WO2023108174A1 - Analogs of 6-methoxy- n, n-dimethyltryptamine - Google Patents

Analogs of 6-methoxy- n, n-dimethyltryptamine Download PDF

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WO2023108174A1
WO2023108174A1 PCT/US2022/081375 US2022081375W WO2023108174A1 WO 2023108174 A1 WO2023108174 A1 WO 2023108174A1 US 2022081375 W US2022081375 W US 2022081375W WO 2023108174 A1 WO2023108174 A1 WO 2023108174A1
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hydrogen
alkyl
formula
compound
cycloalkyl
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Matthew Duncton
Samuel CLARK
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Terran Biosciences, Inc.
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    • 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
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    • 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
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds

Definitions

  • Ketamine is a member of a class of compounds known as psychoplastogens.
  • Psychoplastogens promote neuronal growth through a mechanism involving the activation of AMPA receptors, the tropomyosin receptor kinase B (TrkB), and the mammalian target of rapamycin (mTOR).
  • DMT N,N-dimethyltryptamine
  • R 1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy
  • R 2 is hydrogen, -C(O)OR 3 , -C(O)R 4 , -CH(R 5 )OR 6 , -C(O)OCH(R 5 )OC(O)R 6 , - C(O)OCH(R 5 )OC(O)OR 6 , -C(O)NHCH(R 5 )OC(O)R 6 , -CH(R 5 )C(O)R 6 , -S(O) 2 OR 7 , - P(O)OR 8 [N
  • the compounds of this disclosure are enriched in deuterium. In some embodiments, the compounds of this disclosure are isotopically labeled analogs of 6-methoxy-N,N-dimethyltryptamine. In some embodiments, the compounds of this disclosure are in the form of a pharmaceutically acceptable salt or a solvate. Also disclosed herein are methods for making and using compounds of Formula (I). Also disclosed is a method for increasing neuronal plasticity, comprising contacting a neuron with an effective amount of a disclosed compound. Also disclosed is a method for increasing neuronal plasticity, comprising contacting a neuron with an effective amount of a disclosed compound, wherein contacting comprises administering the compound to a subject.
  • the method for treating a neurological disorder or a psychiatric disorder, or both comprises contacting a subject having the neurological disorder, psychiatric disorder or both with an effective amount of a disclosed compound.
  • Compounds herein include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof.
  • optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclylalkyl groups, heteroaryl groups, cycloalkyl groups, acyl groups
  • acyl refers to the group –C(O)R, where R is H, aliphatic, such as alkyl, heteroaliphatic, heterocyclic or aryl.
  • exemplary acyl moieties include, but are not limited to, -C(O)H, - C(O)alkyl, -C(O)C 1 -C 6 alkyl, -C(O)C 1 -C 6 haloalkyl-C(O)cycloalkyl, -C(O)alkenyl, - C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon having from one to about ten carbon atoms, or from one to six carbon atoms, wherein an sp 3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2- methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1- butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert- amyl, and hexyl, and longer alkyl groups, such as heptyl, octy
  • alkyl groups herein include C1-10 alkyl, C1-6 alkyl and C 1-3 alkyl groups.
  • the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C1 alkyl.
  • Alkyl groups include branched and unbranched alkyl groups. Alkyl groups (e.g., methyl) may be saturated with any stable isotope of hydrogen, e.g., protium, deuterium, and tritium.
  • Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • optionally substituted alkyl refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen, deuterium, or tritium atoms on one or more carbons of the hydrocarbon backbone.
  • Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups.
  • Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec- butyl, and t-butyl.
  • Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl.
  • an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or - OMe. In some embodiments, the alkyl is optionally substituted with halogen.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp 2 - hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • the group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • a numerical range such as "C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated.
  • the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl.
  • an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • alkenyl is optionally substituted with halogen.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like.
  • C 2 -C 6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl” where no numerical range is designated.
  • the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like.
  • an alkynyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • Cycloalkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. Cycloalkyl groups herein include C 3-10 cycloalkyl, C 3-8 cycloalkyl and C 4-6 cycloalkyl groups.
  • a cycloalkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.
  • Non- limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl-cycloprop-1-yl, cycloprop-2-en-1-yl, cyclobutyl, 2,3-dihydroxycyclobut-1-yl, cyclobut-2-en-1-yl, cyclopentyl, cyclopent-2-en-1-yl, cyclopenta-2,4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopent-1-yl, 3,5-dichlorocyclohex-1-yl, 4-hydroxycyclohex-1-yl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, oct
  • a haloalkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
  • a halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms.
  • a halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
  • An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group.
  • An ether or an ether group comprises an alkoxy group.
  • alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
  • a heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom.
  • a heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms.
  • a heterocycle can be aromatic (heteroaryl) or non-aromatic.
  • heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinimide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
  • heterocycles include: heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline; and ii
  • heteroaryl include: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non- limiting examples of which include: 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H- pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[
  • Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined herein. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.
  • an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or - OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Alkoxy groups e.g., methoxy
  • Alkoxy groups may be saturated with any stable isotope of hydrogen, e.g., protium, deuterium, and tritium.
  • Amino refers to the group -NH 2 , -NHR, or -NRR, where each R independently is selected from H, alkyl, cycloalkyl, aryl or heterocyclic, or two R groups together with the nitrogen attached thereto form a heterocyclic ring.
  • heterocyclic rings examples include those wherein two R groups together with the nitrogen to which they are attached form a – (CH 2 ) 2-5 – ring optionally interrupted by one or two heteroatom groups, such as –O– or –N(R g ) such as in the groups g and wherein R is alkyl or acyl.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclylalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -NO 2 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl).
  • the cycloalkyl is a 3- to 6-membered cycloalkyl.
  • the cycloalkyl is a 5- to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • such cycloalkyl moieties can be represented by abbreviations, e.g., cyclopropyl may be abbreviated as "cPr".
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF 3 , -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
  • “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums.
  • the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl include, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD3.
  • “Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halogens.
  • the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens.
  • Haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • the haloalkyl is a perhaloalkyl, such as trifluoromethyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as, oxygen, nitrogen (for example, -NH-, - N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , or - CH(CH3)OCH3.
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heteroalkyl is optionally substituted with halogen.
  • "Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls.
  • Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Heterocyclyl refers to heteroaryl and heterocyclylalkyl ring systems.
  • Heterocyclylalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur.
  • the heterocyclylalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocyclylalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems, e.g., fused-, bridge-d, and spiro-bicycles and higher fused-, bridged-, and spiro-systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclylalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocyclylalkyls include, but are not limited to, heterocyclylalkyls having from two to fifteen carbon atoms (C2-C15 heterocyclylalkyl), from two to ten carbon atoms (C2-C10 heterocyclylalkyl), from two to eight carbon atoms (C2-C8 heterocyclylalkyl), from two to six carbon atoms (C 2 -C 6 heterocyclylalkyl), from two to five carbon atoms (C 2 -C 5 heterocyclylalkyl), or two to four carbon atoms (C 2 -C 4 heterocyclylalkyl).
  • the heterocyclylalkyl is a 3- to 6-membered heterocyclylalkyl.
  • the cycloalkyl is a 5- to 6-membered heterocyclylalkyl.
  • heterocyclylalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,
  • heterocyclylalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocyclylalkyl, the number of carbon atoms in the heterocyclylalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocyclylalkyl (i.e., skeletal atoms of the heterocyclylalkyl ring).
  • a heterocyclylalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like.
  • a heterocyclylalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, - OMe, -NH2, or -NO2.
  • a heterocyclylalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclylalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclylalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5- to 6-membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
  • the heteroaryl is optionally substituted with halogen.
  • Administration refers to any suitable mode of administration, including, oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.
  • Subject refers to an animal, such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human subject.
  • “Therapeutically effective amount” or “therapeutically sufficient amount” or “effective or sufficient amount” refers to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g.
  • Neuronal plasticity refers to the ability of the brain to change its structure and/or function continuously throughout a subject's life.
  • Brain disorder refers to a neurological disorder which affects the brain's structure and function. Brain disorders can include, but are not limited to, Alzheimer's, Parkinson's disease, psychological disorder, depression, treatment resistant depression, addiction, anxiety, post- traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and substance use disorder.
  • Combination therapy refers to a method of treating a disease or disorder, wherein two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents.
  • the compounds of the invention can be used in combination with other pharmaceutically active compounds.
  • the compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy.
  • a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
  • Neurotrophic factors refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons.
  • Modulate or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule.
  • agonists, partial agonists, antagonists, and allosteric modulators e.g., a positive allosteric modulator
  • G protein-coupled receptor e.g., 5HT2A
  • Agonism refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.
  • Ant refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response.
  • 5HT 2A agonist can be used to refer to a compound that exhibits an EC 50 with respect to 5HT 2A activity of no more than about 100 mM.
  • the term “agonist” includes full agonists or partial agonists.
  • Full agonist refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor.
  • Partial agonist refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.
  • “Positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.
  • “Antagonism” refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur.
  • “Antagonist” or “neutral antagonist” refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.
  • Certain compounds according to Formula (I) disclosed herein are isotopically enriched, meaning that they have an isotope present in greater than its natural abundance at one or more position.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope. It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of any compound will inherently contain small amounts of isotopologues, including deuterated isotopologues. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this disclosure.
  • a particular position is designated as having a particular isotope, such as deuterium
  • the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015% (on a mol/mol basis).
  • a position designated as a particular isotope will have a minimum isotopic enrichment factor of at least 3000 (45% incorporation of the indicated isotope).
  • isotopically enriched compounds disclosed herein having deuterium will have a minimum isotopic enrichment factor of at least 3000 (45% deuterium incorporation) at each atom designated as deuterium in the compound.
  • Such compounds may be referred to herein as "deuterated” compounds.
  • disclosed compounds including compounds of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3), have an isotopic enrichment factor for each designated atom of at least 3500 (52.5%).
  • the compounds have an isotopic enrichment factor for each designated hydrogen atom of at least 3500 (52.5% deuterium incorporation at each designated atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • such compounds also are referred to as "deuterated” compounds.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • H or “protium”
  • the position is understood to have hydrogen at about its natural abundance isotopic composition.
  • isotopologue refers to a species that has the same chemical structure and formula as another compound, with the exception of the isotopic composition at one or more positions, e.g., H vs. D. Thus, isotopologues differ in their isotopic composition.
  • Any compound herein can be provided as a substantially pure substance. Compounds that are not prepared in pure form can be purified as is known to those of skill in the art.
  • a compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 4
  • compositions provide for pharmaceutically-acceptable salts of any compound described herein as well as the use of such salts.
  • any compound with an ionizable group such as an acidic hydrogen, or a basic nitrogen
  • Pharmaceutically-acceptable salts include, for example, acid- addition salts and base-addition salts.
  • the acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid.
  • a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt.
  • a pharmaceutically- acceptable salt is an ammonium salt.
  • Metal salts can arise from the addition of an inorganic base to a compound of the present disclosure having an acidic functional group.
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • the metal is a metal cation, such as lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure.
  • the organic amine is trimethyl amine, triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, pyrazolidine, pyrazoline, pyridazine, pyrimidine, imidazole, or pyrazine.
  • an ammonium salt is a triethyl amine salt, trimethyl amine salt, a diisopropyl amine salt, an ethanolamine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.
  • Acid addition salts can arise from the addition of an acid to a compound of the present disclosure that includes a basic functional group.
  • the acid is organic.
  • the acid is inorganic.
  • the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, maleic acid or xinaf
  • the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt,
  • compositions comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in the composition is an amount effective to treat the relevant disease, disorder, or condition in a patient in need thereof (an "effective amount").
  • a composition of the present disclosure is formulated for oral administration to a patient.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the agent with which it is formulated.
  • compositions include, but are not limited to, ion exchangers, alumina, stearates such as aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina
  • stearates such as aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine,
  • compositions of the present disclosure may be administered orally, parenterally, enterally, intracistemally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the composition is administered orally, intraperitoneally, or intravenously.
  • the composition is a transmucosal formulation.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in l,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in l,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, may also be added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • pharmaceutically acceptable compositions can be administered in the form of suppositories for rectal administration.
  • the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In other embodiments, the pharmaceutically acceptable composition is administered with food.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P.
  • injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. To prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection.
  • Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f ) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonit
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. Therapeutic agents can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g ., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • R 1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy
  • R 2 is hydrogen, -C(O)OR 3 , -C(O)R 4 , -CH(R 5 )OR 6 , -C(O)OCH(R 5 )OC(O)R 6 , - C(O)OCH(R 5 )OC(O)OR 6 , -C(O)NHCH(R 5 )OC(O)R 6 , -CH(R 5 )C(O)R 6 , -S(O) 2 OR 7 , - P(O)OR
  • R 2 is -C(O)OR 3 . In some embodiments of Formula (I) R 2 is -C(O)OR 3 , wherein R 3 is alkyl. In some embodiments of a compound of Formula (I) R 2 is -C(O)OR 3 , wherein R 3 is alkyl that is unsubstituted. In some embodiments of Formula (I) R 2 is -C(O)OR 3 , wherein R 3 is heteroalkyl. In some embodiments of Formula (I), R 2 is -C(O)OR 3 , wherein R 3 is heteroalkyl that is unsubstituted.
  • R 2 is -C(O)OR 3 , wherein R 3 is ethyl. In some embodiments of Formula (I), R 2 is -C(O)OR 3 , wherein R 3 is alkyl. In some embodiments of Formula (I), R 2 is -C(O)OR 3 , wherein R 3 is alkyl substituted with heterocyclylalkyl. In some embodiments of Formula (I), R 2 is -C(O)OR 3 , wherein R 3 is alkyl substituted with -N(R 13 )C(O)OR 14 . In some embodiments of Formula (I), R 13 is hydrogen or alkyl.
  • R 14 is alkyl, aryl, or heteroaryl.
  • R 2 is -C(O)OR 3 , wherein R 3 is heteroalkyl.
  • R 2 is -C(O)OR 3 , wherein R 3 is heteroalkyl that is substituted with cycloalkyl.
  • R 2 is -C(O)OR 3 , wherein R 3 is heteroalkyl that is substituted with alkyl.
  • R 2 is -C(O)OR 3 , wherein R 3 is cycloalkyl.
  • R 2 is -C(O)OR 3 , wherein R 3 is cycloalkyl that is substituted with N(R 18 )R 19 .
  • each of R 18 and R 19 is hydrogen, alkyl, or heteroalkyl.
  • R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted.
  • R 2 is -C(O)OR 3 , wherein R 3 is alkyl.
  • R 2 is -C(O)OR 3 , wherein R 3 is alkyl substituted with C(O)R 14 , and wherein R 14 is heteroaryl substituted with one or more R B .
  • R 2 is -C(O)OR 3 , wherein R 3 is alkyl substituted with C(O)R 14 , and wherein R 14 is heteroaryl.
  • R 2 is - C(O)OR 3 , wherein R 3 is alkyl substituted with C(O)R 14 , wherein R 14 is heterocyclylalkyl.
  • R 2 is -C(O)OR 3 , wherein R 3 is alkyl substituted with C(O)R 14 , wherein R 14 is heteroaryl that is unsubstituted.
  • R 2 is - C(O)OR 3 , wherein R 3 is alkyl substituted with C(O)R 14 , and wherein R 14 is heterocyclylalkyl that is unsubstituted.
  • R 2 is -C(O)NHCH(R 5 )OC(O)R 6 , wherein R 5 is hydrogen and R 6 is heteroaryl and substituted with one or more R A and R A is independently alkyl or -OR 13 and R 13 is alkyl.
  • the compound has the structure:
  • compounds having the structure of Formula (Ia), are provided: (Ia), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy, and R 3 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl.
  • R 3 is unsubstituted alkyl.
  • R 1 is deuterated alkoxy, and R 3 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments of Formula (I) and (Ia), R 3 is unsubstituted alkyl. In some embodiments of Formula (I) and (Ia), R 1 is methoxy, and R 3 is unsubstituted alkyl. In some embodiments of Formula (I) and (Ia), R 1 is deuterated methoxy, and R 3 is unsubstituted alkyl. In some embodiments of Formula (I) and (Ia), R 1 is hydrogen, and R 3 is unsubstituted alkyl.
  • R 1 is deuterium, and R 3 is unsubstituted alkyl. In some embodiments of Formula (I) and (Ia), R 3 is unsubstituted heteroalkyl. In some embodiments of Formula (I) and (Ia), R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, or 3-methyl-1-butyl. In other embodiments of Formula (I) and (Ia), R 3 is phenyl.
  • R 3 is 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • R 3 is ethyl.
  • R 1 is hydrogen, and R 3 is ethyl.
  • R 1 is deuterium, and R 3 is ethyl.
  • R 1 is methoxy, and R 3 is ethyl.
  • R 1 is deuterated methoxy, and R 3 is ethyl. In some embodiments of Formula (I) and (Ia), R 1 is alkoxy and R 3 is . In some such embodiments Formula (I) and (Ia), R 1 is methoxy and R 3 is . In some embodiments of Formula (I) and (Ia), R 1 is deuterated alkoxy and R 3 is . In some such embodiment 1 s Formula (I) and (Ia), R is deuterated methoxy and R 3 is . In some embodiments of Formula (I) and (Ia), the compound is:
  • the compound is: In some embodiments of Formulas (I) and (Ia), when R 1 is hydrogen, then R 3 is not tert- butyl. In some embodiments of Formula (I) and (Ia), if R 1 is hydrogen and R 3 is alkyl, then R 3 is bound to the atom to which it is attached via a primary or secondary carbon. In some embodiments of Formulas (I) and (Ia), when R 1 is deuterium, then R 3 is not tert-butyl. In some embodiments of Formula (I) and (Ia), if R 1 is deuterium and R 3 is alkyl, then R 3 is bound to the atom to which it is attached via a primary or secondary carbon.
  • Formula (I) compounds have the structure of Formula (Ib): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof wherein: R 1 is alkoxy or deuterated alkoxy; each of R A1 , R A2 , R A3 , and R A4 is independently hydrogen or alkyl, and R A5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR 13 , -N(R 13 )C(O)OR 14 , - N(R 13 )C(O)R 14 , -C(O)R 14 , -OC(O)R 15 , or -OC(O)OR 16 .
  • one of R A1 , R A2 , R A3 , and R A4 is alkyl, and each of R A1 , R A2 , R A3 , and R A4 that is not alkyl is hydrogen.
  • two of R A1 , R A2 , R A3 , and R A4 are alkyl, and each of R A1 , R A2 , R A3 , and R A4 that is not alkyl is hydrogen.
  • each of R A1 , R A2 , R A3 , and R A4 is hydrogen.
  • compounds having the structure of Formula (Ib1) are provided: (Ib1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof.
  • R A5 is heteroalkyl.
  • R A5 is heteroalkyl that is substituted or unsubstituted.
  • R A5 is heterocyclylalkyl that is unsubstituted.
  • R A5 is methoxy, ethoxy, cyclopropyloxy, methylamino, or dimethylamino. In some embodiments of Formula (Ib) and (Ib1), R A5 is , or . In some embodiments of Formulas (Ib) and (Ib1), R A5 is -OC(O)R 15 , in certain such embodiments of Formula (Ib) and (Ib1), R A5 is -OC(O)R 15 , wherein R 15 is alkyl, cycloalkyl, aryl, or heteroaryl.
  • compounds of Formula (Ib) and (Ib1) have R A5 as - OC(O)R 15 , and R 15 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n- pentyl, or 3-methyl-1-butyl.
  • R A5 is - OC(O)R 15 , wherein R 15 is phenyl.
  • R A5 is -OC(O)R 15 , wherein R 15 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • compounds disclosed herein have R A5 as -N(R 13 )C(O)OR 14 and in certain such embodiments R 13 is hydrogen or alkyl, in such embodiments of Formula (Ib) and (Ib1), wherein R A5 is -N(R 13 )C(O)OR 14 , R 13 is alkyl, such as a substituted alkyl group as described herein.
  • compounds have R A5 as -N(R 13 )C(O)OR 14 , wherein R 13 is unsubstituted alkyl.
  • R A5 is -N(R 13 )C(O)OR 14
  • R 14 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, or 3-methyl-1-butyl.
  • R A5 is -N(R 13 )C(O)R 14 .
  • R A5 is -N(R 13 )C(O)R 14 , wherein R 13 is hydrogen or alkyl.
  • R A5 is -N(R 13 )C(O)R 14 , wherein R 13 is hydrogen. In some embodiments of Formula (Ib) and (Ib1), R A5 is -N(R 13 )C(O)R 14 , wherein R 13 is alkyl. In some embodiments of Formula (Ib) and (Ib1), R A5 is -N(R 13 )C(O)R 14 , wherein R 13 is unsubstituted alkyl.
  • R A5 is -N(R 13 )C(O)R 14 , wherein R 14 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, or 3-methyl-1- butyl.
  • R A5 is -N(R 13 )C(O)R 14 , wherein R 14 is phenyl.
  • R A5 is -N(R 13 )C(O)R 14 , wherein R 14 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • R 14 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • the compound is:
  • disclosed compounds have Formula (I), (Ib), or (Ib1), wherein the compound is:
  • disclosed compounds of Formula (I) have the structure of Formula (Ic):
  • R 1 is alkoxy, such as methoxy
  • each of R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • each of R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • disclosed compounds have Formulas (I) and (Ic), wherein each of R 18 and R 19 is independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, -CH 2 CH- 2OMe, or -CH2CH2SO2Me.
  • the compounds have Formula (Ic), wherein R 18 is hydrogen, and R 19 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert- butyl, -CH 2 CH 2 OMe, or -CH 2 CH 2 SO 2 Me.
  • each of R 18 and R 19 are independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, -CH2CH2OMe, and -CH2CH2SO2Me.
  • R 18 and R 19 together with the nitrogen atom, to which they are attached form a heterocyclylalkyl ring, such as an azetidine ring, a pyrrolidine ring, a morpholine ring, a piperidine ring or a piperazine ring.
  • the compound is:
  • compounds have the structure of Formula (Id): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is alkoxy, such as methoxy, and R 5 is hydrogen, alkyl, or cycloalkyl, and R A6 is hydrogen or alkyl.
  • R 1 is alkoxy, such as methoxy
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • R A6 is hydrogen or alkyl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • R A6 is hydrogen or alkyl.
  • Formula (I) compounds have Formula (Id), wherein R 5 is unsubstituted alkyl.
  • R 5 is hydrogen, methyl, ethyl, or isopropyl.
  • R A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl.
  • R 5 is unsubstituted alkyl
  • R A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl.
  • R 5 is hydrogen
  • R A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl.
  • compounds of Formulas (I) and (Id) are selected from the structures:
  • compounds of Formula (I) have Formula (Ie): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is alkoxy, such as methoxy, and R 5 is hydrogen, alkyl, or cycloalkyl.
  • R 5 is hydrogen.
  • R 5 is unsubstituted alkyl.
  • a compound of Formulas (I) and (Ie) is:
  • compounds of Formula (I) have the structure of Formula (If): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy, such as methoxy, and each of R 9 and R 10 is independently alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments of compounds of Formula (I) and (If), each of R 9 and R 10 is independently unsubstituted alkyl.
  • R 1 is methoxy, and each of R 9 and R 10 is independently unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R 1 is deuterated methoxy, and each of R 9 and R 10 is independently unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R 1 is hydrogen, and each of R 9 and R 10 is independently unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R 1 is deuterium, and each of R 9 and R 10 is independently unsubstituted alkyl.
  • each of R 9 and R 10 is independently unsubstituted heteroalkyl.
  • each of R 9 and R 10 is independently methyl, ethyl, n-propyl, isopropyl, n- butyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tert-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, or 3-methyl-1-butyl.
  • each of R 9 and R 10 is independently selected from haloalkyl, such as CH2CHF2, CH2CF3, and CH2cPr.
  • one or both of R 9 and R 10 is phenyl.
  • at least one of R 9 and R 10 is heteroaryl, such as being independently selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- pyrimidyl and 6-pyrimidyl.
  • a compound of Formula (I) and (If) has each of R 9 and R 10 as alkyl, such as a compound wherein both of R 9 and R 10 are ethyl.
  • R 1 is hydrogen, and each of R 9 and R 10 is ethyl.
  • R 1 is deuterium, and each of R 9 and R 10 is ethyl.
  • R 1 is methoxy, and each of R 9 and R 10 is ethyl.
  • R 1 is deuterated methoxy, and each of R 9 and R 10 is ethyl.
  • R 1 is methoxy or hydrogen
  • R 9 is hydrogen
  • R 10 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl.
  • R 1 is deuterated methoxy, deuterium
  • R 9 is hydrogen
  • R 10 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl.
  • R 9 is hydrogen, and R 10 is unsubstituted alkyl.
  • R 1 is methoxy, R 9 is hydrogen, and R 10 is unsubstituted alkyl.
  • R 1 is deuterated methoxy, R 9 is hydrogen, and R 10 is unsubstituted alkyl.
  • R 1 is hydrogen, R 9 is hydrogen, and R 10 is unsubstituted alkyl.
  • R 1 is deuterium
  • R 9 is hydrogen
  • R 10 is unsubstituted alkyl.
  • R 9 is hydrogen
  • R 10 is unsubstituted heteroalkyl.
  • R 9 is hydrogen
  • R 10 is methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tert-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, or 3-methyl-1-butyl.
  • a disclosed compound is a compound of Formulas (I) and (If), wherein R 9 is hydrogen and R 10 is -CH2CHF2, -CH2CF3, or -CH2cPr.
  • R 9 is hydrogen
  • R 10 is phenyl.
  • R 9 is hydrogen
  • R 10 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • R 9 is hydrogen, and R 10 is methyl or ethyl.
  • R 1 is hydrogen, R 9 is hydrogen, and R 10 is ethyl.
  • R 1 is deuterium, R 9 is hydrogen, and R 10 is ethyl.
  • compounds of Formulas (I) and (If) have R 1 being methoxy, R 9 being hydrogen, and R 10 being ethyl.
  • R 1 is alkoxy, R 9 is hydrogen, and R 10 is , and in some such embodiments of Formulas (I) and (If), R 1 is methoxy, R 9 is hydrogen, and R 10 is .
  • R 1 is deuterated alkoxy
  • R 9 is hydrogen
  • R 10 is and in some such embo 1 diments of Formulas (I) and (If), R is deuterated methoxy, R 9 is hydrogen, and R 10 is .
  • a compound of Formulas (I) and (If) is:
  • compounds of Formulas (I) and (If) are represented by the structure of Formula (If1): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; R 10 is hydrogen, alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl; and each of X 1 and X 2 are independently selected from -CH2-, -O-, -N(Y 1 )-, -S-, -S(O)-, -S(O)2- N(Y 1 )-, wherein each Y 1 is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl.
  • each of X 1 and X 2 are independently selected from -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-N(Y 1 )-, wherein each Y 1 is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 10 is hydrogen, alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl
  • each of X 1 and X 2 are independently selected from -CH2-, -O-, -N(Y 1 )-, -S-, -S(O)-, -S(O)2- N(Y 1 )-, wherein each Y 1 is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl.
  • each of X 1 and X 2 are independently selected from -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-N(Y 1 )-, wherein each Y 1 is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl.
  • each Y 1 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or CH2CH2OMe.
  • X 1 is -CH 2 - and X 2 is -N(Y 1 )-.
  • X 2 is -CH 2 - and X 1 is -N(Y 1 )-.
  • compounds according to Formula (If1) have X 1 as -CH2- and X 2 as -N(Y 1 )-, wherein Y 1 is hydrogen, methyl, ethyl, n- propyl, isopropyl, cyclopropyl, or -CH 2 CH 2 OMe.
  • X 2 is -CH 2 - and X 1 is -N(Y 1 )-, wherein Y 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or -CH2CH2OMe.
  • Y 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or -CH2CH2OMe.
  • compounds according to Formula (If1), each of X 1 and X 2 are -O- or -NH-.
  • R 10 is hydrogen.
  • compounds disclosed herein have the structure of Formula (Ig):
  • R 1 is alkoxy, such as methoxy
  • each of R A1 , R A2 , R A3 , and R A4 is independently hydrogen or alkyl
  • R 10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl
  • R A5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR 13 , -N(R 13 )C(O)OR 14 , - N(R 13 )C(O)R 14 , -C(O)R 14 , -OC(O)R 15 , or -OC(O)OR 16 .
  • R 1 is deuterated alkoxy, such as deuterated methoxy; each of R A1 , R A2 , R A3 , and R A4 is independently hydrogen or alkyl; R 10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and R A5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR 13 , -N(R 13 )C(O)OR 14 , - N(R 13 )C(O)R 14 , -C(O)R 14 , -OC(O)R 15 , or -OC(O)OR 16 .
  • a compound of Formula (Ig) has R A1 , R A2 , R A3 , and R A4 selected from alkyl, and each of R A1 , R A2 , R A3 , and R A4 that is not alkyl is hydrogen.
  • Formula (Ig) two of R A1 , R A2 , R A3 , and R A4 are alkyl, and each of R A1 , R A2 , R A3 , and R A4 that is not alkyl is hydrogen.
  • compounds according to Formula (Ig) have each of R A1 , R A2 , R A3 , and R A4 being hydrogen.
  • disclosed compounds of Formula (Ig) include those wherein R A5 is heterocyclyl that is substituted or unsubstituted.
  • Certain embodiments of Formula (Ig) have R A5 as methoxy, ethoxy, cyclopropyloxy, methylamino, or dimethylamino. Examples of certain embodiments of Formula (Ig), wherein R A5 is heterocyclyl include those wherein R In some embodiments of compounds of Formula (Ig), are those wherein R 10 is hydrogen.
  • R 10 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. With continued reference to Formula (Ig), in certain embodiments of this Formula, R 10 is - CH 2 CH 2 OMe or -CH 2 CH 2 SO 2 Me. In some embodiments of Formula (Ig), R A5 is -OC(O)R 15 , in such embodiments, R 15 typically is alkyl, cycloalkyl, aryl, or heteroaryl.
  • R 15 includes groups selected from those such as methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and 3-methyl-1-butyl.
  • R A5 is -OC(O)R 15
  • R 15 is aryl, such as optionally substituted phenyl.
  • R A5 is -OC(O)R 15
  • R 15 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6- pyrimidyl.
  • R A5 is N(R 13 )C(O)OR 14 .
  • R 13 is hydrogen or alkyl and in particular examples of such embodiments, wherein R A5 is N(R 13 )C(O)OR 14 , R 13 is hydrogen.
  • R 13 is substituted or unsubstituted alkyl.
  • R A5 is - N(R 13 )C(O)OR 14 and R 14 is alkyl
  • examples of particular R 14 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and 3-methyl-1-butyl.
  • R A5 is -N(R 13 )C(O)R 14 .
  • R 13 can be selected from hydrogen and alkyl.
  • R A5 is -N(R 13 )C(O)R 14
  • R 13 is hydrogen.
  • R A5 is - N(R 13 )C(O)R 14
  • R 13 is alkyl, including substituted and unsubstituted alkyl.
  • R 14 can be selected from the group including methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and 3-methyl-1-butyl.
  • R A5 is -N(R 13 )C(O)R 14
  • R 14 is substituted or unsubstituted phenyl.
  • R A5 is -N(R 13 )C(O)R 14
  • R 14 is heteroaryl, such as a heteroaryl selected from 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, and 6-pyrimidyl.
  • the compound is: In some embodiments of a compound of Formula (I) and (Ig), the compound is:
  • compounds having the structure of Formula (Ih) are disclosed: or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; R 10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and each of R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • R 1 is alkoxy, such as methoxy
  • R 10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl
  • each of R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl
  • R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl
  • each of R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • R 10 is hydrogen.
  • R 10 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In some embodiments of a compound of Formulas (I) and (Ih), R 10 is CH2CH2OMe or CH2CH2SO2Me. In some embodiments of a compound of Formula (Ih), each of R 18 and R 19 is independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, CH2CH2OMe, or CH2CH2SO2Me.
  • R 18 is hydrogen, and R 19 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, CH 2 CH 2 OMe, or CH 2 CH 2 SO 2 Me.
  • R 18 and R 19 are independently selected from methyl, ethyl, n- propyl, isopropyl, cyclopropyl, tert-butyl, CH2CH2OMe, and CH2CH2SO2Me.
  • R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • R 18 and R 19 together with the atom to which they are attached form an azetidine ring, a morpholine ring, a pyrrolidine ring, a piperidine ring or a piperazine ring.
  • the compound is:
  • the compounds are represented by the structure of Formula (Ii): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; R 5 is hydrogen, alkyl, or cycloalkyl; R 10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and R A6 is hydrogen or alkyl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • R 10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl
  • R A6 is hydrogen or alkyl.
  • R 5 is unsubstituted alkyl.
  • R 5 is selected from hydrogen, methyl, ethyl, and isopropyl.
  • R A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl.
  • R 5 is unsubstituted alkyl
  • R A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl.
  • R 5 is hydrogen
  • R A6 is selected from hydrogen, methyl, ethyl, n- propyl, isopropyl, n-butyl, and benzyl.
  • R 10 is hydrogen.
  • R 10 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In some embodiments of Formula (Ii), R 10 is CH 2 CH 2 OMe or CH 2 CH 2 SO 2 Me. In some embodiments of compounds of Formulas (I) and (Ii), the compound is: In some embodiments of Formula (I), compounds have Formula (Ij): j , or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, Wherein: R 1 is alkoxy, such as methoxy, and R 5 is hydrogen or alkyl. In some embodiments of compounds of Formulas (I) and (Ij), R 5 is hydrogen.
  • R 5 is unsubstituted alkyl. In some embodiments of Formula (Ij), R 5 is methyl, ethyl, or isopropyl. In some embodiments of Formula (Ij), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, R 1 is deuterated alkoxy, such as deuterated methoxy, and R 5 is hydrogen or alkyl. In some embodiments of compounds of Formulas (I) and (Ij), R 5 is hydrogen. In some embodiments of Formula (Ij), R 5 is unsubstituted alkyl. In some embodiments of Formula (Ij), R 5 is methyl, ethyl, or isopropyl.
  • R 10 is hydrogen. In some embodiments of compounds according to Formula (Ij), R 10 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In certain other embodiments of Formula (Ij), R 10 is CH 2 CH 2 OMe or CH 2 CH 2 SO 2 Me. In one embodiment of a compound of Formula (I) and (Ij), the compound is: .
  • the compounds have the structure of Formula (Ik): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is alkoxy, such as methoxy, and R 4 is alkyl, heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 4 is alkyl, heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl.
  • R 4 is heteroalkyl. In some embodiments of Formula (Ik), R 4 is heterocyclylalkyl. In some embodiments of Formula (Ik), R 1 is hydrogen and R 4 is heteroalkyl. In some embodiments of a compound of Formula (Ik), R 1 is hydrogen and R 4 is heterocyclylalkyl. In some embodiments of Formula (Ik), R 1 is deuterium and R 4 is heteroalkyl. In some embodiments of a compound of Formula (Ik), R 1 is deuterium and R 4 is heterocyclylalkyl. In some embodiments of Formula (Ik), R 1 is methoxy and R 4 is heteroalkyl.
  • R 1 is methoxy and R 4 is heterocyclylalkyl. In some embodiments of Formula (Ik), R 1 is deuterated methoxy and R 4 is heteroalkyl. In some embodiments of Formula (Ik), R 1 is deuterated methoxy and R 4 is heterocyclylalkyl. In some embodiments of Formulas (Ik), R 4 is alkyl. In some embodiments of a compound of Formula (Ik), R 4 is CH2CF3. In some embodiments of a compound of Formula (Ik), R 4 is unsubstituted alkyl. In some embodiments, R 1 is -OMe and R 4 is alkyl substituted with SO 2 Me.
  • R 1 is -OMe and R 4 is ethyl substituted with SO 2 Me.
  • R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 3- methyl-1-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, or n-nonyl.
  • a compound of Formula (Ik) is one wherein R 4 is cycloalkyl. In some embodiments of compound of Formula (Ik), R 4 is unsubstituted cycloalkyl.
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • the compound is one wherein R 4 is aryl.
  • R 4 is substituted or unsubstituted phenyl.
  • R 4 is heteroaryl and in certain such some embodiments of Formula (Ik), R 4 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 3-pyrimidyl, or 6-pyrimidyl.
