing, decreasing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a disorder; and (f) preventing or inhibiting of a worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be understood to one of ordinary skill based on the teachings herein and the knowledge in the art.

[322] Terms such as “an effective amount,” “a therapeutically effective amount,” and “a pharmacologically effective amount” include reference to an amount of a disclosed compound that is sufficient to provide the desired effect, such as a therapeutic effect, at a reasonable benefit/risk ratio such as attends a similar treatment.

[323] Terms such as “therapeutic effect” or “therapeutic efficacy” include reference to the responses(s) in a mammal, such as a human, that are judged to be desirable and beneficial with sufficient or after treatment.

[324] Measures of therapeutic effect include any outcome measure, endpoint, effect measure, or measure of effect within clinical or medical practice or research which can be used to assess the effect, whether positive or negative, or both, of an intervention or treatment, and whether patient-reported (e.g., questionnaires), based on other patient data (e.g., patient monitoring), gathered through laboratory tests such as blood work, urine samples, etc., through medical examination by a doctor or other medical professional, or by digital tools or means, e.g., electronic tools such as online tools, smartphones, wireless devices, biosensors, or health apps.

[325] In some embodiments, measures of therapeutic effect include an assessment. An “assessment” refers to any means or method used with a patient, whether before, during, after, or unrelated in time to administration, to measure, estimate, or evaluate a nature, ability, symptom, disorder, or other characteristic of the patient, whether qualitatively or quantitatively, and whether performed by a clinician (e.g., by interview), by the patient his or herself (e.g., by self-reported questionnaire), by a third-party or by a computer, including a medical device (e.g., as such as defined by the FDA or other regulatory body) or another device (e.g., a medical sensor or biosensor, a watch or fitness tracker, or a “wearable”), and whether graded by a human or by artificial intelligence (Al), machine learning (ML), or a computer algorithm. An assessment may be computer-assisted, including other computer-assisted assessments besides those herein. The term “computer-assisted” in “computer-assisted assessment” includes assessments comprising the use of electronic tools such as online tools, smartphones, wireless devices, or health apps, and includes such methods referred to as “digital phenotyping.” Computer- assisted assessments include the use of an electronic psychiatric notes or other medical records system. Where drug administration is supervised, such as includes any of therapy, support, or monitoring, such administration may comprise supervision that is “computer-assisted,” including where a clinician interacts face-to-face with a patient, where a clinician and a patient interact virtually (either synchronously or asynchronously), and where a patient only interacts with a computer (“computer” broadly including any electronic tool suitable for such purposes, including desktop, laptop, and notebook computers; tablets, smartphones, and other mobile devices; watches, fitness trackers, and personal electronic devices; and the like, as will be appreciated by those of skill). i. Mental, Behavioral, or Neurodevelopmental Disorders

[326] In some embodiments, disclosed compounds are used to treat a mental, behavioral, or neurodevelopmental disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental, behavioral, or neurodevelopmental disorder, thereby treating said mental, behavioral, or neurodevelopmental disorder.

[327] In some embodiments and methods of use herein, the disclosed compounds and compositions comprising such compounds (both, in these sections, as shorthand and equivalently, and unless context clearly indicates otherwise, “compounds”), when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental, behavioral, or neurodevelopmental disorder.

[328] The ICD-11, which is incorporated by reference herein in its entirety, defines “mental, behavioral, or neurodevelopmental disorders” as syndromes characterized by clinically significant disturbance in an individual's cognition, emotional regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes that underlie mental and behavioral functioning. Such disorders include neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically associated with stress, dissociative disorders, feeding (or eating) disorders, elimination disorders, disorders of bodily distress or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or dissocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, sleep-wake disorders, sexual dysfunctions, and gender incongruence.

[329] A mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the I CD-11 . Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or “mental health disorder”) generally refers to a disease condition that involves negative changes in emotion, mood, thinking, and/or behavior. In general, mental health disorders are characterized by clinically significant disturbances in an individual's cognition, emotion, behavior, or a combination thereof, resulting in impaired functioning, distress, or increased risk of suffering.

[330] Although the terms “mental disorder” and “mental health disorder,” as well as terms that define specific diseases and disorders, generally shall refer to the criteria in the ICD-11 , or a patient with a diagnosis based thereon, it will be appreciated that disclosed methods are equally applicable to patients having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in I CD-11 , 1 CD- 10, DSM-5, or DSM- IV (each of which is incorporated by reference herein in its entirety) whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet had a formal clinical diagnosis.

[331] In some embodiments, disclosed compounds are used to treat a mental health disorder. In some embodiments, disclosed compounds are administered, such as in a therapeutically effective amount, to a subject having a mental health disorder, thereby treating said mental health disorder. In some methods herein, the disclosed compounds or compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental health disorder. In some embodiments, the disclosed compounds and compositions are used to reduce the symptoms of a mental health disorder. The symptoms of the mental health disorder to be treated shall be able to be determined by one of skill in the art, by reference to the general understanding of the art regarding that disorder.

[332] In some embodiments, measures of therapeutic efficacy include reports by a subject or an observer. In some embodiments, measures of therapeutic efficacy include responses to a questionnaire. Non-limiting representative examples of applicable measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Interpersonal Reactivity Index (IRI), Short Form (36) Health Survey (SF-36), Self-Compassion Scale (SCS), Trauma History Questionnaire (THQ), Beck Depression Index (BDI), and related subject- or observer-reported measures.

[333] In some embodiments, a disclosed compound is used to treat schizophrenia (or another primary psychotic disorder, as defined in the DSM-IV, DSM-5, ICD-10, or ICD-11). Such disorders may be characterized by significant impairments in reality and alterations in behavior manifest in positive symptoms like persistent delusions, persistent hallucinations, disorganized thinking and speech, grossly disorganized behavior, as well as experience of negative symptoms such as blunted or flat affect and avolition and psychomotor disturbances.

[334] Serotonin receptors, and the 5-HT2A receptor in particular, have been targets for antipsychotic therapeutics for decades (Schmidt et al., Life Sci. 1995;56(25):2209-2222), and recent research supports the use of 5-HT2A antagonists for the treatment of negative symptoms in patients with schizophrenia (Romeo et al., Psychiatry Res. 2023; 321 :115104). In some embodiments, a disclosed compound is used to treat schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or a substance-induced psychotic disorder. In some embodiments, measurements of therapeutic efficacy in treating schizophrenia or a related psychotic disorder include the Clinical Global Impression scale (CGI), the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), the Scale for the Assessment of Positive Symptoms (SAPS), the 16-item Negative Symptoms Assessment (NSA-16), the Schedule for Deficit Syndrome (SDS), the Clinical Assessment Interview for Negative Symptoms (CAINS), and the Brief Negative Symptoms Scale (BNSS).

