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WO2025137730A1 - Tryptamines n-substituées et lysergamides n-substitués et leur utilisation comme agents thérapeutiques - Google Patents

Tryptamines n-substituées et lysergamides n-substitués et leur utilisation comme agents thérapeutiques Download PDF

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Publication number
WO2025137730A1
WO2025137730A1 PCT/US2024/061815 US2024061815W WO2025137730A1 WO 2025137730 A1 WO2025137730 A1 WO 2025137730A1 US 2024061815 W US2024061815 W US 2024061815W WO 2025137730 A1 WO2025137730 A1 WO 2025137730A1
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alkyl
aryl
alkoxy
thioalkyl
halogen
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Nicholas V. Cozzi
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Alexander Shulgin Research Institute Inc
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Alexander Shulgin Research Institute Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
    • C07D457/06—Lysergic acid amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • 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.
  • X is 0, S, or NH
  • R 2 , R 12 , R 13 , and R 14 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,
  • R' is H, D, PO3H2, or C(O)-C1-C8 alkyl.
  • R' is H, D, PO3H2, or C(O)-C1-C8 alkyl
  • 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.
  • R N1 is:
  • R’ is H, D, PO 3 H 2 , 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;
  • 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.
  • 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.
  • 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.
  • the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, or transdermal administration.
  • the composition is in unit dosage form.
  • 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.
  • the composition is an immediate release, controlled release, sustained release, extended release, or modified release formulation.
  • 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, RIMAs, tryptamine
  • the medical condition is a disorder linked to dysregulation or inadequate functioning of neurotransmission.
  • the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of monoaminergic neurotransmission.
  • the disorder linked to dysregulation or inadequate functioning of neurotransmission is that of serotonergic neurotransmission.
  • the medical condition is a mental health disorder.
  • 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.
  • schizophrenia schizoaffective disorder, schizotypal disorder, acute and transient
  • the medical condition is a seizure disorder.
  • the seizure disorder is epilepsy.
  • the medical condition is a disorder linked to dysregulation or inadequate functioning of a voltage-gated ion channel.
  • the voltage-gated ion channel is a voltage-gated sodium channel.
  • the compound inhibits the activity of the voltage-gated sodium channel.
  • the mammal has a genetic variation associated with drug metabolism, associated with a mental health disorder, or relating to a membrane transporter.
  • 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.
  • the mammal is a human.
  • methods of improving mental health or functioning in a human 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.
  • methods of improving mental health or functioning in a human comprising identifying a human in need of said improving, and administering to the human a disclosed pharmaceutical composition.
  • “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.
  • 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.
  • 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).
  • 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)NH 2 , or — SONH2.
  • 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.
  • 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.
  • exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.
  • 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 atom
  • Heterocycloalkyl 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— .
  • 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.
  • groups such as aziridine, azetidine, pyrrolidine, pipe
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • An arylamido can be substituted or unsubstituted.
  • 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.
  • An alkylamido can be substituted or unsubstituted.
  • 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.
  • a halogen e.g., a fluorine, a chlorine, a bromine, or an iodine
  • Haloalkyl groups include difluoromethyl (— CHF2), bromofluoromethyl (— CHBrF), trifluoromethyl (— CF3), and 2-fluoroethyl (— CH2CH2F). Additional examples of haloalkyl groups include — CHF2, -CH 2 F, -CH2CF3, - CH2CHF2, - CH2CH2F, -CH(CH 3 )(CF 3 ), -CH(CH 3 )(CHF 2 ), and -CH(CH 3 )(CH 2 F).
  • “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.
  • “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.
  • Trihalomethanesulfonyl refers to an X3CSO2— group wherein each X is a halogen.
  • Carbamoyl includes O-carbamoyl and N-carbamoyl groups.
  • An O-carbamoyl may be substituted or unsubstituted.
  • 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.
  • 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 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).
  • TMDs transmembrane domains
  • 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).
  • a 5-HT2A-binding e.g., 5-HT2A agonist
  • 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
  • a 5-HT2A exosite-binding fragment e.g., an optionally substituted phenyl ring
  • the compounds are substituted tryptamines.
  • the 5-HT2A- binding fragment is a tryptamine.
  • the compounds are substituted tryptamines bearing an N- linked side chain.
  • 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),
  • 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 lysergamides of the disclosure 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.
  • the side chain has the structure of:
  • 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.
  • 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
  • the compound has the structure of Formula (I):
  • 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 — (CH 2 ) m X(CH 2 ) n Ph; and wherein:
  • R a , R b , R 2 , R 4 , R 5 , R 6 , and R 7 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
  • 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 wherein the * indicates the point of connection to — (CH2) m X(CH2) n Ph; and wherein:
  • R N1 is:
  • R N2 if present, is:
  • R 2 , R 12 , R 13 , and R 14 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,
  • R 9 is H or D
  • R 6 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,
  • R a , R b , R 2 , R 4 , R 5 , R 6 , and R 7 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
  • R 2 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, alkylcar
  • R 2 is hydrogen. In embodiments, R 2 is D. In embodiments, R 2 is D. In embodiments, R 2 is halogen. In embodiments, R 2 is F. In embodiments, R 2 is Cl. In embodiments, R 2 is Br. In embodiments, R 2 is I. In embodiments, R 2 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 2 is OH. In embodiments, R 2 is OPO3H2.
  • R 2 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.
  • R 2 is substituted C(O)-C1-C8 alkyl.
  • R 2 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)- CH3. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 2 is unsubstituted C1-C8 alkyl. In embodiments, R 2 is substituted C1-C8 alkyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 2 is unsubstituted C1-C8 alkoxy. In embodiments, R 2 is methoxy. In embodiments, R 2 is substituted C1-C8 alkoxy. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 2 is unsubstituted C1-C8 alkenyl. In embodiments, R 2 is substituted C1-C8 alkenyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 2 is unsubstituted C1-C8 alkynyl. In embodiments, R 2 is substituted C1-C8 alkynyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 2 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 2 is substituted C3-C8 cycloalkyl. In embodiments, R 2 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 2 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 2 is substituted C3-C8 cycloalkenyl. In embodiments, R 2 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.
  • R 2 is substituted C3-C8 heterocycloalkyl. In embodiments, R 2 is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R 2 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 2 is substituted C3-C8 heterocycloalkenyl. In embodiments, R 2 is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R 2 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 2 is unsubstituted C6-C10 aryl. In embodiments, R 2 is substituted C6-C10 aryl. In embodiments, R 2 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, R 2 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 2 is substituted 6-10 membered heteroaryl.
  • R 4 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, alkylcar
  • R 4 is hydrogen. In embodiments, R 4 is D. In embodiments, R 4 is halogen. In embodiments, R 4 is F. In embodiments, R 4 is Cl. In embodiments, R 4 is Br. In embodiments, R 4 is I. In embodiments, R 4 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 4 is OH. In embodiments, R 4 is OPO3H2.
  • R 4 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.
  • R 4 is substituted C(O)-C1- C8 alkyl.
  • R 4 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 4 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 4 is unsubstituted C1-C8 alkyl. In embodiments, R 4 is substituted C1-C8 alkyl. In embodiments, R 4 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 4 is unsubstituted C1-C8 alkoxy. In embodiments, R 4 is methoxy. In embodiments, R 4 is substituted C1-C8 alkoxy. In embodiments, R 4 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 4 is unsubstituted C1-C8 alkenyl. In embodiments, R 4 is substituted C1-C8 alkenyl. In embodiments, R 4 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 4 is unsubstituted C1-C8 alkynyl. In embodiments, R 4 is substituted C1-C8 alkynyl. In embodiments, R 4 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.