  • compounds of Formulas (I) and (Ik) include those wherein the compound is:
  • the compound in a particular embodiment of a compound of Formulas (I) and (Ik), the compound is: In certain other embodiments of compounds of Formula (Ik), R 4 is , or In some embodiments of compounds of Formula (Ik), the compound is:
  • R 4 is , and in certain such embodiments of a compound of Formula (Ik), wherein R 4 is 14 , R is alkyl, cycloalkyl, or aryl, such as compounds wherein R 14 is methyl, ethyl, n-propyl, isopropyl, or CH 2 CH 2 OMe.
  • R 4 is 14
  • R is phenyl.
  • R 14 is alkyl substituted with alkoxy.
  • R 14 is ethyl substituted with methoxy.
  • the compound is:
  • R 4 is , wherein R A7 is hydrogen or alkyl. In some embodiments of such compounds of Formula (Ik), R 4 is , wherein R A7 is hydrogen. In some embodiments of Formula (Ik), R 4 is A7 , wherein R is alkyl. In some embodiments of Formula (Ik), R 4 is A7 , wherein R is unsubstituted alkyl. In some embodiments of Formula (Ik), R 4 is and R A7 is methyl, ethyl, n- propyl, isopropyl, or n-butyl. In some embodiments of Formula (Ik), R 4 is A7 , and R is benzyl. In particular embodiments of compounds of Formulas (I) and (Ik), the compound is:
  • R 1 is alkoxy, such as methoxy
  • each of R A1 , R A2 , R A3 , and R A4 is independently hydrogen, alkyl, or an amino acid side chain
  • R 10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl
  • R A5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR 13 , -N(R 13 )C(O)OR 14 , - N(R 13 )C(O)R 14 , -C(O)R 14 , -OC(O)R 15 , or -OC(O)OR 16 .
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • each of R A1 , R A2 , R A3 , and R A4 is independently hydrogen, alkyl, or an amino acid side chain
  • R 10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl
  • R A5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR 13 , -N(R 13 )C(O)OR 14 , - N(R 13 )C(O)R 14 , -C(O)R 14 , -OC(O)R 15 , or -OC(O)OR 16 .
  • each of R A1 , R A2 , R A3 , and R A4 is hydrogen. In some embodiments of a compound of Formula (Ik1), each of R A1 , R A2 , R A3 , and R A4 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (Ik1), R A5 is heteroalkyl or heterocyclylalkyl. In some embodiments of Formula (Ik1), R A5 is heterocyclylalkyl. In some embodiments of a compound of Formula (Ik1), R A5 is heteroalkyl.
  • each of R A1 , R A2 , R A3 , and R A4 is hydrogen, and R A5 is methoxy.
  • each of R A1 , R A2 , R A3 , and R A4 is hydrogen, and R A5 is alkylsulfonyl.
  • each of R A1 , R A2 , R A3 , and R A4 is hydrogen, and R A5 is methylsulfonyl.
  • R A5 is -OC(O)R 15 .
  • R A5 is -OC(O)R 15 , wherein R 15 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments of Formula (Ik1), R A5 is -OC(O)R 15 , wherein R 15 is alkyl. In some embodiments of Formula (Ik1), R A5 is -OC(O)R 15 , have R 15 as unsubstituted alkyl.
  • R A5 is -OC(O)R 15
  • R 15 is aryl.
  • R A5 is -OC(O)R 15
  • R 15 is unsubstituted aryl.
  • R A5 is -OC(O)R 15 , wherein R 15 is phenyl.
  • R A5 is -OC(O)R 15
  • R 15 is 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • the compounds have the structure of Formula (Ik2): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy; R 13 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 1 is methoxy.
  • R 1 is deuterated alkoxy
  • R 13 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl
  • p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 1 is deuterated methoxy.
  • R 13 is alkyl.
  • R 13 is unsubstituted alkyl.
  • R 13 is methyl, ethyl, n-propyl, isopropyl n-butyl, tert-butyl, n-pentyl, or 3-methyl- 1-butyl.
  • R 13 is aryl.
  • R 13 is unsubstituted aryl.
  • R 13 is phenyl.
  • R 13 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • R 1 is methoxy.
  • R 1 is deuterated alkoxy
  • R A1 is alkyl or an amino acid side chain
  • R A5 is -N(R 18 )R 19 or -N(R 13 )C(O)R 14 .
  • R 1 is deuterated methoxy.
  • R A5 is -N(R 18 )R 19 .
  • compounds of Formula (Ik3) have R A1 as -N(R 18 )R 19 , wherein each of R 18 and R 19 is hydrogen.
  • R A5 is -N(R 13 )C(O)R 14 .
  • R A5 is -N(R 13 )C(O)R 14 , wherein R 19 is alkyl, cycloalkyl, or aryl.
  • R A5 is -N(R 13 )C(O)R 14 , wherein R 18 is hydrogen, and R 19 is alkyl, cycloalkyl, or aryl.
  • R A5 is -N(R 13 )C(O)R 14 , wherein R 18 is hydrogen, and R 19 is unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted aryl.
  • R A5 is - N(R 13 )C(O)R 14 , wherein R 18 is hydrogen, and R 19 is methyl, ethyl, isopropyl, tert-butyl, or phenyl.
  • compounds of Formula (I) have the structure of Formula (Il): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy; R 5 is hydrogen alkyl, or cycloalkyl; and R 6 is alkyl, cycloalkyl, heterocyclylalkyl, or heteroalkyl. In one embodiment of such compounds according to Formulas (I) and (Il), R 1 is methoxy.
  • R 1 is deuterated alkoxy
  • R 5 is hydrogen alkyl, or cycloalkyl
  • R 6 is alkyl, cycloalkyl, heterocyclylalkyl, or heteroalkyl.
  • R 1 is deuterated methoxy.
  • R 6 is methyl, ethyl, isopropyl, tert-butyl, 2- dimethylaminoethyl, or cyclopropyl.
  • R 1 is hydrogen, R 5 is hydrogen, and R 6 is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl, or cyclopropyl.
  • R 1 is deuterium, R 5 is hydrogen, and R 6 is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl, or cyclopropyl.
  • R 1 is methoxy
  • R 5 is hydrogen
  • R 6 is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl, or cyclopropyl.
  • R 1 is deuterated methoxy
  • R 5 is hydrogen
  • R 6 is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl, or cyclopropyl.
  • R 1 is hydrogen, R 5 is hydrogen, and R 6 is tert-butyl. In some embodiments of Formulas (I) and (Il), R 1 is deuterium, R 5 is hydrogen, and R 6 is tert-butyl. In some embodiments of Formulas (I) and (Il), R 1 is methoxy, R 5 is hydrogen, and R 6 is tert- butyl. In some embodiments of Formulas (I) and (Il), R 1 is deuterated methoxy, R 5 is hydrogen, and R 6 is tert-butyl.
  • compounds of Formula (I) disclosed herein include those having the structure of Formula (Im): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy; R 4 hydrogen, alkyl, cycloalkyl, or heteroalkyl; and each of R 11 and R 12 is independently selected from cycloalkyl, aryl, heteroaryl, or alkyl.
  • R 1 is methoxy.
  • compounds of Formula (Im), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof wherein: R 1 is deuterated alkoxy; R 4 hydrogen, alkyl, cycloalkyl, or heteroalkyl; and each of R 11 and R 12 is independently selected from cycloalkyl, aryl, heteroaryl, or alkyl.
  • R 1 is deuterated methoxy.
  • R 4 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, or alkyl substituted with heteroaryl.
  • each of R 11 and R 12 is independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl.
  • each of R 11 and R 12 is alkyl.
  • each of R 11 and R 12 is unsubstituted alkyl. In some embodiments of compounds according to Formulas (I) and (Im), each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 . In some embodiments compounds of Formulas (I) and (Im) have each of R 11 and R 12 as alkyl substituted with -OC(O)R 15 , wherein each R 15 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein each R 15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl, such as wherein each R 15 is heterocyclylalkyl substituted with alkyl or arylalkyl.
  • R 4 is hydrogen.
  • R 4 is hydrogen, each of R 11 and R 12 is alkyl, heterocyclylalkyl, or cycloalkyl.
  • R 4 is hydrogen or C1-3 alkyl.
  • R 4 is hydrogen and each of R 11 and R 12 is alkyl, such as unsubstituted alkyl.
  • R 1 is methoxy, R 4 is hydrogen, and each of R 11 and R 12 is unsubstituted alkyl.
  • R 1 is deuterated methoxy, R 4 is hydrogen, and each of R 11 and R 12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Im), R 1 is hydrogen, R 4 is hydrogen, and each of R 11 and R 12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Im), R 1 is deuterium, R 4 is hydrogen, and each of R 11 and R 12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Im), R 1 is methoxy, R 4 is hydrogen, and each of R 11 and R 12 is hydrogen or tert-butyl.
  • R 1 is deuterated methoxy
  • R 4 is hydrogen
  • each of R 11 and R 12 is hydrogen or tert-butyl.
  • R 11 and R 12 each hydrogen
  • one or both of the hydrogens of R 11 and R 12 are replaced by a cation, such as a metal or ammonium cation.
  • R 1 is hydrogen
  • R 4 is hydrogen
  • each of R 11 and R 12 is tert-butyl.
  • R 1 is deuterium
  • R 4 is hydrogen
  • each of R 11 and R 12 is tert-butyl
  • one or more of R 11 and R 12 is .
  • o 11 12 f Formulas (I) and (Im) each of R and R is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, or 3-methyl-1-butyl.
  • each of R 11 and R 12 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • one or both of R 11 and R 12 is phenyl.
  • one or both of R 11 and R 12 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • At least one of R 11 and R 12 is 4-nitrophenyl. In some embodiments of Formulas (I) and (Im), at least one of R 11 and R 12 is benzyl. In some embodiments of Formulas (I) and (Im) having structure of Formula (Im1): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy; each of R A1 , R A3 , and R 4 is independently hydrogen, alkyl, or cycloalkyl; and each of R A2 and R A4 is independently alkyl, heteroalkyl, or cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • R 1 is methoxy.
  • R 1 is deuterated methoxy.
  • each of R A1 , R A3 , and R 4 is independently selected from hydrogen, methyl, ethyl, isopropyl, and tert-butyl.
  • R 4 is hydrogen.
  • each of R A1 and R A3 is hydrogen.
  • R A2 and R A4 are -C(O)OR 13 , and in certain compounds of such embodiments, each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is alkyl, cycloalkyl, aryl, or heteroaryl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 , R A3 , and R 4 is hydrogen; and each R 13 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert- butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is phenyl or 4-nitrophenyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 , R A3 , and R 4 is hydrogen; and each R 13 is phenyl or 4-nitrophenyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is benzyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 , R A3 , and R 4 is hydrogen; and each R 13 is benzyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 , R A3 , and R 4 is hydrogen; and each R 13 is 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • each of R A2 and R A4 is - CO(O)OR 16 , and in certain of these embodiments, compounds of Formula (Im1), each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 is alkyl, cycloalkyl, aryl, or heteroaryl.
  • each of R A2 and R A4 is - CO(O)OR 16 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert- butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 , R A3 , and R 4 is hydrogen; and each R 16 is methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl.
  • a compound of Formula (Im1) is one wherein each of R A2 and R A4 is - CO(O)OR 16 ; each of R A1 , R A3 , and R 4 is hydrogen; and each R 16 is isopropyl.
  • each R A2 and R A4 is -CO(O)OR 16 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 is phenyl or 4-nitrophenyl.
  • At least one of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 , R A3 , and R 4 is hydrogen; and each R 16 is phenyl or 4-nitrophenyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 is benzyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 , R A3 , and R 4 is hydrogen; and each R 16 is benzyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 independently is heteroaryl, such as 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each R A1 , R A3 , and R 4 is hydrogen; and each R 16 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • the compound is: ,
  • the compound is:
  • the compound is:
  • Formula (I), (Im), and/or (Im1) the compound is:
  • Formulas (I), (Im), and/or (Im1) compounds have the structure of Formula (Im1a): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; each of R A1 , R A3 , and R 4 is independently hydrogen, alkyl, or cycloalkyl; and each of R B1 and R B2 is independently hydrogen or alkyl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • each of R A1 , R A3 , and R 4 is independently hydrogen, alkyl, or cycloalkyl
  • each of R B1 and R B2 is independently hydrogen or alkyl.
  • each of R B1 and R B2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentan-3-yl, or benzyl.
  • each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of Formula (Im1a), each of R A1 , R A3 , and R 4 is hydrogen.
  • each of R A1 , R A3 , and R 4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each of R B1 and R B2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentan-3-yl, or benzyl.
  • the compound is: In certain embodiments of compounds of Formula (I), (Im), (Im1), and/or (Im1a), the compound is: In some embodiments of a compound of Formula (I), the compound is a phosphoramidate having the structure of Formula (In): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; R 4 is hydrogen, alkyl, or cycloalkyl; R 8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and each of R 9 and R 10 is hydrogen or alkyl.
  • R 1 is alkoxy, such as methoxy
  • R 4 is hydrogen, alkyl, or cycloalkyl
  • R 8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl
  • each of R 9 and R 10 is hydrogen or alkyl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 4 is hydrogen, alkyl, or cycloalkyl
  • R 8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl
  • each of R 9 and R 10 is hydrogen or alkyl.
  • R 4 is hydrogen or unsubstituted alkyl, and in particular embodiments, R 4 is hydrogen, methyl, ethyl, or tert-butyl.
  • R 8 is alkyl or cycloalkyl. In some embodiments of Formulas (I) and (In), R 8 is unsubstituted alkyl or unsubstituted cycloalkyl. In some embodiments of Formulas (I) and (In), R 8 is alkyl, such as methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, isopropyl, tert-butyl, or cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 8 is aryl, such as phenyl. In some embodiments of Formulas (I) and (In), R 8 is 4-nitrophenyl. In some embodiments disclosed herein are compounds of Formula (I) and (In), wherein R 8 is benzyl. In other disclosed embodiments of Formula (I) and (In), R 8 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, or 4-pyrimidyl. In some embodiments of Formulas (I) and (In), R 9 is hydrogen. In some embodiments of compounds according to Formulas (I) and (In), R 9 is hydrogen, and R 10 is alkyl.
  • compounds having the structure of Formula (In1) are provided: or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; each of R 4 and R A1 is hydrogen, alkyl, or cycloalkyl; R 8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and R 13 is alkyl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • each of R 4 and R A1 is hydrogen, alkyl, or cycloalkyl
  • R 8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl
  • R 13 is alkyl.
  • each of R 4 and R A1 is independently selected from hydrogen and unsubstituted alkyl.
  • each of R 4 and R A1 is hydrogen, methyl, ethyl, or tert-butyl.
  • both of R 4 and R A1 is hydrogen.
  • R 8 is alkyl or cycloalkyl.
  • a compound of Formula (In1) has R 8 as unsubstituted alkyl or unsubstituted cycloalkyl.
  • R 8 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 8 is phenyl, such as wherein R 8 is 4-nitrophenyl.
  • R 8 is benzyl.
  • R 8 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, or 4-pyrimidyl.
  • R 13 is unsubstituted alkyl, such as wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH 2 CH(Et) 2 , or more particularly, wherein each of R 4 and R A1 is hydrogen or unsubstituted alkyl; and R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH2CH(Et)2.
  • each of R 4 and R A1 is hydrogen; and R 13 is methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, or -CH 2 CH(Et) 2 .
  • the compound is:
  • a compound of Formula (I) has the structure of Formula (Io): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; and each of R 11 and R 12 is independently selected from cycloalkyl, aryl, heteroaryl, or alkyl; or R 11 and R 12 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • each of R 11 and R 12 is independently selected from cycloalkyl, aryl, heteroaryl, or alkyl; or R 11 and R 12 together with the atom to which they are attached form a heterocyclylalkyl ring.
  • each of R 11 and R 12 is independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl.
  • each of R 11 and R 12 is alkyl.
  • one or both of R 11 and R 12 is unsubstituted alkyl.
  • each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , such as wherein each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein each R 15 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, such as embodiments wherein each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein each R 15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein each R 15 is heterocyclylalkyl substituted with alkyl or arylalkyl.
  • each of R 11 and R 12 is alkyl, heterocyclylalkyl, or cycloalkyl, such as wherein each of R 11 and R 12 is alkyl.
  • one or both of R 11 and R 12 is unsubstituted alkyl.
  • a compound of Formulas (I) and (Io) R 1 is methoxy, and each of R 11 and R 12 is unsubstituted alkyl. In some embodiments a compound of Formulas (I) and (Io), R 1 is deuterated methoxy, and each of R 11 and R 12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Io), R 1 is hydrogen, and each of R 11 and R 12 is unsubstituted alkyl. In some embodiments Formulas (I) and (Io), one or both of R 11 and R 12 are tert-butyl.
  • R 1 is hydrogen, and each of R 11 and R 12 is tert-butyl. In some embodiments of Formulas (I) and (Io), R 1 is deuterium, and each of R 11 and R 12 is unsubstituted alkyl. In some embodiments Formulas (I) and (Io), one or both of R 11 and R 12 are tert-butyl. In some embodiments of Formulas (I) and (Io), R 1 is deuterium, and each of R 11 and R 12 is tert- butyl. In some embodiments of Formulas (I) and (Io), each of R 11 and R 12 is .
  • each of R 11 and R 12 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, or 3-methyl-1-butyl.
  • each of R 11 and R 12 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • each of R 11 and R 12 is phenyl.
  • each of R 11 and R 12 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • each of R 11 and R 12 is 4-nitrophenyl.
  • each of R 11 and R 12 is benzyl.
  • the compound has the structure of Formula (Io1):
  • R 1 is alkoxy, such as methoxy
  • each of R A1 and R A3 is independently hydrogen, alkyl, or cycloalkyl
  • each of R A2 and R A4 is independently alkyl, heteroalkyl, or cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • each of R A1 and R A3 is independently hydrogen, alkyl, or cycloalkyl; and each of R A2 and R A4 is independently alkyl, heteroalkyl, or cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.
  • each of R A1 and R A3 is hydrogen. In some embodiments of Formula (Io1), each of R A2 and R A4 is -C(O)OR 13 . In some embodiments of a compound of Formula (Io1), each of R A2 and R A4 is -C(O)OR 13 ; and each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is alkyl, cycloalkyl, aryl, or heteroaryl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 and R A3 is hydrogen; and each R 13 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is phenyl or 4- nitrophenyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 and R A3 is hydrogen; and each R 13 is phenyl or 4-nitrophenyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is benzyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 and R A3 is hydrogen; and each R 13 is benzyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 13 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • each of R A2 and R A4 is -C(O)OR 13 ; each of R A1 and R A3 is hydrogen; and each R 13 is 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • each of R A2 and R A4 is -CO(O)OR 16 .
  • each of R A2 and R A4 is -CO(O)OR 16 ; and each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 is alkyl, cycloalkyl, aryl, or heteroaryl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl.
  • each of R A2 and R A4 is - CO(O)OR 16 ; each of R A1 and R A3 is hydrogen; and each R 16 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl.
  • each R A2 and R A4 is -CO(O)OR 16 ; each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 is phenyl or 4- nitrophenyl.
  • each R A2 and R A4 is -CO(O)OR 16 ; each of R A1 and R A3 is hydrogen; and each R 16 is phenyl or 4-nitrophenyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 is benzyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 and R A3 is hydrogen; and each R 16 is benzyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R 16 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • each of R A2 and R A4 is -CO(O)OR 16 ; each R A1 and R A3 is hydrogen; and each R 16 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • the compound is:
  • (Io2) or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is alkoxy, such as methoxy; and R A1 is aryl or heteroaryl.
  • R A1 is aryl. In some embodiments of Formula (Io2), R A1 is aryl substituted with halogen. In some embodiments of Formula (Io2), R A1 is , wherein each of Z 1 , Z 2 , and Z 3 is independently hydrogen or halogen. In some embodiments of Formula (Io2), R A1 is 1 2 3 wherein each of Z , Z , and Z is independently hydrogen, fluoro, chloro, bromo, or iodo. In some embodiments of Formula (Io2), R A1 is , or In some embodiments of Formula (Io2), the compound is:
  • compounds having the structure of Formula (Io1a) are provided: (Io1a), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; each of R A1 and R A3 is independently hydrogen, alkyl, or cycloalkyl; and each of R B1 and R B2 is independently hydrogen or alkyl.
  • each of R A1 and R A3 is independently hydrogen, alkyl, or cycloalkyl; and each of R B1 and R B2 is independently hydrogen or alkyl.
  • each of R B1 and R B2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentan-3-yl, or benzyl.
  • each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of a compound of Formula (Io1a), each of R A1 and R A3 is independently hydrogen.
  • each of R A1 and R A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each of R B1 and R B2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentan-3-yl, or benzyl.
  • the compound is:
  • R 1 is alkoxy such as methoxy
  • R 8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl
  • each of R 9 and R 10 is hydrogen or alkyl.
  • R 1 is deuterated alkoxy such as deuterated methoxy
  • R 8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl
  • each of R 9 and R 10 is hydrogen or alkyl.
  • R 8 is alkyl or cycloalkyl.
  • R 8 is unsubstituted alkyl or unsubstituted cycloalkyl.
  • R 8 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 8 is phenyl.
  • R 8 is 4-nitrophenyl.
  • R 8 is benzyl.
  • R 8 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl.
  • R 9 is hydrogen.
  • R 9 is hydrogen, and R 10 is alkyl.
  • Formulas (I) and (Ip) compounds having the structure of Formula (Ip1) are provided: or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy such as methoxy; R A1 is hydrogen, alkyl, or cycloalkyl; R 8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and R 13 is alkyl.
  • R 1 is deuterated alkoxy such as deuterated methoxy
  • R A1 is hydrogen, alkyl, or cycloalkyl
  • R 8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl
  • R 13 is alkyl.
  • R A1 is alkyl substituted with -SR 13 .
  • R A1 is ethyl substituted with -SMe.
  • R A1 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (Ip1), R A1 is hydrogen, methyl, ethyl, or tert-butyl. In some embodiments of Formula (Ip1), R A1 is hydrogen. In some embodiments of Formula (Ip1), R 8 is alkyl or cycloalkyl. In some embodiments of Formula (Ip1), R 8 is unsubstituted alkyl or unsubstituted cycloalkyl.
  • R 8 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 8 is phenyl.
  • R 8 is 4-nitrophenyl.
  • R 8 is benzyl.
  • R 8 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, or 4-pyrimidyl.
  • R 13 is unsubstituted alkyl.
  • R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, or -CH 2 CH(Et) 2 .
  • each of R 4 and R A1 is hydrogen or unsubstituted alkyl; and R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or - CH2CH(Et)2.
  • R A1 is hydrogen; and R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH2CH(Et)2.
  • the compound is:
  • compounds of Formula (I) have the structure of Formula (Iq): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; R 5 is hydrogen, alkyl, or cycloalkyl; and R 6 is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • R 6 is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • R 5 is hydrogen or alkyl.
  • R 5 is hydrogen or unsubstituted alkyl.
  • R 5 is hydrogen.
  • R 6 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formulas (I) and (Iq), R 6 is alkyl. In some embodiments of Formulas (I) and (Iq), R 6 is heteroalkyl. In some embodiments of Formulas (I) and (Iq), R 6 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formulas (I) and (Iq), R 6 is alkyl.
  • R 6 is heteroalkyl. In some embodiments of Formulas (I) and (Iq), R 6 is heterocyclylalkyl substituted with arylalkyl. In some embodiments of Formulas (I) and (Iq), R 5 is methyl, isopropyl, tert-butyl, or -CH(Et)2. In some embodiments of Formulas (I) and (Iq), R 5 is hydrogen, and R 6 is alkyl. In some embodiments of Formulas (I) and (Iq), R 5 is alkyl, and R 6 is alkyl.
  • R 5 is hydrogen, and R 6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Iq), R 5 is unsubstituted alkyl, and R 6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Iq), R 6 is methyl, ethyl, isopropyl, tert-butyl, or cyclopropyl. In some embodiments of Formula (I) and (Iq), R 5 is hydrogen, and R 6 is methyl, ethyl, isopropyl, tert-butyl, or cyclopropyl.
  • R 5 is hydrogen, and R 6 is tert-butyl.
  • R 1 is hydrogen, R 5 is hydrogen, and R 6 is tert-butyl.
  • R 1 is deuterium, R 5 is hydrogen, and R 6 is tert-butyl.
  • R 1 is methoxy, R 5 is hydrogen, and R 6 is tert-butyl.
  • R 1 is deuterated methoxy, R 5 is hydrogen, and R 6 is tert-butyl.
  • R 6 is alkyl. In some embodiments of Formulas (I) and (Iq), R 6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Iq), R 6 is cycloalkyl. In some embodiments of Formulas (I) and (Iq), R 6 is methyl, ethyl, n-propyl, tert-butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 6 is phenyl. In some embodiments of Formulas (I) and (Iq), R 6 is 4-nitrophenyl. In some embodiments of Formulas (I) and (Iq), R 6 is benzyl. In some embodiments of Formulas (I) and (Iq), R 6 is heteroaryl. In some embodiments of Formulas (I) and (Iq), R 6 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formulas (I) and (Iq), R 6 is heteroalkyl.
  • R 6 is CH2CH2OMe or CH2CH2SO2Me. In some embodiments of Formulas (I) and (Iq), R 6 is –(CH 2 ) r CO 2 H, wherein r is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Iq), R 6 is –(CH2)sCO2R 13 , wherein s is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Iq), R 6 is –(CH2)sCO2R 13 , wherein R 13 is alkyl.
  • R 6 is –(CH 2 ) s CO 2 R 13 , wherein R 13 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Iq), R 6 is –(CH 2 ) s CO 2 R 13 , wherein R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et)2. In some embodiments of Formulas (I) and (Iq), R 6 is -CH(R A1 )NH2, wherein R A1 is hydrogen, alkyl, heteroalkyl, or an amino acid side chain.
  • R 6 is -CH(R A1 )NH 2
  • R A1 is an amino acid side chain
  • the amino acid side chain is formed from an ⁇ -amino acid side chain, such as one of the naturally occurring amino acid side chains, such as an amino acid selected from alanine, serine, tryptophan, aspartic acid, glutamic acid and the like.
  • R A1 is formed from alanine
  • R A1 is methyl
  • R 6 is -CH(R A1 )NH 2 , wherein R A1 is an amino acid side chain.
  • R 6 is -CH(R A1 )NH2, wherein R A1 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, CH(Me)Et, CH 2 CH(Me) 2 , or CH 2 CH 2 SMe.
  • R 6 is -CH(R A1 )NH 2 , wherein R A1 is benzyl.
  • the compound is: In some embodiments of Formulas (I) and (Iq), wherein the compound is:
  • the compound is: In some embodiments of Formulas (I) and (Iq), has the structure of Formula (Iq1):
  • R 1 is alkoxy, such as methoxy
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • Q 1 is , or , wherein each of Y 1 , Y 2 , or Y 3 is independently -O-, -S-, -S(O)-, -S(O)2-, -N(R Y1 )-, or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently hydrogen, alkyl, heteroalkyl, or heteroaryl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • Q 1 is , , or , wherein each of Y 1 , Y 2 , or Y 3 is independently -O-, -S-, -S(O)-, -S(O) 2 -, -N(R Y1 )-, or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently hydrogen, alkyl, heteroalkyl, or heteroaryl.
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )-. In some embodiments of Formula (Iq1), each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )-, wherein R Y1 is hydrogen.
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or - NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, CH(Et) 2 ⁇ CH 2 CH 2 OMe, CH 2 CH 2 SO 2 Me, or CH 2 CF 3 .
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is phenyl.
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or - NC(O)R Y2 , wherein each of R Y1 and R Y2 is benzyl.
  • a compound of Formula (Iq1) is one wherein each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , and wherein each of R Y1 and R Y2 is independently 2-pyridyl, 3-pyridyl, or 4-pyridyl.
  • the compound is:
  • the compound is:
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently , wherein R Z1 is hydrogen or alkyl.
  • ach of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently , wherein R Z1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or CH(Et)2.
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , each of R Y1 and R Y2 is independently , wherein R Z1 is benzyl.
  • the compound is:
  • Formula (I) compounds have the structure of Formula (Ir): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; R 5 is hydrogen, alkyl, or cycloalkyl; and R 6 is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • R 6 is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • R 5 is hydrogen or alkyl.
  • R 5 is hydrogen or unsubstituted alkyl.
  • R 5 is hydrogen.
  • R 6 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formulas (I) and (Ir), R 6 is alkyl. In some embodiments of Formulas (I) and (Ir), R 6 is heteroalkyl. In some embodiments of Formulas (I) and (Ir), R 6 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formulas (I) and (Ir), R 6 is alkyl.
  • R 6 is heteroalkyl. In some embodiments of Formulas (I) and (Ir), R 6 is heterocyclylalkyl substituted with arylalkyl. In some embodiments of Formulas (I) and (Ir), R 5 is methyl, ethyl, isopropyl, tert-butyl, or -CH(Et)2. In some embodiments of Formulas (I) and (Ir), R 5 is hydrogen, and R 6 is alkyl. In some embodiments of Formulas (I) and (Ir), R 5 is alkyl, and R 6 is alkyl.
  • R 5 is hydrogen, and R 6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Ir), R 5 is unsubstituted alkyl, and R 6 is unsubstituted alkyl. In some embodiments of Formulas (I)of and (Ir), R 5 is unsubstituted alkyl, and R 6 is heterocyclylalkyl.
  • R 6 is methyl, ethyl, n-propyl, isopropyl, tert- butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • R 6 is aryl.
  • Formulas (I) and (Ir) R 6 is phenyl.
  • R 6 is heterocyclylalkyl.
  • R 6 is oxetan-3-yl or azetidin- 3-yl. In some embodiments of Formulas (I) and (Ir), R 6 is heteroaryl. In some embodiments of Formulas (I) and (Ir), R 6 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyyrimidyl. In some embodiments of Formulas (I) and (Ir), R 6 is benzyl. In some embodiments of a compound according to Formulas (I) and (Ir), R 6 is . In some embodiments of a compound of Formulas (I) and (Ir), the compound is:
  • compounds of Formulas (I) and (Ir) have the structure of Formula (Ir1): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkoxy, such as methoxy; R 5 is hydrogen, alkyl, or cycloalkyl; and Q 1 is , or , wherein each of Y 1 , Y 2 , or Y 3 is independently -O-, -S-, -S(O)-, -S(O) 2 -, -N(R Y1 )-, or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently hydrogen, alkyl, heteroalkyl, or heteroaryl.
  • R 1 is alkoxy, such as methoxy
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • Q 1 is , or , wherein each of Y 1 , Y 2 , or Y 3 is
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • Q 1 is , , or , wherein each of Y 1 , Y 2 , or Y 3 is independently -O-, -S-, -S(O)-, -S(O) 2 -, -N(R Y1 )-, or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently hydrogen, alkyl, heteroalkyl, or heteroaryl.
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )-. In some embodiments of a compound of Formula (Ir1), each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )-, wherein R Y1 is hydrogen.
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or - NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, CH(Et) 2 ⁇ CH 2 CH 2 OMe, CH 2 CH 2 SO 2 Me, or CH 2 CF 3 .
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is phenyl.
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is benzyl.
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently 2-pyridyl, 3- pyridyl, or 4-pyridyl.
  • the compound is:
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently Z1 , wherein R is hydrogen or alkyl.
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or - NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently Z1 , wherein R is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or CH(Et) 2 .
  • each of Y 1 , Y 2 , or Y 3 is -N(R Y1 )- or -NC(O)R Y2 , wherein each of R Y1 and R Y2 is independently
  • the compound is:
  • R 1 is alkoxy, such as methoxy
  • R 15 is alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 15 is alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl.
  • R 1 is methoxy
  • R 15 is methyl substituted with -CO2H.
  • R 15 is alkyl. In some embodiments of Formulas (I) and (Is), R 15 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Is), R 15 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl. In some embodiments of Formulas (I) and (Is), R 15 is cycloalkyl. In some embodiments of Formulas (I) and (Is), R 15 is cyclopropyl. In some embodiments of Formulas (I) and (Is), R 15 is heteroalkyl.
  • R 15 is -CH[CH(Me)2]NH2. In some embodiments of Formulas (I) and (Is), R 15 is -(CH 2 ) q CO 2 H, q is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Is), R 15 is phenyl. In some embodiments of Formulas (I) and (Is), R 15 is 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • R 15 is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of Formula (I) and (Is), R 15 is methyl. In some embodiments of Formula (I) and (Is), R 1 is hydrogen, and R 15 is methyl. In some embodiments of Formula (I) and (Is), R 1 is deuterium, and R 15 is methyl. In some embodiments of Formula (I) and (Is), R 1 is methoxy, and R 15 is methyl. In some embodiments of Formula (I) and (Is), R 1 is deuterated methoxy, and R 15 is methyl.
  • the compound is: In some embodiments of Formula (I) having the structure of Formula (It), or a pharmaceutically acceptable salt thereof: or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is alkoxy, such as methoxy, and R 13 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R 13 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • R 13 is alkyl.
  • R 13 is unsubstituted alkyl.
  • R 13 is methyl, ethyl, isopropyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments of Formula (I) and (It), R 13 is cycloalkyl. In some embodiments of Formula (I) and (It), R 13 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of Formula (I) and (It), R 13 is heteroalkyl.
  • R 13 is -CH 2 CH 2 OMe, CH 2 CH 2 SO 2 Me, or CH2CH 2 NMe 2 .
  • R 13 is (CH2)uCO2H, wherein u is 1, 2, 3, 4, 5, or 6.
  • R 13 is aryl.
  • R 13 is phenyl.
  • R 13 is heteroaryl.
  • R 13 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl.
  • R 13 is heterocyclylalkyl.
  • R 13 is oxetan-3-yl or azetidine- 3-yl.
  • R 13 is In some embodiments of Formula (I) and (It), R 13 is B1 , R is hydrogen or alkyl, and Z 1 is -O-, -S-, -S(O)-, -S(O) 2 -, or -N(R C1 )-, R C1 is hydrogen, alkyl, acetyl, or benzoyl. In some embodiments of Formula (I) and (It), R 13 is , where C1 in R is unsubstituted alkyl. In some embodiments of Formula (I) and (It), R 13 is C1 , R is methyl, acetyl, or benzoyl.
  • R 13 is . In some embodiments of Formula (I) and (It), R 13 is , , or , wherein each of Y 1 , Y 2 , or Y 3 is independently -O-, -S-, -S(O)-, -S(O)2-, or -N(R B2 )-, wherein each R B2 is independently hydrogen, alkyl, acetyl, or benzoyl. In some embodiments of Formula (I) and (It), R 13 is or , wherein R B2 is unsubstituted alkyl.
  • R 13 is , or wherein each R B2 independently is methyl, acetyl, or benzoyl. In some embodiments of Formula (I) and (It), R 13 is , or In some embodiments of a compound of Formulas (I) and (It), R 13 is -CH 2 CH 2 R B3 , R B3 is heteroaryl or heterocyclylalkyl. In some embodiments of Formulas (I) and (It), R 13 is - CH2CH2R B3 , wherein R B3 is heterocyclylalkyl.
  • R 13 is -CH2CH2R B3 , wherein R B3 is , , or .
  • the compound is:
  • the compound is:
  • a compound of Formulas (I) and (It) the compound is:
  • compounds of Formula (I) having the structure of Formula (Iu), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof are provided: wherein: R 1 is alkoxy, such as methoxy; R A1 is hydrogen, alkyl, or cycloalkyl; and each of R 20 and R 21 is independently alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl, or R 20 and R 21 together with the atoms to which they are attached form a heterocyclylalkyl ring.
  • R 1 is deuterated alkoxy, such as deuterated methoxy
  • R A1 is hydrogen, alkyl, or cycloalkyl
  • each of R 20 and R 21 is independently alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl, or R 20 and R 21 together with the atoms to which they are attached form a heterocyclylalkyl ring.
  • R A1 is alkyl.
  • R A1 is unsubstituted alkyl.
  • R A1 is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of a compound of Formula (Iu), R A1 is hydrogen. In some embodiments of Formula (Iu), R A1 is methyl. In some embodiments of Formula (Iu), R A1 is hydrogen. In some embodiments of Formula (Iu), R A1 is methyl, ethyl, isopropyl, -CH(Et) 2 , or tert-butyl. In some embodiments of Formula (Iu), each of R 20 and R 21 is independently unsubstituted alkyl.