[335] In some embodiments, a disclosed compound is used to treat a mood disorder. As defined in the ICD- 11 , mood disorders are categorized according to the specific type(s) of mood episodes, and their pattern over time, with the primary types of mood episodes being depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. Antagonism of the 5-HT2A receptor is a common mechanism of numerous FDA-approved antipsychotic medications used in the treatment of mood disorders (Casey et al., Biochem Pharmacol. 2022;200: 115028). In some embodiments, the mood disorder is a bipolar or related disorder (e.g., bipolar type I disorder, bipolar type II disorder, cyclothymic disorder) a depressive disorder (e.g., single-episode depressive disorder, recurrent depressive disorder, dysthymic disorder, mixed depressive and anxiety disorder), or a substance-induced mood disorder. In some embodiments, measurements of therapeutic efficacy in treating a mood disorder (e.g., bipolar disorder) include the General Behavior Inventory (GBI), Mood Disorder Questionnaire (MDQ), Young Mania Rating Scale, Bech-Rafaelsen Mania Rating Scale, Altman Self-Rating Mania Scale, and the Self-Report Manic Inventory. ii. Neurodegenerative Disorders

[336] In some embodiments, disclosed compounds and compositions are used to treat neurodegenerative conditions, which as shorthand refers broadly to neurodegenerative diseases and disorders. In embodiments, a therapeutically effective amount of a disclosed compound is administered to a subject in need thereof to treat a neurodegenerative condition. In embodiments, administration of a therapeutically effective amountof a disclosed compound slows or prevents the progression of neurodegeneration. In embodiments, administration of a therapeutically effective amount of a disclosed compound reduces the incidence or severity of at least one symptom of a neurodegenerative condition. Neurodegeneration may be assessed, e.g., by measuring markers of neuronal loss, such as cerebrospinal fluid markers, e.g., visinin-like protein 1 (VILIP-1), tau, and p-tau181 (Tarawneh et al., Neurol. 2015; 72(6): 656-665). Cognitive decline may also be used as a measure of neurodegeneration. Methods for assessing cognitive decline, e.g., comprehensive neuropsychological testing, are known to one of skill in the art. Exemplary cognitive evaluations include Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). See, e.g., Toh et al., Transl Neurodegener. 2014;3:15. Cognitive decline and the progression of disease state may also be assessed using a condition-specific measure, e.g., the Unified Huntington’s Disease Rating Scale (UHDRS).

[337] Neurodegenerative conditions, such as diseases or disorders include, e.g., dementia, Alzheimer's disease, Huntington’s disease, multiple sclerosis, and Parkinson’s disease. A feature of neurodegenerative conditions is neuronal cell death, which, among other aspects, has been implicated in the promotion of inflammation. See, e.g., Chan et al., Annu Rev Immunol. 2015; 33: 79-106 and Chi et al., Int J Mol Sci. 2018; 19(10):3082. Neurodegenerative diseases can be classified according to primary clinical features, e.g., dementia, parkinsonism, or motor neuron disease, anatomic distribution of neurodegeneration, e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations, or principal molecular abnormality (Dugger & Dickson, Cold Spring Harbor Perspect Biol. 2017; 9(7):a028035). iii. Pain and Inflammation

[338] In some embodiments, disclosed compounds and compositions thereof are used to treat a pain disorder and/or inflammation. In embodiments, a therapeutically effective amount of a disclosed compound, or a pharmaceutical composition thereof, is administered to a subject in need thereof to treat a pain disorder and/or inflammation. In embodiments, administration of a therapeutically effective amount of a disclosed compound reduces the incidence or severity of at least one symptom of a pain disorder and/or an inflammatory disorder.

[339] In some embodiments, a pain disorder treated by the disclosed compounds is a chronic pain disorder. Chronic pain disorders include, e.g., central pain, complex regional pain syndrome, phantom pain, such as phantom limb pain, neuropathic pain, fibromyalgia, arthritis, spinal stenosis, temporomandibular joint syndrome, bowel disease, pain related to surgery, and pain related to a disease or disorder, e.g., pain related to cancer.

[340] In some embodiments, disclosed compounds and compositions are used to treat headaches. In embodiments, a therapeutically effective amount of a disclosed compound is administered to a subject in need thereof to treat headaches. Headaches include tension headaches, migraine headaches, and cluster headaches.

[341] In some embodiments, disclosed compounds and compositions thereof are used to reduce inflammation, for example, systemic inflammation. In embodiments, disclosed compounds and compositions thereof are used to treat inflammatory diseases. In embodiments, a therapeutically effective amount of a disclosed compound, or a pharmaceutical composition thereof, is administered to a subject in need thereof to treat an inflammatory disease. Inflammatory diseases include, e.g., Alzheimer’s disease, ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), asthma, atherosclerosis, Crohn’s disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson’s disease, and ulcerative colitis.

[342] Pain can be defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (see Int’l Assoc Study of Pain (I ASP)). Although the mechanism remains unclear how serotonin modulators ameliorate pain, such as 5-HT2A agonists and antagonists, the synaptic plasticity associated with such compounds may alter pathologic changes in neural connections seen in chronic pain states, potentially leading to reduced pain intensity and duration (Castellanos et al., Reg Anesth Pain Med. 2020;45(7):486-494). 5-HT2AR activation also has been shown to promote antiinflammatory effects, e.g., a reduction of TNF-a-induced inflammation (see, e.g., Pelletier & Siegel, Mol Interv., 2009;9(6):299-301; Flanagan et al., Sci Rep. 2019;9(1 ):13444; Nichols et al., Clin Pharmacol Ther. 2017;101 (2): 209-219; Int Rev Psych. 2018;30(4):363-375, Okamoto et al., Neurosci. 2005; 130(2):465-74).

[343] Pain, such as chronic pain, and improvements thereof, such as a reduction of symptoms, may be measured according to known methods, e.g., by subject reporting, pain diaries, pain scales, applicable questionnaires (assessments of chronic pain and its impact on physical, emotional and social functions), ecological momentary assessments and computerized versions thereof (see, e.g., Salaffi et al., Best Practice & Research Clinical Rheumatology, 2015; 29(1 ):164-186; Hawker et al., Arthritis Care Res (Hoboken). 2011;63 Suppl 11 :S240-52). Exemplary questionnaires include the Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF- MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP), Migraine Diagnosis Questionnaire, the Migraine-Screen Questionnaire (MS-Q), the Fibromyalgia Survey Questionnaire (FSQ).