  • R 4 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 4 is substituted C3-C8 cycloalkyl. In embodiments, R 4 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 4 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 4 is substituted C3-C8 cycloalkenyl. In embodiments, R 4 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.
  • R 4 is substituted C3-C8 heterocycloalkyl. In embodiments, R 4 is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R 4 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 4 is substituted C3-C8 heterocycloalkenyl. In embodiments, R 4 is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R 4 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 4 is unsubstituted C6-C10 aryl. In embodiments, R 4 is substituted C6-C10 aryl. In embodiments, R 4 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, R 4 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 4 is substituted 6-10 membered heteroaryl.
  • R 5 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, alkylcar
  • R 5 is hydrogen. In embodiments, R 5 is D. In embodiments, R 5 is halogen. In embodiments, R 5 is F. In embodiments, R 5 is Cl. In embodiments, R 5 is Br. In embodiments, R 5 is I. In embodiments, R 5 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 5 is OH. In embodiments, R 5 is OPO3H2.
  • R 5 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.
  • R 5 is substituted C(O)-C1- C8 alkyl.
  • R 5 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 5 is unsubstituted C1-C8 alkyl. In embodiments, R 5 is substituted C1-C8 alkyl. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 5 is unsubstituted C1-C8 alkoxy. In embodiments, R 5 is methoxy. In embodiments, R 5 is substituted C1-C8 alkoxy. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 5 is unsubstituted C1-C8 alkenyl. In embodiments, R 5 is substituted C1-C8 alkenyl. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 5 is unsubstituted C1-C8 alkynyl. In embodiments, R 5 is substituted C1-C8 alkynyl. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 5 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 5 is substituted C3-C8 cycloalkyl. In embodiments, R 5 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 5 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 5 is substituted C3-C8 cycloalkenyl. In embodiments, R 5 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.
  • R 5 is substituted C3-C8 heterocycloalkyl. In embodiments, R 5 is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R 5 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 5 is substituted C3-C8 heterocycloalkenyl. In embodiments, R 5 is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R 5 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 6 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, alkylcar
  • R 6 is hydrogen. In embodiments, R 6 is D. In embodiments, R 6 is halogen. In embodiments, R 6 is F. In embodiments, R 6 is Cl. In embodiments, R 6 is Br. In embodiments, R 6 is I. In embodiments, R 6 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 6 is OH. In embodiments, R 6 is OPO3H2.
  • R 6 is unsubstituted C1-C8 alkyl. In embodiments, R 6 is substituted C1-C8 alkyl. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 6 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 6 is substituted C3-C8 cycloalkyl. In embodiments, R 6 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 6 is substituted C3-C8 heterocycloalkyl. In embodiments, R 6 is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R 6 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 6 is unsubstituted C6-C10 aryl. In embodiments, R 6 is substituted C6-C10 aryl. In embodiments, R 6 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, R 6 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 6 is substituted 6-10 membered heteroaryl.
  • R 7 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, alkylcar
  • R 7 is hydrogen. In embodiments, R 7 is D. In embodiments, R 7 is halogen. In embodiments, R 7 is F. In embodiments, R 7 is Cl. In embodiments, R 7 is Br. In embodiments, R 7 is I. In embodiments, R 7 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 7 is OH. In embodiments, R 7 is OPO3H2.
  • R 7 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.
  • R 7 is substituted C(O)-C1- C8 alkyl.
  • R 7 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 7 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 7 is unsubstituted C1-C8 alkyl. In embodiments, R 7 is substituted C1-C8 alkyl. In embodiments, R 7 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 7 is unsubstituted C1-C8 alkoxy. In embodiments, R 7 is methoxy. In embodiments, R 7 is substituted C1-C8 alkoxy. In embodiments, R 7 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 7 is unsubstituted C1-C8 alkenyl. In embodiments, R 7 is substituted C1-C8 alkenyl. In embodiments, R 7 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 7 is unsubstituted C1-C8 alkynyl. In embodiments, R 7 is substituted C1-C8 alkynyl. In embodiments, R 7 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 7 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 7 is substituted C3-C8 cycloalkyl. In embodiments, R 7 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 7 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 7 is substituted C3-C8 cycloalkenyl. In embodiments, R 7 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.
  • R 7 is substituted C3-C8 heterocycloalkyl. In embodiments, R 7 is unsubstituted C3-C8 heterocycloalkyl. In embodiments, R 7 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 7 is substituted C3-C8 heterocycloalkenyl. In embodiments, R 7 is unsubstituted C3-C8 heterocycloalkenyl. In embodiments, R 7 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 7 is unsubstituted C6-C10 aryl. In embodiments, R 7 is substituted C6-C10 aryl. In embodiments, R 7 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, R 7 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 7 is substituted 6-10 membered heteroaryl.
  • R N H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl.
  • R N is H.
  • R N is D.
  • R N is C1-C8 alkyl.
  • R N is methyl.
  • R N is ethyl.
  • R N is n-propyl.
  • R N is isopropyl.
  • R N is butyl.
  • R N is n-butyl.
  • 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.
  • 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.
  • Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.
  • 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.
  • Ph is phenyl substituted by halogen.
  • Ph is phenyl substituted by D.
  • 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.
  • 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.
  • 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.
  • the compound has the structure 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.
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4.
  • m is 5.
  • m is 6.
  • m is 7.
  • m is 8.
  • m is 9.
  • m is 10.
  • m is 11.
  • m is 12.
  • m is 13.
  • n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5.
  • 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.
  • 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.
  • X is 0, S, or NH. In embodiments, X is 0. In embodiments, X is S. In embodiments, X is NH.
  • R N H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl.
  • R N is H.
  • R N is C1-C8 alkyl.
  • R N is methyl.
  • R N is ethyl.
  • R N is n-propyl.
  • R N is isopropyl.
  • R N is butyl.
  • R N is n-butyl.
  • 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.
  • 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.
  • Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.
  • 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.
  • Ph is phenyl substituted by halogen.
  • Ph is phenyl substituted by D.
  • 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.
  • 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.
  • 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:
  • the compound has the structure 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.
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4.
  • m is 5.
  • m is 6.
  • m is 7.
  • m is 8.
  • m is 9.
  • m is 10.
  • m is 11.
  • m is 12.
  • m is 13.
  • n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5.
  • 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.
  • 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.
  • R 4 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, alkyl
  • R 4 is hydrogen. In embodiments, R 4 is D. In embodiments, R 4 is halogen. In embodiments, R 4 is F. In embodiments, R 4 is Cl. In embodiments, R 4 is Br. In embodiments, R 4 is I. In embodiments, R 4 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 4 is OH. In embodiments, R 4 is OPO3H2.
  • R 4 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.
  • R 4 is substituted C(O)-C1- C8 alkyl.
  • R 4 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 4 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 4 is unsubstituted C1-C8 alkyl. In embodiments, R 4 is substituted C1-C8 alkyl. In embodiments, R 4 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 4 is unsubstituted C1-C8 alkoxy. In embodiments, R 4 is methoxy. In embodiments, R 4 is substituted C1-C8 alkoxy. In embodiments, R 4 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 4 is unsubstituted C1-C8 alkenyl. In embodiments, R 4 is substituted C1-C8 alkenyl. In embodiments, R 4 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 4 is unsubstituted C1-C8 alkynyl. In embodiments, R 4 is substituted C1-C8 alkynyl. In embodiments, R 4 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.