  • each of R 20 and R 21 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, 3-methyl-1-butyl, n-pentyl, or n-hexyl.
  • each of R 20 and R 21 is independently alkyl.
  • each of R 20 and R 21 is benzyl.
  • each of R 20 and R 21 is independently .
  • each of R and R is phenyl.
  • each of R 20 and R 21 is independently cycloalkyl.
  • each of R 20 and R 21 is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some of Formula (Iu), each of R 20 and R 21 is independently heteroaryl. In some embodiments of Formula (Iu), each of R 20 and R 21 is independently 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formula (Iu), each of R 20 and R 21 is independently alkyl or cycloalkyl.
  • each of R 20 and R 21 is independently unsubstituted alkyl, and R A1 is hydrogen. In some embodiments of Formula (Iu), each of R 20 and R 21 is independently unsubstituted alkyl, and R 1 is methyl. In some embodiments of Formula (Iu), each of R 20 and R 21 is tert-butyl, R A1 is hydrogen, and R 1 is methoxy. In some embodiments of Formula (Iu), each of R 20 and R 21 is tert-butyl, R A1 is hydrogen, and R 1 is deuterated methoxy.
  • each of R 20 and R 21 is tert-butyl, R A1 is hydrogen, and R 1 is hydrogen. In some embodiments of Formula (Iu), each of R 20 and R 21 is tert-butyl, R A1 is hydrogen, and R 1 is deuterium.
  • the compound is: In some embodiments of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), and (Iu), R 1 is methoxy.
  • the compound is enriched in a heavy isotope, such as deuterium or tritium.
  • the compound is enriched in deuterium and R 1 is hydrogen.
  • R 1 is deuterated methoxy.
  • the compound is enriched in a heavy isotope, such as deuterium or tritium.
  • the compound is enriched in deuterium and R 1 is deuterium.
  • R 4 is hydrogen or alkyl. In some embodiments of Formula (I), R 4 is alkyl. In some embodiments of Formula (I), R 4 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (I), R 4 is hydrogen. In some embodiments of Formula (I), R 4 is unsubstituted alkyl. In some embodiments of Formula (I), R 5 is hydrogen or alkyl. In some embodiments of Formula (I), R 5 is alkyl. In some embodiments of Formula (I), R 5 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (I), R 5 is hydrogen. In some embodiments of Formula (I), R 5 is unsubstituted alkyl.
  • R 2 is -C(O)OCH(R 5 )OC(O)R 6 . In some embodiments of Formula (I), R 2 is -C(O)OCH(R 5 )OC(O)R 6 , wherein R 5 is hydrogen or alkyl. In some embodiments of Formula (I), R 2 is -C(O)OCH(R 5 )OC(O)R 6 , wherein R 5 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (I), R 2 is -C(O)OCH 2 OC(O)R 6 .
  • R 2 is -C(O)OCH(R 5 )OC(O)R 6 , wherein R 6 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formula (I), R 2 is - C(O)OCH(R 5 )OC(O)R 6 , wherein R 6 is alkyl. In some embodiments of Formula (I), R 2 is - C(O)OCH(R 5 )OC(O)R 6 , wherein R 6 is heteroalkyl.
  • R 2 is -C(O)OCH(R 5 )OC(O)R 6 , wherein R 6 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 2 is -C(O)OCH(R 5 )OC(O)R 6 , wherein R 6 is alkyl.
  • R 2 is -C(O)OCH(R 5 )OC(O)R 6 , wherein R 6 is heteroalkyl.
  • R 2 is -C(O)OCH(R 5 )OC(O)R 6 , wherein R 6 is heterocyclylalkyl substituted with arylalkyl.
  • R 2 is -C(O)OCH(R 5 )OC(O)OR 6 .
  • R 2 is -C(O)OCH 2 OC(O)OR 6 .
  • R 2 is -C(O)OCH(R 5 )OC(O)OR 6 , wherein R 5 is alkyl.
  • R 2 is -C(O)OCH(R 5 )OC(O)OR 6 , wherein R 5 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (I), R 2 is -C(O)OCH(R 5 )OC(O)OR 6 , wherein R 6 is heteroalkyl. In some embodiments of Formula (I), R 2 is -C(O)OCH(R 5 )OC(O)OR 6 , wherein R 6 is alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.
  • R 2 is - C(O)OCH(R 5 )OC(O)OR 6 , wherein R 6 is heterocyclylalkyl substituted with alkyl, heteroalkyl, or arylalkyl.
  • R 2 is -C(O)OCH(R 5 )OC(O)OR 6 , wherein R 6 is unsubstituted heteroalkyl.
  • R 2 is - C(O)OCH(R 5 )OC(O)OR 6 , wherein R 6 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted heterocyclylalkyl.
  • R 2 is -C(O)OCH(R 5 )OC(O)OR 6 , wherein R 6 is heterocyclylalkyl substituted with alkyl, heteroalkyl, or arylalkyl.
  • R 2 is -C(O)OCH(R 5 )OC(O)OR 6 , wherein R 6 is heterocyclylalkyl that is unsubstituted.
  • R 2 is -C(O)N(R 9 )R 10 and in certain of such embodiments, each of R 9 and R 10 is independently alkyl, such as alkyl that is unsubstituted.
  • R 2 is -C(O)N(H)R 10 , wherein R 10 is alkyl, such as alkyl that is unsubstituted.
  • R 2 is -C(O)N(R 9 )R 10 , wherein each of R 9 and R 10 is independently alkyl substituted with -N(R 18 )R 19 or -C(O)OR 13 .
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is unsubstituted alkyl, and R 10 is alkyl substituted with -N(R 18 )R 19 or -C(O)OR 13 .
  • R 2 is - C(O)N(H)R 10 , wherein R 10 is alkyl substituted with -N(R 18 )R 19 or -C(O)OR 13 .
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is unsubstituted alkyl, and R 10 is alkyl substituted with -N(R 18 )R 19 , wherein each of R 18 and R 19 is unsubstituted alkyl.
  • R 2 is -C(O)N(H)R 10 , wherein R 10 is alkyl substituted with - N(R 18 )R 19 , wherein each of R 18 and R 19 is unsubstituted alkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is alkyl, and R 10 is alkyl substituted with -C(O)OR 13 , wherein R 13 is alkyl that is unsubstituted, or hydrogen.
  • R 2 is -C(O)N(H)R 10 , wherein R 10 is alkyl substituted with -C(O)OR 13 , and R 13 is hydrogen or alkyl that is unsubstituted.
  • R 2 is -C(O)N(R 9 )R 10 , wherein each of R 9 and R 10 is independently alkyl substituted with -C(O)OH.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is alkyl, and R 10 is alkyl substituted with - C(O)OH.
  • R 2 is C(O)N(H)R 10 , wherein R 10 is alkyl substituted with -C(O)OH.
  • R 2 is -C(O)N(R 9 )R 10 and in certain of such embodiments, R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is alkyl or heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or unsubstituted heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with heteroalkyl that is unsubstituted.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with heterocyclylalkyl that is unsubstituted.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with cycloalkyl that is unsubstituted.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with heterocyclylalkyl.
  • R 2 is - C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with cycloalkyl substituted with alkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with - OC(O)R 15 .
  • R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with -OC(O)R 15 , wherein R 15 is hydrogen, alkyl, aryl, or heteroaryl.
  • R 2 is - C(O)N(R 9 )R 10
  • R 9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with -OC(O)R 15
  • R 15 is hydrogen, unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, alkyl, cycloalkyl, or heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted heteroalkyl. In some embodiments of Formula (I), R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is alkyl or heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is alkyl or heteroalkyl, each of which is substituted with -N(R 13 )C(O)R 14 , wherein each of R 13 and R 14 is independently hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is alkyl or heteroalkyl, each of which is substituted with -C(O)N(R 18 )R 19 , wherein each of R 18 and R 19 is independently hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is alkyl or heteroalkyl, each of which is substituted with -N(R 13 )C(O)R 14 , wherein each of R 13 and R 14 is independently hydrogen, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or unsubstituted heteroalkyl.
  • R 2 is - C(O)N(R 9 )R 10 , wherein R 10 is alkyl or heteroalkyl, each of which is substituted with - C(O)N(R 18 )R 19 , wherein each of R 18 and R 19 is independently hydrogen, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or unsubstituted heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, alkyl, cycloalkyl, or heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is cycloalkyl substituted with -N(R 18 )R 19 , wherein each of R 18 and R 19 is hydrogen, alkyl, heteroalkyl, or cycloalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is cycloalkyl substituted with -N(R 18 )R 19 , wherein each of R 18 and R 19 is hydrogen, unsubstituted alkyl, unsubstituted heteroalkyl, or unsubstituted cycloalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is cycloalkyl substituted with -N(R 18 )R 19 , and R 18 and R 19 together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, alkyl, cycloalkyl, or heteroalkyl. In some embodiments of Formula (I), R 2 is -C(O)N(R 9 )R 10 , wherein R 9 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted heteroalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is alkyl substituted with -OC(O)N(R 18 )R 19 , and R 18 and R 19 together with the atom to which they are attached form a heteroaryl ring or a heterocyclylalkyl ring, each of which is substituted with alkyl, heteroalkyl, or cycloalkyl.
  • R 2 is -C(O)N(R 9 )R 10 , wherein R 10 is alkyl substituted with -OC(O)R 15 , wherein R 15 is heterocyclylalkyl substituted with alkyl or arylalkyl.
  • R 2 is -C(O)R 4 , wherein R 4 is alkyl, heteroalkyl, heterocyclylalkyl, or cycloalkyl.
  • R 2 is -C(O)R 4 , wherein R 4 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocyclylalkyl, or unsubstituted cycloalkyl.
  • R 4 is heterocyclylalkyl substituted with aryl or arylalkyl.
  • R 2 is -C(O)R 4 , wherein R 4 is alkyl substituted with -C(O)OR 13 .
  • R 2 is -C(O)R 4 , wherein R 4 is alkyl substituted with -C(O)OR 13 , wherein R 13 is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl.
  • R 2 is -C(O)R 4 , wherein R 4 is alkyl substituted with -C(O)OR 13 , wherein R 13 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 4 is alkyl substituted with -OC(O)R 15 , wherein R 15 is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl.
  • R 2 is -C(O)R 4
  • R 4 is alkyl substituted with -OC(O)R 15
  • R 15 is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl.
  • R 2 is -C(O)R 4
  • R 4 is alkyl substituted with -OC(O)R 15 , wherein R 15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, or unsubstituted heterocyclylalkyl.
  • R 2 is -C(O)R 4 , and R 4 is alkyl substituted with -OC(O)R 15 , wherein R 15 is heterocyclylalkyl substituted with alkyl.
  • R 2 is -C(O)R 4 , wherein R 4 is alkyl substituted with -N(R 13 )C(O)R 14 , R 13 is alkyl, cycloalkyl, or hydrogen; and R 14 is alkyl, aryl, or heteroaryl.
  • R 2 is -C(O)R 4 , R 4 is alkyl substituted with - N(R 13 )C(O)R 14 , R 13 is unsubstituted alkyl, unsubstituted cycloalkyl, or hydrogen; and R 14 is unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 2 is -C(O)R 4 , wherein R 4 is alkyl substituted with -NH2.
  • R 2 is -C(O)R 4
  • R 4 is alkyl substituted with aryl, wherein the aryl is substituted with alkyl or -OC(O)OR 16
  • R 16 is alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl.
  • R 2 is -C(O)R 4 , wherein R 4 is alkyl substituted with aryl, the aryl is substituted with alkyl or -OC(O)OR 16 , and R 16 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 2 is -C(O)R 4 , wherein R 4 is heterocyclylalkyl substituted with C(O)R 14 .
  • exemplary embodiments have R 4 as heterocyclylalkyl substituted with C(O)R 14 , wherein R 14 is alkyl, heteroalkyl, cycloalkyl, or aryl.
  • R 2 is -C(O)R 4
  • R 4 is heterocyclylalkyl substituted with C(O)R 14
  • R 14 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted aryl.
  • R 2 is -CH(R 4 )OP(O)OR 11 (OR 12 ). In some embodiments of Formula (I), R 2 is -CH(R 4 )OP(O)OR 11 (OR 12 ), wherein R 4 is hydrogen, alkyl, cycloalkyl, or heteroalkyl. In some embodiments of Formula (I), wherein R 2 is - CH(R 4 )OP(O)OR 11 (OR 12 ), wherein R 4 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, or alkyl substituted with heteroaryl.
  • R 2 is -CH(R 4 )OP(O)OR 11 (OR 12 ) wherein each of R 11 and R 12 is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, or alkyl.
  • R 2 is -CH(R 4 )OP(O)OR 11 (OR 12 ), wherein each of R 11 and R 12 is independently selected from alkyl, hydrogen and a counterion, such as a metal or ammonium cation.
  • R 2 is -CH(R 4 )OP(O)OR 11 (OR 12 ), wherein each of R 11 and R 12 is independently selected from hydrogen and a counterion.
  • R 2 is -CH(R 4 )OP(O)OR 11 (OR 12 ), wherein each of R 11 and R 12 is independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl.
  • each of R 11 and R 12 is alkyl, such as unsubstituted alkyl.
  • R 2 is - CH(R 4 )OP(O)OR 11 (OR 12 )
  • at least one of R 11 and R 12 is alkyl substituted with -OC(O)R 15 .
  • each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein each R 15 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl.
  • each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein each R 15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein each R 15 is heterocyclylalkyl substituted with alkyl or arylalkyl.
  • R 2 is -CH(R 4 )OP(O)OR 8 [N(R 9 )R 10 ].
  • R 4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, or alkyl substituted with heteroaryl.
  • R 4 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, or alkyl substituted with heteroaryl.
  • R 2 is -CH(R 4 )OP(O)OR 8 [N(R 9 )R 10 ], R 8 is alkyl, cycloalkyl, aryl, heteroaryl, alkyl, or alkyl substituted with aryl or heteroaryl; R 9 is hydrogen; and R 12 is alkyl substituted with -C(O)OR 13 .
  • R 2 is -CH(R 4 )OP(O)OR 8 [N(R 9 )R 10 ], R 8 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl; R 9 is hydrogen; and R 12 is alkyl substituted with -C(O)OR 13 , and R 13 is alkyl, such as unsubstituted alkyl.
  • R 2 is -P(O)OR 11 (OR 12 ).
  • each of R 11 and R 12 is selected from alkyl and hydrogen or a counterion, such as a metal or ammonium cation.
  • R 2 is -P(O)OR 11 (OR 12 )
  • one of R 11 and R 12 is alkyl and the other is hydrogen or a counterion, such as a metal or ammonium cation.
  • R 11 and R 12 is hydrogen and the other is a counterion, such as a metal or ammonium cation.
  • each of R 11 and R 12 is unsubstituted alkyl. In some embodiments of Formula (I) wherein R 2 is -P(O)OR 11 (OR 12 ), each of R 11 and R 12 is alkyl substituted with - C(O)OR 13 . In some embodiments of Formula (I) wherein R 2 is -P(O)OR 11 (OR 12 ), R 13 is alkyl, cycloalkyl, aryl, or heteroaryl.
  • R 2 is -P(O)OR 11 (OR 12 ), wherein R 13 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 2 is -P(O)OR 11 (OR 12 ), wherein each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 .
  • R 2 is - P(O)OR 11 (OR 12 ), wherein each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein R 15 is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl.
  • R 2 is -P(O)OR 11 (OR 12 ), wherein each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein R 15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, or unsubstituted heterocyclylalkyl.
  • R 2 is -P(O)OR 11 (OR 12 ), wherein each of R 11 and R 12 is alkyl substituted with -OC(O)R 15 , wherein R 15 is heterocyclylalkyl substituted with alkyl or arylalkyl.
  • R 2 is -P(O)OR 11 (OR 12 ), wherein each of R 11 and R 12 is alkyl substituted with -OC(O)OR 16 , and wherein R 16 is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl.
  • each of R 11 and R 12 is alkyl substituted with -OC(O)OR 16 , wherein R 16 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, or unsubstituted heterocyclylalkyl.
  • R 2 is -P(O)OR 11 (OR 12 ), wherein R 11 and R 12 together with the atom to which they are attached form a heterocyclylalkyl ring such as an unsubstituted heterocyclylalkyl ring or a heterocyclylalkyl ring that is substituted with aryl.
  • R 2 is -P(O)OR 11 (OR 12 ), and R 11 and R 12 together with the atom to which they are attached form a heterocyclylalkyl ring that is substituted with unsubstituted aryl or substituted aryl, such as aryl substituted with halogen.
  • R 2 is -P(O)OR 8 [N(R 9 )R 10 ].
  • R 2 is -P(O)OR 8 [N(R 9 )R 10 ]
  • R 8 is alkyl, aryl, or heteroaryl, such as unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • each of R 9 and R 10 are independently selected from hydrogen and alkyl.
  • R 2 is - P(O)OR 8 [N(R 9 )R 10 ], R 8 is unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl, R 9 is hydrogen, and R 10 is alkyl.
  • R 2 is -P(O)OR 8 [N(R 9 )R 10 ], wherein R 8 is unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl, R 9 is hydrogen, and R 10 is alkyl substituted with -C(O)R 14 .
  • R 2 is - P(O)OR 8 [N(R 9 )R 10 ], R 10 is alkyl substituted with -C(O)R 14 , and R 14 is hydrogen or alkyl.
  • R 14 is unsubstituted alkyl.
  • R 2 is -S(O)2OR 7 , and in some such embodiments, R 7 is alkyl, such as unsubstituted or substituted alkyl.
  • R 2 is -S(O)2OR 7 , wherein R 7 is alkyl substituted with -C(O)R 14 .
  • R 14 is heterocyclylalkyl.
  • R 2 is -S(O) 2 OR 7 , wherein R 7 is alkyl substituted with -C(O)R 14 .
  • R 7 is alkyl substituted with -C(O)R 14 , wherein R 14 is heterocyclylalkyl substituted with alkyl, -C(O)CH3, or C(O)Ph.
  • R 2 is -C(O)OR 3 , wherein R 3 is alkyl substituted with -OP(O)OR 20 (OR 21 ).
  • R 3 is alkyl substituted with - OP(O)OR 20 (OR 21 ), wherein each of R 20 and R 21 is independently hydrogen (or a counterion), alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl.
  • R 3 is alkyl substituted with - OP(O)OR 20 (OR 21 ), wherein each of R 20 and R 21 is independently alkyl, hydrogen, or a counterion, such as a metal cation or ammonium cation.
  • R 3 is alkyl substituted with - OP(O)OR 20 (OR 21 ), wherein each of R 20 and R 21 is independently unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heterocyclylalkyl, or unsubstituted heteroaryl.
  • R 2 is -C(O)OR 3
  • R 3 is alkyl substituted with - OP(O)OR 20 (OR 21 )
  • each of R 20 and R 21 is independently unsubstituted alkyl.
  • the present invention provides a compound of Formula (Iv):
  • R 1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy
  • L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium
  • L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3
  • R 2 is hydrogen, -C(O)OR 3 , -C(O)R 4 , -CH(R 5 )OR 6 , -C(O)OCH(R 5 )OC(O)R 6 , - C(O)OCH(R 5 )OC(O)OR 6 , -C(O)NHCH(R 5 )OC(O)R 6 , -CH(R 5 )C(O)R 6 , -S(O) 2 OR 7 , - P(O)OR 8 [N(R 9 )R 10 ],
  • R 1 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • R 1 is - OCH 3 , -OCH 2 D, -OCHD 2 , or -OCD 3 ; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • R 1 is - OCH3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • R 1 is - OCD3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 1 is hydrogen; R 1 is -OCH 3 ; R 2 is hydrogen; and at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 2 is hydrogen; R 1 is -OCH3; R 2 is hydrogen; and at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 3 is hydrogen; R 1 is -OCH 3 ; R 2 is hydrogen; and at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 4 is hydrogen; R 1 is -OCH3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is deuterium.
  • L 5 is hydrogen; R 1 is -OCH3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is deuterium.
  • L 1 is deuterium; R 1 is -OCH 3 ; R 2 is hydrogen; and at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 2 is deuterium; R 1 is -OCH 3 ; R 2 is hydrogen; and at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 3 is deuterium; R 1 is -OCH 3 ; R 2 is hydrogen; and at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 4 is deuterium; R 1 is -OCH3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is deuterium.
  • L 5 is deuterium; R 1 is -OCH3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is deuterium.
  • R 1 is - OCD3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 1 is hydrogen; R 1 is -OCD3; R 2 is hydrogen; and at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 2 is hydrogen; R 1 is -OCD 3 ; R 2 is hydrogen; and at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 3 is hydrogen; R 1 is -OCD3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 4 is hydrogen; R 1 is -OCD 3 ; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is deuterium.
  • L 5 is hydrogen; R 1 is -OCD3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is deuterium.
  • L 1 is deuterium; R 1 is -OCD3; R 2 is hydrogen; and at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 2 is deuterium; R 1 is -OCD 3 ; R 2 is hydrogen; and at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 3 is deuterium; R 1 is -OCD 3 ; R 2 is hydrogen; and at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is deuterium.
  • L 4 is deuterium; R 1 is -OCD 3 ; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is deuterium.
  • L 5 is deuterium; R 1 is -OCD 3 ; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is deuterium.
  • L 6 is - CH 3 ; R 1 is -OCH 3 ; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is deuterium.
  • L 6 is - CH3; R 1 is -OCD3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is deuterium.
  • L 7 is - CH3; R 1 is -OCH3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is deuterium.
  • L 7 is - CH3; R 1 is -OCD3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is deuterium.
  • L 6 is - CD 3 ; R 1 is -OCH 3 ; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is deuterium.
  • L 6 is - CD3; R 1 is -OCD3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is deuterium.
  • L 7 is - CD 3 ; R 1 is -OCH 3 ; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is deuterium.
  • L 7 is - CD3; R 1 is -OCD3; R 2 is hydrogen; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is deuterium.
  • R 1 is -OCH 3 ; R 2 is hydrogen; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • R 1 is -OCD 3 ;
  • R 2 is hydrogen;
  • L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and
  • L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 1 is hydrogen;
  • R 1 is -OCH 3 ;
  • R 2 is hydrogen;
  • L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium;
  • L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 2 is hydrogen; R 1 is -OCH 3 ; R 2 is hydrogen; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 3 is hydrogen; R 1 is -OCH3; R 2 is hydrogen; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 4 is hydrogen; R 1 is -OCH3; R 2 is hydrogen; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 5 is hydrogen; R 1 is -OCH3; R 2 is hydrogen; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 1 is deuterium; R 1 is -OCH3; R 2 is hydrogen; L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 2 is deuterium; R 1 is -OCH 3 ; R 2 is hydrogen; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 3 is deuterium; R 1 is -OCH 3 ; R 2 is hydrogen; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 4 is deuterium; R 1 is -OCH 3 ; R 2 is hydrogen; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 5 is deuterium; R 1 is -OCH 3 ; R 2 is hydrogen; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 1 is hydrogen; R 1 is -OCD 3 ; R 2 is hydrogen; L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 2 is hydrogen; R 1 is -OCD 3 ; R 2 is hydrogen; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 3 is hydrogen; R 1 is -OCD3; R 2 is hydrogen; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 4 is hydrogen; R 1 is -OCD3; R 2 is hydrogen; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 5 is hydrogen; R 1 is -OCD3; R 2 is hydrogen; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 1 is deuterium; R 1 is -OCD3; R 2 is hydrogen; L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 2 is deuterium; R 1 is -OCD 3 ; R 2 is hydrogen; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 3 is deuterium; R 1 is -OCD 3 ; R 2 is hydrogen; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 4 is deuterium; R 1 is -OCD 3 ; R 2 is hydrogen; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 5 is deuterium; R 1 is -OCD 3 ; R 2 is hydrogen; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 6 is -CH 3 ; R 1 is -OCH 3 or -OCD 3 ; R 2 is hydrogen; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 7 is selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 7 is -CH 3 ; R 1 is -OCH 3 or -OCD 3 ; R 2 is hydrogen; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 is selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 6 is -CD3; R 1 is -OCH3 or -OCD3; R 2 is hydrogen; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 7 is selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 7 is -CD3; R 1 is -OCH3 or -OCD3; R 2 is hydrogen; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 is selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3.
  • R 1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy
  • L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium
  • L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • At least one of R 1 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • R 1 is - OCH 3 , -OCH 2 D, -OCHD 2 , or -OCD 3 ; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • R 1 is - OCH 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • R 1 is - OCD3; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 1 is hydrogen; R 1 is -OCH 3 ; and optionally at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 2 is hydrogen; R 1 is -OCH 3 ; and optionally at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 3 is hydrogen; R 1 is -OCH 3 ; and optionally at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 4 is hydrogen; R 1 is -OCH3; and optionally at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 5 is hydrogen; R 1 is -OCH3; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is enriched in deuterium.
  • L 1 is deuterium; R 1 is -OCH3; and optionally at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 2 is deuterium; R 1 is -OCH3; and optionally at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 3 is deuterium; R 1 is -OCH3; and optionally at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 4 is deuterium; R 1 is -OCH 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 5 is deuterium; R 1 is -OCH 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is enriched in deuterium.
  • L 1 is hydrogen; R 1 is -OCD 3 ; and optionally at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 2 is hydrogen; R 1 is -OCD 3 ; and optionally at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 3 is hydrogen; R 1 is -OCD 3 ; and optionally at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 4 is hydrogen; R 1 is -OCD3; and optionally at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 5 is hydrogen; R 1 is -OCD3; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is enriched in deuterium.
  • L 1 is deuterium; R 1 is -OCD3; and optionally at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 2 is deuterium; R 1 is -OCD3; and optionally at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 3 is deuterium; R 1 is -OCD3; and optionally at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 4 is deuterium; R 1 is -OCD 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 5 is deuterium; R 1 is -OCD 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is enriched in deuterium.
  • L 6 is - CH 3 ; R 1 is -OCH 3 or -OCD 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is enriched in deuterium.
  • L 7 is - CH 3 ; R 1 is -OCH 3 or -OCD 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is enriched in deuterium.
  • L 6 is - CD 3 ; R 1 is -OCH 3 or -OCD 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is enriched in deuterium.
  • L 7 is - CD3; R 1 is -OCH3 or -OCD3; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is enriched in deuterium.
  • At least one of R 1 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • R 1 is - OCH 3 , -OCH 2 D, -OCHD 2 , or -OCD 3 ; and at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • R 1 is -OCH 3 ; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • R 1 is -OCD3; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 1 is hydrogen; R 1 is -OCH3; L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 2 is hydrogen; R 1 is -OCH3; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 3 is hydrogen; R 1 is -OCH3; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 4 is hydrogen; R 1 is -OCH3; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 5 is hydrogen; R 1 is -OCH3; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 1 is deuterium; R 1 is -OCH3; L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 2 is deuterium; R 1 is -OCH3; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 3 is deuterium; R 1 is -OCH 3 ; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 4 is deuterium; R 1 is -OCH 3 ; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 5 is deuterium; R 1 is -OCH 3 ; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 1 is hydrogen; R 1 is -OCD 3 ; L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 2 is hydrogen; R 1 is -OCD 3 ; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 3 is hydrogen; R 1 is -OCD 3 ; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 4 is hydrogen; R 1 is -OCD3; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 5 is hydrogen; R 1 is -OCD3; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 1 is deuterium; R 1 is -OCD3; L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 2 is deuterium; R 1 is -OCD3; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 3 is deuterium; R 1 is -OCD 3 ; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 4 is deuterium; R 1 is -OCD 3 ; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 5 is deuterium; R 1 is -OCD 3 ; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 6 is -CH 3 ; R 1 is -OCH 3 or -OCD 3 ; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 7 is selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 7 is -CH 3 ; R 1 is -OCH 3 or -OCD 3 ; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 is selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 6 is -CD 3 ; R 1 is -OCH 3 or -OCD 3 ; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 7 is selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 7 is -CD3; R 1 is -OCH3 or -OCD3; L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 is selected from -CH3, -CH2D, -CHD2, and -CD3.
  • Particular embodiments of Formula (Iv) when R 1 is -OCH3 and R 2 is hydrogen have formula (Iv-2): (Iv-2), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 1 is hydrogen; and optionally at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 2 is hydrogen; and optionally at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 3 is hydrogen; and optionally at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 4 is hydrogen; and optionally at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 5 is hydrogen; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is enriched in deuterium.
  • L 1 is deuterium; and optionally at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 2 is deuterium; and optionally at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 3 is deuterium; and optionally at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 4 is deuterium; and optionally at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 5 is deuterium; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is enriched in deuterium.
  • L 6 is - CH 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is enriched in deuterium.
  • L 7 is - CH3; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is enriched in deuterium.
  • L 6 is - CD 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is enriched in deuterium.
  • L 7 is - CD3; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is enriched in deuterium.
  • L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from - CH3, -CH2D, -CHD2, and -CD3.
  • L 1 is hydrogen;
  • L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 2 is hydrogen; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 3 is hydrogen; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 4 is hydrogen; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 5 is hydrogen; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 1 is deuterium; L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 2 is deuterium; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 3 is deuterium; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 4 is deuterium; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 5 is deuterium;
  • L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and
  • L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • Particular embodiments of Formula (Iv) when R 1 is -OCD 3 and R 2 is hydrogen have formula (Iv-3): (Iv-3), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 1 is hydrogen; and optionally at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 2 is hydrogen; and optionally at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 3 is hydrogen; and optionally at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 4 is hydrogen; and optionally at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 5 is hydrogen; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is enriched in deuterium.
  • L 1 is deuterium; and optionally at least one of L 2 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 2 is deuterium; and optionally at least one of L 1 , L 3 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 3 is deuterium; and optionally at least one of L 1 , L 2 , L 4 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 4 is deuterium; and optionally at least one of L 1 , L 2 , L 3 , L 5 , L 6 and L 7 is enriched in deuterium.
  • L 5 is deuterium; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 6 and L 7 is enriched in deuterium.
  • L 6 is - CH 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is enriched in deuterium.
  • L 7 is - CH3; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is enriched in deuterium.
  • L 6 is - CD 3 ; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 7 is enriched in deuterium.
  • L 7 is - CD3; and optionally at least one of L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 is enriched in deuterium.
  • L 1 , L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from - CH3, -CH2D, -CHD2, and -CD3.
  • L 1 is hydrogen;
  • L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 2 is hydrogen; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 3 is hydrogen; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • L 4 is hydrogen; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 5 is hydrogen; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 1 is deuterium; L 2 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 2 is deuterium; L 1 , L 3 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 3 is deuterium; L 1 , L 2 , L 4 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 4 is deuterium; L 1 , L 2 , L 3 , and L 5 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
  • L 5 is deuterium; L 1 , L 2 , L 3 , and L 4 are each independently selected from hydrogen and deuterium; and L 6 and L 7 are each independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 .
  • Selected compounds of the disclosure with corresponding simplified molecular-input line-entry system (SMILES) strings are provided in Table 1. TABLE 1
  • the present disclosure provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising a compound according to any formula selected from those including those recited in Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.
  • the deuterated compounds disclosed herein may be made by any method known to a person of ordinary skill in the art.
  • the compound is made using a known synthetic method for making the analogous non-deuterated compound, but with one or more deuterated starting materials, and/or reactants used in the synthesis.
  • Methods for making non- deuterium enriched 6-methoxy-N,N, -dimethyltryptame are known in the art and a person of ordinary skill in the art understands which deuterated reactants and reagents are available and may be used in the synthesis of the disclosed compounds. Additional information concerning synthetic methods to make non-deuterated analogs of the disclosed compounds is available in the art.
  • An exemplary method for making compounds of the present disclosure are provided by the following Schemes. Conditions and reagent amounts for the steps illustrated in the Deuterated Scheme are described in detail in the Examples section of the present disclosure.
  • the present disclosure provides a method of treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine psychedelic such as a DMT analog disclosed herein is beneficial, comprising administering to a subject in need thereof an effective amount of a compound selected from those recited in Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2
  • the condition comprises post-traumatic stress disorder, major depression, schizophrenia, or substance abuse. Additional examples of methods for using the disclosed compounds are described below.
  • the compounds of the present invention including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3), and pharmaceutically acceptable salts thereof can be used for increasing neuronal plasticity.
  • the compounds of the present invention can also be used to treat any brain disease.
  • the compounds of the present invention can also be used for increasing at least one of translation, transcription or secretion of neurotrophic factors.
  • a compound of the present invention including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3), and pharmaceutically acceptable salts thereof, is used to treat neurological diseases
  • the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • the neurological disease is a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • the neurological disease is a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).
  • the neurological disease is a migraine or cluster headache.
  • the neurological disease is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease.
  • the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety.
  • the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post- traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety.
  • the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder).
  • the neuropsychiatric disease or neurological disease is depression.
  • the neuropsychiatric disease or neurological disease is anxiety.
  • the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD).
  • the neurological disease is stroke or traumatic brain injury.
  • the neuropsychiatric disease or neurological disease is schizophrenia.
  • a compound of the present invention including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), (Iv-3) and pharmaceutically acceptable salts thereof, is used for increasing neuronal plasticity.
  • the compounds described herein are used for treating a brain disorder. In some embodiments, the compounds described herein are used for increasing at least one of translation, transcription, or secretion of neurotrophic factors.
  • the compounds of the present invention including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), (Iv-3) and pharmaceutically acceptable salts thereof, have activity
  • the compounds of the present invention have activity as 5-HT 2A modulators.
  • the compounds of the present invention elicit a biological response by activating the 5-HT2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor).
  • 5-HT2A agonism has been correlated with the promotion of neural plasticity (Ly et al., 2018).
  • 5-HT 2A antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT2A agonist activity, for example., DMT, LSD, and DOI.
  • the compounds of the present invention are 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds of the present invention are selective 5-HT 2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain.
  • the 5-HT 2A modulators are non- hallucinogenic.
  • non-hallucinogenic 5-HT2A modulators e.g., 5-HT2A agonists
  • the hallucinogenic potential of the compounds described herein is assessed in vitro.
  • the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs.
  • the compounds described herein elicit less hallucinogenic potential in vitro than the hallucinogenic homologs.
  • non-hallucinogenic 5-HT2A modulators are used to treat neurological diseases.
  • the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT 2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.
  • non-hallucinogenic 5-HT2A modulators e.g., 5-HT2A agonists
  • non-hallucinogenic 5-HT2A modulators e.g., 5-HT 2A agonists
  • non-hallucinogenic 5-HT2A modulators e.g., 5-HT2A agonists
  • the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, volinanserin (MDL-100,907), olanzapine, risperidone, pimavanserin, nelotanserin and lorcaserin.
  • Neuronal plasticity refers to the ability of the brain to change structure and/or function throughout a subject's life. New neurons can be produced and integrated into the central nervous system throughout the subject's life. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain.
  • increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.
  • increasing neuronal plasticity can treat neurodegenerative disorder, Alzheimer's, Parkinson's disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.
  • the present invention provides methods for increasing neuronal plasticity, comprising contacting a neuronal cell with any of the compounds of the present invention, including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), (Iv-3) and pharmaceutically acceptable salts thereof.
  • Table 1 Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (
  • a compound of the present invention including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), (Iv-3) and pharmaceutically acceptable salts thereof, is used to increase neuronal plasticity.
  • the compounds used to increase neuronal plasticity have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • decreased neuronal plasticity is associated with a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • the neuropsychiatric disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder).
  • brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
  • the experiment or assay to determine increased neuronal plasticity of any compound of the present invention is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration-response experiment, a 5-HT 2A agonist assay, a 5-HT 2A antagonist assay, a 5-HT 2A binding assay, or a 5- HT2A blocking experiment (e.g., ketanserin blocking experiments).
  • the experiment or assay to determine the hallucinogenic potential of any compound of the present invention is a mouse head-twitch response (HTR) assay.
  • HTR mouse head-twitch response
  • the present invention provides a method for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), or (Iv-3), or a pharmaceutically acceptable salt thereof.
  • Table 1 Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (
  • the present invention provides a method of treating a disease, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention.
  • the present invention provides a method of treating a brain disorder, including administering to a subject in need thereof, a therapeutically effective amount of a compound disclosed herein, such as a compound of Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (Is), (I
  • the present invention provides a method of treating a brain disorder with combination therapy, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention and at least one additional therapeutic agent.
  • serotonin receptor modulators such as modulators of serotonin receptor 2A (5-HT2A modulators, e.g., 5-HT2A agonists) are used to treat a brain disorder.