[344] A reduction in inflammation, such as chronic systemic inflammation, may be measured according to various methods known by one of skill. Inflammatory biomarkers may be detected from biological specimens, for example, a subject’s blood, such as plasma or serum, or saliva. In one example, inflammation is detected by measuring high-sensitivity C-reactive protein (CRP) and white blood cell count from a blood test. CRP also may be detected in a saliva sample. Salivary CRP is not synthesized locally in the mouth and may reflect more systemic levels of inflammation compared to other inflammatory biomarkers, such as cytokines (Szabo & Slavish, Psychoneuroendocrinol. 202;124:105069). Additionally, clinical pathology data can provide an initial indication of the presence and potentially the location of inflammation, in the absence of specific data on immune tissues, e.g., hematology data on erythrocyte parameters, platelet count, total number of leukocytes, and leukocyte differentials and morphology, coagulation data on clotting times and fibrinogen, and clinical chemistry data on total protein, albumin and globulin, liver enzymes, renal parameters, electrolytes, and bilirubin (see, e.g., Germolec et al., Methods Mol Biol. 2018;1803:57-79; Luo et al., Clin Lab. 2019 1 ;65(3)). iv. Ion Channel-Mediated Conditions

[345] In some embodiments, disclosed compounds are used to treat an ion channel-mediated condition.

[346] An “ion channel-mediated condition” refers to a disease or disorder that is related to dysfunction of an ion channel, such as a voltage-gated ion channel or a ligand-gated ion channel.

[347] In embodiments, a therapeutically effective amount of a disclosed compound, or a pharmaceutical composition thereof, is administered to a subject in need thereof to treat an ion channel-mediated condition.

[348] In embodiments, the ion channel-mediated condition is one or more of a calcium ion (Ca²⁺) channel, a chloride ion (Cl ) channel, a potassium ion (K⁺) channel, and a sodium ion (Na⁺) channel.

[349] In some embodiments, a disclosed compound modulates the activity of one or more of a calcium ion (Ca²⁺) channel, a chloride ion (Cl ) channel, a potassium ion (K⁺) channel, and a sodium ion (Na⁺) channel.

[350] In embodiments, the ion channel is voltage-gated. In embodiments, the ion channel is ligand-gated. In embodiments, a disclosed compound modulates the activity of one or more of a voltage-gated calcium ion (Ca²⁺) channel, a voltage-gated chloride ion (CI-) channel, a voltage-gated potassium ion (K⁺) channel, and a voltagegated sodium ion (Na⁺) channel. In embodiments, modulating the activity of an ion channel comprises blocking, such as inhibiting or decreasing the activity of, said ion channel. In embodiments, modulating the activity of an ion channel comprises activating said ion channel.

[351] In some embodiments, disclosed compounds or compositions thereof are used to treat a seizure disorder, such as epilepsy. In embodiments, a therapeutically effective amount of a disclosed compound, or a pharmaceutical composition thereof, is administered to a subject in need thereof to treat a seizure disorder.

[352] In embodiments, administration of a therapeutically effective amount of a disclosed compound reduces the incidence of seizures and/or the severity of a seizure disorder. In embodiments, the seizure disorder is epileptic seizure disorder. In embodiments, the seizure is a focal seizure. In embodiments, the seizure is a generalized seizure. In embodiments, administration of a disclosed compound to a subject results in a reduction in severity of epilepsy comorbidities, for example, anxiety and depression, and/or an increase in quality of life, for example, as evaluated using the Quality-of-Life questionnaire in Epilepsy (QOLIE-31).

[353] A seizure can be defined as a burst of uncontrolled electrical activity between neurons that causes temporary abnormalities in muscle tone or movements, behaviors, sensations, or states of awareness. Due to their roles in maintaining cellular ionic and electrical homeostasis, ion channels are crucial components of neuronal functioning. Certain subunits are expressed exclusively in the brain, and ion channel dysfunction may lead to epilepsy, which is characterized by recurring seizures (Armijo et al., CurrPharm Des. 2005; 11 (15): 1975- 2003; Graves, QJM: An Int’l J Med., 2006;99(4):201— 217). Various antiepileptic treatment options decrease membrane excitability by interacting with neurotransmitter receptors or ion channels, e.g., phenytoin and carbamazepine inhibit sodium channel activation, thereby decreasing high-frequency repetitive firing of associated action potentials (Macdonald & Kelly, Epilepsia. 1995;36 Suppl 2:S2-12).

[354] Besides treatment for seizure disorders, such as epilepsy, disclosed compounds may treat one or more comorbidities thereof. Non-limiting examples of comorbidities of epilepsy, which may benefit from the disclosed compounds, include depression, anxiety, and migraines (Keezer et al., Lancet Neurol. 2016; 15(1): 106-15).

[355] Determining whether a disclosed compound modulates the activity of an ion channel may be accomplished by monitoring the electrophysiological activity of cells. For example, the patch-clamp technique allows for measurements of currents through ion channels in a cell membrane (see, e.g., Lenkey et al., PLoS One. 2010;5(12):e15568; Liu et al., Assay Drug Dev Technol. 201 ;9(6):628-34; and Dolzer, Methods Mol Biol. 2021 ;2188:21-49). Patch-clamp experiments can be performed on cultured cells, acutely dissociated cells, or on acute vibratome slices. Additionally, fluorescence resonance energy transfer (FRET) technology using membrane potential-sensitive dyes can provide a measurement of voltage-gated sodium channel activity in stably transfected cell lines (Felix et al., Assay Drug Dev Technol. 2004 Jun;2(3):260-8). v. Mental Functioning

[356] In some further aspects are provided methods of improving mental health and/or functioning, such as cognitive functioning. Improvements in mental health and functioning may include one or more of a reduction of neuroticism or psychological defensiveness, an increase in creativity or openness to experience, an increase in decision-making ability, an increase in feelings of wellness or satisfaction, or an increase in ability to fall or stay asleep. Additionally, improvements in mental health and functioning may include improvements in or a return to baseline in processing speed, learning and memory, autobiographical memory, shifting, and IQ. Measurements of such will be readily understood and appreciated according to ordinary skill (see, e.g., Ahern & Semskova, Neuropsychol. 2017;31 (1 ):52-72). Exemplary measures of improvements of mental health and/or functioning include the Global Assessment of Functioning (GAF) scale, the Sleep Quality Scale (SQS), and other measures of sleep quality (see, e.g., Fabbri et al., Int J Environ Res Public Health. 2021 ; 18(3): 1082), and the Social Functioning Scale (SFS) (Chan et al., Psychiatry Res. 2019;276:45-55). In some embodiments, the invention provides methods of improving mental health and/or functioning, such as cognitive functioning, in healthy people, such as “healthy normals,” and the invention will thus include in some embodiments the “betterment of the well.” vi. Administration in Conjunction with Psychotherapy