  • R 4 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 4 is substituted C3-C8 cycloalkyl. In embodiments, R 4 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 4 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 4 is substituted C3-C8 cycloalkenyl. In embodiments, R 4 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R N H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl.
  • R N is H.
  • R N is D.
  • R N is C1-C8 alkyl.
  • R N is methyl.
  • R N is ethyl.
  • R N is n-propyl.
  • R N is isopropyl.
  • R N is butyl.
  • R N is n-butyl.
  • 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.
  • 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.
  • Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.
  • 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.
  • Ph is phenyl substituted by halogen.
  • Ph is phenyl substituted by D.
  • 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.
  • 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.
  • 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.
  • the compound is selected from Table 3:
  • the compound has the structure 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.
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4.
  • m is 5.
  • m is 6.
  • m is 7.
  • m is 8.
  • m is 9.
  • m is 10.
  • m is 11.
  • m is 12.
  • m is 13.
  • n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5.
  • 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.
  • 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.
  • X is 0, S, or NH. In embodiments, X is O. In embodiments, X is S. In embodiments, X is NH.
  • R 5 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, alkylcar
  • R 5 is hydrogen. In embodiments, R 5 is D. In embodiments, R 5 is halogen. In embodiments, R 5 is F. In embodiments, R 5 is Cl. In embodiments, R 5 is Br. In embodiments, R 5 is I. In embodiments, R 5 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 5 is OH. In embodiments, R 5 is OPO3H2.
  • R 5 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.
  • R 5 is substituted C(O)-C1- C8 alkyl.
  • R 5 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 5 is unsubstituted C1-C8 alkyl. In embodiments, R 5 is substituted C1-C8 alkyl. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 5 is unsubstituted C1-C8 alkoxy. In embodiments, R 5 is methoxy. In embodiments, R 5 is substituted C1-C8 alkoxy. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 5 is unsubstituted C1-C8 alkenyl. In embodiments, R 5 is substituted C1-C8 alkenyl. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 5 is unsubstituted C1-C8 alkynyl. In embodiments, R 5 is substituted C1-C8 alkynyl. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 5 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 5 is substituted C3- C8 cycloalkyl. In embodiments, R 5 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 5 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 5 is substituted C3-C8 cycloalkenyl. In embodiments, R 5 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 5 is unsubstituted C6-C10 aryl. In embodiments, R 5 is substituted C6-C10 aryl. In embodiments, R 5 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 5 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 5 is substituted 6-10 membered heteroaryl.
  • R N H, D, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkylene— C3-C8 cycloalkyl, C2-C8 alkenyl, or C2-C8 alkynyl.
  • R N is H.
  • R N is D.
  • R N is C1-C8 alkyl.
  • R N is methyl.
  • R N is ethyl.
  • R N is n-propyl.
  • 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.
  • 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.
  • 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.
  • Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.
  • 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.
  • Ph is phenyl substituted by halogen.
  • Ph is phenyl substituted by D.
  • 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.
  • 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.
  • 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.
  • the compound is selected from Table 4: Table 4.
  • Exemplary Compounds of Formula (IIC) is selected from Table 4: Table 4.
  • the compound has the structure of Formula (III): wherein:
  • R N1 is:
  • R N2 is:
  • R 2 , R 12 , R 13 , and R 14 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,
  • R 9 is H or D; R 6 is:
  • 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.
  • 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.
  • 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.
  • 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.
  • halogen D
  • alkyl, alkyl ester hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulf
  • 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.
  • halogen D
  • alkyl, alkyl ester hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl
  • 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.
  • 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.
  • halogen D
  • alkyl, alkyl ester hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl,
  • 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
  • R N2 is (CH2) m X(CH2) n Ph, 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.
  • R N2 or R 6 is (CH2) m X(CH2) n Ph
  • m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14.
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4.
  • m is 5.
  • m is 6.
  • m is 7.
  • m is 8.
  • m is 9.
  • m is 10.
  • m is 11.
  • m is 12.
  • m is 13.
  • n is 1. In embodiments, n is 2.
  • 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.
  • 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.
  • X is 0, S, or NH. In embodiments, X is 0. In embodiments, X is S. In embodiments, X is NH.
  • R N2 or R 6 is (CH2) m X(CH2) n Ph
  • 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.
  • Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.
  • 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.
  • Ph is phenyl substituted by halogen.
  • Ph is phenyl substituted by D.
  • 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.
  • 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.
  • 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.
  • R 2 , R 12 , R 13 , and R 14 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
  • R 2 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
  • R 2 is hydrogen. In embodiments, R 2 is D. In embodiments, R 2 is D. In embodiments, R 2 is halogen. In embodiments, R 2 is F. In embodiments, R 2 is Cl. In embodiments, R 2 is Br. In embodiments, R 2 is I. In embodiments, R 2 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 2 is OH. In embodiments, R 2 is OPO3H2.
  • R 2 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.
  • R 2 is substituted C(O)-C1-C8 alkyl.
  • R 2 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 2 is unsubstituted C1-C8 alkyl. In embodiments, R 2 is substituted C1- C8 alkyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 2 is unsubstituted C1-C8 alkoxy. In embodiments, R 2 is methoxy. In embodiments, R 2 is substituted C1-C8 alkoxy. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 2 is unsubstituted C1-C8 alkenyl. In embodiments, R 2 is substituted C1-C8 alkenyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 2 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 2 is substituted C3-C8 cycloalkyl. In embodiments, R 2 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 12 is hydrogen. In embodiments, R 12 is D. In embodiments, R 12 is halogen. In embodiments, R 12 is F. In embodiments, R 12 is Cl. In embodiments, R 12 is Br. In embodiments, R 4 is I. In embodiments, R 4 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 12 is OH. In embodiments, R 12 is OPO3H2.
  • R 12 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.
  • R 12 is substituted C(O)-C1-C8 alkyl.
  • R 12 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 12 is unsubstituted C1-C8 alkyl. In embodiments, R 12 is substituted C1- C8 alkyl. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 12 is unsubstituted C1-C8 alkoxy. In embodiments, R 12 is methoxy. In embodiments, R 12 is substituted C1-C8 alkoxy. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 12 is unsubstituted C1-C8 alkenyl. In embodiments, R 12 is substituted C1-C8 alkenyl. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 12 is unsubstituted C1-C8 alkynyl. In embodiments, R 12 is substituted C1-C8 alkynyl. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 12 is unsubstituted C3- C8 cycloalkyl. In embodiments, R 12 is substituted C3-C8 cycloalkyl. In embodiments, R 12 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 12 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 12 is substituted C3-C8 cycloalkenyl. In embodiments, R 12 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 12 is unsubstituted C6-C10 aryl. In embodiments, R 12 is substituted C6-C10 aryl. In embodiments, R 12 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, R 12 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 12 is substituted 6-10 membered heteroaryl.
  • R 13 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
  • R 13 is unsubstituted C1-C8 alkyl. In embodiments, R 13 is substituted C1- C8 alkyl. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 13 is unsubstituted C1-C8 alkenyl. In embodiments, R 13 is substituted C1-C8 alkenyl. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 13 is unsubstituted C3- C8 cycloalkyl. In embodiments, R 13 is substituted C3-C8 cycloalkyl. In embodiments, R 13 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 13 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 13 is substituted C3-C8 cycloalkenyl. In embodiments, R 13 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 13 is unsubstituted C6-C10 aryl. In embodiments, R 13 is substituted C6-C10 aryl. In embodiments, R 13 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, R 13 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 13 is substituted 6-10 membered heteroaryl.