  • the second therapeutic agent can be an agonist or an antagonist.
  • Serotonin receptor modulators useful as second therapeutic agents for combination therapy as described herein are known to those of skill in the art and include, without limitation, ketanserin, volinanserin (MDL-100907), eplivanserin (SR- 46349), pimavanserin (ACP-103), glemanserin (MDL-11939), ritanserin, flibanserin, nelotanserin, blonanserin, mianserin, mirtazapine, roluperiodone (CYR-101, MIN-101), quetiapine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, pruvanserin, AC- 90179,
  • the serotonin receptor modulator used as a second therapeutic is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.
  • the serotonin receptor modulator is administered prior to a compound disclosed herein, such as about three or about one hours prior to administration of a compound according to Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv),
  • the serotonin receptor modulator is administered at most about one hour prior to the presently disclosed compound.
  • the second therapeutic agent is a serotonin receptor modulator.
  • the second therapeutic agent serotonin receptor modulator is provided at a dose of from about 10 mg to about 350 mg.
  • the serotonin receptor modulator is provided at a dose of from about 20 mg to about 200 mg.
  • the serotonin receptor modulator is provided at a dose of from about 10 mg to about 100 mg.
  • the compound of the present invention is provided at a dose of from about 10 mg to about 100 mg, or from about 20 to about 200 mg, or from about 15 to about 300 mg, and the serotonin receptor modulator is provided at a dose of about 10 mg to about 100 mg.
  • the brain disorders that can be treated as disclosed herein comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof.
  • a compound of the present invention is used to treat brain disorders.
  • the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof.
  • the brain disorder is a neuropsychiatric disease.
  • the neuropsychiatric disease is a mood or anxiety disorder.
  • brain disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, schizophrenia, and addiction (e.g., substance abuse disorder).
  • brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.
  • the brain disorder is a neurodegenerative disorder, Alzheimer's, Parkinson's disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.
  • the brain disorder is a neurodegenerative disorder, Alzheimer's, or Parkinson's disease.
  • the brain disorder is a psychological disorder, depression, addiction, anxiety, or a post-traumatic stress disorder.
  • the brain disorder is depression.
  • the brain disorder is addiction.
  • the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury or substance use disorder.
  • the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, persistent depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.
  • the brain disorder is stroke or traumatic brain injury.
  • the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, or substance use disorder.
  • the brain disorder is schizophrenia.
  • the brain disorder is alcohol use disorder.
  • the method further comprises administering one or more additional therapeutic agent that is lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil),
  • Suitable empathogenic agents for use in combination with a compound according to Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), or (Iv-3), are selected from the phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA) and analogs thereof.
  • MDMA 3,4-methylenedioxymethamphetamine
  • Suitable empathogenic agents for use in combination with the presently disclosed compounds include, without limitation, N-Allyl-3,4-methylenedioxy-amphetamine (MDAL) N-Butyl-3,4-methylenedioxyamphetamine (MDBU) N-Benzyl-3,4-methylenedioxyamphetamine (MDBZ) N-Cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM) N,N-Dimethyl-3,4-methylenedioxyamphetamine (MDDM) N-Ethyl-3,4-methylenedioxyamphetamine (MDE; MDEA) N-(2-Hydroxyethyl)-3,4-methylenedioxy amphetamine (MDHOET) N-Isopropyl-3,4-methylenedioxyamphetamine (MDIP) N-Methyl-3,4-ethylenedioxyamphetamine (MDMC) N-Methoxy-3,4-methylenedioxyamphet
  • the compounds of the present invention are used in combination with the standard of care therapy for a neurological disease described herein.
  • the standard of care therapies may include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof.
  • Nonlimiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole.
  • Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. Additional examples of standard of care therapeutics are known to those of ordinary skill in the art.
  • Methods of increasing at least one of translation, transcription, or secretion of neurotrophic factors refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons.
  • Increasing at least one of translation, transcription, or secretion of neurotrophic factors can be useful for, but not limited to, increasing neuronal plasticity, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain.
  • increasing at least one of translation, transcription, or secretion of neurotrophic factors can increasing neuronal plasticity.
  • increasing at least one of translation, transcription, or secretion of neurotrophic factors can promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and/or increasing dendritic spine density.
  • 5-HT2A modulators e.g., 5-HT2A agonists
  • a compound of the present invention is used to increase at least one of translation, transcription, or secretion of neurotrophic factors.
  • increasing at least one of translation, transcription or secretion of neurotrophic factors treats a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).
  • the experiment or assay used to determine increase translation of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry.
  • the experiment or assay used to determine increase transcription of neurotrophic factors includes gene expression assays, PCR, and microarrays. In some embodiments, the experiment or assay used to determine increase secretion of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry.
  • the present invention provides a method for increasing at least one of translation, transcription or secretion of neurotrophic factors, comprising contacting a neuronal cell with a compound disclosed herein, such as a compound of Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), or (Iv-3), or a pharmaceutically acceptable salt thereof.
  • a compound disclosed herein such as a compound of Table 1,
  • NMR analysis NMR analyses were conducted on a 400 MHz NMR spectrometer using deuterated chloroform, deuterated methanol or deuterated dimethyl sulfoxide as solvent.
  • the shift (d) of each signal was measured in parts per million (ppm) relative to the residual solvent peak, and the multiplicity reported together with the associated coupling constant (J), where applicable.
  • Agilent LC-MS Analysis Methodology Instrument Agilent 1260 infinity HPLC with Agilent 6130 single quadrupole mass spec.
  • Step 2 Preparation of 2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl-2-oxo-acetamide
  • THF 3.0 mL, 6.0 mmol
  • DIPEA 1.14 mL, 6.65 mmol
  • Step 3 Preparation of 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl- ethanamine
  • 2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl-2- oxo-acetamide 200 mg, 0.80 mmol.
  • Ice-cold anhydrous THF (4.5 mL) was added under a stream of N 2 and LiAlD 4 (205 mg, 4.87 mmol) was added under a stream of N 2 with vigorous stirring in an ice-water bath.
  • Example 2 Synthesis of 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl) ethanamine (Compound 269) To a microwave vial was added a stirrer bar and 2-(6-methoxy-1H-indol-3-yl)-2-oxo-N,N- bis(trideuteriomethyl)acetamide (200 mg, 0.80 mmol). Ice-cold anhydrous THF (4.5 mL) was added under a stream of N2 and LiAlD4 (198 mg, 4.72 mmol) was added under a stream of N2 with vigorous stirring in an ice-water bath.
  • LiAlD4 198 mg, 4.72 mmol
  • the tube was sealed, and the mixture was heated to 150 °C under microwave irradiation (Biotage Initiator+) for 5 min. After cooling, the mixture was poured slowly into a mixture of ice-H 2 O. The mixture was extracted with EtOAc (3 x 20 mL) and the combined layers were washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified column chromatography on silica gel (7N NH 3 in MeOH / EtOAc 5:95) to give the title compound (156 mg, 86%) as a viscous oil.
  • Example 3 Synthesis of 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl- ethanamine (Compound 270)
  • Step 1 Preparation of 2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl-acetamide
  • HOBT monohydrate 0.45 g, 2.92 mmol
  • 1-Ethyl-3-(3- dimethylaminopropyl) carbodiimide HCl (0.56 g, 2.92 mmol) was added portion-wise over 5 min, and the mixture was stirred at rt for 2 h.
  • Step 2 Preparation of 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl- ethanamine
  • a microwave vial was added a stirrer bar and 2-(6-methoxyindolin-3-yl)-N,N-dimethyl- acetamide (250 mg, 1.07 mmol).
  • Ice-cold anhydrous THF (10 mL) was added under a stream of N2 and LiAlD4 (134 mg, 3.20 mmol) was added with vigorous stirring under a stream of N2 (the vial placed in an ice-water bath).
  • Example 4 Synthesis of 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl)ethanamine (Compound 271)
  • Step 1 Preparation of 2-(6-methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl)acetamide
  • HOBT monohydrate 0.45 g, 2.92 mmol
  • 0.561 g, 2.92mmol was then added portion- wise over 5 min and the mixture was stirred at rt for 2 h.
  • Step 2 Preparation of 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl)ethanamine
  • a microwave vial was added a stirrer bar and 2-(6-methoxyindolin-3-yl)-N,N- bis(trideuteriomethyl)acetamide (250 mg, 1.04 mmol).
  • Ice-cold anhydrous THF (4.5 mL) was added under a stream of N2 and LiAlD4 (131 mg, 3.12 mmol) was added with vigorous stirring under a stream of N 2 (the vial placed in an ice-water bath).
  • Step 1 Preparation of 1-methyl-2-nitro-4-(trideuteriomethoxy)benzene To a mixture of 4-methyl-3-nitro-phenol (3.00 g, 19.6 mmol) in DMF (20 mL) at rt was added Cs2CO3 (7.02 g, 21.5 mmol) followed by CD3I (0.98 mL, 20.6 mmol) in one portion. The mixture was stirred at rt overnight, then poured into H2O (200 mL) and extracted with Et2O (2 x 100 mL).
  • Step 2 Preparation of 1-[(E)-2-[2-nitro-4-(trideuteriomethoxy)phenyl]vinyl]pyrrolidine
  • a mixture of 1-methyl-2-nitro-4-(trideuteriomethoxy)benzene (3.34 g, 19.6 mmol), DMF.DMA (3.27 g, 27.5 mmol) and pyrrolidine (1.95 g, 27.5 mmol) in DMF (15 mL) was heated to 115 °C and stirred for 7 h. The mixture was cooled, added to ice-H2O (300 mL) and extracted with Et2O (2 x 100 mL).
  • Step 3 Preparation of 6-(trideuteriomethoxy)-1H-indole
  • a mixture of crude 1-[(E)-2-[2-nitro-4-(trideuteriomethoxy)phenyl]vinyl]pyrrolidine (93% purity, 5.30 g, 19.7 mmol) in EtOAc (70 mL) was added 10% Pd on carbon (0.403 g) under a blanket of N2.
  • the mixture was then placed under an atmosphere of H2 (100 psi) and stirred for 19 h, then filtered through celite and the filter cake was washed with EtOAc (100 mL).
  • Step 4 Preparation of 2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetyl chloride
  • 6-(trideuteriomethoxy)-1H-indole 0.50 g, 3.33 mmol
  • Et 2 O 15 mL
  • oxalyl dichloride 0.42 mL, 4.99 mmol
  • Step 5 Preparation of N,N-dimethyl-2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3- yl]acetamide
  • DCM DCM
  • DIPEA 0.427 mL, 2.49 mmol
  • 2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3- yl]acetyl chloride 0.30 g, 1.25 mmol
  • THF 7.5 mL
  • Step 6 Preparation of 1,1,2,2-tetradeuterio-N,N-dimethyl-2-[6-(trideuteriomethoxy)-1H- indol-3-yl]ethanamine
  • N,N-dimethyl-2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetamide 240 mg, 0.96 mmol
  • LiAlD4 242 mg, 5.76 mmol
  • Example 6 Synthesis of 1,1,2,2-tetradeuterio-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]- N,N-bis(trideuteriomethyl)ethanamine (Compound 273) Step 1: Preparation of N,N-di-(trideuteriomethyl)-2-oxo-2-[6-(trideuteriomethoxy)-1H- indol-3-yl]acetamide To a mixture of (CD3)2NH (230 mg, 2.63 mmol) in DCM (5 mL) at 0 °C was added DIPEA (0.64 mL, 3.74 mmol), followed by a dropwise addition of a mixture of 2-oxo-2-[6- (trideuteriomethoxy)-1H-indol-3-yl]acetyl chloride (0.30 g, 1.25 mmol) in THF (7.5 mL).
  • Step 2 Preparation of 1,1,2,2-tetradeuterio-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl)ethanamine
  • N,N-dimethyl-2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3- yl]acetamide 156 mg, 0.61 mmol
  • LiAlD 4 154 mg, 3.67 mmol
  • Example 7 Synthesis of 1,1-dideuterio-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl)ethanamine (Compound 274)
  • Step 1 Preparation of ethyl 2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetate
  • 6-(trideuteriomethoxy)-1H-indole 565 mg, 3.76 mmol
  • DCM 20 mL
  • N2 copper(II) trifluoromethanesulfonate
  • Step 2 Preparation of 2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetic acid
  • ethyl 2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetate as the major component (0.525g, 1.93 mmol) in THF (6 mL) at 0 °C
  • 1M NaOH 5.79 mL, 5.8 mmol
  • the mixture was warmed to rt and stirred overnight, then concentrated in vacuo, the residue dissolved in H2O, cooled to 0 °C and acidified using 2N HCl.
  • Step 3 Preparation of 2-[6-(trideuteriomethoxy)indolin-3-yl]-N,N- bis(trideuteriomethyl)acetamide
  • 2-[6-(trideuteriomethoxy)-1H-indol-3- yl]acetic acid 130 mg, 0.62 mmol
  • hydroxybenzotriazole monohydrate 115 mg, 0.75mmol
  • DCM 5 mL
  • 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride 144 mg, 0.75 mmol
  • 1,1,1-trideuterio-N-(trideuteriomethyl)methanamine hydrochloride 109 mg, 1.25 mmol was added portion wise, followed by DIPEA (0.214 mL, 1.
  • Step 4 Preparation of 1,1-dideuterio-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl) ethanamine
  • a stirrer bar 2-[6-(trideuteriomethoxy)indolin-3-yl]-N,N- bis(trideuteriomethyl)acetamide (109 mg, 0.45 mmol).
  • Ice-cold anhydrous THF (10 mL) was added under an atmosphere of N2, the mixture was cooled in an ice-batch and LiAlD4 (75.2 mg, 1.79 mmol) was added.
  • Example 8 Synthesis of 1,1-dideuterio-N,N-dimethyl-2-[6-(trideuteriomethoxy)-1H-indol- 3-yl]ethanamine (Compound 275)
  • Step 1 Preparation of N,N-dimethyl-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetamide
  • 2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetic acid 130 mg, 0.624 mmol
  • hydroxybenzotriazole monohydrate (0.115 g, 0.75 mmol
  • DCM 10 mL
  • 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.144 g, 0.75 mmol) was added portion wise over 5 min.
  • Step 2 Preparation of 1,1-dideuterio-N,N-dimethyl-2-[6-(trideuteriomethoxy)-1H-indol-3- yl]ethanamine
  • N,N-dimethyl-2-[6-(trideuteriomethoxy)indolin-3-yl]acetamide 66 mg, 1.07 mmol, 71% purity
  • THF 5 mL
  • LiAlD4 (46.7 mg, 1.1 mmol.
  • the mixture was heated to reflux and stirred for 3 h, then cooled to 0 °C, and poured carefully into a mixture of ice-H 2 O (10 mL).
  • Step 1 Preparation of 1-bromo-2-(2H3)-methoxy-5-methyl-4-nitrobenzene
  • 2-bromo-4-methyl-5-nitrophenol (2.52 g, 10.9 mmol) in DMF (20 mL)
  • Cs 2 CO 3 (5.31 g, 16.3 mmol)
  • trideuterio(iodo)methane 0.11 mL, 13.0 mmol
  • the mixture was stirred at rt for 20 h, poured into H2O (200 mL) and extracted with Et 2 O (3 x 70 mL).
  • Step 2 Preparation of [2-(5-bromo-4-(2H3)-methoxy-2-nitrophenyl)ethenyl]dimethylamine
  • a solution of 1-bromo-2-(2H3)-methoxy-5-methyl-4-nitrobenzene (1.60 g, 6.4 mmol) and DMF.DMA (3 mL, 25.5 mmol) in DMF (6 mL) was heated to 145 °C and stirred for 6 h. The mixture was cooled to rt, H 2 O (30 mL) added and the mixture was extracted with Et 2 O (2 x 50 mL).
  • Step 3 Preparation of 5-bromo-6-(2H3)methoxy-1H-indole To a stirred solution of [2-(5-bromo-4-(2H3)methoxy-2-nitrophenyl)ethenyl]dimethylamine (crude, 1.69 g) in AcOH (38 mL) and PhMe (64 mL) was added florisil (16.1 g) and Fe powder (6.44 g).
  • Step 4 Preparation of 6-(2H3)-Methoxy-(5-2H)-1H-indole
  • a suspension of 5-bromo-6-(2H3)methoxy-1H-indole (328 mg, 1.43 mmol) and 10% Pd/C (122 mg) with i Pr 2 NEt (0.3 mL, 1.72 mmol) in CD 3 OD (5 ml) was stirred in a pressure vessel under D 2 (initially 20 psi) for a total of 23 h.
  • the mixture was filtered through Celite, and the filter cake was washed with DCM (3 x 5mL).
  • Step 5 Preparation of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-2-oxo-acetyl chloride
  • oxalyl dichloride 0.060 mL, 0.71 mmol
  • Step 6 Preparation of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl- 2-oxo-acetamide
  • 2M solution in THF (0.31 mL, 0.62 mmol) in THF (2 mL) was added i Pr2NEt (0.071 mL, 0.41 mmol) at 0 °C.
  • 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-2- oxo-acetyl chloride 50 mg, 2.1 mmol
  • THF 7.5 mL
  • Step 7 Preparation of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl- ethanamine LiAlH 4 (33 mg, 0.86 mmol) was taken up in anhydrous THF (3 mL) at 0 °C under an atmosphere of N 2 and 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl-2-oxo-acetamide (0.036 g, 0.144 mmol) was added portion-wise with stirring at 0 °C.
  • Step 2 Preparation of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl)ethanamine LiAlH 4 (33 mg, 0.86 mmol) was taken up in anhydrous THF (3 mL) at 0 °C under an atmosphere of N2 and 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-2-oxo-N,N- bis(trideuteriomethyl)acetamide (36 mg, 0.144 mmol) was added portion-wise with stirring at 0°C.
  • Example 11 Synthesis of 1,1,2,2-tetradeuterio-2-[5-deuterio-6-(trideuteriomethoxy)-1H- indol-3-yl]-N,N-dimethyl-ethanamine (Compound 278) LiAlD4 (92 mg, 2.2 mmol) was taken up in anhydrous THF (3 mL) at 0 °C under a atmosphere of N 2 and 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl-2-oxo-acetamide (92 mg, 0.37 mmol) was added portion-wise with stirring at 0 °C.
  • Example 12 Synthesis of 1,1,2,2-tetradeuterio-2-[5-deuterio-6-(trideuteriomethoxy)-1H- indol-3-yl]-N,N-bis(trideuteriomethyl)ethanamine (Compound 279) LiAlD4 (72 mg, 1.73 mmol) was taken up in anhydrous THF (7 mL) at 0 °C under an atmosphere of N2 and 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-2-oxo-N,N- bis(trideuteriomethyl)acetamide (74 mg, 0.29 mmol) was added portion-wise with stirring at 0°C.
  • Example 13 Evaluation of Metabolic Stability in Human Liver Microsomes
  • the test compound at 1.0 ⁇ M in singlet or positive controls including Testosterone (CYP3A4 substrate), Propafenone (CYP2D6 substrate) or Diclofenac (CYP2C9 substrate) were incubated with the liver microsomes at 0.5 mg/mL, respectively.
  • the mixture was warmed up at 37 °C for 10 minutes and the reactions were initiated by the addition of a NADPH regenerating system ( ⁇ 1.0 mM).
  • the test compound incubated with the liver microsomes at 37 °C without the NADPH regenerating system served as the negative control reaction.
  • the reaction samples were removed at multiple time points (such as 0, 5, 15, 30, 45 and 60 minutes) and the sample without NADPH (NCF) was removed at 60 minutes. All the samples were immediately mixed with cold acetonitrile containing internal standard (IS) to stop the reaction. Samples were analyzed by LC/MS/MS and the disappearance of test compound was assessed based on peak area ratios of analyte/IS (no standard curve).
  • the microsomal intrinsic clearance and T 1/2 values were calculated using the following equation:
  • the microsomal intrinsic clearance and T 1/2 values were calculated using the following equation:
  • the mg microsomal protein / g liver weight was 45 for 5 species
  • the liver weight values used 40 g/kg, 30 g/kg, 32 g/kg, 20 g/kg and 88 g/kg for rat, monkey, dog, human and mouse, respectively.
  • the liver clearance was calculated using CL int(mic) with,
  • the comparator compound may be a suitable reference standard.
  • the comparator compound was 2-(6-methoxy-1H-indol-3-yl)-N,N- dimethylethanamine (6-MeO-DMT).
  • Table 2 Metabolic stability in human liver microsomes of representative deuterated compounds
  • Example 14 Behavioral Despair Test in the rat
  • Environmental enrichment (such as tunnel, gnawing material, nesting material) was provided.
  • the animal house was maintained under artificial lighting (12 hours) between 7:00 and 19:00 in a controlled ambient temperature of 22 ⁇ 2°C, and relative humidity between 30-70%. All animals had free access to food and water.
  • the batches of diet and wood litter are analyzed by the suppliers for composition and contaminant levels. Bacterial and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrates by-products).
  • the test, reference or vehicle formulations was administered intraperitoneally 3 times: 24 hours (after Session 1), 4 hours and 30 minutes before the test session (Session 2).
  • Treatment schedule 6 rats are studied per group and the test is performed blind.1,1,2,2-tetradeuterio-2-(6- methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl) ethanamine HCl (HCl salt of Compound 269) was evaluated at 4 doses, administered intraperitoneally (i.p.) 3 times: 24 hours, 4 hours and 30 minutes before the test (Session 2), and compared with a vehicle control group.
  • Imipramine 32 mg/kg i.p.
  • Table 3 Table 3.
  • Imipramine (32 mg/kg), administered i.p.30 minutes before the test, significantly decreased the duration of immobility, as compared with vehicle controls (-70%, p ⁇ 0.001).
  • These results suggest the presence of antidepressant-like activity for 1,1,2,2-tetradeuterio- 2-(6-methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl) ethanamine HCl (HCl salt of Compound 269) over the dose range 10 – 30 mg/kg i.p. in the Behavioral Despair Test in the rat.
  • Imipramine exhibited antidepressant-like activity at 32 mg/kg i.p. in the same experimental conditions.
  • anxiolytic drugs such as alprazolam and buspirone show significant reductions in the forced swim test (Flugy, Anna, et al. "Antidepressant and anxiolytic effects of alprazolam versus the conventional. antidepressant desipramine and the anxiolytic diazepam in the forced swim test in rats.” European journal of pharmacology 214.2-3 (1992): 233-238). This data also supports that 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl) ethanamine is both an antidepressant and an anxiolytic therapeutic.

Abstract

The present disclosure relates to compound Formula (I): or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, methods for making the compounds and methods for their use.

Description

ANALOGS OF 6-METHOXY-N,N-DIMETHYLTRYPTAMINE CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/288,367, filed on December 10, 2021, which is incorporated by reference herein for all purposes. BACKGROUND Major depressive disorder and related neuropsychiatric diseases are among the leading causes of disability worldwide. Despite recent advances, there remains a need for new therapeutics to support treatment of debilitating neuropsychiatric diseases. Recently, psychedelic compounds have received renewed interest for the treatment of depression and other disorders. For example, the Food and Drug Administration (FDA) recently approved the dissociative anesthetic ketamine for treatment-resistant depression, making it the first mechanistically distinct medicine to be introduced to psychiatry in nearly thirty years. Ketamine is a member of a class of compounds known as psychoplastogens. Psychoplastogens promote neuronal growth through a mechanism involving the activation of AMPA receptors, the tropomyosin receptor kinase B (TrkB), and the mammalian target of rapamycin (mTOR). As pyramidal neurons in the PFC exhibit top-down control over areas of the brain controlling motivation, fear, and reward, these effects support clinical development of psychoplastogenic compounds for their antidepressant, anxiolytic, and anti-addictive effects properties. A common pharmacophore in psychoactive compounds, particularly psychedelic compounds appears to be the N,N-dimethyltryptamine (DMT) skeleton. Recently, DMT was used as the starting point for identifying psychoplastogenic compounds (WO 2020/176597). However, DMT derivatives, like many current medicines exhibit pharmacokinetic properties that undermine their use in clinical treatment. For example, such compounds may have undesirable absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. While these compounds are useful in a variety of in vitro and in vivo contexts, there remains a need for compounds with improved effects and increased duration of actions. Compounds with such improved characteristics are disclosed herein. SUMMARY Disclosed herein are compounds of Formula (I):
Figure imgf000004_0001
(I), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy, R2 is hydrogen, -C(O)OR3, -C(O)R4, -CH(R5)OR6, -C(O)OCH(R5)OC(O)R6, - C(O)OCH(R5)OC(O)OR6, -C(O)NHCH(R5)OC(O)R6, -CH(R5)C(O)R6, -S(O)2OR7, - P(O)OR8[N(R9)R10], -C(O)N(R9)R10, -P(O)OR11(OR12), -CH(R4)OP(O)OR8[N(R9)R10], or -CH(R4)OP(O)OR11(OR12); each of R3, R6, R7, and R8 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, each of R4 and R5, is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, each of R9 and R10 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R9 and R10 together with the atom to which they are attached form a heterocyclylalkyl ring or a heteroaryl ring that is unsubstituted or substituted with one or more RA; each of R11 and R12 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R11 and R12 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RA; each RA is independently alkyl, heteroalkyl, oxo, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, an amino acid side chain, -OR13, -N(R18)R19, -NHC(=NH)NH2, -C(O)OR13, - N(R13)C(O)OR14, -N(R13)C(O)R14, -C(O)R14, -OC(O)R15, -OC(O)OR16, - OP(O)OR17[N(R18)R19], -C(O)N(R18)R19, -OC(O)N(R18)R19, -SR13, -SO2R13, or - OP(O)OR20(OR21), wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with alkyl, aryl, halogen, -OR13, -N (R18)R19, - C(O)R14, -OC(O)R15, -OC(O)OR16, or -OC(O)N(R18)R19; each of R13, R14, R15, R16, or R17 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is unsubstituted or substituted with one or more RB; each of R18 and R19 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one or more RB; each of R20 and R21 is independently alkyl, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB, or R20 and R21 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RB; and each RB is independently halogen, amino, cyano, hydroxyl, alkoxy, benzyl, -CO2H, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, -C(O)CH3, - C(O)Ph, or heteroarylalkyl, wherein cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more halogen, amino, cyano, hydroxyl, alkyl, acetyl, or benzoyl; provided that when R2 is hydrogen, the molecule is isotopically enriched. In some embodiments, the compounds of this disclosure are enriched in deuterium. In some embodiments, the compounds of this disclosure are isotopically labeled analogs of 6-methoxy-N,N-dimethyltryptamine. In some embodiments, the compounds of this disclosure are in the form of a pharmaceutically acceptable salt or a solvate. Also disclosed herein are methods for making and using compounds of Formula (I). Also disclosed is a method for increasing neuronal plasticity, comprising contacting a neuron with an effective amount of a disclosed compound. Also disclosed is a method for increasing neuronal plasticity, comprising contacting a neuron with an effective amount of a disclosed compound, wherein contacting comprises administering the compound to a subject. In some embodiments, the method for treating a neurological disorder or a psychiatric disorder, or both, comprises contacting a subject having the neurological disorder, psychiatric disorder or both with an effective amount of a disclosed compound. The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 illustrates effects of 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl) ethanamine HCl (HCl salt of Compound 269) on duration of immobility in the forced swim test measured in seconds (s). DETAILED DESCRIPTION Terms and Abbreviations: Compounds herein include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof. Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclylalkyl groups, heteroaryl groups, cycloalkyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, ureido groups, epoxy groups, and ester groups. "Acyl" refers to the group –C(O)R, where R is H, aliphatic, such as alkyl, heteroaliphatic, heterocyclic or aryl. Exemplary acyl moieties include, but are not limited to, -C(O)H, - C(O)alkyl, -C(O)C1-C6alkyl, -C(O)C1-C6haloalkyl-C(O)cycloalkyl, -C(O)alkenyl, - C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include, -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl. "Alkyl" refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon having from one to about ten carbon atoms, or from one to six carbon atoms, wherein an sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2- methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1- butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert- amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as "C1-C6 alkyl" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. By way of example, alkyl groups herein include C1-10 alkyl, C1-6 alkyl and C1-3 alkyl groups. In some embodiments, the alkyl is a C1-C10 alkyl, a C1-C9 alkyl, a C1-C8 alkyl, a C1-C7 alkyl, a C1-C6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a C1 alkyl. Alkyl groups include branched and unbranched alkyl groups. Alkyl groups (e.g., methyl) may be saturated with any stable isotope of hydrogen, e.g., protium, deuterium, and tritium. Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen, deuterium, or tritium atoms on one or more carbons of the hydrocarbon backbone. Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec- butyl, and t-butyl. Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl.Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or - OMe. In some embodiments, the alkyl is optionally substituted with halogen. "Alkenyl" refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2- hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkenyl" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. "Alkynyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cycloalkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. Cycloalkyl groups herein include C3-10 cycloalkyl, C3-8 cycloalkyl and C4-6 cycloalkyl groups. A cycloalkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups. Non- limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl-cycloprop-1-yl, cycloprop-2-en-1-yl, cyclobutyl, 2,3-dihydroxycyclobut-1-yl, cyclobut-2-en-1-yl, cyclopentyl, cyclopent-2-en-1-yl, cyclopenta-2,4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopent-1-yl, 3,5-dichlorocyclohex-1-yl, 4-hydroxycyclohex-1-yl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a- hexahydro-3H-inden-4-yl, decahydroazulenyl, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. A haloalkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms. An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or an ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy. A heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms. A heterocycle can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinimide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran. Non-limiting examples of heterocycles include: heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydroquinoline; and ii) heterocyclic units having 2 or more rings one of which is a heterocyclic ring, non-limiting examples of which include hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H- benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, and decahydro-1H-cycloocta[b]pyrrolyl. Non-limiting examples of heteroaryl include: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non- limiting examples of which include: 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H- pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 4,5,6,7- tetrahydro-1-H-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl. "Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined herein. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or - OMe. In some embodiments, the alkoxy is optionally substituted with halogen. Alkoxy groups (e.g., methoxy) may be saturated with any stable isotope of hydrogen, e.g., protium, deuterium, and tritium. "Amino" refers to the group -NH2, -NHR, or -NRR, where each R independently is selected from H, alkyl, cycloalkyl, aryl or heterocyclic, or two R groups together with the nitrogen attached thereto form a heterocyclic ring. Examples of such heterocyclic rings include those wherein two R groups together with the nitrogen to which they are attached form a – (CH2)2-5– ring optionally interrupted by one or two heteroatom groups, such as –O– or –N(Rg) such as in the groups g
Figure imgf000011_0001
and
Figure imgf000011_0002
wherein R is alkyl or acyl. "Aryl" refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclylalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. "Cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), bridged, or spiro ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. As is known to those of skill in the art, such cycloalkyl moieties can be represented by abbreviations, e.g., cyclopropyl may be abbreviated as "cPr". Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. "Deuteroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3. "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is a perhaloalkyl, such as trifluoromethyl. "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as, oxygen, nitrogen (for example, -NH-, - N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or - CH(CH3)OCH3. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. "Heterocyclyl" refers to heteroaryl and heterocyclylalkyl ring systems. "Heterocyclylalkyl" refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclylalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocyclylalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems, e.g., fused-, bridge-d, and spiro-bicycles and higher fused-, bridged-, and spiro-systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclylalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocyclylalkyls include, but are not limited to, heterocyclylalkyls having from two to fifteen carbon atoms (C2-C15 heterocyclylalkyl), from two to ten carbon atoms (C2-C10 heterocyclylalkyl), from two to eight carbon atoms (C2-C8 heterocyclylalkyl), from two to six carbon atoms (C2-C6 heterocyclylalkyl), from two to five carbon atoms (C2-C5 heterocyclylalkyl), or two to four carbon atoms (C2-C4 heterocyclylalkyl). In some embodiments, the heterocyclylalkyl is a 3- to 6-membered heterocyclylalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocyclylalkyl. Examples of such heterocyclylalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1- yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocyclylalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocyclylalkyl, the number of carbon atoms in the heterocyclylalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocyclylalkyl (i.e., skeletal atoms of the heterocyclylalkyl ring). Unless stated otherwise specifically in the specification, a heterocyclylalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, a heterocyclylalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a heterocyclylalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclylalkyl is optionally substituted with halogen. "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclylalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. "Administering" refers to any suitable mode of administration, including, oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. "Subject" refers to an animal, such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human subject. "Therapeutically effective amount" or "therapeutically sufficient amount" or "effective or sufficient amount" refers to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g. , Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non- sensitized cells. "Neuronal plasticity" refers to the ability of the brain to change its structure and/or function continuously throughout a subject's life. Examples of the changes to the brain include, but are not limited to, the ability to adapt or respond to internal and/or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses. "Brain disorder" refers to a neurological disorder which affects the brain's structure and function. Brain disorders can include, but are not limited to, Alzheimer's, Parkinson's disease, psychological disorder, depression, treatment resistant depression, addiction, anxiety, post- traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and substance use disorder. "Combination therapy" refers to a method of treating a disease or disorder, wherein two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents. For example, the compounds of the invention can be used in combination with other pharmaceutically active compounds. The compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy. "Neurotrophic factors" refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons. "Modulate" or "modulating" or "modulation" refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., a positive allosteric modulator) of a G protein-coupled receptor (e.g., 5HT2A) are modulators of the receptor. "Agonism" refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response. "Agonist" refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, "5HT2A agonist" can be used to refer to a compound that exhibits an EC50 with respect to 5HT2A activity of no more than about 100 mM. In some embodiments, the term "agonist" includes full agonists or partial agonists. "Full agonist" refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor. "Partial agonist" refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist. "Positive allosteric modulator" refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist. "Antagonism" refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur. "Antagonist" or "neutral antagonist" refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response. Certain compounds according to Formula (I) disclosed herein are isotopically enriched, meaning that they have an isotope present in greater than its natural abundance at one or more position. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of any compound will inherently contain small amounts of isotopologues, including deuterated isotopologues. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this disclosure. In a compound of this disclosure, when a particular position is designated as having a particular isotope, such as deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015% (on a mol/mol basis). A position designated as a particular isotope will have a minimum isotopic enrichment factor of at least 3000 (45% incorporation of the indicated isotope). Thus, isotopically enriched compounds disclosed herein having deuterium will have a minimum isotopic enrichment factor of at least 3000 (45% deuterium incorporation) at each atom designated as deuterium in the compound. Such compounds may be referred to herein as "deuterated" compounds. In other embodiments, disclosed compounds, including compounds of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3), have an isotopic enrichment factor for each designated atom of at least 3500 (52.5%). For example, for such disclosed compounds that are deuterium isotopologues, the compounds have an isotopic enrichment factor for each designated hydrogen atom of at least 3500 (52.5% deuterium incorporation at each designated atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As above, such compounds also are referred to as "deuterated" compounds. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "protium", the position is understood to have hydrogen at about its natural abundance isotopic composition. The term "isotopologue" refers to a species that has the same chemical structure and formula as another compound, with the exception of the isotopic composition at one or more positions, e.g., H vs. D. Thus, isotopologues differ in their isotopic composition. Any compound herein can be provided as a substantially pure substance. Compounds that are not prepared in pure form can be purified as is known to those of skill in the art. A compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. Pharmaceutically acceptable salts: The present disclosure provides for pharmaceutically-acceptable salts of any compound described herein as well as the use of such salts. As is understood by those of skill in the art, any compound with an ionizable group, such as an acidic hydrogen, or a basic nitrogen, can be provided in the form of a salt, and pharmaceutically acceptable salt forms of such compounds are specifically contemplated herein. Pharmaceutically-acceptable salts include, for example, acid- addition salts and base-addition salts. The acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically- acceptable salt is an ammonium salt. Metal salts can arise from the addition of an inorganic base to a compound of the present disclosure having an acidic functional group. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is a metal cation, such as lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc. In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt. Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure. In some embodiments, the organic amine is trimethyl amine, triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, pyrazolidine, pyrazoline, pyridazine, pyrimidine, imidazole, or pyrazine. In some embodiments, an ammonium salt is a triethyl amine salt, trimethyl amine salt, a diisopropyl amine salt, an ethanolamine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt. Acid addition salts can arise from the addition of an acid to a compound of the present disclosure that includes a basic functional group. In some embodiments, the acid is organic. In other embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, maleic acid or xinafoic acid. In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, a maleate salt or a xinafoate salt. Pharmaceutical compositions: According to another embodiment, the present disclosure provides a composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition is an amount effective to treat the relevant disease, disorder, or condition in a patient in need thereof (an "effective amount"). In some embodiments, a composition of the present disclosure is formulated for oral administration to a patient. The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the agent with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the disclosed compositions include, but are not limited to, ion exchangers, alumina, stearates such as aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. Compositions of the present disclosure may be administered orally, parenterally, enterally, intracistemally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously. In some embodiments, the composition is a transmucosal formulation. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. To aid in delivery of the composition, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. Pharmaceutically acceptable compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, may also be added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, pharmaceutically acceptable compositions can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. In some embodiments, the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In other embodiments, the pharmaceutically acceptable composition is administered with food. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. To prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f ) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. Therapeutic agents can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g ., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Compounds of the disclosure: In one aspect, the present disclosure provides a compound of Formula (I):
Figure imgf000026_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy R2 is hydrogen, -C(O)OR3, -C(O)R4, -CH(R5)OR6, -C(O)OCH(R5)OC(O)R6, - C(O)OCH(R5)OC(O)OR6, -C(O)NHCH(R5)OC(O)R6, -CH(R5)C(O)R6, -S(O)2OR7, - P(O)OR8[N(R9)R10], -C(O)N(R9)R10, -P(O)OR11(OR12), -CH(R4)OP(O)OR8[N(R9)R10], or - CH(R4)OP(O)OR11(OR12); each of R3, R6, R7, and R8 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, each of R4 and R5, is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, each of R9 and R10 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R9 and R10 together with the atom to which they are attached form a heterocyclylalkyl ring or a heteroaryl ring that is unsubstituted or substituted with one or more RA; each of R11 and R12 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R11 and R12 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RA; each RA is independently alkyl, heteroalkyl, oxo, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, an amino acid side chain, -OR13, -N(R18)R19, -NHC(=NH)NH2, -C(O)OR13, - N(R13)C(O)OR14, -N(R13)C(O)R14, -C(O)R14, -OC(O)R15, -OC(O)OR16, - OP(O)OR17[N(R18)R19], -C(O)N(R18)R19, -OC(O)N(R18)R19, -SR13, -SO2R13, or - OP(O)OR20(OR21), wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with alkyl, aryl, halogen, -OR13, -N (R18)R19, - C(O)R14, -OC(O)R15, -OC(O)OR16, or -OC(O)N(R18)R19; each of R13, R14, R15, R16, or R17 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is unsubstituted or substituted with one or more RB; each of R18 and R19 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one or more RB; each of R20 and R21 is independently alkyl, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB, or R20 and R21 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RB; and each RB is independently halogen, amino, cyano, hydroxyl, alkoxy, benzyl, -CO2H, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, -C(O)CH3, -C(O)Ph, or heteroarylalkyl, wherein cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more halogen, amino, cyano, hydroxyl, alkyl, acetyl, or benzoyl; provided that when R2 is hydrogen, the molecule is isotopically enriched. In some embodiments of a compound of Formula (I), R2 is -C(O)OR3. In some embodiments of Formula (I) R2 is -C(O)OR3, wherein R3 is alkyl. In some embodiments of a compound of Formula (I) R2 is -C(O)OR3, wherein R3 is alkyl that is unsubstituted. In some embodiments of Formula (I) R2 is -C(O)OR3, wherein R3 is heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is heteroalkyl that is unsubstituted. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is ethyl. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is alkyl. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is alkyl substituted with heterocyclylalkyl. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is alkyl substituted with -N(R13)C(O)OR14. In some embodiments of Formula (I), R13 is hydrogen or alkyl. In some embodiments of Formula (I), R14 is alkyl, aryl, or heteroaryl. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is heteroalkyl that is substituted with cycloalkyl. In some embodiments of Formula (I) R2 is -C(O)OR3, wherein R3 is heteroalkyl that is substituted with alkyl. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is cycloalkyl. In some embodiments of Formula (I) R2 is -C(O)OR3, wherein R3 is cycloalkyl that is substituted with N(R18)R19. In some embodiments of Formula (I) each of R18 and R19 is hydrogen, alkyl, or heteroalkyl. In some embodiments of Formula (I), R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments of Formula (I), R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments of Formula (I), R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is alkyl. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is alkyl substituted with C(O)R14, and wherein R14 is heteroaryl substituted with one or more RB. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is alkyl substituted with C(O)R14, and wherein R14 is heteroaryl. In some embodiments of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is - C(O)OR3, wherein R3 is alkyl substituted with C(O)R14, wherein R14 is heterocyclylalkyl. In some embodiments Formula (I) R2 is -C(O)OR3, wherein R3 is alkyl substituted with C(O)R14, wherein R14 is heteroaryl that is unsubstituted. In some embodiments of Formula (I), R2 is - C(O)OR3, wherein R3 is alkyl substituted with C(O)R14, and wherein R14 is heterocyclylalkyl that is unsubstituted. In some embodiments of Formula (I), R2 is -C(O)NHCH(R5)OC(O)R6, wherein R5 is hydrogen and R6 is heteroaryl and substituted with one or more RA and RA is independently alkyl, heteroalkyl, oxo, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, an amino acid side chain, - OR13, -N(R18)R19, -NHC(=NH)NH2, -C(O)OR13, -N(R13)C(O)OR14, -N(R13)C(O)R14, -C(O)R14, - OC(O)R15, -OC(O)OR16, -OP(O)OR17[N(R18)R19], -C(O)N(R18)R19, -OC(O)N(R18)R19, -SR13, - SO2R13, or -OP(O)OR20(OR21), wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with alkyl, aryl, halogen, -OR13, -N(R18)R19, -C(O)R14, -OC(O)R15, -OC(O)OR16, or -OC(O)N(R18)R19. In some embodiments of Formula (I), R2 is -C(O)NHCH(R5)OC(O)R6, wherein R5 is hydrogen and R6 is heteroaryl and substituted with one or more RA and RA is independently alkyl or -OR13 and R13 is alkyl. In some embodiments of Formula (I), the compound has the structure:
Figure imgf000029_0001
In some embodiments of Formula (I), compounds having the structure of Formula (Ia), are provided:
Figure imgf000029_0002
(Ia), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy, and R3 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments of Formula (I) and (Ia), R3 is unsubstituted alkyl. R1 is deuterated alkoxy, and R3 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments of Formula (I) and (Ia), R3 is unsubstituted alkyl. In some embodiments of Formula (I) and (Ia), R1 is methoxy, and R3 is unsubstituted alkyl. In some embodiments of Formula (I) and (Ia), R1 is deuterated methoxy, and R3 is unsubstituted alkyl. In some embodiments of Formula (I) and (Ia), R1 is hydrogen, and R3 is unsubstituted alkyl. In some embodiments of Formula (I) and (Ia), R1 is deuterium, and R3 is unsubstituted alkyl. In some embodiments of Formula (I) and (Ia), R3 is unsubstituted heteroalkyl. In some embodiments of Formula (I) and (Ia), R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, or 3-methyl-1-butyl. In other embodiments of Formula (I) and (Ia), R3 is phenyl. In some compounds of Formula (I) and (Ia), R3 is 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In some embodiments of Formula (I) and (Ia), R3 is ethyl. In some of Formula (I) and (Ia), R1 is hydrogen, and R3 is ethyl. In some of Formula (I) and (Ia), R1 is deuterium, and R3 is ethyl. In some embodiments of Formula (I) and (Ia), R1 is methoxy, and R3 is ethyl. In some embodiments of Formula (I) and (Ia), R1 is deuterated methoxy, and R3 is ethyl. In some embodiments of Formula (I) and (Ia), R1 is alkoxy and R3 is . In some such embodiments Formula (I) and (Ia), R1 is
Figure imgf000030_0001
methoxy and R3 is
Figure imgf000030_0002
. In some embodiments of Formula (I) and (Ia), R1 is deuterated alkoxy and R3 is . In some such embodiment 1
Figure imgf000030_0003
s Formula (I) and (Ia), R is deuterated methoxy and R3 is
Figure imgf000030_0004
. In some embodiments of Formula (I) and (Ia), the compound is:
Figure imgf000031_0001
In some embodiments of Formulas (I) and (Ia), the compound is:
Figure imgf000031_0002
In some embodiments of Formulas (I) and (Ia), when R1 is hydrogen, then R3 is not tert- butyl. In some embodiments of Formula (I) and (Ia), if R1 is hydrogen and R3 is alkyl, then R3 is bound to the atom to which it is attached via a primary or secondary carbon. In some embodiments of Formulas (I) and (Ia), when R1 is deuterium, then R3 is not tert-butyl. In some embodiments of Formula (I) and (Ia), if R1 is deuterium and R3 is alkyl, then R3 is bound to the atom to which it is attached via a primary or secondary carbon. In some embodiments of Formula (I) compounds have the structure of Formula (Ib):
Figure imgf000031_0003
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof wherein: R1 is alkoxy or deuterated alkoxy; each of RA1, RA2, RA3, and RA4 is independently hydrogen or alkyl, and RA5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR13, -N(R13)C(O)OR14, - N(R13)C(O)R14, -C(O)R14, -OC(O)R15, or -OC(O)OR16. In some embodiments of Formula (Ib) one of RA1, RA2, RA3, and RA4 is alkyl, and each of RA1, RA2, RA3, and RA4 that is not alkyl is hydrogen. In some of Formula (Ib), two of RA1, RA2, RA3, and RA4 are alkyl, and each of RA1, RA2, RA3, and RA4 that is not alkyl is hydrogen. In some embodiments of Formula (Ib), each of RA1, RA2, RA3, and RA4 is hydrogen. In some embodiments of Formulas (I) and (Ib) compounds having the structure of Formula (Ib1) are provided:
Figure imgf000032_0001
(Ib1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof. In some embodiments of Formulas (Ib) and (Ib1), RA5 is heteroalkyl. In some embodiments of Formulas (Ib) and (Ib1) RA5 is heteroalkyl that is substituted or unsubstituted. In some embodiments of Formulas (Ib) and (Ib1), RA5 is heterocyclylalkyl that is unsubstituted. In some embodiments of Formulas (Ib) and (Ib1), RA5 is methoxy, ethoxy, cyclopropyloxy, methylamino, or dimethylamino. In some embodiments of Formula (Ib) and (Ib1), RA5 is , or
Figure imgf000032_0003
.