[357] in some embodiments, disclosed compounds and compositions are administered together with therapy, such as psychotherapy, together with psychological support, or together with patient monitoring. Where a disclosed compound or composition is administered together with therapy, it may include any modality thereof, such as psychosocial or behavioral therapy, including (or adapted from) any of Acceptance and Commitment Therapy (ACT), Internal Family Systems (IFS) Therapy, Cognitive Behavioral Therapy (CBT) (see, e.g., Arch Gen Psych., 1999; 56:493-502), interpersonal therapy (see, e.g., Psychol Addict Behav., 2009; 23(1): 168-174), contingency management based therapy (see, e.g., id.; J. Consul. Clin. Psychol., 2005; 73(2): 354-59; Case Reports in Psychiatry, Vol. 2012, ID731638), motivational interviewing-based therapy (see, e.g., J Consul Clin Psychol., 2001 ; 69(5): 858-62), and meditation and mindfulness-based therapy (see, e.g., J Consul Clin Psychol., 2000; 68(3): 515-52) (see also generally, e.g., Johnson et al., J Psychopharmacol., 2008,22, 603-620).

[358] In some embodiments, a disclosed compound or composition can be, and is, administered without or with reduced risk of side effects that would require physician or clinician supervision, and allows for treatment at home or otherwise outside of a clinic and without the need for such supervision, including any form of monitoring.

[359] In some embodiments, disclosed compounds and compositions are administered in conjunction with or as an adjunct to psychotherapy. In other embodiments, psychotherapy is neither necessitated nor utilized.

[360] In some embodiments, a patient participates in one or more beneficial activities, including where such participation is together with administration of a disclosed compound, such as part of a dosing regimen or protocol. Beneficial activities, which include therapeutically beneficial activities, include breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, yoga, stretching or bodywork, journaling, grounding techniques, positive self-talk, and engaging with a pet or animal. Participation can occur with or without the supervision or direct guidance of a clinician or professional.

H. Examples

[361] The following examples are included for illustrative purposes only and are not intended to be limiting.

[362] In general, the described pharmacology experiments can be conducted according to procedures set out in Applicant’s Int’l Appl. No. PCT/US2023/026258, which is incorporated by reference as if fully set forth herein.

Example 1 : Measuring target engagement in transiently expressed HiBiT-5-HT receptors

[363] Purpose: To determine binding characteristics (e.g., binding affinity, binding kinetics) of disclosed compounds (and any comparators) at several 5-HT receptors using a NanoBRET Target Engagement Assay.

[364] This assay quantifies dynamic interactions between ligands and their cognate HiBiT-tagged GPCRs on the surface of living cells through competitive binding with fluorescent tracers (Boursier et al. J Biol Chem. 2020;295(15):5124-5135). This evaluation will use DNA constructs encoding for either 5-HTIA, 5-HT2A, or 5-HT2c receptors genetically fused to an N-terminal HIBIT tag, which can generate bright luminescence upon high affinity complementation with LgBiT, an impermeable 18 kDa subunit derived from NanoLuc (Killoran et al. Molecules. 2021 ;26(10):2857). For each receptor, the binding constant for one of two fluorescent tracers comprising a NanoBRET-590 fluorophore conjugated to either clozapine or NAN-190 (ibid.) will be determined. To this end, HEK293 cells transiently expressing a HiBiT-tagged receptor will be treated with increasing concentrations of a fluorescent tracer in the absences or presence of excess unmodified ligands. Binding constants (KD) for the tracers at 5-HTIA, 5-HT2A, and 5-HT2C will then be derived from these saturation binding analyses.

[365] Additional evaluation will be performed to determine the binding affinities for test compounds (e.g., disclosed compounds and any comparators) at these receptors. HEK293 cells transiently expressing the HiBiT- tagged receptors will be tested for competitive displacement of a fixed ECso concentration of a fluorescent tracer by increasing concentrations (1 pM-30 pM) of test compound. Binding constants will then be calculated according to the Cheng-Prusoff equation (Cheng & Prusoff. Biochem Pharmacol. 1973;22(23):3099-3108).

[366] Binding kinetics of test compounds at 5-HT2A receptors will then be investigated, as the binding kinetics may be predictive of a compound’s potency. First, the kinetic constants for the clozapine tracer are determined. To this end, HEK293 cells transiently expressing HiBiT-5-HT2A receptors will be treated with varying concentrations of clozapine tracer in the presence and absence of excess unmodified clozapine and binding was monitored over 30 minutes. Binding affinity and association and dissociation rates will be derived from this kinetic analysis. Then, binding of test compounds to HiBiT-5-HT2A receptors in the presence of a fixed ECso concentration of clozapine tracer will be monitored for 30 minutes.

[367] Methods: NanoBRET-based ligand binding assays: HEK293 cells expressing a HiBiT-tagged 5-HT receptor are treated with a serial dilution of a fluorescent tracer in the presence or absence of 30 pM competing unmodified ligand. Plates are mixed briefly and incubated for 90 minutes at room temperature. To measure BRET, cells are treated with a 2X detection solution comprising 100-fold dilution of LgBiT (Promega) and 50-fold dilution of furimazine Live Cell Substrate (Promega) in Opti-MEM. Plates are mixed for 10 minutes to allow HiBiT/LgBiT complementation. Filtered luminescence is measured using GloMax Discover Microplate Reader (Promega) equipped with a 450 nm (8-nm bandpass) filter (donor) and a 600-nm long pass filter (acceptor). BRET is calculated by dividing the acceptor >600 nm light output by the donor 450 nm emission. Values are background corrected by subtracting the BRET values from samples treated with excess unmodified ligand.

[368] For competitive displacement experiments, cells are treated with serial dilution of unmodified ligand in the presence of a fixed EC80 concentration of a fluorescent tracer. Plates are mixed briefly and incubated for 90 minutes at room temperature. Cells are then treated with a 2X detection solution and BRET measurements are performed as described above. Affinity values (Ki) are calculated from the observed IC50 values according to the Cheng-Prusoff equation (Cheng & Prusoff, op. cit.).