  • R 14 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
  • R 14 is hydrogen. In embodiments, R 14 is D. In embodiments, R 14 is halogen. In embodiments, R 14 is F. In embodiments, R 14 is Cl. In embodiments, R 14 is Br. In embodiments, R 14 is I. In embodiments, R 14 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 14 is OH. In embodiments, R 14 is OPO3H2.
  • R 14 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.
  • R 14 is substituted C(O)-C1-C8 alkyl.
  • R 14 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 14 is unsubstituted C1-C8 alkyl. In embodiments, R 14 is substituted C1- C8 alkyl. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 14 is unsubstituted C1-C8 alkoxy. In embodiments, R 14 is methoxy. In embodiments, R 14 is substituted C1-C8 alkoxy. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 14 is unsubstituted C1-C8 alkenyl. In embodiments, R 14 is substituted C1-C8 alkenyl. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 14 is unsubstituted C1-C8 alkynyl. In embodiments, R 14 is substituted C1-C8 alkynyl. In embodiments, R 14 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.
  • R 14 is unsubstituted C3- C8 cycloalkyl. In embodiments, R 14 is substituted C3-C8 cycloalkyl. In embodiments, R 14 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 14 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 14 is substituted C3-C8 cycloalkenyl. In embodiments, R 14 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 14 is unsubstituted C6-C10 aryl. In embodiments, R 14 is substituted C6-C10 aryl. In embodiments, R 14 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, R 14 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 14 is substituted 6-10 membered heteroaryl.
  • R 6 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
  • R 6 is hydrogen. In embodiments, R 6 is D. In embodiments, R 6 is D. In embodiments, R 6 is halogen. In embodiments, R 6 is F. In embodiments, R 6 is Cl. In embodiments, R 6 is Br. In embodiments, R 6 is I. In embodiments, R 6 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 6 is OH. In embodiments, R 6 is OPO3H2.
  • R 6 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.
  • R 6 is substituted C(O)-C1-C8 alkyl.
  • R 6 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 6 is unsubstituted C1-C8 alkyl. In embodiments, R 6 is substituted C1- C8 alkyl. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 6 is unsubstituted C1-C8 alkoxy. In embodiments, R 6 is methoxy. In embodiments, R 6 is substituted C1-C8 alkoxy. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 6 is unsubstituted C1-C8 alkenyl. In embodiments, R 6 is substituted C1-C8 alkenyl. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 6 is unsubstituted C1-C8 alkynyl. In embodiments, R 6 is substituted C1-C8 alkynyl. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 6 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 6 is substituted C3-C8 cycloalkyl. In embodiments, R 6 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 6 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 6 is substituted C3-C8 cycloalkenyl. In embodiments, R 6 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 6 is unsubstituted C6-C10 aryl. In embodiments, R 6 is substituted C6-C10 aryl. In embodiments, R 6 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, R 6 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 6 is substituted 6-10 membered heteroaryl.
  • R 6 is (CH2) m X(CH2) n Ph, 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.
  • R 9 is H or D. In embodiments, R 9 is H. In embodiments, R 9 is D.
  • the compound has the structure 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.
  • 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.
  • 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.
  • R 2 , R 12 , R 13 , and R 14 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, alkylcarbamo
  • R 2 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
  • R 2 is hydrogen. In embodiments, R 2 is D. In embodiments, R 2 is D. In embodiments, R 2 is halogen. In embodiments, R 2 is F. In embodiments, R 2 is Cl. In embodiments, R 2 is Br. In embodiments, R 2 is I. In embodiments, R 2 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 2 is OH. In embodiments, R 2 is OPO3H2.
  • R 2 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.
  • R 2 is substituted C(O)-C1-C8 alkyl.
  • R 2 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 2 is unsubstituted C1-C8 alkyl. In embodiments, R 2 is substituted C1- C8 alkyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 2 is unsubstituted C1-C8 alkoxy. In embodiments, R 2 is methoxy. In embodiments, R 2 is substituted C1-C8 alkoxy. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 2 is unsubstituted C1-C8 alkenyl. In embodiments, R 2 is substituted C1-C8 alkenyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 2 is unsubstituted C1-C8 alkynyl. In embodiments, R 2 is substituted C1-C8 alkynyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 2 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 2 is substituted C3-C8 cycloalkyl. In embodiments, R 2 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 2 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 2 is substituted C3-C8 cycloalkenyl. In embodiments, R 2 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 2 is unsubstituted C6-C10 aryl. In embodiments, R 2 is substituted C6-C10 aryl. In embodiments, R 2 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, R 2 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 2 is substituted 6-10 membered heteroaryl.
  • R 6 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
  • R 6 is hydrogen. In embodiments, R 6 is D. In embodiments, R 6 is D. In embodiments, R 6 is halogen. In embodiments, R 6 is F. In embodiments, R 6 is Cl. In embodiments, R 6 is Br. In embodiments, R 6 is I. In embodiments, R 6 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 6 is OH. In embodiments, R 6 is OPO3H2.
  • R 6 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.
  • R 6 is substituted C(O)-C1-C8 alkyl.
  • R 6 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 6 is unsubstituted C1-C8 alkyl. In embodiments, R 6 is substituted C1- C8 alkyl. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 6 is unsubstituted C1-C8 alkoxy. In embodiments, R 6 is methoxy. In embodiments, R 6 is substituted C1-C8 alkoxy. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 6 is unsubstituted C1-C8 alkenyl. In embodiments, R 6 is substituted C1-C8 alkenyl. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 6 is unsubstituted C1-C8 alkynyl. In embodiments, R 6 is substituted C1-C8 alkynyl. In embodiments, R 6 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 6 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 6 is substituted C3-C8 cycloalkyl. In embodiments, R 6 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 6 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 6 is substituted C3-C8 cycloalkenyl. In embodiments, R 6 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 6 is unsubstituted C6-C10 aryl. In embodiments, R 6 is substituted C6-C10 aryl. In embodiments, R 6 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, R 6 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 6 is substituted 6-10 membered heteroaryl.
  • R 12 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
  • R 12 is hydrogen. In embodiments, R 12 is D. In embodiments, R 12 is halogen. In embodiments, R 12 is F. In embodiments, R 12 is Cl. In embodiments, R 12 is Br. In embodiments, R 4 is I. In embodiments, R 4 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 12 is OH. In embodiments, R 12 is OPO3H2.
  • R 12 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.
  • R 12 is substituted C(O)-C1-C8 alkyl.
  • R 12 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 12 is unsubstituted C1-C8 alkyl. In embodiments, R 12 is substituted C1- C8 alkyl. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 12 is unsubstituted C1-C8 alkoxy. In embodiments, R 12 is methoxy. In embodiments, R 12 is substituted C1-C8 alkoxy. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 12 is unsubstituted C1-C8 alkenyl. In embodiments, R 12 is substituted C1-C8 alkenyl. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 12 is unsubstituted C1-C8 alkynyl. In embodiments, R 12 is substituted C1-C8 alkynyl. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 12 is unsubstituted C3- C8 cycloalkyl. In embodiments, R 12 is substituted C3-C8 cycloalkyl. In embodiments, R 12 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 12 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 12 is substituted C3-C8 cycloalkenyl. In embodiments, R 12 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 12 is unsubstituted C6-C10 aryl. In embodiments, R 12 is substituted C6-C10 aryl. In embodiments, R 12 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, R 12 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 12 is substituted 6-10 membered heteroaryl.