Figure imgf000032_0002
In some embodiments of Formulas (Ib) and (Ib1), RA5 is -OC(O)R15, in certain such embodiments of Formula (Ib) and (Ib1), RA5 is -OC(O)R15, wherein R15 is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments compounds of Formula (Ib) and (Ib1), have RA5 as - OC(O)R15, and R15 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n- pentyl, or 3-methyl-1-butyl. In some embodiments of Formulas (Ib) and (Ib1), RA5 is - OC(O)R15, wherein R15 is phenyl. Alternatively, in some embodiments of Formula (Ib) and (Ib1), RA5 is -OC(O)R15, wherein R15 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In certain embodiments of Formulas (Ib) and (Ib1), compounds disclosed herein have RA5 as -N(R13)C(O)OR14 and in certain such embodiments R13 is hydrogen or alkyl, in such embodiments of Formula (Ib) and (Ib1), wherein RA5 is -N(R13)C(O)OR14, R13 is alkyl, such as a substituted alkyl group as described herein. In particular embodiments of Formula (Ib) and (Ib1), compounds have RA5 as -N(R13)C(O)OR14, wherein R13 is unsubstituted alkyl. In some embodiments of Formulas (Ib) and (Ib1), wherein RA5 is -N(R13)C(O)OR14, R14 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments of Formulas (Ib) and (Ib1), RA5 is -N(R13)C(O)R14. In some embodiments of Formulas (Ib) and (Ib1), RA5 is -N(R13)C(O)R14, wherein R13 is hydrogen or alkyl. In some embodiments of Formula (Ib) and (Ib1), RA5 is -N(R13)C(O)R14, wherein R13 is hydrogen. In some embodiments of Formula (Ib) and (Ib1), RA5 is -N(R13)C(O)R14, wherein R13 is alkyl. In some embodiments of Formula (Ib) and (Ib1), RA5 is -N(R13)C(O)R14, wherein R13 is unsubstituted alkyl. In some embodiments of Formulas (Ib) and (Ib1), RA5 is -N(R13)C(O)R14, wherein R14 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, or 3-methyl-1- butyl. In some embodiments of Formulas (Ib) and (Ib1), RA5 is -N(R13)C(O)R14, wherein R14 is phenyl. In some embodiments of Formulas (Ib) and (Ib1), RA5 is -N(R13)C(O)R14, wherein R14 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In some embodiments of compounds according to Formulas (I), (Ib), and (Ib1), the compound is:
Figure imgf000034_0001
. In some embodiments disclosed compounds have Formula (I), (Ib), or (Ib1), wherein the compound is:
Figure imgf000034_0002
In some embodiments, disclosed compounds of Formula (I) have the structure of Formula (Ic):
Figure imgf000035_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy, such as methoxy, and each of R18 and R19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments, disclosed are compounds of Formula (Ic), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is deuterated alkoxy, such as deuterated methoxy, and each of R18 and R19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments, disclosed compounds have Formulas (I) and (Ic), wherein each of R18 and R19 is independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, -CH2CH- 2OMe, or -CH2CH2SO2Me. In some embodiments of Formula (I), the compounds have Formula (Ic), wherein R18 is hydrogen, and R19 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert- butyl, -CH2CH2OMe, or -CH2CH2SO2Me. In some embodiments of Formulas (I) and (Ic), each of R18 and R19 are independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, -CH2CH2OMe, and -CH2CH2SO2Me. In some embodiments of Formulas (I) and (Ic), R18 and R19, together with the nitrogen atom, to which they are attached form a heterocyclylalkyl ring, such as an azetidine ring, a pyrrolidine ring, a morpholine ring, a piperidine ring or a piperazine ring. In some embodiments of compounds of Formulas (I) and (Ic), the compound is:
Figure imgf000036_0001
In some embodiments of Formula (I), compounds have the structure of Formula (Id):
Figure imgf000036_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy, such as methoxy, and R5 is hydrogen, alkyl, or cycloalkyl, and RA6 is hydrogen or alkyl. In some embodiments, disclosed are compounds of Formula (Id), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is deuterated alkoxy, such as deuterated methoxy, and R5 is hydrogen, alkyl, or cycloalkyl, and RA6 is hydrogen or alkyl. In some embodiments of Formula (I) compounds have Formula (Id), wherein R5 is unsubstituted alkyl. In some embodiments of Formula (I) and (Id, R5 is hydrogen, methyl, ethyl, or isopropyl. In some embodiments of Formula (Id), RA6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments of Formula (Id), R5 is unsubstituted alkyl, and RA6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments of Formula (Id), R5 is hydrogen, and RA6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments compounds of Formulas (I) and (Id), are selected from the structures:
Figure imgf000037_0001
In some embodiments compounds of Formula (I) have Formula (Ie):
Figure imgf000037_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy, such as methoxy, and R5 is hydrogen, alkyl, or cycloalkyl. In some embodiments, disclosed are compounds of Formula (Ie), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is deuterated alkoxy, such as deuterated methoxy, and R5 is hydrogen, alkyl, or cycloalkyl. In some embodiments of Formulas (I) and (Ie), R5 is hydrogen. In some embodiments of Formulas (I) and (Id), R5 is unsubstituted alkyl. Certain embodiments of Formulas (I) and (Ie), have R5 as methyl, ethyl, or isopropyl. In some embodiments a compound of Formulas (I) and (Ie) is:
Figure imgf000038_0001
In some embodiments, compounds of Formula (I) have the structure of Formula (If):
Figure imgf000038_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy, such as methoxy, and each of R9 and R10 is independently alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments of compounds of Formula (I) and (If), each of R9 and R10 is independently unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R1 is methoxy, and each of R9 and R10 is independently unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R1 is deuterated methoxy, and each of R9 and R10 is independently unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R1 is hydrogen, and each of R9 and R10 is independently unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R1 is deuterium, and each of R9 and R10 is independently unsubstituted alkyl. In some embodiments of Formulas (I) and (If), each of R9 and R10 is independently unsubstituted heteroalkyl. In some embodiments of Formulas (I) and (If), each of R9 and R10 is independently methyl, ethyl, n-propyl, isopropyl, n- butyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tert-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, or 3-methyl-1-butyl. In some embodiments of Formulas (I) and (If), each of R9 and R10 is independently selected from haloalkyl, such as CH2CHF2, CH2CF3, and CH2cPr. In some embodiments of Formulas (I) and (If), one or both of R9 and R10 is phenyl. In some embodiments of Formulas (I) and (If), at least one of R9 and R10 is heteroaryl, such as being independently selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- pyrimidyl and 6-pyrimidyl. In some embodiments a compound of Formula (I) and (If) has each of R9 and R10 as alkyl, such as a compound wherein both of R9 and R10 are ethyl. In some embodiments of Formulas (I) and (If), R1 is hydrogen, and each of R9 and R10 is ethyl. In some embodiments of Formulas (I) and (If), R1 is deuterium, and each of R9 and R10 is ethyl. In some embodiments of Formulas (I) and (If), R1 is methoxy, and each of R9 and R10 is ethyl. In some embodiments of Formulas (I) and (If), R1 is deuterated methoxy, and each of R9 and R10 is ethyl. In some embodiments of Formulas (I) and (If), R1 is methoxy or hydrogen, R9 is hydrogen, and R10 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments of Formulas (I) and (If), R1 is deuterated methoxy, deuterium, R9 is hydrogen, and R10 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments of a compound of Formula (I) and (If), R9 is hydrogen, and R10 is unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R1 is methoxy, R9 is hydrogen, and R10 is unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R1 is deuterated methoxy, R9 is hydrogen, and R10 is unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R1 is hydrogen, R9 is hydrogen, and R10 is unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R1 is deuterium, R9 is hydrogen, and R10 is unsubstituted alkyl. In some embodiments of Formulas (I) and (If), R9 is hydrogen, and R10 is unsubstituted heteroalkyl. In some embodiments of Formulas (I) and (If), R9 is hydrogen, and R10 is methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tert-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, or 3-methyl-1-butyl. In some embodiments a disclosed compound is a compound of Formulas (I) and (If), wherein R9 is hydrogen and R10 is -CH2CHF2, -CH2CF3, or -CH2cPr. In some embodiments of Formulas (I) and (If), R9 is hydrogen, and R10 is phenyl. In some embodiments of Formulas (I) and (If), R9 is hydrogen, and R10 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In some of Formulas (I) and (If), R9 is hydrogen, and R10 is methyl or ethyl. In some embodiments of Formulas (I) and (If), R1 is hydrogen, R9 is hydrogen, and R10 is ethyl. In some embodiments of Formulas (I) and (If), R1 is deuterium, R9 is hydrogen, and R10 is ethyl. In some embodiments, compounds of Formulas (I) and (If), have R1 being methoxy, R9 being hydrogen, and R10 being ethyl. In some embodiments of Formulas (I) and (If), R1 is alkoxy, R9 is hydrogen, and R10 is
Figure imgf000040_0001
, and in some such embodiments of Formulas (I) and (If), R1 is methoxy, R9 is hydrogen, and R10 is
Figure imgf000040_0002
. In some embodiments of Formulas (I) and (If), R1 is deuterated alkoxy, R9 is hydrogen, and R10 is and in some such embo 1
Figure imgf000040_0003
diments of Formulas (I) and (If), R is deuterated methoxy, R9 is hydrogen, and R10 is .
Figure imgf000040_0004
In one embodiment, a compound of Formulas (I) and (If), is:
Figure imgf000040_0005
In some embodiments, compounds of Formulas (I) and (If) are represented by the structure of Formula (If1):
Figure imgf000040_0006
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; R10 is hydrogen, alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl; and each of X1 and X2 are independently selected from -CH2-, -O-, -N(Y1)-, -S-, -S(O)-, -S(O)2- N(Y1)-, wherein each Y1 is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl. With reference to Formula (If1), in one embodiment of this Formula, each of X1 and X2 are independently selected from -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-N(Y1)-, wherein each Y1 is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl. In some embodiments, disclosed are compounds of Formula (If1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; R10 is hydrogen, alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl; and each of X1 and X2 are independently selected from -CH2-, -O-, -N(Y1)-, -S-, -S(O)-, -S(O)2- N(Y1)-, wherein each Y1 is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl. With reference to Formula (If1), in one embodiment of this Formula, each of X1 and X2 are independently selected from -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-N(Y1)-, wherein each Y1 is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl. With continued reference to Formula (If1), in some embodiments of this Formula, each Y1 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or CH2CH2OMe. In some embodiments of Formula (If1), X1 is -CH2- and X2 is -N(Y1)-. In some embodiments of Formula (If1), X2 is -CH2- and X1 is -N(Y1)-. In certain embodiments, compounds according to Formula (If1), have X1 as -CH2- and X2 as -N(Y1)-, wherein Y1 is hydrogen, methyl, ethyl, n- propyl, isopropyl, cyclopropyl, or -CH2CH2OMe. In some embodiments of Formula (If1), X2 is -CH2- and X1 is -N(Y1)-, wherein Y1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or -CH2CH2OMe. In some embodiments, compounds according to Formula (If1), each of X1 and X2 are -O- or -NH-. In some embodiments of Formula (If1), R10 is hydrogen. In some embodiments of Formula (I), compounds disclosed herein have the structure of Formula (Ig):
Figure imgf000042_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof. wherein: R1 is alkoxy, such as methoxy; each of RA1, RA2, RA3, and RA4 is independently hydrogen or alkyl; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and RA5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR13, -N(R13)C(O)OR14, - N(R13)C(O)R14, -C(O)R14, -OC(O)R15, or -OC(O)OR16. In some embodiments of Formula (Ig), R1 is deuterated alkoxy, such as deuterated methoxy; each of RA1, RA2, RA3, and RA4 is independently hydrogen or alkyl; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and RA5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR13, -N(R13)C(O)OR14, - N(R13)C(O)R14, -C(O)R14, -OC(O)R15, or -OC(O)OR16. In some embodiments, a compound of Formula (Ig) has RA1, RA2, RA3, and RA4 selected from alkyl, and each of RA1, RA2, RA3, and RA4 that is not alkyl is hydrogen. In some embodiments Formula (Ig), two of RA1, RA2, RA3, and RA4 are alkyl, and each of RA1, RA2, RA3, and RA4 that is not alkyl is hydrogen. In some embodiments, compounds according to Formula (Ig), have each of RA1, RA2, RA3, and RA4 being hydrogen. In some embodiments disclosed is a compound of Formula (Ig), wherein RA5 is heteroalkyl that is substituted or unsubstituted. In some embodiments disclosed compounds of Formula (Ig), include those wherein RA5 is heterocyclyl that is substituted or unsubstituted. Certain embodiments of Formula (Ig) have RA5 as methoxy, ethoxy, cyclopropyloxy, methylamino, or dimethylamino. Examples of certain embodiments of Formula (Ig), wherein RA5 is heterocyclyl include those wherein R
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000043_0003
In some embodiments of compounds of Formula (Ig), are those wherein R10 is hydrogen. In some embodiments of Formula (Ig), R10 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. With continued reference to Formula (Ig), in certain embodiments of this Formula, R10 is - CH2CH2OMe or -CH2CH2SO2Me. In some embodiments of Formula (Ig), RA5 is -OC(O)R15, in such embodiments, R15 typically is alkyl, cycloalkyl, aryl, or heteroaryl. In embodiments of Formula (Ig), wherein RA5 is -OC(O)R15 and R15 is alkyl, R15 includes groups selected from those such as methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and 3-methyl-1-butyl. In particular embodiments of Formula (Ig), wherein RA5 is -OC(O)R15, wherein R15 is aryl, such as optionally substituted phenyl. In other particular embodiments of Formula (Ig), wherein RA5 is -OC(O)R15, R15 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6- pyrimidyl. In some embodiments according to Formula (Ig), RA5 is N(R13)C(O)OR14. In certain such embodiments having Formula (Ig), wherein RA5 is N(R13)C(O)OR14, R13 is hydrogen or alkyl and in particular examples of such embodiments, wherein RA5 is N(R13)C(O)OR14, R13 is hydrogen. In other embodiments of Formula (Ig), wherein RA5 is N(R13)C(O)OR14, R13 is substituted or unsubstituted alkyl. In such embodiments of Formula (Ig), wherein RA5 is - N(R13)C(O)OR14 and R14 is alkyl, examples of particular R14 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and 3-methyl-1-butyl. In some embodiments of compounds of Formula (Ig), RA5 is -N(R13)C(O)R14. In certain such embodiments of Formula (Ig), wherein RA5 is -N(R13)C(O)R14, R13 can be selected from hydrogen and alkyl. Thus, in some embodiments of Formula (Ig), wherein RA5 is - N(R13)C(O)R14, R13 is hydrogen. In other certain embodiments of Formula (Ig), wherein RA5 is - N(R13)C(O)R14, R13 is alkyl, including substituted and unsubstituted alkyl. In particular embodiments of Formula (Ig), wherein RA5 is -N(R13)C(O)R14, and R14 is alkyl, R14 can be selected from the group including methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and 3-methyl-1-butyl. In other embodiments of Formula (Ig), wherein RA5 is -N(R13)C(O)R14, R14 is substituted or unsubstituted phenyl. In other embodiments of a compound of Formula (Ig), wherein RA5 is -N(R13)C(O)R14, wherein R14 is heteroaryl, such as a heteroaryl selected from 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, and 6-pyrimidyl. In certain embodiments of Formula (I) and (Ig), the compound is:
Figure imgf000044_0001
In some embodiments of a compound of Formula (I) and (Ig), the compound is:
, or
Figure imgf000045_0001
Figure imgf000045_0002
In some embodiments of Formula (I), compounds having the structure of Formula (Ih) are disclosed:
Figure imgf000045_0003
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and each of R18 and R19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments of Formula (Ih), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and each of R18 and R19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments of a compound of Formulas (I) and (Ih), R10 is hydrogen. In some embodiments of a compound of Formulas (I) and (Ih), R10 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In some embodiments of a compound of Formulas (I) and (Ih), R10 is CH2CH2OMe or CH2CH2SO2Me. In some embodiments of a compound of Formula (Ih), each of R18 and R19 is independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, CH2CH2OMe, or CH2CH2SO2Me. In some embodiments of Formula (Ih), R18 is hydrogen, and R19 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, CH2CH2OMe, or CH2CH2SO2Me. In some embodiments of Formula (Ih), R18 and R19 are independently selected from methyl, ethyl, n- propyl, isopropyl, cyclopropyl, tert-butyl, CH2CH2OMe, and CH2CH2SO2Me. In some embodiments of Formula (Ih), R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments of Formula (Ih), R18 and R19 together with the atom to which they are attached form an azetidine ring, a morpholine ring, a pyrrolidine ring, a piperidine ring or a piperazine ring. In some embodiments of a compound according to Formulas (I) and (Ih), the compound is:
Figure imgf000046_0001
Figure imgf000047_0001
In some embodiments of compounds of Formula (I), the compounds are represented by the structure of Formula (Ii):
Figure imgf000047_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; R5 is hydrogen, alkyl, or cycloalkyl; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and RA6 is hydrogen or alkyl. In some embodiments of compounds of (Ii), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; R5 is hydrogen, alkyl, or cycloalkyl; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and RA6 is hydrogen or alkyl. In some embodiments of Formulas I and (Ii), R5 is unsubstituted alkyl. In some embodiments of compounds of Formula (Ii), R5 is selected from hydrogen, methyl, ethyl, and isopropyl. In some embodiments of Formula (Ii), RA6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments Formula (Ii), R5 is unsubstituted alkyl, and RA6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments of compounds of Formula (Ii), R5 is hydrogen, and RA6 is selected from hydrogen, methyl, ethyl, n- propyl, isopropyl, n-butyl, and benzyl. In some embodiments of Formula (Ii), R10 is hydrogen. In some embodiments of Formula (Ii), R10 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In some embodiments of Formula (Ii), R10 is CH2CH2OMe or CH2CH2SO2Me. In some embodiments of compounds of Formulas (I) and (Ii), the compound is:
Figure imgf000048_0001
In some embodiments of Formula (I), compounds have Formula (Ij):
Figure imgf000048_0002
j , or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, Wherein: R1 is alkoxy, such as methoxy, and R5 is hydrogen or alkyl. In some embodiments of compounds of Formulas (I) and (Ij), R5 is hydrogen. In some embodiments of Formula (Ij), R5 is unsubstituted alkyl. In some embodiments of Formula (Ij), R5 is methyl, ethyl, or isopropyl. In some embodiments of Formula (Ij), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, R1 is deuterated alkoxy, such as deuterated methoxy, and R5 is hydrogen or alkyl. In some embodiments of compounds of Formulas (I) and (Ij), R5 is hydrogen. In some embodiments of Formula (Ij), R5 is unsubstituted alkyl. In some embodiments of Formula (Ij), R5 is methyl, ethyl, or isopropyl. In some embodiments of compounds according to Formula (Ij), R10 is hydrogen. In some embodiments of compounds according to Formula (Ij), R10 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In certain other embodiments of Formula (Ij), R10 is CH2CH2OMe or CH2CH2SO2Me. In one embodiment of a compound of Formula (I) and (Ij), the compound is:
Figure imgf000049_0001
. In some embodiments of compounds of Formula (I), the compounds have the structure of Formula (Ik):
Figure imgf000049_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy, such as methoxy, and R4 is alkyl, heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl. In some embodiments of compounds of Formula (Ik), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, R1 is deuterated alkoxy, such as deuterated methoxy, and R4 is alkyl, heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl. In some embodiments of compounds of Formula (Ik), R4 is heteroalkyl. In some embodiments of Formula (Ik), R4 is heterocyclylalkyl. In some embodiments of Formula (Ik), R1 is hydrogen and R4 is heteroalkyl. In some embodiments of a compound of Formula (Ik), R1 is hydrogen and R4 is heterocyclylalkyl. In some embodiments of Formula (Ik), R1 is deuterium and R4 is heteroalkyl. In some embodiments of a compound of Formula (Ik), R1 is deuterium and R4 is heterocyclylalkyl. In some embodiments of Formula (Ik), R1 is methoxy and R4 is heteroalkyl. In some embodiments of Formula (Ik), R1 is methoxy and R4 is heterocyclylalkyl. In some embodiments of Formula (Ik), R1 is deuterated methoxy and R4 is heteroalkyl. In some embodiments of Formula (Ik), R1 is deuterated methoxy and R4 is heterocyclylalkyl. In some embodiments of Formulas (Ik), R4 is alkyl. In some embodiments of a compound of Formula (Ik), R4 is CH2CF3. In some embodiments of a compound of Formula (Ik), R4 is unsubstituted alkyl. In some embodiments, R1 is -OMe and R4 is alkyl substituted with SO2Me. In some embodiments, R1 is -OMe and R4 is ethyl substituted with SO2Me. In some embodiments of Formula (Ik), R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 3- methyl-1-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, or n-nonyl. In some embodiments a compound of Formula (Ik) is one wherein R4 is cycloalkyl. In some embodiments of compound of Formula (Ik), R4 is unsubstituted cycloalkyl. In some embodiments of compounds of Formula (Ik), R4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of a compound of Formula (Ik), the compound is one wherein R4 is aryl. In some embodiments of Formula (Ik), wherein R4 is substituted or unsubstituted phenyl. In other embodiments of Formula (Ik), R4 is heteroaryl and in certain such some embodiments of Formula (Ik), R4 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 3-pyrimidyl, or 6-pyrimidyl. In some embodiments, compounds of Formulas (I) and (Ik), include those wherein the compound is:
Figure imgf000050_0001
Figure imgf000051_0001
In a particular embodiment of a compound of Formulas (I) and (Ik), the compound is:
Figure imgf000051_0002
In certain other embodiments of compounds of Formula (Ik), R4 is , or
Figure imgf000051_0003
Figure imgf000051_0004
In some embodiments of compounds of Formula (Ik), the compound is:
Figure imgf000052_0001
In some embodiments of Formula (Ik), R4 is
Figure imgf000052_0002
, and in certain such embodiments of a compound of Formula (Ik), wherein R4 is 14
Figure imgf000052_0003
, R is alkyl, cycloalkyl, or aryl, such as compounds wherein R14 is methyl, ethyl, n-propyl, isopropyl, or CH2CH2OMe. In some embodiments of Formula (Ik), wherein R4 is 14
Figure imgf000052_0004
, R is phenyl. In some embodiments, R14 is alkyl substituted with alkoxy. In some embodiments, R14 is ethyl substituted with methoxy. In some embodiments of Formulas (I) and (Ik), the compound is:
Figure imgf000053_0001
In some embodiments of compounds of Formula (Ik), R4 is
Figure imgf000053_0002
, wherein RA7 is hydrogen or alkyl. In some embodiments of such compounds of Formula (Ik), R4 is
Figure imgf000053_0003
, wherein RA7 is hydrogen. In some embodiments of Formula (Ik), R4 is A7
Figure imgf000053_0004
, wherein R is alkyl. In some embodiments of Formula (Ik), R4 is A7
Figure imgf000053_0005
, wherein R is unsubstituted alkyl. In some embodiments of Formula (Ik), R4 is and RA7 is methyl, ethyl, n-
Figure imgf000053_0006
propyl, isopropyl, or n-butyl. In some embodiments of Formula (Ik), R4 is A7
Figure imgf000053_0007
, and R is benzyl. In particular embodiments of compounds of Formulas (I) and (Ik), the compound is:
Figure imgf000054_0001
In some embodiments disclosed are compounds of Formula (I) and (Ik) having the structure of Formula (Ik1):
Figure imgf000054_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; each of RA1, RA2, RA3, and RA4 is independently hydrogen, alkyl, or an amino acid side chain; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and RA5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR13, -N(R13)C(O)OR14, - N(R13)C(O)R14, -C(O)R14, -OC(O)R15, or -OC(O)OR16. In some embodiments disclosed are compounds of Formula (Ik1), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; each of RA1, RA2, RA3, and RA4 is independently hydrogen, alkyl, or an amino acid side chain; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and RA5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR13, -N(R13)C(O)OR14, - N(R13)C(O)R14, -C(O)R14, -OC(O)R15, or -OC(O)OR16. In some embodiments of a compound of Formula (Ik1), each of RA1, RA2, RA3, and RA4 is hydrogen. In some embodiments of a compound of Formula (Ik1), each of RA1, RA2, RA3, and RA4 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (Ik1), RA5 is heteroalkyl or heterocyclylalkyl. In some embodiments of Formula (Ik1), RA5 is heterocyclylalkyl. In some embodiments of a compound of Formula (Ik1), RA5 is heteroalkyl. In some embodiments of a compound of Formula (Ik1), each of RA1, RA2, RA3, and RA4 is hydrogen, and RA5 is methoxy. In some embodiments of a compound of Formula (Ik1), each of RA1, RA2, RA3, and RA4 is hydrogen, and RA5 is alkylsulfonyl. In some embodiments of Formula (Ik1), each of RA1, RA2, RA3, and RA4 is hydrogen, and RA5 is methylsulfonyl. In some embodiments of Formulas (Ik1), RA5 is -OC(O)R15. In some embodiments of Formula (Ik1 RA5 is -OC(O)R15, wherein R15 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments of Formula (Ik1), RA5 is -OC(O)R15, wherein R15 is alkyl. In some embodiments of Formula (Ik1), RA5 is -OC(O)R15, have R15 as unsubstituted alkyl. In some embodiments compounds of Formula (Ik1), wherein RA5 is -OC(O)R15, wherein R15 is methyl, ethyl, n-propyl, isopropyl n-butyl, tert-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments of Formula (Ik1), wherein RA5 is -OC(O)R15, R15 is aryl. In some embodiments of Formula (Ik1), wherein RA5 is -OC(O)R15, R15 is unsubstituted aryl. In some embodiments of a compound of Formula (Ik1), RA5 is -OC(O)R15, wherein R15 is phenyl. In some embodiments of Formula (Ik1), RA5 is -OC(O)R15, and R15 is 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In one embodiment of compounds of Formulas (I) and (Ik) the compounds have the structure of Formula (Ik2):
Figure imgf000055_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy; R13 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of such compounds according to Formulas (I), (Ik) and (Ik2), R1 is methoxy. In one embodiment disclosed are compounds of Formula (Ik2), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy; R13 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl; and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment of such compounds according to Formulas (I), (Ik) and (Ik2), R1 is deuterated methoxy. In some embodiments of Formulas (I), (Ik) and (Ik2), R13 is alkyl. In some embodiments of Formulas (I), (Ik) and (Ik2), R13 is unsubstituted alkyl. In some embodiments of Formulas (I), (Ik) and (Ik2), R13 is methyl, ethyl, n-propyl, isopropyl n-butyl, tert-butyl, n-pentyl, or 3-methyl- 1-butyl. In some embodiments of Formulas (I), (Ik) and (Ik2), R13 is aryl. In some embodiments of a compound of Formulas (I), (Ik) and (Ik2), R13 is unsubstituted aryl. In some embodiments of compounds of Formula (I), (Ik) and (Ik2), R13 is phenyl. In some embodiments of Formula (I), (Ik) and (Ik2), R13 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In some embodiments, compounds of Formula (I) and (Ik) have the structure of Formula (Ik3):
Figure imgf000056_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy; RA1 is alkyl, alkyl substituted with -NHC(=NH)NH2, or an amino acid side chain; and RA5 is -N(R18)R19 or -N(R13)C(O)R14. In one embodiment of such compounds according to Formulas (I), (Ik) and (Ik3), R1 is methoxy. In some embodiments, disclosed are compounds of Formula (Ik3), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy; RA1 is alkyl or an amino acid side chain; and RA5 is -N(R18)R19 or -N(R13)C(O)R14. In one embodiment of such compounds according to Formulas (I), (Ik) and (Ik3), R1 is deuterated methoxy. In some embodiments of Formula (Ik3), RA5 is -N(R18)R19. In some embodiments of Formula (Ik3), RA1 is alkyl substituted with -NHC(=NH)NH2. In some embodiments, compounds of Formula (Ik3), have RA1 as -N(R18)R19, wherein each of R18 and R19 is hydrogen. In some embodiments of Formula (Ik3), RA5 is -N(R13)C(O)R14. In some embodiments of compounds according to Formula (Ik3), RA5 is -N(R13)C(O)R14, wherein R19 is alkyl, cycloalkyl, or aryl. In some embodiments of Formula (Ik3), RA5 is -N(R13)C(O)R14, wherein R18 is hydrogen, and R19 is alkyl, cycloalkyl, or aryl. In some embodiments of Formula (Ik3), RA5 is -N(R13)C(O)R14, wherein R18 is hydrogen, and R19 is unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted aryl. In some embodiments of Formula (Ik3), RA5 is - N(R13)C(O)R14, wherein R18 is hydrogen, and R19 is methyl, ethyl, isopropyl, tert-butyl, or phenyl. In particular embodiments of compounds according to Formula (Ik3), the compound is:
Figure imgf000057_0001
In some embodiments compounds of Formula (I) have the structure of Formula (Il):
Figure imgf000058_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy; R5 is hydrogen alkyl, or cycloalkyl; and R6 is alkyl, cycloalkyl, heterocyclylalkyl, or heteroalkyl. In one embodiment of such compounds according to Formulas (I) and (Il), R1 is methoxy. In some embodiments disclosed are compounds of Formula (Il), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy; R5 is hydrogen alkyl, or cycloalkyl; and R6 is alkyl, cycloalkyl, heterocyclylalkyl, or heteroalkyl. In one embodiment of such compounds according to Formulas (I) and (Il), R1 is deuterated methoxy. In some embodiments of Formula (I) and (Il) R6 is methyl, ethyl, isopropyl, tert-butyl, 2- dimethylaminoethyl, or cyclopropyl. In some embodiments Formulas (I) and (Il), R1 is hydrogen, R5 is hydrogen, and R6 is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl, or cyclopropyl. In some embodiments Formulas (I) and (Il), R1 is deuterium, R5 is hydrogen, and R6 is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl, or cyclopropyl. In some embodiments of a compound of Formulas (I) and (Il), R1 is methoxy, R5 is hydrogen, and R6 is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl, or cyclopropyl. In some embodiments of a compound of Formulas (I) and (Il), R1 is deuterated methoxy, R5 is hydrogen, and R6 is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl, or cyclopropyl. In some embodiments of Formulas (I) and (Il), R1 is hydrogen, R5 is hydrogen, and R6 is tert-butyl. In some embodiments of Formulas (I) and (Il), R1 is deuterium, R5 is hydrogen, and R6 is tert-butyl. In some embodiments of Formulas (I) and (Il), R1 is methoxy, R5 is hydrogen, and R6 is tert- butyl. In some embodiments of Formulas (I) and (Il), R1 is deuterated methoxy, R5 is hydrogen, and R6 is tert-butyl. In some embodiments of a compound according to Formulas (I) and (Il), the compound is:
Figure imgf000059_0001
In some embodiments, compounds of Formula (I) disclosed herein include those having the structure of Formula (Im):
Figure imgf000059_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy; R4 hydrogen, alkyl, cycloalkyl, or heteroalkyl; and each of R11 and R12 is independently selected from cycloalkyl, aryl, heteroaryl, or alkyl. In one embodiment of such compounds according to Formulas (I) and (Im), R1 is methoxy. In some embodiments, compounds of Formula (Im), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy; R4 hydrogen, alkyl, cycloalkyl, or heteroalkyl; and each of R11 and R12 is independently selected from cycloalkyl, aryl, heteroaryl, or alkyl. In one embodiment of such compounds according to Formulas (I) and (Im), R1 is deuterated methoxy. In some embodiments of Formulas (I) and (Im), R4 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, or alkyl substituted with heteroaryl. In some embodiments of compounds according to Formulas (I) and (Im), each of R11 and R12 is independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl. In some embodiments of Formulas (I) and (Im), each of R11 and R12 is alkyl. In some embodiments of compounds of Formula (I) and (Im), each of R11 and R12 is unsubstituted alkyl. In some embodiments of compounds according to Formulas (I) and (Im), each of R11 and R12 is alkyl substituted with -OC(O)R15. In some embodiments compounds of Formulas (I) and (Im) have each of R11 and R12 as alkyl substituted with -OC(O)R15, wherein each R15 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formulas (I) and (Im), each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein each R15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl, such as wherein each R15 is heterocyclylalkyl substituted with alkyl or arylalkyl. In some embodiments of compounds of Formulas (I) and (Im), R4 is hydrogen. In some such embodiments of Formulas (I) and (Im), wherein R4 is hydrogen, each of R11 and R12 is alkyl, heterocyclylalkyl, or cycloalkyl. In further embodiments of compounds of Formulas (I) and (Im), R4 is hydrogen or C1-3 alkyl. In some embodiments of compounds of Formulas (I) and (Im), R4 is hydrogen and each of R11 and R12 is alkyl, such as unsubstituted alkyl. In some embodiments of Formulas (I) and (Im), R1 is methoxy, R4 is hydrogen, and each of R11 and R12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Im), R1 is deuterated methoxy, R4 is hydrogen, and each of R11 and R12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Im), R1 is hydrogen, R4 is hydrogen, and each of R11 and R12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Im), R1 is deuterium, R4 is hydrogen, and each of R11 and R12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Im), R1 is methoxy, R4 is hydrogen, and each of R11 and R12 is hydrogen or tert-butyl. In some embodiments of Formulas (I) and (Im), R1 is deuterated methoxy, R4 is hydrogen, and each of R11 and R12 is hydrogen or tert-butyl. In some embodiments of Formulas (I) and (Im), wherein R11 and R12 each hydrogen, one or both of the hydrogens of R11 and R12 are replaced by a cation, such as a metal or ammonium cation. In some embodiments of compounds of Formulas (I) and (Im), R1 is hydrogen, R4 is hydrogen, and each of R11 and R12 is tert-butyl. In some embodiments of compounds of Formulas (I) and (Im), R1 is deuterium, R4 is hydrogen, and each of R11 and R12 is tert-butyl In some embodiments of a compound of Formulas (I) and (Im), one or more of R11 and R12 is . In some embodiments o 11 12
Figure imgf000061_0001
f Formulas (I) and (Im), each of R and R is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, or 3-methyl-1-butyl. In some embodiments of Formulas (I) and (Im), each of R11 and R12 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of a compound of Formulas (I) and (Im), one or both of R11 and R12 is phenyl. In some embodiments of a compound of Formulas (I) and (Im), one or both of R11 and R12 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In some embodiments of Formulas (I) and (Im), at least one of R11 and R12 is 4-nitrophenyl. In some embodiments of Formulas (I) and (Im), at least one of R11 and R12 is benzyl. In some embodiments of Formulas (I) and (Im) having structure of Formula (Im1):
Figure imgf000061_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy; each of RA1, RA3, and R4 is independently hydrogen, alkyl, or cycloalkyl; and each of RA2 and RA4 is independently alkyl, heteroalkyl, or cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In one embodiment of such compounds according to Formulas (I), (Im) and (Im1), R1 is methoxy. In some embodiments, disclosed are compounds of Formula (Im1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy; each of RA1, RA3, and R4 is independently hydrogen, alkyl, or cycloalkyl; and each of RA2 and RA4 is independently alkyl, heteroalkyl, or cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In one embodiment of such compounds according to Formulas (I), (Im) and (Im1), R1 is deuterated methoxy. In some embodiments of compounds according to Formula (Im1), each of RA1, RA3, and R4 is independently selected from hydrogen, methyl, ethyl, isopropyl, and tert-butyl. In some embodiments of Formula (Im1), R4 is hydrogen. In some embodiments of Formula (Im1), each of RA1 and RA3 is hydrogen. In some embodiments of Formula (Im1), at least one of RA2 and RA4 is -C(O)OR13, and in certain compounds of such embodiments, each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -C(O)OR13; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -C(O)OR13; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -C(O)OR13; each of RA1, RA3, and R4 is hydrogen; and each R13 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert- butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -C(O)OR13; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is phenyl or 4-nitrophenyl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -C(O)OR13; each of RA1, RA3, and R4 is hydrogen; and each R13 is phenyl or 4-nitrophenyl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -C(O)OR13; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is benzyl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -C(O)OR13; each of RA1, RA3, and R4 is hydrogen; and each R13 is benzyl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -C(O)OR13; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -C(O)OR13; each of RA1, RA3, and R4 is hydrogen; and each R13 is 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of compounds of Formula (Im1), each of RA2 and RA4 is - CO(O)OR16, and in certain of these embodiments, compounds of Formula (Im1), each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In certain embodiments of Formula (Im1), each of RA2 and RA4 is -CO(O)OR16; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments of Formula (Im1), each of RA2 and RA4 is - CO(O)OR16; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert- butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl. In of Formula (Im1), each of RA2 and RA4 is -CO(O)OR16; each of RA1, RA3, and R4 is hydrogen; and each R16 is methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl. In some embodiments, a compound of Formula (Im1), is one wherein each of RA2 and RA4 is - CO(O)OR16; each of RA1, RA3, and R4 is hydrogen; and each R16 is isopropyl. In some embodiments of a compound of Formula (Im1), each RA2 and RA4 is -CO(O)OR16; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 is phenyl or 4-nitrophenyl. In some embodiments of Formula (Im1), at least one of RA2 and RA4 is -CO(O)OR16; each of RA1, RA3, and R4 is hydrogen; and each R16 is phenyl or 4-nitrophenyl. In some embodiments of Formula (Im1), wherein each of RA2 and RA4 is -CO(O)OR16; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 is benzyl. In some of Formula (Im1), each of RA2 and RA4 is -CO(O)OR16; each of RA1, RA3, and R4 is hydrogen; and each R16 is benzyl. In some embodiments of a compound of Formula (Im1), each of RA2 and RA4 is -CO(O)OR16; each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 independently is heteroaryl, such as 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formula (Im1), each of RA2 and RA4 is -CO(O)OR16; each RA1, RA3, and R4 is hydrogen; and each R16 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of compounds according to Formulas (I), (Im), and/or (Im1), the compound is: ,