[369] Kinetic measurements of ligand binding to HiBiT-tagged 5-HT receptors: For binding kinetics of clozapine tracer, cells are treated with a 2X detection solution comprising 100-fold dilution of LgBiT (Promega) and 50-fold dilution of furimazine Live Cell Substrate (Promega) in Opti-MEM without phenol red. To determine specific binding, control wells are also treated with a final concentration of 30 pM clozapine. Plates are mixed for 15 minutes prior to the addition of serially diluted clozapine tracer. Following brief mixing kinetic reads are immediately collected on a GloMax Discover Microplate Reader (Promega). For binding kinetics of an unmodified ligand, as described above, cells are first treated with a 2X detection solution and control wells are additionally treated with excess clozapine. Following 15 minutes incubation, cells are treated with serially diluted unmodified ligand and a fixed EC80 concentration of clozapine tracer. Following brief mixing, kinetic measurements are immediately collected on a GloMax Discover Microplate Reader (Promega).

[370] Data analysis: Software, such as GraphPad Prism, is used to derive saturation KD values from a “one site-binding” fitting and competition IC50 values from a “log(inhibitor) vs. response-variable slope” fitting. The IC50 values are then used to derive binding affinities for unmodified ligands (Ki) according to the Cheng-Prusoff equation, Ki = IC50 / (1 + [L] / KD), where [L] is the concentration of the fluorescent ligand in the assay and KD is its affinity in a saturation binding experiment (Cheng & Prusoff, op. cit.).

[371] Kinetic analysis for the fluorescent tracer is graphed using the association kinetics-two or more concentrations of hot fit. Kinetic constants (k_on and k_Off) and binding constant (KD) for the fluorescent tracer are determined from the resulting curves (Tummino et al., Biochemistry-US., 2008:47(20):5481 -5492). Kinetic analyses for unmodified compounds are graphed using the kinetics of competitive binding fit (Motulsky-Mahan model for kinetics of competitive binding) (Motulsky and Mahan, Mol Pharmacol., 1984;25(1 ):1 -9).

[372] Results: Binding affinity and other kinetic constants are determined for compounds at 5-HT receptors.

Example 2: 5-HT Receptor Functional Assay

[373] Purpose: Determining the functional activity of compounds at 5-HTIA and 5-HT2A, 2B, and 2c receptors.

[374] Methods: A stably expressing 5-HT2 receptor, such as Flp-ln 293 T-Rex Tetracycline inducible system (Invitrogen, mycoplasma-free), is used for calcium flux assays, as described and utilized previously (Klein 2021). Cell lines are maintained in DMEM containing 10% FBS, 10 pg/mL Blasticidin (Invivogen), and 100 pg/mL Hygromycin B (GoldBio). The day before the assay, receptor expression is induced with tetracycline (2 pL/mL) and seeded into 384-well poly-L-lysine-coated black plates at a density of 7500 cells/well in DMEM containing 1 % dialyzed FBS. On the day of the assay, the cells are incubated with Fluo-4 Direct dye (Invitrogen, 20 pl/well) for 1 h at 37°C, which is reconstituted in drug buffer (20 mM HEPES-buffered HBSS, pH 7.4) containing 2.5 mM probenecid. After dye load, cells are allowed to equilibrate to room temperature for 15 minutes, and then placed in a FLIPRTETRA fluorescence imaging plate reader (Molecular Devices). Drug dilutions are prepared at 5X final concentration in drug buffer (20 mM HEPES-buffered HBSS, pH 7.4) supplemented with 0.3% BSA fattyacid free and 0.03% ascorbic acid. Drug dilutions are aliquoted into 384-well plastic plates and placed in the FLIPRTETRA for drug stimulation. Fluorescence reads are programmed to record baseline fluorescence for 10 s (1 read/s), and afterward 5 pl of drug per well is added and read for a total of 2 min (1 read/s). Fluorescence in each well is normalized to the average of the first 10 reads for baseline fluorescence, and maximum-fold peak increase is calculated. Peak is plotted as a function of drug concentration, and data are normalized to percent 5-HT stimulation. For antagonist mode, plates are challenged with 3.2 nM 5-HT to measure calcium flux blockade response. Data are plotted and non-linear regression is performed using “log(agonist) vs. response” in GraphPad Prism 9 to yield Emax and ECso parameter estimates.

[375] Results: Functional activity of compounds at the 5-HTIA and 5-HT2A, 2B, and 2c receptors is determined, which indicates if compounds are agonists or antagonists, and provides insight into therapeutic applications.

Example 3: Effects of Compounds on Na_v1.1 -generated Sodium Current

[376] Purpose: Sodium currents (Ina) generated by human voltage-gated sodium channel (VGSC) Na_v1 .1 a subunits co-expressed with Na_vpi subunits in human embryonic kidney (HEK) cells are observed to determine the acute effects of disclosed compounds.

[377] Methods: Cell culture: Cells are cultured in Dulbecco’s Modified Eagle Medium containing (4.5 g/L D- glucose, L-glutamine, 110 mg/L sodium pyruvate, 200 pg/mL G418, 100 U/mL penicillin/streptomycin). All cells are maintained in an incubator at 37°C with 5% CO2.

[378] Manual Sodium Current Recording: Sodium current (INS) is measured at room temperature using the manual whole-cell patch clamp technique with previously described electrophysiological methods (Chen et al. J Biol Chem. 2012;287(46):39061-39069). Cells are plated on 12 mm diameter clear glass poly-D-lysine coated coverslips (Neuvitro) and used for electrophysiological recordings within 48 hours after plating. Cells are identified with an A1 R upright confocal microscope (Nikon). Micropipettes are obtained from 1.5 mm outer diameter capillary glass tubing (Harvard Apparatus) using a P-97 horizontal puller (Sutter Instrument Co.). Micropipettes are then polished using a MF-830 micro forge (Narishige) to obtain a resistance between 2.0 to 5.0 MQ. The intracellular solution contains the following (in mM): 1 NaCI, 125 N-methyl-D-glucamine, 2 MgCI2, 10 EGTA, 40 HEPES, 5 phosphocreatine-tris, 2 Mg-ATP, 0.2 Na2-GTP, 0.1 leupeptin, 270-275 mOsm, pH 7.2 with H2SO4. Extracellular solution contains the following (in mM): 120 NaCI, 1 BaCI2, 2 MgCI2, 0.2 CdCI2, 1 CaCI2, 20 sucrose, 10 glucose, 10 HEPES, 10 tetraethylammonium chloride, 300-305 mOsm, pH 7.35 with NaOH. Signals are amplified using a Multiclamp 700B amplifier (Molecular Devices).

[379] Data are acquired with a Digidata 1440A interface (Molecular Devices) and analyzed using pCIampI O offline. Pipette and whole-cell capacitance are fully compensated, and series resistance is predicted and compensated at 50%. Signals are low pass-filtered at 10 kHz, and data are sampled at 20 kHz. Residual linear capacity and leak currents are eliminated using online P/4 subtraction. Gravity-powered perfusion of disclosed compounds is used in all manual patch clamp experiments with a flow rate of 2-3 mL/min. All manual whole-cell I Na recorded under test compound conditions is conducted after 3.9 mins of perfusion unless indicated otherwise.