  • R 13 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,
  • R 13 is hydrogen. In embodiments, R 13 is D. In embodiments, R 13 is halogen. In embodiments, R 13 is F. In embodiments, R 13 is Cl. In embodiments, R 13 is Br. In embodiments, R 13 is I. In embodiments, R 13 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 13 is OH. In embodiments, R 13 is OPO3H2.
  • R 13 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.
  • R 13 is substituted C(O)-C1-C8 alkyl.
  • R 13 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 13 is unsubstituted C1-C8 alkyl. In embodiments, R 13 is substituted C1- C8 alkyl. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 13 is unsubstituted C1-C8 alkoxy. In embodiments, R 13 is methoxy. In embodiments, R 13 is substituted C1-C8 alkoxy. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 13 is unsubstituted C1-C8 alkenyl. In embodiments, R 13 is substituted C1-C8 alkenyl. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 13 is unsubstituted C1-C8 alkynyl. In embodiments, R 13 is substituted C1-C8 alkynyl. In embodiments, R 13 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.
  • R 13 is unsubstituted C3- C8 cycloalkyl. In embodiments, R 13 is substituted C3-C8 cycloalkyl. In embodiments, R 13 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 13 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 13 is substituted C3-C8 cycloalkenyl. In embodiments, R 13 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 13 is unsubstituted C6-C10 aryl. In embodiments, R 13 is substituted C6-C10 aryl. In embodiments, R 13 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, R 13 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 13 is substituted 6-10 membered heteroaryl.
  • R 14 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,
  • R 14 is hydrogen. In embodiments, R 14 is D. In embodiments, R 14 is halogen. In embodiments, R 14 is F. In embodiments, R 14 is Cl. In embodiments, R 14 is Br. In embodiments, R 14 is I. In embodiments, R 14 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 14 is OH. In embodiments, R 14 is OPO3H2.
  • R 14 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.
  • R 14 is substituted C(O)-C1-C8 alkyl.
  • R 14 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 14 is unsubstituted C1-C8 alkyl. In embodiments, R 14 is substituted C1- C8 alkyl. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 14 is unsubstituted C1-C8 alkoxy. In embodiments, R 14 is methoxy. In embodiments, R 14 is substituted C1-C8 alkoxy. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 14 is unsubstituted C1-C8 alkenyl. In embodiments, R 14 is substituted C1-C8 alkenyl. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 14 is unsubstituted C1-C8 alkynyl. In embodiments, R 14 is substituted C1-C8 alkynyl. In embodiments, R 14 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.
  • R 14 is unsubstituted C3- C8 cycloalkyl. In embodiments, R 14 is substituted C3-C8 cycloalkyl. In embodiments, R 14 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 14 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 14 is substituted C3-C8 cycloalkenyl. In embodiments, R 14 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 14 is unsubstituted C6-C10 aryl. In embodiments, R 14 is substituted C6-C10 aryl. In embodiments, R 14 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, R 14 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 14 is substituted 6-10 membered heteroaryl.
  • m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14.
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4.
  • m is 5.
  • m is 6.
  • m is 7.
  • m is 8.
  • m is 9.
  • m is 10.
  • m is 11.
  • m is 12.
  • m is 13.
  • n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5.
  • 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.
  • 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.
  • X is O, S, or NH. In embodiments, X is O. In embodiments, X is S. In embodiments, X is 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • R 9 is H or D. In embodiments, R 9 is H. In embodiments, R 9 is D.
  • the compound is selected from Table 5:
  • the compound has the structure of Formula (I IIB):
  • R N1 is H. In embodiments, R N1 is D.
  • 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.
  • 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.
  • R N2 is (CH2) m X(CH2) n Ph, 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.
  • m and n are each independently an integer from 1 to 13, provided that the sum of m + n is from 6 to 14.
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4.
  • m is 5.
  • m is 6.
  • m is 7.
  • m is 8.
  • m is 9.
  • m is 10.
  • m is 11.
  • m is 12.
  • m is 13.
  • n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5.
  • 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.
  • 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.
  • X is 0, S, or NH. In embodiments, X is 0. In embodiments, X is S. In embodiments, X is 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.
  • Ph is phenyl. In embodiments, Ph is unsubstituted phenyl.
  • 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.
  • Ph is phenyl substituted by halogen.
  • Ph is phenyl substituted by D.
  • 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.
  • 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.
  • 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.
  • R 2 , R 12 , R 13 , and R 14 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
  • R 2 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
  • R 2 is hydrogen. In embodiments, R 2 is D. In embodiments, R 2 is D. In embodiments, R 2 is halogen. In embodiments, R 2 is F. In embodiments, R 2 is Cl. In embodiments, R 2 is Br. In embodiments, R 2 is I. In embodiments, R 2 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 2 is OH. In embodiments, R 2 is OPO3H2.
  • R 2 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.
  • R 2 is substituted C(O)-C1-C8 alkyl.
  • R 2 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 2 is unsubstituted C1-C8 alkyl. In embodiments, R 2 is substituted C1- C8 alkyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 2 is unsubstituted C1-C8 alkoxy. In embodiments, R 2 is methoxy. In embodiments, R 2 is substituted C1-C8 alkoxy. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 2 is unsubstituted C1-C8 alkenyl. In embodiments, R 2 is substituted C1-C8 alkenyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 2 is unsubstituted C1-C8 alkynyl. In embodiments, R 2 is substituted C1-C8 alkynyl. In embodiments, R 2 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 2 is unsubstituted C3-C8 cycloalkyl. In embodiments, R 2 is substituted C3-C8 cycloalkyl. In embodiments, R 2 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 2 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 2 is substituted C3-C8 cycloalkenyl. In embodiments, R 2 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 2 is unsubstituted C6-C10 aryl. In embodiments, R 2 is substituted C6-C10 aryl. In embodiments, R 2 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, R 2 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 2 is substituted 6-10 membered heteroaryl.
  • R 12 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
  • R 12 is hydrogen. In embodiments, R 12 is D. In embodiments, R 12 is halogen. In embodiments, R 12 is F. In embodiments, R 12 is Cl. In embodiments, R 12 is Br. In embodiments, R 4 is I. In embodiments, R 4 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 12 is OH. In embodiments, R 12 is OPO3H2.
  • R 12 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.
  • R 12 is substituted C(O)-C1-C8 alkyl.
  • R 12 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 12 is unsubstituted C1-C8 alkyl. In embodiments, R 12 is substituted C1- C8 alkyl. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 12 is unsubstituted C1-C8 alkoxy. In embodiments, R 12 is methoxy. In embodiments, R 12 is substituted C1-C8 alkoxy. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 12 is unsubstituted C1-C8 alkenyl. In embodiments, R 12 is substituted C1-C8 alkenyl. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 12 is unsubstituted C1-C8 alkynyl. In embodiments, R 12 is substituted C1-C8 alkynyl. In embodiments, R 12 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamid
  • R 12 is unsubstituted C3- C8 cycloalkyl. In embodiments, R 12 is substituted C3-C8 cycloalkyl. In embodiments, R 12 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 12 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 12 is substituted C3-C8 cycloalkenyl. In embodiments, R 12 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 12 is unsubstituted C6-C10 aryl. In embodiments, R 12 is substituted C6-C10 aryl. In embodiments, R 12 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, R 12 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 12 is substituted 6-10 membered heteroaryl.