Figure imgf000063_0001
.
Figure imgf000064_0001
or a pharmaceutically acceptable salt thereof. In some embodiments of compounds according to Formula (I), (Im), and/or (Im1), the compound is:
Figure imgf000064_0002
Figure imgf000065_0001
In some embodiments of compounds of Formulas (I), (Im), and/or (Im1), the compound is:
Figure imgf000065_0002
Figure imgf000066_0001
In some embodiments Formula (I), (Im), and/or (Im1), the compound is:
Figure imgf000066_0002
In some embodiments of Formulas (I), (Im), and/or (Im1) compounds have the structure of Formula (Im1a):
Figure imgf000066_0003
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; each of RA1, RA3, and R4 is independently hydrogen, alkyl, or cycloalkyl; and each of RB1 and RB2 is independently hydrogen or alkyl. In some embodiments of Formula (Im1a), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; each of RA1, RA3, and R4 is independently hydrogen, alkyl, or cycloalkyl; and each of RB1 and RB2 is independently hydrogen or alkyl. In some embodiments of Formula (Im1a), each of RB1 and RB2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentan-3-yl, or benzyl. In some embodiments of Formula (Im1a), each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of Formula (Im1a), each of RA1, RA3, and R4 is hydrogen. In some embodiments of a compound of Formula (Im1a), each of RA1, RA3, and R4 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each of RB1 and RB2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentan-3-yl, or benzyl. In some embodiments of compounds according to Formulas (I), (Im), (Im1), and/or (Im1a), the compound is:
Figure imgf000067_0001
In certain embodiments of compounds of Formula (I), (Im), (Im1), and/or (Im1a), the compound is:
Figure imgf000068_0001
In some embodiments of a compound of Formula (I), the compound is a phosphoramidate having the structure of Formula (In):
Figure imgf000068_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; R4 is hydrogen, alkyl, or cycloalkyl; R8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and each of R9 and R10 is hydrogen or alkyl. In some embodiments of a compound of Formula (In), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; R4 is hydrogen, alkyl, or cycloalkyl; R8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and each of R9 and R10 is hydrogen or alkyl. In some embodiments of a compound of Formulas (I) and (In), R4 is hydrogen or unsubstituted alkyl, and in particular embodiments, R4 is hydrogen, methyl, ethyl, or tert-butyl. In some embodiments of Formulas (I) and (In), R8 is alkyl or cycloalkyl. In some embodiments of Formulas (I) and (In), R8 is unsubstituted alkyl or unsubstituted cycloalkyl. In some embodiments of Formulas (I) and (In), R8 is alkyl, such as methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, isopropyl, tert-butyl, or cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of Formula (I) and (In), R8 is aryl, such as phenyl. In some embodiments of Formulas (I) and (In), R8 is 4-nitrophenyl. In some embodiments disclosed herein are compounds of Formula (I) and (In), wherein R8 is benzyl. In other disclosed embodiments of Formula (I) and (In), R8 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, or 4-pyrimidyl. In some embodiments of Formulas (I) and (In), R9 is hydrogen. In some embodiments of compounds according to Formulas (I) and (In), R9 is hydrogen, and R10 is alkyl. In particular embodiments of Formulas (I) and (In), compounds having the structure of Formula (In1) are provided:
Figure imgf000069_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; each of R4 and RA1 is hydrogen, alkyl, or cycloalkyl; R8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and R13 is alkyl. In particular embodiments of Formula (I) and (In1), or enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; each of R4 and RA1 is hydrogen, alkyl, or cycloalkyl; R8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and R13 is alkyl. In some embodiments of Formula (In1), each of R4 and RA1 is independently selected from hydrogen and unsubstituted alkyl. In some embodiments of Formula (In1), each of R4 and RA1 is hydrogen, methyl, ethyl, or tert-butyl. In some embodiments of a compound of Formula (In1), both of R4 and RA1 is hydrogen. In some embodiments of a compound of Formula (In1), wherein R8 is alkyl or cycloalkyl. In certain embodiments, a compound of Formula (In1), has R8 as unsubstituted alkyl or unsubstituted cycloalkyl. In particular embodiments of Formula (In1), R8 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of Formula (In1), R8 is phenyl, such as wherein R8 is 4-nitrophenyl. In certain other embodiments Formula (In1), R8 is benzyl. In still other embodiments of Formula (In1), R8 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, or 4-pyrimidyl. In some embodiments of Formula (In1), R13 is unsubstituted alkyl, such as wherein R13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH2CH(Et)2, or more particularly, wherein each of R4 and RA1 is hydrogen or unsubstituted alkyl; and R13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH2CH(Et)2. In some embodiments of Formula (In1), each of R4 and RA1 is hydrogen; and R13 is methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, or -CH2CH(Et)2. In certain embodiments of compounds of Formulas (I), (In), and/or (In1), the compound is:
Figure imgf000070_0001
Figure imgf000071_0001
In some embodiments a compound of Formula (I) has the structure of Formula (Io):
Figure imgf000071_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; and each of R11 and R12 is independently selected from cycloalkyl, aryl, heteroaryl, or alkyl; or R11 and R12 together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments, disclosed are compounds of Formula (Io), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; and each of R11 and R12 is independently selected from cycloalkyl, aryl, heteroaryl, or alkyl; or R11 and R12 together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments of compounds of Formula (I) and (Io), each of R11 and R12 is independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl. In some embodiments Formula (I) and (Io), each of R11 and R12 is alkyl. In some embodiments of Formulas (I) and (Io), one or both of R11 and R12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Io), each of R11 and R12 is alkyl substituted with -OC(O)R15, such as wherein each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein each R15 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, such as embodiments wherein each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein each R15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formulas (I) and (Io), each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein each R15 is heterocyclylalkyl substituted with alkyl or arylalkyl. In some embodiments of Formulas (I) and (Io), each of R11 and R12 is alkyl, heterocyclylalkyl, or cycloalkyl, such as wherein each of R11 and R12 is alkyl. In some embodiments of Formulas (I) and (Io), one or both of R11 and R12 is unsubstituted alkyl. In some embodiments a compound of Formulas (I) and (Io), R1 is methoxy, and each of R11 and R12 is unsubstituted alkyl. In some embodiments a compound of Formulas (I) and (Io), R1 is deuterated methoxy, and each of R11 and R12 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Io), R1 is hydrogen, and each of R11 and R12 is unsubstituted alkyl. In some embodiments Formulas (I) and (Io), one or both of R11 and R12 are tert-butyl. In some embodiments of Formulas (I) and (Io), R1 is hydrogen, and each of R11 and R12 is tert-butyl. In some embodiments of Formulas (I) and (Io), R1 is deuterium, and each of R11 and R12 is unsubstituted alkyl. In some embodiments Formulas (I) and (Io), one or both of R11 and R12 are tert-butyl. In some embodiments of Formulas (I) and (Io), R1 is deuterium, and each of R11 and R12 is tert- butyl. In some embodiments of Formulas (I) and (Io), each of R11 and R12 is . In
Figure imgf000072_0001
some embodiments Formulas (I) and (Io), each of R11 and R12 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, or 3-methyl-1-butyl. In some embodiments of a compound of Formulas (I) and (Io), each of R11 and R12 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of Formulas (I) and (Io), each of R11 and R12 is phenyl. In some embodiments of Formulas (I) and (Io), each of R11 and R12 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In some embodiments of Formulas (I) and (Io), each of R11 and R12 is 4-nitrophenyl. In some embodiments of Formulas (I) and (Io), each of R11 and R12 is benzyl. In certain embodiments of a compound of Formulas (I) and (Io), the compound has the structure of Formula (Io1):
Figure imgf000073_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; each of RA1 and RA3 is independently hydrogen, alkyl, or cycloalkyl; and each of RA2 and RA4 is independently alkyl, heteroalkyl, or cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In certain embodiments, disclosed are compounds of Formula (Io1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; each of RA1 and RA3 is independently hydrogen, alkyl, or cycloalkyl; and each of RA2 and RA4 is independently alkyl, heteroalkyl, or cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (Io1), each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of a compound of Formula (Io1), each of RA1 and RA3 is hydrogen. In some embodiments of Formula (Io1), each of RA2 and RA4 is -C(O)OR13. In some embodiments of a compound of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; and each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl. In some embodiments of a compound of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; each of RA1 and RA3 is hydrogen; and each R13 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is phenyl or 4- nitrophenyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; each of RA1 and RA3 is hydrogen; and each R13 is phenyl or 4-nitrophenyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is benzyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; each of RA1 and RA3 is hydrogen; and each R13 is benzyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R13 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -C(O)OR13; each of RA1 and RA3 is hydrogen; and each R13 is 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -CO(O)OR16. In some embodiments of Formula (Io1), each of RA2 and RA4 is -CO(O)OR16; and each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -CO(O)OR16; each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -CO(O)OR16; each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is - CO(O)OR16; each of RA1 and RA3 is hydrogen; and each R16 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl, or cyclobutyl. In some embodiments of Formula (Io1), each RA2 and RA4 is -CO(O)OR16; each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 is phenyl or 4- nitrophenyl. In some embodiments of Formula (Io1), each RA2 and RA4 is -CO(O)OR16; each of RA1 and RA3 is hydrogen; and each R16 is phenyl or 4-nitrophenyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -CO(O)OR16; each RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 is benzyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -CO(O)OR16; each of RA1 and RA3 is hydrogen; and each R16 is benzyl. In some embodiments of Formula (Io1), each of RA2 and RA4 is -CO(O)OR16; each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R16 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of a compound of Formula (Io1), each of RA2 and RA4 is -CO(O)OR16; each RA1 and RA3 is hydrogen; and each R16 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of a compound of Formulas (I), (Io), and (Io1), the compound is:
Figure imgf000075_0001
In some embodiments of Formulas (I) and (Io) compounds having the structure of Formula (Io2), are provided:
Figure imgf000076_0001
(Io2), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy, such as methoxy; and RA1 is aryl or heteroaryl. In some embodiments, disclosed are compounds o Formula (Io2), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is deuterated alkoxy, such as deuterated methoxy; and RA1 is aryl or heteroaryl. In some embodiments of Formula (Io2), RA1 is aryl. In some embodiments of Formula (Io2), RA1 is aryl substituted with halogen. In some embodiments of Formula (Io2), RA1 is , wherein each of Z1, Z2, and Z3 is independently hydrogen or halogen. In some
Figure imgf000076_0002
embodiments of Formula (Io2), RA1 is 1 2 3
Figure imgf000076_0003
wherein each of Z , Z , and Z is independently hydrogen, fluoro, chloro, bromo, or iodo. In some embodiments of Formula (Io2), RA1 is
Figure imgf000076_0004
,
Figure imgf000076_0005
or
Figure imgf000076_0006
In some embodiments of Formula (Io2), the compound is:
Figure imgf000077_0001
In some embodiments of Formula (I), (Io), and (Io1), compounds having the structure of Formula (Io1a) are provided:
Figure imgf000077_0002
(Io1a), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; each of RA1 and RA3 is independently hydrogen, alkyl, or cycloalkyl; and each of RB1 and RB2 is independently hydrogen or alkyl. In some embodiments, disclosed are compounds of Formula (Io1a), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; each of RA1 and RA3 is independently hydrogen, alkyl, or cycloalkyl; and each of RB1 and RB2 is independently hydrogen or alkyl. In some embodiments of Formula (Io1a), each of RB1 and RB2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentan-3-yl, or benzyl. In some embodiments of Formula (Io1a), each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of a compound of Formula (Io1a), each of RA1 and RA3 is independently hydrogen. In some embodiments of a compound of Formula (Io1a), each of RA1 and RA3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each of RB1 and RB2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentan-3-yl, or benzyl. In some embodiments of a compound of Formula (Io1a), the compound is:
Figure imgf000079_0001
Figure imgf000079_0003
Figure imgf000079_0002
In some embodiments of Formula (I) compounds having the structure of Formula (Ip) are provided:
Figure imgf000079_0004
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy such as methoxy; R8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and each of R9 and R10 is hydrogen or alkyl. In some embodiments, disclosed are compounds of Formula (Ip), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy such as deuterated methoxy; R8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and each of R9 and R10 is hydrogen or alkyl. In some embodiments of a compound of Formulas (I) and (Ip), R8 is alkyl or cycloalkyl. In some embodiments of a compound of Formulas (I) and (Ip), R8 is unsubstituted alkyl or unsubstituted cycloalkyl. In some embodiments of a compound of Formulas (I) and (Ip), R8 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of Formulas (I) and (Ip), R8 is phenyl. In some embodiments of Formulas (I) and (Ip), R8 is 4-nitrophenyl. In some embodiments of Formulas (I) and (Ip), R8 is benzyl. In some embodiments of Formulas (I) and (Ip), R8 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formulas (I) and (Ip), R9 is hydrogen. In some embodiments of Formulas (I) and (Ip), R9 is hydrogen, and R10 is alkyl. In some embodiments of Formulas (I) and (Ip) compounds having the structure of Formula (Ip1) are provided:
Figure imgf000080_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy such as methoxy; RA1 is hydrogen, alkyl, or cycloalkyl; R8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and R13 is alkyl. In some embodiments, disclosed are compounds of Formula (Ip1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy such as deuterated methoxy; RA1 is hydrogen, alkyl, or cycloalkyl; R8 is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and R13 is alkyl. In some embodiments, of (Ip1), RA1 is alkyl substituted with -SR13. In some embodiments, of (Ip1), RA1 is ethyl substituted with -SMe. In some embodiments of a compound of Formula (Ip1), RA1 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (Ip1), RA1 is hydrogen, methyl, ethyl, or tert-butyl. In some embodiments of Formula (Ip1), RA1 is hydrogen. In some embodiments of Formula (Ip1), R8 is alkyl or cycloalkyl. In some embodiments of Formula (Ip1), R8 is unsubstituted alkyl or unsubstituted cycloalkyl. In some embodiments of Formula (Ip), R8 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of Formula (Ip1), R8 is phenyl. In some embodiments of Formula (Ip1), R8 is 4-nitrophenyl. In some embodiments of Formula (Ip1), R8 is benzyl. In some embodiments of Formula (Ip1), R8 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, or 4-pyrimidyl. In some embodiments of Formula (Ip1), R13 is unsubstituted alkyl. In some embodiments of Formula (Ip1), R13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, or -CH2CH(Et)2. In some embodiments of Formula (Ip1), each of R4 and RA1 is hydrogen or unsubstituted alkyl; and R13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or - CH2CH(Et)2. In some embodiments of Formula (Ip1), RA1 is hydrogen; and R13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH2CH(Et)2. In some embodiments of compounds according to Formula (Ip1), the compound is:
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000082_0002
In some embodiments compounds of Formula (I) have the structure of Formula (Iq):
Figure imgf000082_0003
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; R5 is hydrogen, alkyl, or cycloalkyl; and R6 is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments compounds of Formula (Iq), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; R5 is hydrogen, alkyl, or cycloalkyl; and R6 is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formulas (I) and (Iq), R5 is hydrogen or alkyl. In some embodiments of Formulas (I) and (Iq), R5 is hydrogen or unsubstituted alkyl. In some embodiments of Formulas (I) and (Iq), R5 is hydrogen. In some embodiments of Formulas (I) and (Iq), R6 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formulas (I) and (Iq), R6 is alkyl. In some embodiments of Formulas (I) and (Iq), R6 is heteroalkyl. In some embodiments of Formulas (I) and (Iq), R6 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formulas (I) and (Iq), R6 is alkyl. In some embodiments of Formulas (I) and (Iq), R6 is heteroalkyl. In some embodiments of Formulas (I) and (Iq), R6 is heterocyclylalkyl substituted with arylalkyl. In some embodiments of Formulas (I) and (Iq), R5 is methyl, isopropyl, tert-butyl, or -CH(Et)2. In some embodiments of Formulas (I) and (Iq), R5 is hydrogen, and R6 is alkyl. In some embodiments of Formulas (I) and (Iq), R5 is alkyl, and R6 is alkyl. In some embodiments of Formulas (I) and (Iq), R5 is hydrogen, and R6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Iq), R5 is unsubstituted alkyl, and R6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Iq), R6 is methyl, ethyl, isopropyl, tert-butyl, or cyclopropyl. In some embodiments of Formula (I) and (Iq), R5 is hydrogen, and R6 is methyl, ethyl, isopropyl, tert-butyl, or cyclopropyl. In some embodiments of Formulas (I) and (Iq), R5 is hydrogen, and R6 is tert-butyl. In some embodiments of Formulas (I) and (Iq), R1 is hydrogen, R5 is hydrogen, and R6 is tert-butyl. In some embodiments of Formulas (I) and (Iq), R1 is deuterium, R5 is hydrogen, and R6 is tert-butyl. In some embodiments of Formulas (I) and (Iq), R1 is methoxy, R5 is hydrogen, and R6 is tert-butyl. In some embodiments of Formulas (I) and (Iq), R1 is deuterated methoxy, R5 is hydrogen, and R6 is tert-butyl. In some embodiments of Formulas (I) and (Iq), R6 is alkyl. In some embodiments of Formulas (I) and (Iq), R6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Iq), R6 is cycloalkyl. In some embodiments of Formulas (I) and (Iq), R6 is methyl, ethyl, n-propyl, tert-butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of Formulas (I) and (Iq), R6 is phenyl. In some embodiments of Formulas (I) and (Iq), R6 is 4-nitrophenyl. In some embodiments of Formulas (I) and (Iq), R6 is benzyl. In some embodiments of Formulas (I) and (Iq), R6 is heteroaryl. In some embodiments of Formulas (I) and (Iq), R6 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formulas (I) and (Iq), R6 is heteroalkyl. In some embodiments of Formulas (I) and (Iq), R6 is CH2CH2OMe or CH2CH2SO2Me. In some embodiments of Formulas (I) and (Iq), R6 is –(CH2)rCO2H, wherein r is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Iq), R6 is –(CH2)sCO2R13, wherein s is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Iq), R6 is –(CH2)sCO2R13, wherein R13 is alkyl. In some embodiments of Formulas (I) and (Iq), R6 is –(CH2)sCO2R13, wherein R13 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Iq), R6 is –(CH2)sCO2R13, wherein R13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or -CH(Et)2. In some embodiments of Formulas (I) and (Iq), R6 is -CH(RA1)NH2, wherein RA1 is hydrogen, alkyl, heteroalkyl, or an amino acid side chain. In one such embodiment of Formulas (I) and (Iq), R6 is -CH(RA1)NH2, and RA1 is an amino acid side chain, the amino acid side chain is formed from an α-amino acid side chain, such as one of the naturally occurring amino acid side chains, such as an amino acid selected from alanine, serine, tryptophan, aspartic acid, glutamic acid and the like. By way of illustration, when RA1 is formed from alanine, RA1 is methyl. In some embodiments of Formulas (I) and (Iq), R6 is -CH(RA1)NH2, wherein RA1 is an amino acid side chain. In some embodiments of Formulas (I) and (Iq), R6 is -CH(RA1)NH2, wherein RA1 is methyl, ethyl, n-propyl, isopropyl, tert-butyl, CH(Me)Et, CH2CH(Me)2, or CH2CH2SMe. In some embodiments of Formulas (I) and (Iq), wherein R6 is -CH(RA1)NH2, wherein RA1 is benzyl. In some embodiments of Formulas (I) and (Iq), the compound is:
Figure imgf000084_0001
Figure imgf000084_0003
Figure imgf000084_0002
In some embodiments of Formulas (I) and (Iq), wherein the compound is:
Figure imgf000085_0001
In some embodiments of Formulas (I) and (Iq), the compound is:
Figure imgf000085_0002
In some embodiments of Formulas (I) and (Iq) has the structure of Formula (Iq1):
Figure imgf000086_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; R5 is hydrogen, alkyl, or cycloalkyl; and Q1 is
Figure imgf000086_0002
, or , wherein
Figure imgf000086_0003
each of Y1, Y2, or Y3 is independently -O-, -S-, -S(O)-, -S(O)2-, -N(RY1)-, or -NC(O)RY2, wherein each of RY1 and RY2 is independently hydrogen, alkyl, heteroalkyl, or heteroaryl. In some embodiments, disclosed are compounds of Formula (Iq1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; R5 is hydrogen, alkyl, or cycloalkyl; and Q1 is
Figure imgf000086_0004
, , or
Figure imgf000086_0005
, wherein each of Y1, Y2, or Y3 is independently -O-, -S-, -S(O)-, -S(O)2-, -N(RY1)-, or -NC(O)RY2, wherein each of RY1 and RY2 is independently hydrogen, alkyl, heteroalkyl, or heteroaryl. In some embodiments of Formula (Iq1), each of Y1, Y2, or Y3 is -N(RY1)-. In some embodiments of Formula (Iq1), each of Y1, Y2, or Y3 is -N(RY1)-, wherein RY1 is hydrogen. In some embodiments of a compound of Formula (Iq1), each of Y1, Y2, or Y3 is -N(RY1)- or - NC(O)RY2, wherein each of RY1 and RY2 is independently methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, CH(Et)2¸ CH2CH2OMe, CH2CH2SO2Me, or CH2CF3. In some embodiments Formula (Iq1), each of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, wherein each of RY1 and RY2 is phenyl. In some embodiments of Formula (Iq1), each of Y1, Y2, or Y3 is -N(RY1)- or - NC(O)RY2, wherein each of RY1 and RY2 is benzyl. In some embodiments a compound of Formula (Iq1), is one wherein each of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, and wherein each of RY1 and RY2 is independently 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments of a compound according to Formulas (Iq) and (Iq1), the compound is:
Figure imgf000087_0001
In some embodiments of a compound of Formulas (Iq) and (Iq1), the compound is:
Figure imgf000088_0001
In some embodiments of Formula (Iq1), each of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, wherein each of RY1 and RY2 is independently
Figure imgf000088_0002
, wherein RZ1 is hydrogen or alkyl. In some embodiments of Formula (Iq1), ach of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, wherein each of RY1 and RY2 is independently , wherein RZ1 is methyl, ethyl, n-propyl,
Figure imgf000088_0003
isopropyl, n-butyl, tert-butyl, or CH(Et)2. In some embodiments of Formula (Iq1), each of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, each of RY1 and RY2 is independently
Figure imgf000088_0004
, wherein RZ1 is benzyl. In some embodiments of compounds according to Formula (Iq1), the compound is:
Figure imgf000089_0001
In some embodiments of Formula (I) compounds have the structure of Formula (Ir):
Figure imgf000089_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; R5 is hydrogen, alkyl, or cycloalkyl; and R6 is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments, disclosed are compounds of Formula (Ir), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; R5 is hydrogen, alkyl, or cycloalkyl; and R6 is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments Formulas (I) and (Ir), R5 is hydrogen or alkyl. In some embodiments of Formulas (I) and (Ir), R5 is hydrogen or unsubstituted alkyl. In some embodiments of Formulas (I) and (Ir), R5 is hydrogen. In some embodiments of Formulas (I) and (Ir), R6 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formulas (I) and (Ir), R6 is alkyl. In some embodiments of Formulas (I) and (Ir), R6 is heteroalkyl. In some embodiments of Formulas (I) and (Ir), R6 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formulas (I) and (Ir), R6 is alkyl. In some embodiments of Formulas (I) and (Ir), R6 is heteroalkyl. In some embodiments of Formulas (I) and (Ir), R6 is heterocyclylalkyl substituted with arylalkyl. In some embodiments of Formulas (I) and (Ir), R5 is methyl, ethyl, isopropyl, tert-butyl, or -CH(Et)2. In some embodiments of Formulas (I) and (Ir), R5 is hydrogen, and R6 is alkyl. In some embodiments of Formulas (I) and (Ir), R5 is alkyl, and R6 is alkyl. In some embodiments of Formulas (I) and (Ir), R5 is hydrogen, and R6 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Ir), R5 is unsubstituted alkyl, and R6 is unsubstituted alkyl. In some embodiments of Formulas (I)of and (Ir), R5 is unsubstituted alkyl, and R6 is heterocyclylalkyl. In some embodiments of Formulas (I) and (Ir ), R6 is methyl, ethyl, n-propyl, isopropyl, tert- butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of Formulas (I) and (Ir), R6 is aryl. In some embodiments Formulas (I) and (Ir), R6 is phenyl. In some embodiments of Formulas (I) and (Ir), R6 is heterocyclylalkyl. In some embodiments of Formulas (I) and (Ir), R6 is oxetan-3-yl or azetidin- 3-yl. In some embodiments of Formulas (I) and (Ir), R6 is heteroaryl. In some embodiments of Formulas (I) and (Ir), R6 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyyrimidyl. In some embodiments of Formulas (I) and (Ir), R6 is benzyl. In some embodiments of a compound according to Formulas (I) and (Ir), R6 is
Figure imgf000090_0001
. In some embodiments of a compound of Formulas (I) and (Ir), the compound is:
Figure imgf000091_0001
In some embodiments, compounds of Formulas (I) and (Ir) have the structure of Formula (Ir1):
Figure imgf000091_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy, such as methoxy; R5 is hydrogen, alkyl, or cycloalkyl; and Q1 is
Figure imgf000091_0003
, or
Figure imgf000091_0004
, wherein each of Y1, Y2, or Y3 is independently -O-, -S-, -S(O)-, -S(O)2-, -N(RY1)-, or -NC(O)RY2, wherein each of RY1 and RY2 is independently hydrogen, alkyl, heteroalkyl, or heteroaryl. In some embodiments, disclosed are compounds of Formula (Ir1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; R5 is hydrogen, alkyl, or cycloalkyl; and Q1 is
Figure imgf000092_0001
, , or
Figure imgf000092_0002
, wherein each of Y1, Y2, or Y3 is independently -O-, -S-, -S(O)-, -S(O)2-, -N(RY1)-, or -NC(O)RY2, wherein each of RY1 and RY2 is independently hydrogen, alkyl, heteroalkyl, or heteroaryl. In some embodiments of Formula (Ir1), each of Y1, Y2, or Y3 is -N(RY1)-. In some embodiments of a compound of Formula (Ir1), each of Y1, Y2, or Y3 is -N(RY1)-, wherein RY1 is hydrogen. In some embodiments of Formula (Ir1), each of Y1, Y2, or Y3 is -N(RY1)- or - NC(O)RY2, wherein each of RY1 and RY2 is independently methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, CH(Et)2¸ CH2CH2OMe, CH2CH2SO2Me, or CH2CF3. In some embodiments of Formula (Ir1), each of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, wherein each of RY1 and RY2 is phenyl. In some embodiments of Formula (Ir1), each of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, wherein each of RY1 and RY2 is benzyl. In some embodiments of Formula (Ir1), each of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, wherein each of RY1 and RY2 is independently 2-pyridyl, 3- pyridyl, or 4-pyridyl. In some embodiments of a compound according to Formulas (I) and (Ir), the compound is:
Figure imgf000092_0003
Figure imgf000093_0001
In some embodiments of a compound of Formulas (I) and (Ir), the compound is:
Figure imgf000093_0002
In some embodiments of Formula (Ir1), each of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, wherein each of RY1 and RY2 is independently Z1
Figure imgf000094_0001
, wherein R is hydrogen or alkyl. In some embodiments of a compound of Formula (Ir1), each of Y1, Y2, or Y3 is -N(RY1)- or - NC(O)RY2, wherein each of RY1 and RY2 is independently Z1
Figure imgf000094_0002
, wherein R is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or CH(Et)2. In some embodiments of Formula (Ir1), each of Y1, Y2, or Y3 is -N(RY1)- or -NC(O)RY2, wherein each of RY1 and RY2 is independently
Figure imgf000094_0003
In some embodiments of compounds according to Formula (Ir1), the compound is:
Figure imgf000094_0004
Some embodiments of compounds according to Formula (I) have the structure of Formula (Is):
Figure imgf000095_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy, such as methoxy; and R15 is alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl. Some embodiments of compounds according to Formula (Is), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, R1 is deuterated alkoxy, such as deuterated methoxy; and R15 is alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments, of Formula (Is), R1 is methoxy; and R15 is methyl substituted with -CO2H. In some embodiments of Formulas (I) and (Is), R15 is alkyl. In some embodiments of Formulas (I) and (Is), R15 is unsubstituted alkyl. In some embodiments of Formulas (I) and (Is), R15 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl. In some embodiments of Formulas (I) and (Is), R15 is cycloalkyl. In some embodiments of Formulas (I) and (Is), R15 is cyclopropyl. In some embodiments of Formulas (I) and (Is), R15 is heteroalkyl. In some embodiments of Formulas (I) and (Is), R15 is -CH[CH(Me)2]NH2. In some embodiments of Formulas (I) and (Is), R15 is -(CH2)qCO2H, q is 1, 2, 3, 4, 5, or 6. In some embodiments of Formulas (I) and (Is), R15 is phenyl. In some embodiments of Formulas (I) and (Is), R15 is 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In some embodiments of Formula (I) and (Is), R15 is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of Formula (I) and (Is), R15 is methyl. In some embodiments of Formula (I) and (Is), R1 is hydrogen, and R15 is methyl. In some embodiments of Formula (I) and (Is), R1 is deuterium, and R15 is methyl. In some embodiments of Formula (I) and (Is), R1 is methoxy, and R15 is methyl. In some embodiments of Formula (I) and (Is), R1 is deuterated methoxy, and R15 is methyl. In some embodiments of a compound according to Formulas (I) and (Is), the compound is:
Figure imgf000096_0001
In some embodiments of Formula (I) having the structure of Formula (It), or a pharmaceutically acceptable salt thereof:
Figure imgf000096_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy, such as methoxy, and R13 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formula (It), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, R1 is deuterated alkoxy, such as deuterated methoxy, and R13 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formula (I) and (It), R13 is alkyl. In some embodiments of Formula (I) and (It), R13 is unsubstituted alkyl. In some embodiments of Formula (I) and (It), R13 is methyl, ethyl, isopropyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments of Formula (I) and (It), R13 is cycloalkyl. In some embodiments of Formula (I) and (It), R13 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments of Formula (I) and (It), R13 is heteroalkyl. In some embodiments of Formula (I) and (It), R13 is -CH2CH2OMe, CH2CH2SO2Me, or CH2CH2NMe2. In some embodiments of Formula (I) and (It), R13 is (CH2)uCO2H, wherein u is 1, 2, 3, 4, 5, or 6. In some embodiments of Formula (I) and (It), R13 is aryl. In some embodiments of Formula (I) and (It), R13 is phenyl. In some embodiments of Formula (I) and (It), R13 is heteroaryl. In some embodiments of Formula (I) and (It), R13 is heteroaryl, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-pyrimidyl, or 6-pyrimidyl. In some embodiments of Formula (I) and (It), R13 is heterocyclylalkyl. In some embodiments of Formula (I) and (It), R13 is oxetan-3-yl or azetidine- 3-yl. In some embodiments of Formula (I) and (It), R13 is
Figure imgf000097_0001
In some embodiments of Formula (I) and (It), R13 is B1
Figure imgf000097_0002
, R is hydrogen or alkyl, and Z1 is -O-, -S-, -S(O)-, -S(O)2-, or -N(RC1)-, RC1 is hydrogen, alkyl, acetyl, or benzoyl. In some embodiments of Formula (I) and (It), R13 is , where C1
Figure imgf000097_0003
in R is unsubstituted alkyl. In some embodiments of Formula (I) and (It), R13 is C1
Figure imgf000097_0004
, R is methyl, acetyl, or benzoyl. In some embodiments of Formula (I) and (It), R13 is
Figure imgf000097_0005
. In some embodiments of Formula (I) and (It), R13 is
Figure imgf000097_0006
, , or
Figure imgf000097_0007
, wherein each of Y1, Y2, or Y3 is independently -O-, -S-, -S(O)-, -S(O)2-, or -N(RB2)-, wherein each RB2 is independently hydrogen, alkyl, acetyl, or benzoyl. In some embodiments of Formula (I) and (It), R13 is or
Figure imgf000098_0002
, wherein RB2 is unsubstituted alkyl. In
Figure imgf000098_0001
some embodiments of Formula (I) and (It), R13 is
Figure imgf000098_0003
, or
Figure imgf000098_0004
wherein each RB2 independently is methyl, acetyl, or benzoyl. In some embodiments of Formula (I) and (It), R13 is , or
Figure imgf000098_0005
Figure imgf000098_0006
In some embodiments of a compound of Formulas (I) and (It), R13 is -CH2CH2RB3, RB3 is heteroaryl or heterocyclylalkyl. In some embodiments of Formulas (I) and (It), R13 is - CH2CH2RB3, wherein RB3 is heterocyclylalkyl. In some embodiments of Formulas (I) and (It), R13 is -CH2CH2RB3, wherein RB3 is
Figure imgf000098_0007
Figure imgf000098_0008
, , or
Figure imgf000098_0009
. In some embodiments of a compound of Formulas (I) and (It), the compound is:
Figure imgf000098_0010
Figure imgf000099_0001
In some embodiments of a compound of Formulas (I) and (It), the compound is:
Figure imgf000099_0002
Figure imgf000100_0001
In some embodiments of a compound of Formulas (I) and (It), the compound is:
Figure imgf000100_0002
In some embodiments compounds of Formula (I) having the structure of Formula (Iu), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof are provided:
Figure imgf000100_0003
wherein: R1 is alkoxy, such as methoxy; RA1 is hydrogen, alkyl, or cycloalkyl; and each of R20 and R21 is independently alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl, or R20 and R21 together with the atoms to which they are attached form a heterocyclylalkyl ring. In some embodiments, disclosed are compounds of Formula (Iu), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is deuterated alkoxy, such as deuterated methoxy; RA1 is hydrogen, alkyl, or cycloalkyl; and each of R20 and R21 is independently alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl, or R20 and R21 together with the atoms to which they are attached form a heterocyclylalkyl ring. In some embodiments of Formula (Iu), RA1 is alkyl. In some embodiments of Formula (Iu), RA1 is unsubstituted alkyl. In some embodiments of a compound of Formula (Iu), RA1 is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of a compound of Formula (Iu), RA1 is hydrogen. In some embodiments of Formula (Iu), RA1 is methyl. In some embodiments of Formula (Iu), RA1 is hydrogen. In some embodiments of Formula (Iu), RA1 is methyl, ethyl, isopropyl, -CH(Et)2, or tert-butyl. In some embodiments of Formula (Iu), each of R20 and R21 is independently unsubstituted alkyl. In some embodiments of Formula (Iu), each of R20 and R21 is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, 3-methyl-1-butyl, n-pentyl, or n-hexyl. In some embodiments of Formula (Iu), each of R20 and R21 is independently alkyl. In some embodiments of Formula (Iu), each of R20 and R21 is benzyl. In some embodiments of Formula (Iu), each of R20 and R21 is independently . In of Formula (I 20 21
Figure imgf000101_0001
u), each of R and R is phenyl. In some embodiments of Formula (Iu), each of R20 and R21 is independently cycloalkyl. In some embodiments of Formula (Iu), each of R20 and R21 is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some of Formula (Iu), each of R20 and R21 is independently heteroaryl. In some embodiments of Formula (Iu), each of R20 and R21 is independently 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, or 4-pyrimidyl. In some embodiments of Formula (Iu), each of R20 and R21 is independently alkyl or cycloalkyl. In some embodiments of Formula (Iu), each of R20 and R21 is independently unsubstituted alkyl, and RA1 is hydrogen. In some embodiments of Formula (Iu), each of R20 and R21 is independently unsubstituted alkyl, and R1 is methyl. In some embodiments of Formula (Iu), each of R20 and R21 is tert-butyl, RA1 is hydrogen, and R1 is methoxy. In some embodiments of Formula (Iu), each of R20 and R21 is tert-butyl, RA1 is hydrogen, and R1 is deuterated methoxy. In some embodiments of Formula (Iu), each of R20 and R21 is tert-butyl, RA1 is hydrogen, and R1 is hydrogen. In some embodiments of Formula (Iu), each of R20 and R21 is tert-butyl, RA1 is hydrogen, and R1 is deuterium. In some embodiments of a compound of Formula (Iu), the compound is:
Figure imgf000102_0001