[380] Automated Sodium Current Recording (SyncroPatch): Automated whole cell sodium current recordings are conducted on the SyncroPatch 384, housed in the University of Michigan Center for Chemical Genomics, according to Nanion’s standard procedures. Single-hole medium resistance chips are used. Immediately prior to recording, HEK 293 cells are dissociated with TryplE, quantified with an automated cell counter (Nano EnTek) and resuspended in extracellular solution at a concentration of 800 thousand cells per mL. Extracellular solution contains the following (in mM): 140 NaCI, 4 KCI, 2 CaCh, 1 MgCh, 5 glucose, 10 HEPES, 298 mOsm. pH 7.4 with NaOH. Intracellular solution contains the following (in mM): 110 KF, 10 NaCI, 10 KCI, 10 EGTA, 10 HEPES, 285 mOsm, pH 7.2 with KOH. Currents are digitized at 20 kHz and lowpass filtered at 5 kHz. Series resistance is automatically compensated. Currents are leak subtracted using the leak correction method implemented in PatchControl384 with 1 or 2 square pulses stepping from the holding potential of -80 mV to -60 mV for 10 ms. The combined l-V protocol used to examine activation and inactivation is sampled at 10 kHz and lowpass filtered at 5 kHz. To determine the I Na amplitude and the voltage dependence of activation, IN_S is evoked from a holding potential of -80 mV to -120 mV for 500 ms followed by a pre-step to -10 mV for 50 ms. The membrane is hyperpolarized back to -120 mV for 500 ms before a 500 ms test pulse ranging from -120 mV to +30 mV (in 5 mV increments). Immediately following the test pulse, the voltage-dependence of inactivation is determined by stepping to -10 mV for 50 ms from the same voltages as described for the voltage dependence of activation. SyncroPatch quality control criteria for the l-V protocol are set to capacitance <35 pF, peak IN_S more negative than -200 pA, series resistance between 1 and 35 MQ, and seal resistance> 200 MQ. Peak IN_S is normalized to cell capacitance to obtain current density, used to plot l-V curves and calculate conductance with the equation g = I / (V - Vrev), where g is conductance, I is current, V is the test potential, and V_rev is the measured reversal potential. Peak currents are normalized to the maximum peak IN_S amplitude. The V1/2 of activation represents the voltage of the membrane at which half-maximal peak IN_S amplitude occurs. Normalized voltage-dependence of activation and inactivation curves are fit with the Boltzmann equation, 1 / (1 + e^A((V - V1/2) / k)).

[381] where V 2 is the membrane potential in the midpoint of the curve, and k is the slope factor. The peak IN_S protocol is sampled at 20 kHz and low pass filtered at 5 kHz. The membrane is brought from the holding potential of -80 mV to -120 mV for 500 ms, then stepped to -10 mV for 500 ms to elicit peak IN_S before returning to -80 mV. The peak IN_S protocol is implemented as a repeating sweep running at 0.1 Hz throughout drug perfusion to monitor compound effects over 42 sweeps. Normalized peak IN_S inhibition is calculated using the equation Peak INa Density Inhibition = 1 - (Ldrug / Lreference).

[382] Where Reference is the average peak IN_S density elicited from the first 10 sweeps under perfusion of the Nanion standard external (reference) solution, and hrug is the average peak IN_S density elicited during the last 10 sweeps after 3.5 minutes of vehicle, TTX or disclosed compound perfusion. The quality control settings for the peak INa protocol are the same as the l-V protocol except the cell capacitance is <30 pF. To obtain the disclosed compound concentration response curve, the normalized peak IN_S density inhibition data is fit with nonlinear regression using the four-parameter variable slope inhibitor vs response equation in GraphPad Prism. The data point for 1 pM of disclosed compound is set equivalent to the vehicle response and 1 mM of disclosed compound is set equivalent to the response of 1 pM TTX.

[383] Results: Results show that compounds decrease peak INA density and hyperpolarize the voltagedependence of INA fast inactivation; and that compounds inhibit INA generated by hNavl .1 + hpi in HEK cells. Targeted sequencing of large patient populations has implicated voltage-gated sodium channels in the pathophysiology of schizophrenia. Accordingly, compounds have therapeutic value as antipsychotic drugs.

Example 4: Effects of Compounds on Neuronal Excitability

[384] Purpose: Patch clamp electrophysiology is utilized to test the acute effects of disclosed compounds on neuronal excitability in mouse cortical brain slices.

[385] Methods: Animals: Wildtype C57BL/6J mice are obtained from the Jackson Labs. Male and female pups, age postnatal day (P) 17-23, are used for electrophysiological experiments, in accordance with NIH procedures.

[386] Brain Slice Preparation: Acute brain slices are prepared as described in Hull et al. Ann Clin Transl Neur. 2020;7(11):2137-2149. Briefly, mice are anesthetized with isoflurane anesthesia and decapitated. Brains are carefully removed from the skull and placed in ice-cold carbogen-aerated slice solution containing (in mM): 110 sucrose, 62.5 NaCI, 2.5 KCI, 6 MgCh, 1.25 KH2PO4, 26 NaHCC , 0.5 CaCh, 20 D-glucose, pH 7.35-7.40. Brains are blocked and slices are cut using a vibrating microtome (Electron Microscopy Sciences) in 250 pm thick coronal sections from the prefrontal cortex. Slices are incubated in an aerated holding chamber containing a slice solution for 30 minutes at room temperature and then incubated in 1 :1 slice:artificial cerebrospinal solution (ACSF) for 30 minutes at 35°C. ACSF contains in mM (125 NaCI; 2.5 KCI; 1 MgCh; 1.25 KH2PO4; 26 NaHCOs; 2 CaCh; and 20 D-glucose (pH 7.35-7.40). Slices are then aerated in a holding chamber containing 100% ACSF for at least 30 min at room temperature before recording.