  • R 13 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,
  • R 13 is hydrogen. In embodiments, R 13 is D. In embodiments, R 13 is halogen. In embodiments, R 13 is F. In embodiments, R 13 is Cl. In embodiments, R 13 is Br. In embodiments, R 13 is I. In embodiments, R 13 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 13 is OH. In embodiments, R 13 is OPO3H2.
  • R 13 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.
  • R 13 is substituted C(O)-C1-C8 alkyl.
  • R 13 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 13 is unsubstituted C1-C8 alkyl. In embodiments, R 13 is substituted C1- C8 alkyl. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 13 is unsubstituted C1-C8 alkoxy. In embodiments, R 13 is methoxy. In embodiments, R 13 is substituted C1-C8 alkoxy. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 13 is unsubstituted C1-C8 alkenyl. In embodiments, R 13 is substituted C1-C8 alkenyl. In embodiments, R 13 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 13 is unsubstituted C1-C8 alkynyl. In embodiments, R 13 is substituted C1-C8 alkynyl. In embodiments, R 13 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.
  • R 13 is unsubstituted C3- C8 cycloalkyl. In embodiments, R 13 is substituted C3-C8 cycloalkyl. In embodiments, R 13 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 13 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 13 is substituted C3-C8 cycloalkenyl. In embodiments, R 13 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 13 is unsubstituted C6-C10 aryl. In embodiments, R 13 is substituted C6-C10 aryl. In embodiments, R 13 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, R 13 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 13 is substituted 6-10 membered heteroaryl.
  • R 14 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,
  • R 14 is hydrogen. In embodiments, R 14 is D. In embodiments, R 14 is halogen. In embodiments, R 14 is F. In embodiments, R 14 is Cl. In embodiments, R 14 is Br. In embodiments, R 14 is I. In embodiments, R 14 is OR', wherein R’ is H, PO3H2, or C(O)-C1-C8 alkyl. In embodiments, R 14 is OH. In embodiments, R 14 is OPO3H2.
  • R 14 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.
  • R 14 is substituted C(O)-C1-C8 alkyl.
  • R 14 is unsubstituted C(O)-C1-C8 alkyl. In embodiments, C(O)-CH3. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido,
  • R 14 is unsubstituted C1-C8 alkyl. In embodiments, R 14 is substituted C1- C8 alkyl. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido
  • R 14 is unsubstituted C1-C8 alkoxy. In embodiments, R 14 is methoxy. In embodiments, R 14 is substituted C1-C8 alkoxy. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino
  • R 14 is unsubstituted C1-C8 alkenyl. In embodiments, R 14 is substituted C1-C8 alkenyl. In embodiments, R 14 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.
  • a halogen D, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 14 is unsubstituted C1-C8 alkynyl. In embodiments, R 14 is substituted C1-C8 alkynyl. In embodiments, R 14 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.
  • R 14 is unsubstituted C3- C8 cycloalkyl. In embodiments, R 14 is substituted C3-C8 cycloalkyl. In embodiments, R 14 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, al
  • R 14 is unsubstituted C3-C8 cycloalkenyl. In embodiments, R 14 is substituted C3-C8 cycloalkenyl. In embodiments, R 14 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.
  • D alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkyla
  • R 14 is unsubstituted C6-C10 aryl. In embodiments, R 14 is substituted C6-C10 aryl. In embodiments, R 14 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, R 14 is unsubstituted 6-10 membered heteroaryl. In embodiments, R 14 is substituted 6-10 membered heteroaryl.
  • R 6 is (CH2) m X(CH2) n Ph, 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.
  • R 9 is H or D. In embodiments, R 9 is H. In embodiments, R 9 is D.
  • the compound is selected from Table 6:
  • 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.
  • 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.
  • 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) n Ph as defined herein, with all other substituents as otherwise defined therein.
  • 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) m X(CH2) n Ph as defined herein, with all other substituents as otherwise defined therein.
  • 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) m X(CH2) n Ph as defined herein, with all other substituents as otherwise defined therein.
  • 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) m X(CH2) n Ph as defined herein, with all other substituents as otherwise defined therein.
  • 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) m X(CH2) n Ph as defined herein, with all other substituents as otherwise defined therein.
  • additional N-substituted lysergamides comprise the compounds of Formula (I) disclosed in WO2023/073423, wherein any of R4, R6, or R7 is — (CH2) m X(CH2) n Ph as defined herein, with all other substituents as otherwise defined therein.
  • 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) m X(CH2) n Ph as defined herein, with all other substituents as otherwise defined therein.
  • 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.
  • 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.
  • nonaqueous media e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
  • 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, dodecyl
  • 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.
  • 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.
  • 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.
  • a polymorph of a disclosed compound has at least one different physical property, such as related to shape, density, hardness, deformability, stability, and dissolution.
  • 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.
  • 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.
  • 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).
  • Isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 0, 18 O, and 36 CI respectively.
  • isotopically labeled compounds can be used in metabolic studies (with 14 C), reaction kinetic studies (with, e.g., 2 H or 3 H), 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.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F-labeled compound is used for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H, 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.
  • 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.
  • 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.
  • a prodrug includes compounds with biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • 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.
  • 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.
  • the choice of functional group may depend on factors such as stability, ease of synthesis, enzymatic activity, and desired rate of prodrug conversion.
  • Disclosed compounds may be provided as isolated or purified compounds.
  • isolated refers 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.
  • 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.
  • “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.
  • 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) m X(CH2) n Ph 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.
  • a side chain precursor e.g., Br(CH2) m X(CH2) n Ph as shown above
  • an amine precursor (R N -NH2) is alkylated with a side chain precursor (e.g., as shown above, Br(CH2) m X(CH2) n Ph).
  • a side chain precursor e.g., as shown above, Br(CH2) m X(CH2) n Ph.
  • 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).
  • a suitable leaving group here, e.g., bromide
  • This reaction sequence can be used in the synthesis of, e.g., a substituted tryptamine having an N- methyltryptamine component:
  • potassium iodide is used to accelerate the nucleophilic substitution reaction.
  • Addition of an inorganic iodide salt e.g., potassium iodide, sodium iodide
  • 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.
  • triethylamine is used as an exemplary base.
  • bases may be used.
  • DIPEA diisopropylethylamine
  • pyridine are common organic bases.
  • 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.
  • an amine precursor (R N -NH2) is alkylated with a side chain precursor (e.g., as shown above, Br(CH2) m X(CH2) n Ph).
  • a side chain precursor e.g., as shown above, Br(CH2) m X(CH2) n Ph.
  • the resulting (secondary amine) intermediate is then reacted with a lysergic acid precursor to produce the compound of Formula (II).
  • lysergic acid precursors is known to those of skill in the art.
  • 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.
  • potassium iodide is used to accelerate the nucleophilic substitution reaction.
  • Addition of an inorganic iodide salt e.g., potassium iodide, sodium iodide
  • 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.
  • triethylamine is used as an exemplary base.
  • bases may be used.
  • DIPEA diisopropylethylamine
  • pyridine are common organic bases.
  • 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.