In some embodiments of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), and (Iu), R1 is methoxy. In some embodiments of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), and (Iu) R1 is hydrogen. In some embodiments of a compound according to any one of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), and (Iu), the compound is enriched in a heavy isotope, such as deuterium or tritium. In some embodiments of a compound according to any one of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), and (Iu), the compound is enriched in deuterium and R1 is hydrogen. In some embodiments of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), and (Iu), R1 is deuterated methoxy. In some embodiments of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), and (Iu) R1 is deuterium. In some embodiments of a compound according to any one of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), and (Iu), the compound is enriched in a heavy isotope, such as deuterium or tritium. In some embodiments of a compound according to any one of Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io1a), (Io2), (Ip), (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), and (Iu), the compound is enriched in deuterium and R1 is deuterium. In some embodiments of a compound of Formula (I), R4 is hydrogen or alkyl. In some embodiments of Formula (I), R4 is alkyl. In some embodiments of Formula (I), R4 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (I), R4 is hydrogen. In some embodiments of Formula (I), R4 is unsubstituted alkyl. In some embodiments of Formula (I), R5 is hydrogen or alkyl. In some embodiments of Formula (I), R5 is alkyl. In some embodiments of Formula (I), R5 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (I), R5 is hydrogen. In some embodiments of Formula (I), R5 is unsubstituted alkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)R6. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)R6, wherein R5 is hydrogen or alkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)R6, wherein R5 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (I), R2 is -C(O)OCH2OC(O)R6. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)R6, wherein R6 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formula (I), R2 is - C(O)OCH(R5)OC(O)R6, wherein R6 is alkyl. In some embodiments of Formula (I), R2 is - C(O)OCH(R5)OC(O)R6, wherein R6 is heteroalkyl. In some embodiments of Formula (I), wherein R2 is -C(O)OCH(R5)OC(O)R6, wherein R6 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)R6, wherein R6 is alkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)R6, wherein R6 is heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)R6, wherein R6 is heterocyclylalkyl substituted with arylalkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)OR6. In some embodiments of Formula (I), R2 is -C(O)OCH2OC(O)OR6. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)OR6, wherein R5 is alkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)OR6, wherein R5 is hydrogen or unsubstituted alkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)OR6, wherein R6 is heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)OR6, wherein R6 is alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl. In some embodiments of Formula (I), R2 is - C(O)OCH(R5)OC(O)OR6, wherein R6 is heterocyclylalkyl substituted with alkyl, heteroalkyl, or arylalkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)OR6, wherein R6 is unsubstituted heteroalkyl. In some embodiments of Formula (I), R2 is - C(O)OCH(R5)OC(O)OR6, wherein R6 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted heterocyclylalkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)OR6, wherein R6 is heterocyclylalkyl substituted with alkyl, heteroalkyl, or arylalkyl. In some embodiments of Formula (I), R2 is -C(O)OCH(R5)OC(O)OR6, wherein R6 is heterocyclylalkyl that is unsubstituted. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10 and in certain of such embodiments, each of R9 and R10 is independently alkyl, such as alkyl that is unsubstituted. In other embodiments of Formula (I), R2 is -C(O)N(H)R10, wherein R10 is alkyl, such as alkyl that is unsubstituted. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein each of R9 and R10 is independently alkyl substituted with -N(R18)R19 or -C(O)OR13. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is unsubstituted alkyl, and R10 is alkyl substituted with -N(R18)R19 or -C(O)OR13. In some embodiments of Formula (I), R2 is - C(O)N(H)R10, wherein R10 is alkyl substituted with -N(R18)R19 or -C(O)OR13. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is unsubstituted alkyl, and R10 is alkyl substituted with -N(R18)R19, wherein each of R18 and R19 is unsubstituted alkyl. In some embodiments of Formula (I), R2 is -C(O)N(H)R10, wherein R10 is alkyl substituted with - N(R18)R19, wherein each of R18 and R19 is unsubstituted alkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is alkyl, and R10 is alkyl substituted with -C(O)OR13, wherein R13 is alkyl that is unsubstituted, or hydrogen. In some embodiments of Formula (I), R2 is -C(O)N(H)R10, wherein R10 is alkyl substituted with -C(O)OR13, and R13 is hydrogen or alkyl that is unsubstituted. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein each of R9 and R10 is independently alkyl substituted with -C(O)OH. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is alkyl, and R10 is alkyl substituted with - C(O)OH. In some embodiments of Formula (I), wherein R2 is C(O)N(H)R10, wherein R10 is alkyl substituted with -C(O)OH. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10 and in certain of such embodiments, R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is alkyl or heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with heteroalkyl that is unsubstituted. In some embodiments of Formula (I), wherein R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with heterocyclylalkyl that is unsubstituted. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with cycloalkyl that is unsubstituted. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with heterocyclylalkyl. In some embodiments of Formula (I), R2 is - C(O)N(R9)R10, wherein R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with cycloalkyl substituted with alkyl. In some of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with - OC(O)R15. In some embodiments of Formula (I), wherein R2 is -C(O)N(R9)R10, R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with -OC(O)R15, wherein R15 is hydrogen, alkyl, aryl, or heteroaryl. In some embodiments of Formula (I), wherein R2 is - C(O)N(R9)R10, R9 is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, each of which is substituted with -OC(O)R15, and R15 is hydrogen, unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, alkyl, cycloalkyl, or heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is alkyl or heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is alkyl or heteroalkyl, each of which is substituted with -N(R13)C(O)R14, wherein each of R13 and R14 is independently hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is alkyl or heteroalkyl, each of which is substituted with -C(O)N(R18)R19, wherein each of R18 and R19 is independently hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is alkyl or heteroalkyl, each of which is substituted with -N(R13)C(O)R14, wherein each of R13 and R14 is independently hydrogen, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments of Formula (I), R2 is - C(O)N(R9)R10, wherein R10 is alkyl or heteroalkyl, each of which is substituted with - C(O)N(R18)R19, wherein each of R18 and R19 is independently hydrogen, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, alkyl, cycloalkyl, or heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is cycloalkyl substituted with -N(R18)R19, wherein each of R18 and R19 is hydrogen, alkyl, heteroalkyl, or cycloalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is cycloalkyl substituted with -N(R18)R19, wherein each of R18 and R19 is hydrogen, unsubstituted alkyl, unsubstituted heteroalkyl, or unsubstituted cycloalkyl. In some of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is cycloalkyl substituted with -N(R18)R19, and R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, alkyl, cycloalkyl, or heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R9 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted heteroalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is alkyl substituted with -OC(O)N(R18)R19, and R18 and R19 together with the atom to which they are attached form a heteroaryl ring or a heterocyclylalkyl ring, each of which is substituted with alkyl, heteroalkyl, or cycloalkyl. In some embodiments of Formula (I), R2 is -C(O)N(R9)R10, wherein R10 is alkyl substituted with -OC(O)R15, wherein R15 is heterocyclylalkyl substituted with alkyl or arylalkyl. In some embodiments of Formula (I), R2 is -C(O)R4, wherein R4 is alkyl, heteroalkyl, heterocyclylalkyl, or cycloalkyl. In some embodiments of Formula (I), R2 is -C(O)R4, wherein R4 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocyclylalkyl, or unsubstituted cycloalkyl. In some embodiments of Formula (I), wherein R2 is -C(O)R4, wherein R4 is heterocyclylalkyl substituted with aryl or arylalkyl. In some embodiments of Formula (I), R2 is -C(O)R4, wherein R4 is alkyl substituted with -C(O)OR13. In some embodiments of Formula (I), R2 is -C(O)R4, wherein R4 is alkyl substituted with -C(O)OR13, wherein R13 is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments of Formula (I), R2 is -C(O)R4, wherein R4 is alkyl substituted with -C(O)OR13, wherein R13 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formula (I), wherein R2 is -C(O)R4, R4 is alkyl substituted with -OC(O)R15, wherein R15 is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl. In some embodiments of Formula (I), wherein R2 is -C(O)R4, R4 is alkyl substituted with -OC(O)R15, and R15 is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl. In some embodiments of Formula (I), R2 is -C(O)R4, and R4 is alkyl substituted with -OC(O)R15, wherein R15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, or unsubstituted heterocyclylalkyl. In some embodiments of Formula (I), R2 is -C(O)R4, and R4 is alkyl substituted with -OC(O)R15, wherein R15 is heterocyclylalkyl substituted with alkyl. In some embodiments of a compound of Formula (I), R2 is -C(O)R4, wherein R4 is alkyl substituted with -N(R13)C(O)R14, R13 is alkyl, cycloalkyl, or hydrogen; and R14 is alkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I), R2 is -C(O)R4, R4 is alkyl substituted with - N(R13)C(O)R14, R13 is unsubstituted alkyl, unsubstituted cycloalkyl, or hydrogen; and R14 is unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formula (I), R2 is -C(O)R4, wherein R4 is alkyl substituted with -NH2. In some embodiments of a compound of Formula (I), R2 is -C(O)R4, R4 is alkyl substituted with aryl, wherein the aryl is substituted with alkyl or -OC(O)OR16, and R16 is alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments of Formula (I) R2 is -C(O)R4, wherein R4 is alkyl substituted with aryl, the aryl is substituted with alkyl or -OC(O)OR16, and R16 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formula (I), R2 is -C(O)R4, wherein R4 is heterocyclylalkyl substituted with C(O)R14. With reference to embodiments of Formula (I) wherein R2 is -C(O)R4, exemplary embodiments have R4 as heterocyclylalkyl substituted with C(O)R14, wherein R14 is alkyl, heteroalkyl, cycloalkyl, or aryl. In some embodiments of Formula (I), R2 is -C(O)R4, R4 is heterocyclylalkyl substituted with C(O)R14, and R14 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted aryl. In some embodiments of a compound of Formula (I), R2 is -CH(R4)OP(O)OR11(OR12). In some embodiments of Formula (I), R2 is -CH(R4)OP(O)OR11(OR12), wherein R4 is hydrogen, alkyl, cycloalkyl, or heteroalkyl. In some embodiments of Formula (I), wherein R2 is - CH(R4)OP(O)OR11(OR12), wherein R4 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, or alkyl substituted with heteroaryl. In some embodiments of Formula (I), R2 is -CH(R4)OP(O)OR11(OR12) wherein each of R11 and R12 is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, or alkyl. In some embodiments of a compound of Formula (I), R2 is -CH(R4)OP(O)OR11(OR12), wherein each of R11 and R12 is independently selected from alkyl, hydrogen and a counterion, such as a metal or ammonium cation. In some embodiments of a compound of Formula (I), R2 is -CH(R4)OP(O)OR11(OR12), wherein each of R11 and R12 is independently selected from hydrogen and a counterion. In some embodiments of a compound of Formula (I), R2 is -CH(R4)OP(O)OR11(OR12), wherein each of R11 and R12 is independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl. In some embodiments of Formula (I) wherein R2 is -CH(R4)OP(O)OR11(OR12), each of R11 and R12 is alkyl, such as unsubstituted alkyl. In some embodiments of Formula (I), wherein R2 is - CH(R4)OP(O)OR11(OR12), at least one of R11 and R12 is alkyl substituted with -OC(O)R15. In some embodiments of Formula (I) wherein R2 is -CH(R4)OP(O)OR11(OR12), each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein each R15 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of Formula (I) wherein R2 is - CH(R4)OP(O)OR11(OR12), each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein each R15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formula (I) wherein R2 is -CH(R4)OP(O)OR11(OR12), each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein each R15 is heterocyclylalkyl substituted with alkyl or arylalkyl. In some embodiments of Formula (I), R2 is -CH(R4)OP(O)OR8[N(R9)R10]. In some embodiments of Formula (I) wherein R2 is -CH(R4)OP(O)OR8[N(R9)R10], R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, or alkyl substituted with heteroaryl. In some embodiments of Formula (I) wherein R2 is -CH(R4)OP(O)OR8[N(R9)R10], R4 is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, or alkyl substituted with heteroaryl. In some embodiments of a compound of Formula (I) R2 is -CH(R4)OP(O)OR8[N(R9)R10], R8 is alkyl, cycloalkyl, aryl, heteroaryl, alkyl, or alkyl substituted with aryl or heteroaryl; R9 is hydrogen; and R12 is alkyl substituted with -C(O)OR13. In some embodiments of Formula (I) wherein R2 is -CH(R4)OP(O)OR8[N(R9)R10], R8 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl; R9 is hydrogen; and R12 is alkyl substituted with -C(O)OR13, and R13 is alkyl, such as unsubstituted alkyl. In some embodiments of Formula (I), R2 is -P(O)OR11(OR12). In some embodiments of Formula (I) wherein R2 is -P(O)OR11(OR12), each of R11 and R12 is selected from alkyl and hydrogen or a counterion, such as a metal or ammonium cation. In some embodiments of Formula (I) wherein R2 is -P(O)OR11(OR12), one of R11 and R12 is alkyl and the other is hydrogen or a counterion, such as a metal or ammonium cation. In some embodiments of Formula (I) wherein R2 is -P(O)OR11(OR12), one of R11 and R12 is hydrogen and the other is a counterion, such as a metal or ammonium cation. In some embodiments of Formula (I) wherein R2 is -P(O)OR11(OR12), each of R11 and R12 is unsubstituted alkyl. In some embodiments of Formula (I) wherein R2 is -P(O)OR11(OR12), each of R11 and R12 is alkyl substituted with - C(O)OR13. In some embodiments of Formula (I) wherein R2 is -P(O)OR11(OR12), R13 is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments of Formula (I), R2 is -P(O)OR11(OR12), wherein R13 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formula (I), R2 is -P(O)OR11(OR12), wherein each of R11 and R12 is alkyl substituted with -OC(O)R15. In some embodiments of Formula (I), R2 is - P(O)OR11(OR12), wherein each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein R15 is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl. In some embodiments of Formula (I), R2 is -P(O)OR11(OR12), wherein each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein R15 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, or unsubstituted heterocyclylalkyl. In some embodiments of Formula (I), R2 is -P(O)OR11(OR12), wherein each of R11 and R12 is alkyl substituted with -OC(O)R15, wherein R15 is heterocyclylalkyl substituted with alkyl or arylalkyl. In some embodiments of Formula (I), R2 is -P(O)OR11(OR12), wherein each of R11 and R12 is alkyl substituted with -OC(O)OR16, and wherein R16 is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl. In some embodiments Formula (I), wherein R2 is - P(O)OR11(OR12), each of R11 and R12 is alkyl substituted with -OC(O)OR16, wherein R16 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, or unsubstituted heterocyclylalkyl. In some embodiments of Formula (I), R2 is -P(O)OR11(OR12), wherein R11 and R12 together with the atom to which they are attached form a heterocyclylalkyl ring such as an unsubstituted heterocyclylalkyl ring or a heterocyclylalkyl ring that is substituted with aryl. In some embodiments of a compound of Formula (I), R2 is -P(O)OR11(OR12), and R11 and R12 together with the atom to which they are attached form a heterocyclylalkyl ring that is substituted with unsubstituted aryl or substituted aryl, such as aryl substituted with halogen. In some embodiments of Formula (I), R2 is -P(O)OR8[N(R9)R10]. In some embodiments of Formula (I), wherein R2 is -P(O)OR8[N(R9)R10], wherein R8 is alkyl, aryl, or heteroaryl, such as unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments of Formula (I), wherein R2 is -P(O)OR8[N(R9)R10], each of R9 and R10 are independently selected from hydrogen and alkyl. In some embodiments of Formula (I), wherein R2 is - P(O)OR8[N(R9)R10], R8 is unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl, R9 is hydrogen, and R10 is alkyl. In some embodiments of Formula (I), R2 is -P(O)OR8[N(R9)R10], wherein R8 is unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl, R9 is hydrogen, and R10 is alkyl substituted with -C(O)R14. In some embodiments of Formula (I), wherein R2 is - P(O)OR8[N(R9)R10], R10 is alkyl substituted with -C(O)R14, and R14 is hydrogen or alkyl. In some embodiments (I), R14 is unsubstituted alkyl. In some of Formula (I), R2 is -S(O)2OR7, and in some such embodiments, R7 is alkyl, such as unsubstituted or substituted alkyl. In some embodiments Formula (I), wherein R2 is - S(O)2OR7, R7 is alkyl substituted with -C(O)R14, wherein R14 is alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I), R2 is -S(O)2OR7, wherein R7 is alkyl substituted with -C(O)R14. In some embodiments of Formula (I), wherein R7 is alkyl substituted with -C(O)R14, R14 is heterocyclylalkyl. In some embodiments of Formula (I), R2 is -S(O)2OR7, wherein R7 is alkyl substituted with -C(O)R14. In some embodiments of Formula (I), R7 is alkyl substituted with -C(O)R14, wherein R14 is heterocyclylalkyl substituted with alkyl, -C(O)CH3, or C(O)Ph. In some embodiments of Formula (I), R2 is -C(O)OR3, wherein R3 is alkyl substituted with -OP(O)OR20(OR21). In some embodiments of Formula (I), wherein R2 is -C(O)OR3, R3 is alkyl substituted with - OP(O)OR20(OR21), wherein each of R20 and R21 is independently hydrogen (or a counterion), alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl. In some embodiments of a compound of Formula (I), wherein R2 is -C(O)OR3, R3 is alkyl substituted with - OP(O)OR20(OR21), wherein each of R20 and R21 is independently alkyl, hydrogen, or a counterion, such as a metal cation or ammonium cation. In some embodiments of a compound of Formula (I), wherein R2 is -C(O)OR3, R3 is alkyl substituted with - OP(O)OR20(OR21), wherein each of R20 and R21 is independently unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heterocyclylalkyl, or unsubstituted heteroaryl. In some embodiments of Formula (I), wherein R2 is -C(O)OR3, wherein R3 is alkyl substituted with - OP(O)OR20(OR21), wherein each of R20 and R21 is independently unsubstituted alkyl. In one aspect of the disclosed embodiments, the present invention provides a compound of Formula (Iv):
Figure imgf000112_0001
an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3; R2 is hydrogen, -C(O)OR3, -C(O)R4, -CH(R5)OR6, -C(O)OCH(R5)OC(O)R6, - C(O)OCH(R5)OC(O)OR6, -C(O)NHCH(R5)OC(O)R6, -CH(R5)C(O)R6, -S(O)2OR7, - P(O)OR8[N(R9)R10], -C(O)N(R9)R10, -P(O)OR11(OR12), -CH(R4)OP(O)OR8[N(R9)R10], or -CH(R4)OP(O)OR11(OR12); each of R3, R6, R7, and R8 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, each of R4 and R5, is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, each of R9 and R10 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R9 and R10 together with the atom to which they are attached form a heterocyclylalkyl ring or a heteroaryl ring that is unsubstituted or substituted with one or more RA; each of R11 and R12 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R11 and R12 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RA; each RA is independently alkyl, heteroalkyl, oxo, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, an amino acid side chain, -OR13, -N(R18)R19, -NHC(=NH)NH2, -C(O)OR13, - N(R13)C(O)OR14, -N(R13)C(O)R14, -C(O)R14, -OC(O)R15, -OC(O)OR16, - OP(O)OR17[N(R18)R19], -C(O)N(R18)R19, -OC(O)N(R18)R19, -SR13, -SO2R13, or - OP(O)OR20(OR21), wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with alkyl, aryl, halogen, -OR13, -N(R18)R19, - C(O)R14, -OC(O)R15, -OC(O)OR16, or -OC(O)N(R18)R19; each of R13, R14, R15, R16, or R17 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is unsubstituted or substituted with one or more RB; each of R18 and R19 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one or more RB; each of R20 and R21 is independently alkyl, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB, or R20 and R21 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RB; and each RB is independently halogen, amino, cyano, hydroxyl, alkoxy, benzyl, -CO2H, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, -C(O)CH3, - C(O)Ph, or heteroarylalkyl, wherein cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more halogen, amino, cyano, hydroxyl, alkyl, acetyl, or benzoyl; provided that when R2 is hydrogen, the molecule is isotopically enriched. In some embodiments of the isotopically enriched compounds of Formula (Iv), at least one of R1, L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), R1 is - OCH3, -OCH2D, -OCHD2, or -OCD3; and at least one of L1, L2, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), R1 is - OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), R1 is - OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L1 is hydrogen; R1 is -OCH3; R2 is hydrogen; and at least one of L2, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L2 is hydrogen; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L3 is hydrogen; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L4 is hydrogen; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L5 is hydrogen; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L1 is deuterium; R1 is -OCH3; R2 is hydrogen; and at least one of L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L2 is deuterium; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L3 is deuterium; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L4 is deuterium; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L5 is deuterium; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), R1 is - OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L1 is hydrogen; R1 is -OCD3; R2 is hydrogen; and at least one of L2, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L2 is hydrogen; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L3 is hydrogen; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L4 is hydrogen; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L5 is hydrogen; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L1 is deuterium; R1 is -OCD3; R2 is hydrogen; and at least one of L2, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L2 is deuterium; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L3, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L3 is deuterium; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L4, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L4 is deuterium; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L5, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L5 is deuterium; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L6 and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L6 is - CH3; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L6 is - CH3; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L7 is - CH3; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L6 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L7 is - CH3; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L6 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L6 is - CD3; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L6 is - CD3; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L7 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L7 is - CD3; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L6 is deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv), L7 is - CD3; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L6 is deuterium. In some embodiments of Formula (Iv), R1 is -OCH3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), R1 is -OCD3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L1 is hydrogen; R1 is -OCH3; R2 is hydrogen; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L2 is hydrogen; R1 is -OCH3; R2 is hydrogen; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L3 is hydrogen; R1 is -OCH3; R2 is hydrogen; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L4 is hydrogen; R1 is -OCH3; R2 is hydrogen; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L5 is hydrogen; R1 is -OCH3; R2 is hydrogen; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L1 is deuterium; R1 is -OCH3; R2 is hydrogen; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L2 is deuterium; R1 is -OCH3; R2 is hydrogen; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L3 is deuterium; R1 is -OCH3; R2 is hydrogen; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L4 is deuterium; R1 is -OCH3; R2 is hydrogen; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L5 is deuterium; R1 is -OCH3; R2 is hydrogen; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L1 is hydrogen; R1 is -OCD3; R2 is hydrogen; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L2 is hydrogen; R1 is -OCD3; R2 is hydrogen; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L3 is hydrogen; R1 is -OCD3; R2 is hydrogen; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L4 is hydrogen; R1 is -OCD3; R2 is hydrogen; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L5 is hydrogen; R1 is -OCD3; R2 is hydrogen; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L1 is deuterium; R1 is -OCD3; R2 is hydrogen; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L2 is deuterium; R1 is -OCD3; R2 is hydrogen; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L3 is deuterium; R1 is -OCD3; R2 is hydrogen; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L4 is deuterium; R1 is -OCD3; R2 is hydrogen; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L5 is deuterium; R1 is -OCD3; R2 is hydrogen; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L6 is -CH3; R1 is -OCH3 or -OCD3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L7 is selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L7 is -CH3; R1 is -OCH3 or -OCD3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 is selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L6 is -CD3; R1 is -OCH3 or -OCD3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L7 is selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv), L7 is -CD3; R1 is -OCH3 or -OCD3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 is selected from -CH3, -CH2D, -CHD2, and -CD3. Particular embodiments of Formula (Iv) when R2 is hydrogen have formula (Iv-1):
Figure imgf000119_0001
(Iv-1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), at least one of R1, L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), R1 is - OCH3, -OCH2D, -OCHD2, or -OCD3; and at least one of L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), R1 is - OCH3; and optionally at least one of L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), R1 is - OCD3; and optionally at least one of L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L1 is hydrogen; R1 is -OCH3; and optionally at least one of L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L2 is hydrogen; R1 is -OCH3; and optionally at least one of L1, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L3 is hydrogen; R1 is -OCH3; and optionally at least one of L1, L2, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L4 is hydrogen; R1 is -OCH3; and optionally at least one of L1, L2, L3, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L5 is hydrogen; R1 is -OCH3; and optionally at least one of L1, L2, L3, L4, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L1 is deuterium; R1 is -OCH3; and optionally at least one of L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L2 is deuterium; R1 is -OCH3; and optionally at least one of L1, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L3 is deuterium; R1 is -OCH3; and optionally at least one of L1, L2, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L4 is deuterium; R1 is -OCH3; and optionally at least one of L1, L2, L3, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L5 is deuterium; R1 is -OCH3; and optionally at least one of L1, L2, L3, L4, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L1 is hydrogen; R1 is -OCD3; and optionally at least one of L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L2 is hydrogen; R1 is -OCD3; and optionally at least one of L1, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L3 is hydrogen; R1 is -OCD3; and optionally at least one of L1, L2, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L4 is hydrogen; R1 is -OCD3; and optionally at least one of L1, L2, L3, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L5 is hydrogen; R1 is -OCD3; and optionally at least one of L1, L2, L3, L4, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L1 is deuterium; R1 is -OCD3; and optionally at least one of L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L2 is deuterium; R1 is -OCD3; and optionally at least one of L1, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L3 is deuterium; R1 is -OCD3; and optionally at least one of L1, L2, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L4 is deuterium; R1 is -OCD3; and optionally at least one of L1, L2, L3, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L5 is deuterium; R1 is -OCD3; and optionally at least one of L1, L2, L3, L4, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L6 is - CH3; R1 is -OCH3 or -OCD3; and optionally at least one of L1, L2, L3, L4, L5, and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L7 is - CH3; R1 is -OCH3 or -OCD3; and optionally at least one of L1, L2, L3, L4, L5, and L6 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L6 is - CD3; R1 is -OCH3 or -OCD3; and optionally at least one of L1, L2, L3, L4, L5, and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), L7 is - CD3; R1 is -OCH3 or -OCD3; and optionally at least one of L1, L2, L3, L4, L5, and L6 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), at least one of R1, L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-1), R1 is - OCH3, -OCH2D, -OCHD2, or -OCD3; and at least one of L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of Formula (Iv-1), R1 is -OCH3; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), R1 is -OCD3; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L1 is hydrogen; R1 is -OCH3; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L2 is hydrogen; R1 is -OCH3; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L3 is hydrogen; R1 is -OCH3; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L4 is hydrogen; R1 is -OCH3; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L5 is hydrogen; R1 is -OCH3; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L1 is deuterium; R1 is -OCH3; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L2 is deuterium; R1 is -OCH3; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L3 is deuterium; R1 is -OCH3; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L4 is deuterium; R1 is -OCH3; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L5 is deuterium; R1 is -OCH3; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L1 is hydrogen; R1 is -OCD3; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L2 is hydrogen; R1 is -OCD3; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L3 is hydrogen; R1 is -OCD3; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L4 is hydrogen; R1 is -OCD3; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L5 is hydrogen; R1 is -OCD3; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L1 is deuterium; R1 is -OCD3; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L2 is deuterium; R1 is -OCD3; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L3 is deuterium; R1 is -OCD3; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L4 is deuterium; R1 is -OCD3; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L5 is deuterium; R1 is -OCD3; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L6 is -CH3; R1 is -OCH3 or -OCD3; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L7 is selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L7 is -CH3; R1 is -OCH3 or -OCD3; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 is selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L6 is -CD3; R1 is -OCH3 or -OCD3; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L7 is selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-1), L7 is -CD3; R1 is -OCH3 or -OCD3; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 is selected from -CH3, -CH2D, -CHD2, and -CD3. Particular embodiments of Formula (Iv) when R1 is -OCH3 and R2 is hydrogen have formula (Iv-2):
Figure imgf000125_0001
(Iv-2), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), at least one of L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), optionally at least one of L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L1 is hydrogen; and optionally at least one of L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L2 is hydrogen; and optionally at least one of L1, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L3 is hydrogen; and optionally at least one of L1, L2, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L4 is hydrogen; and optionally at least one of L1, L2, L3, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L5 is hydrogen; and optionally at least one of L1, L2, L3, L4, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L1 is deuterium; and optionally at least one of L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L2 is deuterium; and optionally at least one of L1, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L3 is deuterium; and optionally at least one of L1, L2, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L4 is deuterium; and optionally at least one of L1, L2, L3, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L5 is deuterium; and optionally at least one of L1, L2, L3, L4, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L6 is - CH3; and optionally at least one of L1, L2, L3, L4, L5, and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L7 is - CH3; and optionally at least one of L1, L2, L3, L4, L5, and L6 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L6 is - CD3; and optionally at least one of L1, L2, L3, L4, L5, and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-2), L7 is - CD3; and optionally at least one of L1, L2, L3, L4, L5, and L6 is enriched in deuterium. In some embodiments of Formula (Iv-2), L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from - CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L1 is hydrogen; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L2 is hydrogen; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L3 is hydrogen; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L4 is hydrogen; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L5 is hydrogen; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L1 is deuterium; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L2 is deuterium; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L3 is deuterium; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L4 is deuterium; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-2), L5 is deuterium; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. Particular embodiments of Formula (Iv) when R1 is -OCD3 and R2 is hydrogen have formula (Iv-3):
Figure imgf000127_0001
(Iv-3), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), at least one of L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), optionally at least one of L1, L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L1 is hydrogen; and optionally at least one of L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L2 is hydrogen; and optionally at least one of L1, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L3 is hydrogen; and optionally at least one of L1, L2, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L4 is hydrogen; and optionally at least one of L1, L2, L3, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L5 is hydrogen; and optionally at least one of L1, L2, L3, L4, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L1 is deuterium; and optionally at least one of L2, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L2 is deuterium; and optionally at least one of L1, L3, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L3 is deuterium; and optionally at least one of L1, L2, L4, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L4 is deuterium; and optionally at least one of L1, L2, L3, L5, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L5 is deuterium; and optionally at least one of L1, L2, L3, L4, L6 and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L6 is - CH3; and optionally at least one of L1, L2, L3, L4, L5, and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L7 is - CH3; and optionally at least one of L1, L2, L3, L4, L5, and L6 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L6 is - CD3; and optionally at least one of L1, L2, L3, L4, L5, and L7 is enriched in deuterium. In some embodiments of the isotopically enriched compounds of Formula (Iv-3), L7 is - CD3; and optionally at least one of L1, L2, L3, L4, L5, and L6 is enriched in deuterium. In some embodiments of Formula (Iv-3), L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from - CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L1 is hydrogen; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L2 is hydrogen; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L3 is hydrogen; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L4 is hydrogen; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L5 is hydrogen; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L1 is deuterium; L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L2 is deuterium; L1, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L3 is deuterium; L1, L2, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L4 is deuterium; L1, L2, L3, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. In some embodiments of Formula (Iv-3), L5 is deuterium; L1, L2, L3, and L4 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3. Also disclosed herein are methods for making and using compounds of Formula (Iv), (Iv- 1), (Iv-2) and (Iv-3). Selected compounds of the disclosure with corresponding simplified molecular-input line-entry system (SMILES) strings are provided in Table 1. TABLE 1
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
5 10 15 20 25 30
Figure imgf000133_0001
Figure imgf000134_0001
5 10 15 20 25 30
Figure imgf000135_0001
Figure imgf000136_0001
5 10 15 20 25 30
Figure imgf000137_0001
Figure imgf000138_0001
5 10 15 20 25 30
Figure imgf000139_0001
Figure imgf000140_0001
5 10 15 20 25
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
5 10 15 20 25 30
Figure imgf000144_0001
5 10 15 20 25 30
Figure imgf000145_0001
5 10 15 20 25 30
Figure imgf000146_0001
Figure imgf000147_0001
5 10 15 20 25
Figure imgf000148_0001
Figure imgf000149_0001
5 10 15 20 25 30
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
In another aspect, the present disclosure provides a pharmaceutically acceptable composition comprising a compound according to any formula selected from those including those recited in Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. Method of Making Compounds The deuterated compounds disclosed herein may be made by any method known to a person of ordinary skill in the art. In some embodiments, the compound is made using a known synthetic method for making the analogous non-deuterated compound, but with one or more deuterated starting materials, and/or reactants used in the synthesis. Methods for making non- deuterium enriched 6-methoxy-N,N, -dimethyltryptame are known in the art and a person of ordinary skill in the art understands which deuterated reactants and reagents are available and may be used in the synthesis of the disclosed compounds. Additional information concerning synthetic methods to make non-deuterated analogs of the disclosed compounds is available in the art. An exemplary method for making compounds of the present disclosure are provided by the following Schemes. Conditions and reagent amounts for the steps illustrated in the Deuterated Scheme are described in detail in the Examples section of the present disclosure.