[387] Action Potential Recording and Analysis: Individual brain slices are placed in an RC-26 recording chamber (Warner Instruments) and superfused with aerated ACSF at a flowrate of 2-3 mL/min equipped with an inline heater (Warner Instruments) to maintain the recording temperature at 33-35°C. Layer 5 pyramidal neurons are identified based on their large soma size, shape, and location using an A1 R upright confocal microscope (Nikon) equipped with IR-DIC optics and a 40X water immersion objective. Only vertically oriented pyramidal cells are selected for recording. Recording electrodes have a resistance of 4-8 MQ with solutions containing (in mM): 140 K-Gluconate, 4 NaCI, 0.5 CaCI2, 10 HEPES, 5 EGTA, 5 phosphocreatine, 2 Mg-ATP, and 0.4 GTP (pH 7.2-7.3 with KOH). The junction potential is calculated using the P-clamp junction potential calculator and all values presented in the study are uncorrected. Following break in at -94.3 mV in voltage clamp mode, the resting membrane potential is defined as the membrane potential in current clamp <10 s after initial break in for baseline or immediately after perfusion of test compound. Repetitive action potential firing is elicited in wholecell current clamp from the resting membrane potential in 1 s long current injections in 10 pA steps from -20 pA to +400 pA. There is a 1 s long 0 pA current injection between each sweep. Data are acquired at 20 kHz and are filtered at 10 kHz. Cells with an access resistance measured in voltage clamp >20 MQ or RMP more depolarized than -64.3 mV are not used. Access resistance and pipette capacitance are compensated using bridge balance. Whole cell capacitance is measured using P-clamp whole cell capacitance compensation in voltage clamp with 10 mV depolarizing steps from -94.3 mV. Automated action potential (AP) quantification and analysis is performed using custom MATLAB (MathWorks) software. APs are defined as the voltage crossing 0 mV after a dV/dt >10 mV/ms, defined here as the AP threshold. Input resistance is calculated using Ohm’s law with a -10 pA current injection from the resting membrane potential after 250 ms.

[388] Results: Disclosed compounds will reduce one or more of: maximum AP firing frequency, AP peak amplitude, rates of AP depolarization and repolarization (dV/dt), and depolarization of the resting membrane potential and AP threshold of mouse PDF layer V pyramidal neurons in brain slices.

Example 5: Assessing In Vitro Pharmacological Activity of Disclosed Compounds

[389] Purpose: A receptor screen is performed to characterize the binding profiles and functional activity of disclosed compounds at various receptors, channels, and transporters. The results will facilitate comparisons to unsubstituted tryptamines and lysergamides (e.g., lacking an N-linked side chain) and other psychedelics. The data support the primary exosite hypothesis, and structure activity analyses of the data confirm drug design.

[390] Methods: Disclosed compounds are synthesized and submitted to the Psychoactive Drug Screening Program (PDSP) sponsored by NIMH, and evaluated at 45 receptor and transporter binding sites. Screenings are performed with cloned human receptors, with some exceptions (see, e.g., Cozzi and Daley, Bioorg Med Chem Lett. 2016;26(3):959-964; Klein et al., Neuropharmacol, 2018;142:231-239).

[391] Briefly, test compounds are dissolved in DMSO and tested at 10 mM in competition assays against radioactive probe compounds. Sites exhibiting > 50% inhibition at 10 mM are tested in secondary assays at the identified receptor or transporter using 12 concentrations of the test compound, measured in triplicate, to generate competition binding isotherms. Ki values are obtained from nonlinear regression of the binding isotherms from best-fit IC50 values using the Cheng-Prusoff equation (Cheng & Prusoff, op. cit.). For purposes of data analysis and comparison, K, values are converted to p Ki (-log Ki) values.

[392] Binding assays are performed using the following radioligands: [³H]8-OH-DPAT (5-HTi A), [³H]G R 125743 (5-HTIB/ID), [³H]5-HT (5-HTIE), [³H]ketanserin (5-HT₂A), [³H]LSD (5-HT₂A/2B/6/7), [³H]mesulergine (5-HT₂c), [³H]citalopram (serotonin transporter), [³H]prazocin (a1 A/1 B/1 D), [³H]rauwolscine (a2, 5-HT₂A/2B), [¹²⁵l]pindolol (b1), [³H]CGP12177 (b2, b3), [³H] nisoxetine (norepinephrine transporter), [³H]SCH23390 (D1 , D5), I[³H]N- methylspiperone (D2/3/4), [³H]WIN35428 (dopamine transporter), [³H]DAMGO (p-opioid), [³H]DADLE (5-opioid), [³H]U69593 (K-opioid), [³H]muscimol (GABAA), [³H]funitrazepam (central benzodiazepine), [³H]PK11195 (peripheral benzodiazepine), [³H]pyrilamine (H1), [³H]tiotidine (H2), [3H]a-methyl-histamine (H3), [³H]histamine (H4), [³H]QNB (M1e5), [³H](|o)-pentazocine (s1), and [³H]DTG (s2).

[393] Experimental protocols are available from the NIMH PDSP website, e.g., ‘Assay Protocol Book, Version III, March 2018, Bryan L. Roth, MD, PhD.” Briefly, both primary and secondary radioligand binding assays are carried out in appropriate binding buffers. The hot ligand concentration is comparable to the Kd. Total binding and nonspecific binding are determined in the absence and presence of 10 pM of the appropriate reference compound, respectively. Plates are incubated at room temperature and in the dark for 90 min. Reactions are stopped by vacuum filtration onto 0.3% polyethyleneimine (PEI) soaked 96-well filter mats using a 96-well Filtermate harvester, followed by three washes with cold wash buffers. Scintillation cocktail is then melted onto the microwave-dried filters on a hot plate and radioactivity is counted in a Microbeta counter.

[394] Results: Compounds show affinity for the 5-HT2A based on the head groups of the psychedelic compound component. Binding affinity and efficacy is altered if the side chain interacts with the 5-HT2A exosite.

Example 6: Metabolic Stability

[395] Purpose: To determine the metabolic stability of disclosed compounds. Metabolic stability assays measure the intrinsic clearance (CLmt) of a compound, providing data that can be used to calculate other key pharmacokinetic parameters such as bioavailability and half-life (ti/2).

[396] Methods: A high-throughput assay is used to determine metabolic stability of compounds in various matrices, including human liver microsomes, using LCMS analysis to quantify the percent compound remaining after incubation. Briefly, the disclosed compound is mixed with liver microsomes and activated. Following this incubation, acetonitrile is added to terminate the reaction. Samples are centrifuged and the supernatant is dried. The residue is reconstituted and analyzed using liquid chromatography-mass spectrometry. Pharmacokinetic parameters are calculated using a noncompartmental model. The half-life (ti/2) is estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) versus time, assuming first order kinetics.

[397] Results & Significance: Compounds have altered clearance and half-life relative to a comparator, such as a corresponding unsubstituted tryptamine or lysergamide (i.e., lacking an N-linked side chain). Such features provide advantages, such as an increased or reduced duration of action, that facilitate use in disclosed methods.

Example 7: In Vitro Metabolic Profiling

[398] Purpose: To determine whether disclosed compounds are metabolized and to identify metabolites.