  • lysergamide-containing compounds of the disclosure can be prepared by dealkylation (e.g., demethylation) of a lysergamide precursor wherein R 6 is alkyl (e.g., methyl), followed by N(6) alkylation with a suitable 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.
  • 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).
  • “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.
  • compositions can be administered by a variety of routes including oral, mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, and intranasal.
  • 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).
  • 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.
  • Unit dosage forms include capsules, troches, cachets, lozenges, and tablets.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 including a sterile packaged powder
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • oils such as peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil
  • 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
  • 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.
  • 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.
  • Liquid formulations also may be prepared as single dose or multi-dose beverages.
  • 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.
  • 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.
  • 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.
  • 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.
  • “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.
  • “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.”
  • 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.
  • 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, aphro
  • 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.
  • an additional active compound is a serotonin receptor antagonist.
  • the serotonin receptor antagonist is a 5-HT2A antagonist.
  • the serotonin receptor antagonist is a 5- HT2B antagonist.
  • the serotonin receptor antagonist is peripherally-restricted antagonist.
  • an additional active compound is a tryptamine.
  • a tryptamine will have the general structure below, wherein R N1 , R N2 , R a , RP, R 2 , R 4 , R 5 , R 6 , and R 7 are as disclosed herein and as generally understood in the art:
  • R N1 , R N2 , R a , RP, R 2 , R 4 , R 5 , R 6 , and R 7 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.
  • any two of R N1 , R N2 , R a , RP, R 2 , R 4 , R 5 , R 6 , and R 7 and the intervening atoms can be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclyl.
  • 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.
  • 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,
  • 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.
  • the additional active compound is a phenethylamine.
  • a phenethylamine will have the general structure below, wherein R N1 , R N2 , R a , RP, and each of R 2 -R 6 are as disclosed herein and generally understood in the art:
  • 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
  • 6-APB and DiFMDA, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.
  • phenethylamines such as herein, uses prefixes and suffixes to indicate substitutions on the phenyl ring and/or side chain of the phenethylamine core structure.
  • MDBZ stands for methylenedioxybenzyl-amphetamine (i.e., 3,4-methylenedioxy-N-benzylamphetamine) (see also, e.g., PiHKAL).
  • 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.
  • a lysergamide will have the general structure below, wherein R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are as disclosed herein and as generally understood in the art:
  • R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 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.
  • any two of R N1 , R N2 , R 1 , R 2 , R 4 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 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.
  • the lysergamide is a quaternary salt, in which an additional R 6A is connected to the nitrogen to which R 6 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.
  • 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.
  • 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.
  • 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).
  • 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
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • a single dose is between about 10 mg and 100 mg.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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
  • an additional active compound such as
  • 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).
  • 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.
  • 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.
  • dose, frequency, and timing 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.
  • 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.
  • suggested dosages may be known by reference to the format of the preparation itself.
  • 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.
  • kits comprising a disclosed composition, suggested administration guidelines or prescribing information therefor, and a suitable container.
  • 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.
  • Kits generally comprise suitable packaging.
  • a kit may comprise one or more containers comprising any disclosed composition.
  • Each component if there is more than one component
  • Kits 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).
  • Kits 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.
  • disclosed compounds are used to modulate neurotransmission.
  • disclosed compounds are used to treat a condition, e.g., a disease or a disorder.
  • 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.
  • disclosed compounds are administered under direct supervision.
  • 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.
  • disclosed compounds are administered to a subject.
  • disclosed compounds are administered, in a therapeutically effective amount, to a subject having a condition, such as a disease or a disorder.
  • the condition is a mental health disorder.
  • the condition is a neurodegenerative disorder.
  • the condition is inflammation or an inflammatory disorder.
  • the condition is pain or a pain disorder.
  • 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.
  • a route of administration may include orally, mucosally, rectally, subcutaneously, intravenously, intramuscularly, intranasally, by inhalation, and transdermally.
  • the disclosed compounds and compositions thereof are useful, such as to treat a patient in need of such treatment.
  • 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.
  • 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.
  • 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.
  • 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.
  • disclosed compounds are used in receptor, ion channel, enzyme, and transporter binding studies.
  • disclosed compounds are used in mapping, and functional studies.
  • disclosed compounds are radiolabeled.
  • radiolabeled compounds are used to identify binding sites.
  • radiolabeled compounds are used to assess receptor binding affinity.
  • radiolabeled compounds are used fortissue imaging.
  • radiolabeled compounds are used for receptor expression mapping.
  • radiolabeled compounds are used to track the metabolic fate of a disclosed compound.
  • disclosed compounds are used as research tools for 5-HT2 receptors.
  • disclosed compounds are used as research tools for 5-HT2A receptors.
  • disclosed compounds are used as research tools for 5-HT2B receptors.
  • disclosed compounds are used as research tools for 5-HT2C receptors.
  • 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.
  • the receptor is a recombinant receptor. In other embodiments, it is a wild-type receptor.
  • 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.
  • disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of human (Homo sapiens) origin.
  • 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.
  • disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of rodent origin.
  • 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.
  • 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.
  • disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of nematode origin.
  • 5-HT2 receptors of C. elegans are probed with a disclosed compound.
  • disclosed compounds are used as research tools, such as receptor probes, for 5-HT2 receptors of a dog, chicken, frog, or cow.
  • 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.
  • a nucleotide database e.g., Genbank
  • amino acid database e.g., UniProtKB
  • 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.
  • 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).
  • GPCR G- protein coupled receptors
  • 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.
  • the side-extended cavity may be referred to herein as an “extended binding site” or an “exosite.”
  • the receptor is of mammalian origin. In embodiments, the receptor is of human origin. In embodiments, the receptor is recombinant.
  • 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.
  • a disclosed compound binds to a 5-HTi receptor at one or more sites, such as an orthosteric site and an extended binding site.
  • a disclosed compound binds to a 5-HT2 receptor at one or more sites, such as an orthosteric site and an extended binding site.
  • 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.
  • 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.
  • 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.
  • TMDs transmembrane domains
  • ECL extracellular loop
  • 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).
  • 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.
  • 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.
  • 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).
  • ADRB2 exosite may be applied to a 5-HT receptor, such as docking and mutagenic studies.
  • 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • a disclosed compound has increased selectivity or specificity for a 5-HT receptor relative to a comparator.
  • 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.
  • a disclosed compound has fewer off-target effects, including, e.g., adverse effects, relative to a comparator.
  • 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).
  • Affinity can be evaluated by determining the inhibition constant of a disclosed compound and a receptor, such as a 5-HT2 receptor.
  • a competition binding assay otherwise referred to as a radioligand displacement assay, can be used to determine Ki.
  • a radioligand displacement assay can be used to determine Ki.
  • 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.
  • displaced radioligands are antagonists, for example, [ 3 H]ketanserin for 5-HT2A and [ 3 H]mesulergine for 5-HT2C.
  • displaced radioligands are agonists, for example [ 3 H]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.
  • 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.
  • a disclosed compound has decreased binding affinity for any one or more of 5-HT2A, 5-HT2B, and 5-HT2C, relative to a comparator.
  • 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.
  • the comparator is the corresponding tryptamine lacking an N-linked side chain.
  • 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.
  • 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.
  • 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.
  • 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).
  • EC50 half-maximal effective concentration
  • another receptor e.g., a serotonin receptor, such as the 5-HT2B receptor, or the 5-HT2C receptor.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the comparator is serotonin.
  • 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.
  • 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.