[399] Methods: An in vitro study is conducted to evaluate metabolism and metabolites of compounds in human liver microsomes, such as S9 hepatocytes. Briefly, compounds are incubated with human liver microsomes and/or various recombinant enzymes to determine metabolism and formation of metabolites. Following incubation, supernatant is analyzed directly by UHPLC-MS. Phase I and/or Phase II metabolites are identified using MS. The % compound remaining and half-life of the disclosed compound (parent compound) are determined. MS data, such as extracted ion chromatograms, show parent and major metabolites. Metabolic transformation for each observed metabolite is elucidated, and metabolite masses, peak areas, and retention times are determined. Metabolic profiling is conducted according to the methods described in Muller & Rentsch. Anal Bioanal Chem. 2012;402:2141-2151, and Pedersen et al. Drug Metab Dispos. 2013;41 :1247-1255.

[400] Results & Significance: Compounds that undergo metabolism in vivo produce pharmacologically active or chemically reactive metabolites that produce unexpected effects or potential toxicities. The FDA Guidance for Industry on Safety Testing of Drug Metabolites highlights the relevance of in vitro metabolite profiling early in drug development, as metabolites which are unique to or disproportionate in humans may require additional toxicological studies. No pharmacologically active or chemically reactive metabolites are identified.

Example 8: In Vitro CYP Enzyme Inhibition

[401] Purpose: To assess the interactions between compounds and cytochrome P450 enzymes. Such interactions provide insight into metabolism-mediated drug-drug interactions, which can occur when a compound affects the pharmacokinetics, such as the absorption, distribution, metabolism, and excretion, of simultaneously administered drugs by altering the activities of drug metabolizing enzymes and/or drug transporters.

[402] Methods: An in vitro study is conducted to assess the inhibitory effect of the disclosed compound on recombinant human CYP450 isoenzymes. Recombinant human CYP450 isoenzymes are used to metabolize pro-fluorescent probe substrates to fluorescent products. Inhibition of human P450 isoforms is measured by reduced fluorescence following treatment with the disclosed compound at various concentrations.

[403] Briefly, a disclosed compound is incubated in different concentrations in a mix containing buffer, enzymes, and substrate. Then, fluorescence is measured using a plate reader and percentage inhibition may be extrapolated out from the readings. Alternatively, the inhibitory effects of the disclosed compound on CYP enzymes may be assessed using high-performance liquid chromatography. Inhibition is evaluated using the Michaelis-Menten method. CYP enzyme inhibition may be conducted according to the methods described in Lin et al. J Pharm Sci. 2007;96(9):2485-95 and Wojcikowski et al. Pharmacol Rep. 2020;72(3):612-621.

[404] Results & Significance: Metabolizing enzymes in the liver, such as CYP450 enzymes, are responsible for the majority of drug metabolism that occurs in the body. Six CYP450 class enzymes metabolize 90 percent of drugs, and two of the most significant metabolizers are CYP3A4 and CYP2D6 (Lynch and Price. Am Fam Physician. 2007; 76(3): 391 -6). Compounds can interact with such enzymes by inhibiting their enzymatic activity (CYP inhibition) or by inducing their gene expression (CYP induction).

Example 9: In vitro evaluation of membrane permeability and interactions with P-glycoprotein

[405] Purpose: To assess the permeability and transport liability of compounds. Permeability is assessed using MDCK cells, and the effects of P-glycoprotein (P-gp) are evaluated to determine drug transport.

[406] Methods: A bidirectional permeability study (apical to basolateral [AB] and basolateral to apical [BA]) is conducted to evaluate the apparent permeability of the compounds. Additionally, an evaluation to determine if the compounds act as a P-gp substrate in MDCKII-MDR1 and mock MDCKII cell lines is performed.

[407] Briefly, disclosed compounds and reference compounds are evaluated in two directions in the absence and presence of a P-gp inhibitor. The MDCKII and MDCKII-MDR1 cells are incubated in a transport buffer on both apical [A] and basolateral [B] sides. Then, the disclosed compounds are added to each side of the cells and incubated. The rate of transport of the disclosed compounds is determined in the absence or presence of a P- gp inhibitor. Following incubation, where the disclosed compounds will permeate the cells in both AB and BA directions, the permeability of the cells is measured using a LC MS/MS system. The efflux ratio of the disclosed compounds is calculated to determine if it is a P-gp substrate. LY RFU values are normalized by background mean values. A test item is considered to be a P-gp substrate when the efflux ratio in the absence of the inhibitor is >2 and if the ratio is significantly reduced in the presence of a P-gp inhibitor. Where CD(t) is the measured concentration in the donor well at time t (expressed as IS ratio), CR(t) is the measured concentration in the receiver well at time t (expressed as IS ratio), Co is the initial concentration in the donor solution (expressed as IS ratio). Mass balance as a percentage is calculated with the equation %Recovery = 100 x (CD(t) + CR(t)) / Co. The % of cell integrity is calculated using the equation: %lntegrity = 100 x [1 -RFUbasolateral/RFUapical].

[408] Compounds are classified according to Cambridge MedChem Consulting, ADME, 2019, where a compound with a Papp (nm/s) of >150 is classified as “High Permeability”; with a Papp (nm/s) of 50-150 is classified as “Medium Permeability”; and with a Papp (nm/s) of <50 is classified as “Low Permeability.”

[409] Results & Significance: The movement of the compounds in a biological system is determined.

[410] The foregoing description, for purposes of explanation, uses specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one of skill that specific details are not required in order to practice the invention. Thus, the foregoing description of specific embodiments of the invention is presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise forms disclosed; obviously, many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, through the elucidation of specific examples, and to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated, when such uses are beyond the specific examples disclosed. Accordingly, the scope of the invention shall be defined solely by the following claims and their equivalents.

Claims

The invention claimed is:

1. A compound of Formula (I):

X is 0, S, or NH;

R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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;

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

R^N1 is:

R^N2, if present, is:

R⁹ is H or D; and

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. The compound of claim 1 , wherein

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;

R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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 R^a, R^b, R², R⁴, R⁵, R⁶, and R⁷ are 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;

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

3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R⁴ is 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 R⁵ is C1-C8 alkoxy.

9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R⁵ is 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 R^N is H.

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

15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R^N is 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 R^N is C2-C8 alkenyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R^N is allyl.

18. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isotopic derivative thereof, wherein R^N is 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 isotopic derivative 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 , wherein

and wherein:

R^N1 is:

R^N2 is:

(c) - (CH₂)mX(CH₂)nPh;

R⁹ is H or D;

R⁶ is:

(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.