  • disclosed compounds modulate neurotransmission in a subject, such as following administration of an effective amount to the subject.
  • modulating neurotransmission by administering a disclosed compound to a subject also treats a disease or disorder in the subject.
  • modulating neurotransmission comprises modulating serotonergic neurotransmission.
  • 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).
  • 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.
  • 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).
  • PLC phospholipase C
  • the released inositol phosphate 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 Ca 2+ sensitive fluorescent dyes, applying a test ligand, and measuring spectral shifts that result from the dye binding to released Ca 2+ . 5-HT2 receptor functional assay methods are described in, e.g., Klein et al., ACS Pharmacol Transl Sci.
  • 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.
  • a decrease in basal levels of IP3 provides a measure of antagonism (Raote 2007).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • modulating neurotransmission comprises modulating voltage-gated ion channel activity.
  • a disclosed compound modulates the activity of one or more of a voltage-gated calcium ion (Ca 2+ ) channel, a voltage-gated chloride ion (Cl ) channel, a voltage-gated potassium ion (K + ) channel, and a voltage-gated sodium ion (Na + ) channel (VGSC).
  • VGSC voltage-gated sodium ion channel
  • 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.
  • 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.
  • 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.
  • disclosed compounds are used to treat a medical condition, such as a disease or disorder.
  • disclosed compounds are used in the manufacture of a medicament to treat a condition, such as a disease or disorder.
  • disclosed compounds and compositions thereof are used to treat serotonin- mediated disorders.
  • 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.
  • 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.
  • 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.
  • 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.
  • treating 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.
  • an effective amount includes 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.
  • terapéutica 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.
  • 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.
  • patient-reported e.g., questionnaires
  • other patient data e.g., patient monitoring
  • laboratory tests such as blood work, urine samples, etc.
  • digital tools or means e.g., electronic tools such as online tools, smartphones, wireless devices, biosensors, or health apps.
  • 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.
  • Al artificial intelligence
  • ML machine learning
  • 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.
  • 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).
  • 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.
  • disclosed compounds are used to treat a mental, behavioral, or neurodevelopmental disorder.
  • 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.
  • the disclosed compounds and compositions comprising such compounds when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental, behavioral, or neurodevelopmental disorder.
  • 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.
  • a mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the I CD-11 .
  • 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.
  • 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.
  • 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.
  • disclosed compounds are used to treat a mental health disorder.
  • 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.
  • the disclosed compounds or compositions when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental health disorder.
  • 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.
  • measures of therapeutic efficacy include reports by a subject or an observer.
  • measures of therapeutic efficacy include responses to a questionnaire.
  • 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.
  • GID-7 Generalized Anxiety Disorder Scale-7
  • MADRS Montgomery-Asberg Depression Rating Scale
  • GAF Global Assessment of Functioning Scale
  • CGI Clinical Global Impression
  • 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).
  • 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.
  • 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.
  • 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).
  • CGI Clinical Global Impression scale
  • BPRS Brief Psychiatric Rating Scale
  • PANSS Positive and Negative Syndrome Scale
  • SANS Scale for the Assessment of Negative Symptoms
  • SAPS Scale for the Assessment of Positive Symptoms
  • SAPS Scale for the Assessment of Positive Symptoms
  • SAPS 16-item Negative Symptoms Assessment
  • SDS Schedule for Deficit Syndrome
  • CAINS Clinical Assessment Interview for Negative Symptoms
  • a disclosed compound is used to treat a mood disorder.
  • 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).
  • 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.
  • a mood disorder e.g., bipolar disorder
  • measurements of therapeutic efficacy in treating a mood 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.
  • disclosed compounds and compositions are used to treat neurodegenerative conditions, which as shorthand refers broadly to neurodegenerative diseases and disorders.
  • a therapeutically effective amount of a disclosed compound is administered to a subject in need thereof to treat a neurodegenerative condition.
  • administration of a therapeutically effective amountof a disclosed compound slows or prevents the progression of neurodegeneration.
  • 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).
  • VILIP-1 visinin-like protein 1
  • tau tau
  • 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).
  • UHDRS Unified Huntington’s Disease
  • 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
  • disclosed compounds and compositions thereof are used to treat a pain disorder and/or inflammation.
  • 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.
  • 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.
  • 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.
  • disclosed compounds and compositions are used to treat headaches.
  • 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.
  • disclosed compounds and compositions thereof are used to reduce inflammation, for example, systemic inflammation.
  • disclosed compounds and compositions thereof are used to treat inflammatory diseases.
  • 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.
  • 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), n
  • 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.
  • 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).
  • 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 O ff) 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • VGSC voltage-gated sodium channel
  • HEK human embryonic kidney
  • 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.
  • Dulbecco 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.
  • Sodium current 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).
  • 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.
  • 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).
  • 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.
  • 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)).
  • V 2 is the membrane potential in the midpoint of the curve
  • 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.
  • 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.
  • Patch clamp electrophysiology is utilized to test the acute effects of disclosed compounds on neuronal excitability in mouse cortical brain slices.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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).

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Abstract

L'invention concerne des composés de tryptamine N-substituée et de lysergamide N-substituée, leurs procédés de fabrication et des procédés d'utilisation de tels composés, par exemple, comme sondes de récepteur, comme modulateurs de neurotransmission, et comme agents thérapeutiques, par exemple comme agents destinés au SNC. L'invention concerne également des compositions pharmaceutiques comprenant les composés divulgués et leurs procédés d'utilisation, tels que dans le traitement de troubles liés à la neurotransmission sérotonergique, y compris des troubles neuropsychiatriques multidimensionnels et complexes, tels que le trouble obsessionnel compulsif (TOC), le trouble bipolaire et les troubles psychotiques tels que la schizophrénie, ainsi que dans le traitement d'états à médiation par canal ionique, tels que des troubles épileptiques.
PCT/US2024/061815 2023-12-22 2024-12-23 Tryptamines n-substituées et lysergamides n-substitués et leur utilisation comme agents thérapeutiques Pending WO2025137730A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050020664A1 (en) * 2000-10-03 2005-01-27 Neurim Pharmaceuticals (1991) Ltd. Derivatives of tryptamine and analogous compounds, and pharmaceutical formulations containing them
US20110319387A1 (en) * 2009-03-02 2011-12-29 Centre National De La Recherche Scientifique (Cnrs) Indole derivatives for treating neurodegenerative diseases
WO2023034645A2 (fr) * 2021-09-03 2023-03-09 Alexander Shulgin Research Institute Allyl tryptamines asymétriques
US20230330063A1 (en) * 2017-10-26 2023-10-19 Consejo Superior De Investigaciones Científicas (Csic) Combination product for the treatment of neurological and/or psychiatric disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050020664A1 (en) * 2000-10-03 2005-01-27 Neurim Pharmaceuticals (1991) Ltd. Derivatives of tryptamine and analogous compounds, and pharmaceutical formulations containing them
US20110319387A1 (en) * 2009-03-02 2011-12-29 Centre National De La Recherche Scientifique (Cnrs) Indole derivatives for treating neurodegenerative diseases
US20230330063A1 (en) * 2017-10-26 2023-10-19 Consejo Superior De Investigaciones Científicas (Csic) Combination product for the treatment of neurological and/or psychiatric disorders
WO2023034645A2 (fr) * 2021-09-03 2023-03-09 Alexander Shulgin Research Institute Allyl tryptamines asymétriques

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