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Methods of Treatment: In yet another aspect, the present disclosure provides a method of treating or preventing a disease, disorder, or condition in which an increased level of a tryptamine psychedelic such as a DMT analog disclosed herein is beneficial, comprising administering to a subject in need thereof an effective amount of a compound selected from those recited in Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3) or a pharmaceutically acceptable salt thereof. In some embodiments, the condition comprises post-traumatic stress disorder, major depression, schizophrenia, or substance abuse. Additional examples of methods for using the disclosed compounds are described below. The compounds of the present invention, including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3), and pharmaceutically acceptable salts thereof can be used for increasing neuronal plasticity. The compounds of the present invention can also be used to treat any brain disease. The compounds of the present invention can also be used for increasing at least one of translation, transcription or secretion of neurotrophic factors. In some embodiments, a compound of the present invention, including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3), and pharmaceutically acceptable salts thereof, is used to treat neurological diseases. In some embodiments, the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neurological disease is a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disease is a migraine or cluster headache. In some embodiments, the neurological disease is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease. In some embodiments, the neurological disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease is a psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post- traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disease is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia. In some embodiments, a compound of the present invention, including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), (Iv-3) and pharmaceutically acceptable salts thereof, is used for increasing neuronal plasticity. In some embodiments, the compounds described herein are used for treating a brain disorder. In some embodiments, the compounds described herein are used for increasing at least one of translation, transcription, or secretion of neurotrophic factors. In some embodiments, the compounds of the present invention, including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), (Iv-3) and pharmaceutically acceptable salts thereof, have activity as 5-HT2A modulators. In some embodiments, the compounds of the present invention have activity as 5-HT2A modulators. In some embodiments, the compounds of the present invention elicit a biological response by activating the 5-HT2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT2A receptor). 5-HT2A agonism has been correlated with the promotion of neural plasticity (Ly et al., 2018). 5-HT2A antagonists abrogate the neuritogenesis and spinogenesis effects of hallucinogenic compounds with 5-HT2A agonist activity, for example., DMT, LSD, and DOI. In some embodiments, the compounds of the present invention are 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, the compounds of the present invention are selective 5-HT2A modulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neural plasticity includes, for example, increased dendritic spine growth, increased synthesis of synaptic proteins, strengthened synaptic responses, increased dendritic arbor complexity, increased dendritic branch content, increased spinogenesis, increased neuritogenesis, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increased cortical structural plasticity in the anterior parts of the brain. In some embodiments, the 5-HT2A modulators (e.g., 5-HT2A agonists) are non- hallucinogenic. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used to treat neurological diseases, which modulators do not elicit dissociative side- effects. In some embodiments, the hallucinogenic potential of the compounds described herein is assessed in vitro. In some embodiments, the hallucinogenic potential assessed in vitro of the compounds described herein is compared to the hallucinogenic potential assessed in vitro of hallucinogenic homologs. In some embodiments, the compounds described herein elicit less hallucinogenic potential in vitro than the hallucinogenic homologs. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used to treat neurological diseases. In some embodiments, the neurological diseases comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used for increasing neuronal plasticity. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used for treating a brain disorder. In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT2A agonists) are used for increasing at least one of translation, transcription, or secretion of neurotrophic factors. In some embodiments, the 5-HT2A antagonist is selected from MDL-11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, volinanserin (MDL-100,907), olanzapine, risperidone, pimavanserin, nelotanserin and lorcaserin. Methods for Increasing Neuronal Plasticity Neuronal plasticity refers to the ability of the brain to change structure and/or function throughout a subject's life. New neurons can be produced and integrated into the central nervous system throughout the subject's life. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density. In some embodiments, increasing neuronal plasticity can treat neurodegenerative disorder, Alzheimer's, Parkinson's disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder. In some embodiments, the present invention provides methods for increasing neuronal plasticity, comprising contacting a neuronal cell with any of the compounds of the present invention, including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), (Iv-3) and pharmaceutically acceptable salts thereof. In some embodiments, increasing neuronal plasticity improves a brain disorder described herein. In some embodiments, a compound of the present invention, including compounds of Table 1, Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), (Iv-3) and pharmaceutically acceptable salts thereof, is used to increase neuronal plasticity. In some embodiments, the compounds used to increase neuronal plasticity have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, decreased neuronal plasticity is associated with a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neuropsychiatric disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety. In some embodiments, the experiment or assay to determine increased neuronal plasticity of any compound of the present invention is a phenotypic assay, a dendritogenesis assay, a spinogenesis assay, a synaptogenesis assay, a Sholl analysis, a concentration-response experiment, a 5-HT2A agonist assay, a 5-HT2A antagonist assay, a 5-HT2A binding assay, or a 5- HT2A blocking experiment (e.g., ketanserin blocking experiments). In some embodiments, the experiment or assay to determine the hallucinogenic potential of any compound of the present invention is a mouse head-twitch response (HTR) assay. In some embodiments, the present invention provides a method for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), or (Iv-3), or a pharmaceutically acceptable salt thereof. Methods of Treating a Brain Disorder In some embodiments, the present invention provides a method of treating a disease, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention. In some embodiments, the present invention provides a method of treating a brain disorder, including administering to a subject in need thereof, a therapeutically effective amount of a compound disclosed herein, such as a compound of Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), or (Iv-3), or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method of treating a brain disorder with combination therapy, including administering to a subject in need thereof, a therapeutically effective amount of a compound of the present invention and at least one additional therapeutic agent. In some embodiments, serotonin receptor modulators, such as modulators of serotonin receptor 2A (5-HT2A modulators, e.g., 5-HT2A agonists), are used to treat a brain disorder. The presently disclosed compounds of Table 1 and Formulas (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1), (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), and (Iv-3) can function as 5-HT2A agonists alone, or in combination with a second therapeutic agent that also is a 5-HT2A modulator. In such cases the second therapeutic agent can be an agonist or an antagonist. In some instances, it may be helpful administer a 5-HT2A antagonist in combination with a compound of the present invention to mitigate undesirable effects of 5-HT2A agonism, such as potential hallucinogenic effects. Serotonin receptor modulators useful as second therapeutic agents for combination therapy as described herein are known to those of skill in the art and include, without limitation, ketanserin, volinanserin (MDL-100907), eplivanserin (SR- 46349), pimavanserin (ACP-103), glemanserin (MDL-11939), ritanserin, flibanserin, nelotanserin, blonanserin, mianserin, mirtazapine, roluperiodone (CYR-101, MIN-101), quetiapine, olanzapine, altanserin, acepromazine, nefazodone, risperidone, pruvanserin, AC- 90179, AC-279, adatanserin, fananserin, HY10275, benanserin, butanserin, manserin, iferanserin, lidanserin, pelanserin, seganserin, tropanserin, lorcaserin, ICI-169369, methiothepin, methysergide, trazodone, cinitapride, cyproheptadine, brexpiprazole, cariprazine, agomelatine, setoperone, 1-(1-Naphthyl)piperazine, LY-367265, pirenperone, metergoline, deramciclane, amperozide, cinanserin, LY-86057, GSK-215083, cyamemazine, mesulergine, BF-1, LY- 215840, sergolexole, spiramide, LY-53857, amesergide, LY-108742, pipamperone, LY-314228, 5-I-R91150, 5-MeO-NBpBrT, 9-Aminomethyl-9,10-dihydroanthracene, niaprazine, SB-215505, SB-204741 , SB-206553, SB-242084, LY-272015, SB-243213, SB-200646, RS-102221, zotepine, clozapine, chlorpromazine, sertindole, iloperidone, paliperidone, asenapine, amisulpride, aripiprazole, lurasidone, ziprasidone, lumateperone, perospirone, mosapramine, AMDA (9-Aminomethyl-9,10-dihydroanthracene), methiothepin, buspirone, xanomeline, an extended-release form of olanzapine (e.g., ZYPREXA RELPREVV), an extended-release form of quetiapine, an extended-release form of risperidone (e.g., Risperdal Consta), an extended- release form of paliperidone (e.g., Invega Sustenna and Invega Trinza), an extended-release form of fluphenazine decanoate including Prolixin Decanoate, an extended-release form of aripiprazole lauroxil including Aristada, an extended-release form of aripiprazole including Abilify Maintena, 3-(2-(4-(4-Fluorobenzoyl)piperazin-1-yl)ethyl)-5-methyl-5- phenylimidazolidine-2,4-dione, 3‑(2‑(4‑Benzhydrylpiperazin‑1‑yl)ethyl)‑5‑methyl‑5‑phe‑ nylimidazolidine‑2,4‑dione, 3‑(3‑(4‑(2‑Fluorophenyl)piperazin‑1‑yl)propyl)‑5‑me‑ thyl‑5‑phenylimidazolidine‑2,4‑dione, 3‑(3‑(4‑(3‑Fluorophenyl)piperazin‑1‑yl)propyl)‑5‑me‑ thyl‑5‑phenylimidazolidine‑2,4‑dione, 3‑(3‑(4‑(4‑Fluorophenyl)piperazin‑1‑yl)propyl)‑5‑me‑ thyl‑5‑phenylimidazolidine‑2,4‑dione, 3-(3-(4-(4-Fluorobenzoyl)piperazin-1-yl)propyl)-5- methyl-5-phenylimidazolidine-2,4-dione, 3-(2-(4-(4-Fluorobenzoyl)piperazin-1-yl)ethyl)-8- phenyl-1,3-diazaspiro[4.5]decane-2,4-dione, 3-(2-(4-Benzhydrylpiperazin-1-yl)ethyl)-8-phenyl- 1,3-diazaspiro[4.5]decane-2,4-dione, 3‑(3‑(4‑(2‑Fluorophenyl)piperazin‑1‑yl)propyl)‑8‑phe‑ nyl‑1,3‑diazaspiro[4.5]decane‑2,4‑dione, 3‑(3‑(4‑(3‑Fluorophenyl)piperazin‑1‑yl)propyl)‑8‑phe‑ nyl‑1,3‑diazaspiro[4.5]decane‑2,4‑dione, 3‑(3‑(4‑(4‑Fluorophenyl)piperazin‑1‑yl)propyl)‑8‑phe‑ nyl‑1,3‑diazaspiro[4.5]decane‑2,4‑dione, and 3-(3-(4-(4-Fluorobenzoyl)piperazin-1-yl)propyl)-8- phenyl-1,3-diazaspiro[4.5]decane-2,4-dione, or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analog, derivative, prodrug, or combinations thereof. In some embodiments, the serotonin receptor modulator used as a second therapeutic is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the serotonin receptor modulator is administered prior to a compound disclosed herein, such as about three or about one hours prior to administration of a compound according to Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), or (Iv-3) or a pharmaceutically acceptable salt thereof. In some embodiments, the serotonin receptor modulator is administered at most about one hour prior to the presently disclosed compound. Thus, in some embodiments of combination therapy with the presently disclosed compounds, the second therapeutic agent is a serotonin receptor modulator. In some embodiments the second therapeutic agent serotonin receptor modulator is provided at a dose of from about 10 mg to about 350 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 20 mg to about 200 mg. In some embodiments, the serotonin receptor modulator is provided at a dose of from about 10 mg to about 100 mg. In certain such embodiments, the compound of the present invention is provided at a dose of from about 10 mg to about 100 mg, or from about 20 to about 200 mg, or from about 15 to about 300 mg, and the serotonin receptor modulator is provided at a dose of about 10 mg to about 100 mg. In some embodiments, the brain disorders that can be treated as disclosed herein comprise decreased neural plasticity, decreased cortical structural plasticity, decreased 5-HT2A receptor content, decreased dendritic arbor complexity, loss of dendritic spines, decreased dendritic branch content, decreased spinogenesis, decreased neuritogenesis, retraction of neurites, or any combination thereof. In some embodiments, a compound of the present invention is used to treat brain disorders. In some embodiments, the compounds have, for example, anti- addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the brain disorder is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, brain disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, schizophrenia, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety. In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer's, Parkinson's disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder. In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer's, or Parkinson's disease. In some embodiments, the brain disorder is a psychological disorder, depression, addiction, anxiety, or a post-traumatic stress disorder. In some embodiments, the brain disorder is depression. In some embodiments, the brain disorder is addiction. In some embodiments, the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury or substance use disorder. In some embodiments, the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, persistent depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the brain disorder is stroke or traumatic brain injury. In some embodiments, the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, or substance use disorder. In some embodiments, the brain disorder is schizophrenia. In some embodiments, the brain disorder is alcohol use disorder. In some embodiments, the method further comprises administering one or more additional therapeutic agent that is lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin). In certain embodiments of the method for treating a brain disorder disclosed herein with a compound according to Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), or (Iv-3) or a pharmaceutically acceptable salt thereof., a second therapeutic agent that is an empathogenic agent is administered. Examples of suitable empathogenic agents for use in combination with a compound according to Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), or (Iv-3), are selected from the phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA) and analogs thereof. Other suitable empathogenic agents for use in combination with the presently disclosed compounds include, without limitation, N-Allyl-3,4-methylenedioxy-amphetamine (MDAL) N-Butyl-3,4-methylenedioxyamphetamine (MDBU) N-Benzyl-3,4-methylenedioxyamphetamine (MDBZ) N-Cyclopropylmethyl-3,4-methylenedioxyamphetamine (MDCPM) N,N-Dimethyl-3,4-methylenedioxyamphetamine (MDDM) N-Ethyl-3,4-methylenedioxyamphetamine (MDE; MDEA) N-(2-Hydroxyethyl)-3,4-methylenedioxy amphetamine (MDHOET) N-Isopropyl-3,4-methylenedioxyamphetamine (MDIP) N-Methyl-3,4-ethylenedioxyamphetamine (MDMC) N-Methoxy-3,4-methylenedioxyamphetamine (MDMEO) N-(2-Methoxyethyl)-3,4-methylenedioxyamphetamine (MDMEOET) alpha,alpha,N-Trimethyl-3,4-methylenedioxyphenethylamine (MDMP; 3,4-Methylenedioxy-N-methylphentermine) N-Hydroxy-3,4-methylenedioxyamphetamine (MDOH) 3,4-Methylenedioxyphenethylamine (MDPEA) alpha,alpha-Dimethyl-3,4-methylenedioxyphenethylamine (MDPH; 3,4- methylenedioxyphentermine) N-Propargyl-3,4-methylenedioxyamphetamine (MDPL) N-Propyl-3,4-methylenedioxyamphetamine (MDPR), and the like. In some embodiments, the compounds of the present invention are used in combination with the standard of care therapy for a neurological disease described herein. Non-limiting examples of the standard of care therapies, may include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Nonlimiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. Additional examples of standard of care therapeutics are known to those of ordinary skill in the art. Methods of increasing at least one of translation, transcription, or secretion of neurotrophic factors Neurotrophic factors refers to a family of soluble peptides or proteins which support the survival, growth, and differentiation of developing and mature neurons. Increasing at least one of translation, transcription, or secretion of neurotrophic factors can be useful for, but not limited to, increasing neuronal plasticity, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain. In some embodiments, increasing at least one of translation, transcription, or secretion of neurotrophic factors can increasing neuronal plasticity. In some embodiments, increasing at least one of translation, transcription, or secretion of neurotrophic factors can promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and/or increasing dendritic spine density. In some embodiments, 5-HT2A modulators (e.g., 5-HT2A agonists) are used to increase at least one of translation, transcription, or secretion of neurotrophic factors. In some embodiments, a compound of the present invention is used to increase at least one of translation, transcription, or secretion of neurotrophic factors. In some embodiments, increasing at least one of translation, transcription or secretion of neurotrophic factors treats a migraine, headaches (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, psychological disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the experiment or assay used to determine increase translation of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry. In some embodiments, the experiment or assay used to determine increase transcription of neurotrophic factors includes gene expression assays, PCR, and microarrays. In some embodiments, the experiment or assay used to determine increase secretion of neurotrophic factors includes ELISA, western blot, immunofluorescence assays, proteomic experiments, and mass spectrometry. In some embodiments, the present invention provides a method for increasing at least one of translation, transcription or secretion of neurotrophic factors, comprising contacting a neuronal cell with a compound disclosed herein, such as a compound of Table 1, Formula (I), (Ia), (Ib), (Ib1), (Ic), (Id), (Ie), (If), (If1), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik1), (Ik2), (Ik3), (Il), (Im), (Im1), (Im1a), (In), (In1), (Io), (Io1), (Io2), (Io1a), (Ip) (Ip1), (Iq), (Iq1) , (Ir), (Ir1), (Is), (It), (Iu), (Iv), (Iv-1), (Iv-2), or (Iv-3), or a pharmaceutically acceptable salt thereof. Examples NMR analysis NMR analyses were conducted on a 400 MHz NMR spectrometer using deuterated chloroform, deuterated methanol or deuterated dimethyl sulfoxide as solvent. The shift (d) of each signal was measured in parts per million (ppm) relative to the residual solvent peak, and the multiplicity reported together with the associated coupling constant (J), where applicable. Agilent LC-MS Analysis Methodology Instrument: Agilent 1260 infinity HPLC with Agilent 6130 single quadrupole mass spec. Column: Phenomenex Kinetex XB-C18, 50 x 4.6mm, 2.6µm Elution profile: See table below
Figure imgf000171_0001
Flow rate: 2mL/min Detector wavelength: 225 ± 50nm bandwidth Column temperature: 40◦C Injection volume: 1µl Mass spec parameters: Scanning in ES+/- & APCI over 70 – 1000m/z Needle wash: MeOH wash in vial 4, autosampler set up to do 5 needle washes (to wash the outside of the needle prior to injecting the sample). Sample preparation: 0.5 – 1.0mg/ml in either acetonitrile or DMSO depending on the nature of the sample in terms of solubility. Waters Alliance LCMS method details Acidic method (named as Formic_8min) Instrument: Waters 2795 Alliance HPLC system equipped with a 2996 PDA detector and Micromass ZQ mass spectrometer detector. Column: Gemini C18, 5µm, 110Å, 50 x 4.6mm ID Mobile phase A: 0.1% Formic acid in water Mobile phase B: 100% acetonitrile Gradient program (overall run time per injection is 8 minutes):
Figure imgf000172_0002
Flow rate: 1ml/min Injection volume: 10µl Column oven temperature: 40°C Detector: PDA UV at 190 – 400nm, also fixed λ at 225nm Mass spec parameters: MS scan in ES+, ES-, ranging from M/Z 100 – 1000 Purge solvent involved in injection Example 1: Synthesis of 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl- ethanamine (Compound 267)
Figure imgf000172_0001
Step 1: Preparation of 2-(6-methoxy-1H-indol-3-yl)-2-oxo-acetyl chloride To a mixture of 6-methoxy-1H-indole (2.0 g, 13.6 mmol) in dry Et2O (10 mL) at 0 °C under an atmosphere of N2was added oxalyl dichloride (1.72 mL, 20.4 mmol) dropwise. The mixture was warmed to 15 °C stirred at for 2 h. On completion, the mixture was concentrated in vacuo to obtain the desired compound as a solid. The solid was triturated with 1:1 Et2O-hexane and isolated by filtration, then washed with 1:1 Et2O-hexane to give the title compound (3.09 g, 95%) as a solid.1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.26 (d, J = 3.2 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 2.3, 8.7 Hz, 1H), 3.80 (s, 3H). Step 2: Preparation of 2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl-2-oxo-acetamide To a mixture of Me2NH, 2M in THF (3.0 mL, 6.0 mmol) in THF (5 mL) at 0 °C was added DIPEA (1.14 mL, 6.65 mmol). A mixture of 2-(6-methoxy-1H-indol-3-yl)-2-oxo-acetyl chloride (0.50 g, 2.1 mmol) in THF (7.5 mL) was then added dropwise at 0 °C. The mixture was warmed to 15 °C and stirred for 2 h, then brine (30 mL) was added, and the mixture was stirred for 5 min. The aqueous phase was extracted with DCM (3 x 50 mL) and the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc / hexane, 1:4 to 1:0) to give the title compound (360 mg, 69%) as a solid. Retention time: 1.33 min; m/z = [M+H]+ calculated for C13H14N2O3 247.3; found 247.0; 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.06 – 7.82 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 3.80 (s, 3H), 2.98 (s, 3H), 2.91 (s, 3H). Step 3: Preparation of 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl- ethanamine To a microwave vial and stirrer bar was added 2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl-2- oxo-acetamide (200 mg, 0.80 mmol). Ice-cold anhydrous THF (4.5 mL) was added under a stream of N2 and LiAlD4 (205 mg, 4.87 mmol) was added under a stream of N2 with vigorous stirring in an ice-water bath. The tube was sealed, and the reaction mixture was heated to 150 °C under microwave irradiation (Biotage Initiator+) for 5 min. After cooling, the mixture was poured slowly into a mixture of ice-H2O and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (7N NH3 in MeOH / EtOAc 5:95) to give the title compound (149 mg, 82%) as a solid. Retention time: 1.01 min; m/z = [M+H]+ calculated for C13H14D4N2O 223.3; found 223.3; 1H NMR (400 MHz, CDCl3) δ 7.87 (br. s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 3.83 (s, 3H), 2.32 (s, 6H). Example 2: Synthesis of 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl) ethanamine (Compound 269)
Figure imgf000174_0001
To a microwave vial was added a stirrer bar and 2-(6-methoxy-1H-indol-3-yl)-2-oxo-N,N- bis(trideuteriomethyl)acetamide (200 mg, 0.80 mmol). Ice-cold anhydrous THF (4.5 mL) was added under a stream of N2 and LiAlD4 (198 mg, 4.72 mmol) was added under a stream of N2 with vigorous stirring in an ice-water bath. The tube was sealed, and the mixture was heated to 150 °C under microwave irradiation (Biotage Initiator+) for 5 min. After cooling, the mixture was poured slowly into a mixture of ice-H2O. The mixture was extracted with EtOAc (3 x 20 mL) and the combined layers were washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified column chromatography on silica gel (7N NH3 in MeOH / EtOAc 5:95) to give the title compound (156 mg, 86%) as a viscous oil. Retention time: 1.02 min; m/z = [M+H]+ calculated for C13H8D10N2O 229.2; found 229.2; 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.47 (dt, J = 8.7, 0.6 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.84 (dd, J = 2.3, 0.6 Hz, 1H), 6.79 (dd, J = 8.6, 2.3 Hz, 1H), 3.84 (s, 3H). Example 3: Synthesis of 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl- ethanamine (Compound 270)
Figure imgf000174_0002
Step 1: Preparation of 2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl-acetamide To a mixture of 2-(6-methoxy-1H-indol-3-yl)acetic acid (500 mg, 2.44 mmol) in DCM (10 mL) at rt was added HOBT monohydrate (0.45 g, 2.92 mmol) in one portion.1-Ethyl-3-(3- dimethylaminopropyl) carbodiimide HCl (0.56 g, 2.92 mmol) was added portion-wise over 5 min, and the mixture was stirred at rt for 2 h. Me2NH, 2M in THF (1.83 mL, 3.65 mmol) was added dropwise over 5 min and the mixture was stirred at rt for 12 h. K2CO3, 10% aqueous solution (10 mL) was added, and the mixture was stirred for 5 min, then the layers were separated and the aqueous layer was extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (MeOH / DCM 1:99 to 1:9) to give the title compound (404 mg, 71%) as a solid. Retention time: 1.348 min; m/z = [M+H]+ calculated for C13H16N2O2233.1; found 233.0; 1H NMR (400 MHz, DMSO- d6) δ 10.62 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.02 (dt, J = 2.1, 1.0 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 6.63 (dd, J = 8.7, 2.3 Hz, 1H), 3.75 (s, 3H), 3.68 (d, J = 1.0 Hz, 2H), 3.00 (s, 3H), 2.81 (s, 3H). Step 2: Preparation of 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-dimethyl- ethanamine To a microwave vial was added a stirrer bar and 2-(6-methoxyindolin-3-yl)-N,N-dimethyl- acetamide (250 mg, 1.07 mmol). Ice-cold anhydrous THF (10 mL) was added under a stream of N2 and LiAlD4 (134 mg, 3.20 mmol) was added with vigorous stirring under a stream of N2 (the vial placed in an ice-water bath). The tube was sealed, and the mixture was heated at 150 °C under microwave irradiation (Biotage Initiator+) for 5 min. After cooling, the mixture was poured slowly into a mixture of ice-H2O and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (7N NH3 in MeOH / EtOAc 5:95) to give the title compound (202 mg, 85%) as a viscous oil. Retention time: 1.02 min; m/z = [M+H]+ calculated for C13H16D2N2O 221.3; found 221.3; 1H NMR (400 MHz, CDCl3) δ 7.88 (br. s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 2.4, 1.2 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 3.83 (s, 3H), 2.89 (s, 2H), 2.34 (s, 6H). Example 4: Synthesis of 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl)ethanamine (Compound 271)
Figure imgf000175_0001
Step 1: Preparation of 2-(6-methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl)acetamide To a mixture of 2-(6-methoxy-1H-indol-3-yl)acetic acid (500 mg, 2.44 mmol) in DCM (10 mL) at rt was added HOBT monohydrate (0.45 g, 2.92 mmol) in one portion.1-Ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (0.561 g, 2.92mmol) was then added portion- wise over 5 min and the mixture was stirred at rt for 2 h. (CD3)2NH HCl (427 mg, 4.87 mmol) was added portion-wise over 5 min, followed by DIPEA (0.834 mL, 4.87 mmol) and the mixture was stirred at rt for 12 h. K2CO3, 10% aqueous solution (10 mL) was added, and the mixture was stirred for 5 min, then the layers were separated and the aqueous layer was extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (MeOH / DCM 1:99 to 1:9) to give the title compound (438 mg, 75%) as a solid. Retention time: 1.34 min; m/z = [M+H]+ calculated for C13H10D6N2O2239.3; found 239.2; 1H NMR (400 MHz, CDCl3) δ 8.00 (br. s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.98 – 6.97 (m, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.79 (dd, J = 8.8, 2.4 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 2H). Step 2: Preparation of 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl)ethanamine To a microwave vial was added a stirrer bar and 2-(6-methoxyindolin-3-yl)-N,N- bis(trideuteriomethyl)acetamide (250 mg, 1.04 mmol). Ice-cold anhydrous THF (4.5 mL) was added under a stream of N2 and LiAlD4 (131 mg, 3.12 mmol) was added with vigorous stirring under a stream of N2 (the vial placed in an ice-water bath). The tube was sealed, and the mixture was heated at 150 °C under microwave irradiation (Biotage Initiator+) for 5 min. After cooling, the mixture was poured slowly into a mixture of ice-H2O and extracted with EtOAc (3 x 20 mL). After cooling, the reaction mixture was poured slowly into a mixture of ice and water. The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (7N NH3 in MeOH / EtOAc 5:95) to give the title compound (212 mg, 90%) as a solid. Retention time: 1.02 min; m/z = [M+H]+ calculated for C13H10D8N2O 227.3; found 227.2; 1H NMR (400 MHz, CDCl3) δ 7.87 (br. s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.89 (dd, J = 2.4, 2.4 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 3.83 (s, 3H), 2.88 (s, 2H). Example 5: Synthesis of 1,1,2,2-tetradeuterio-N,N-dimethyl-2-[6-(trideuteriomethoxy)-1H- indol-3-yl]ethanamine (Compound 272)
Figure imgf000177_0001
Step 1: Preparation of 1-methyl-2-nitro-4-(trideuteriomethoxy)benzene To a mixture of 4-methyl-3-nitro-phenol (3.00 g, 19.6 mmol) in DMF (20 mL) at rt was added Cs2CO3 (7.02 g, 21.5 mmol) followed by CD3I (0.98 mL, 20.6 mmol) in one portion. The mixture was stirred at rt overnight, then poured into H2O (200 mL) and extracted with Et2O (2 x 100 mL). The combined organic layers were washed with 5% LiCl (aq), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to afford the title compound (3.34 g, 100 %) as a solid. Retention time 1.70 min; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 2.7 Hz, 1H), 7.23 (dq, J = 8.4, 0.8 Hz, 1H), 7.06 (dd, J = 8.5, 2.7 Hz, 1H), 2.53 (d, J = 0.8 Hz, 3H). Step 2: Preparation of 1-[(E)-2-[2-nitro-4-(trideuteriomethoxy)phenyl]vinyl]pyrrolidine A mixture of 1-methyl-2-nitro-4-(trideuteriomethoxy)benzene (3.34 g, 19.6 mmol), DMF.DMA (3.27 g, 27.5 mmol) and pyrrolidine (1.95 g, 27.5 mmol) in DMF (15 mL) was heated to 115 °C and stirred for 7 h. The mixture was cooled, added to ice-H2O (300 mL) and extracted with Et2O (2 x 100 mL). The combined organic layers were washed with 5% LiCl (aq) and concentrated in vacuo to leave the title compound (5.30 g, >100%) as a colored oil. The material was used immediately in the next step without purification.1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 2.8 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.09 (d, J = 13.6 Hz, 1H), 6.98 (ddd, J = 9.0, 2.8, 0.6 Hz, 1H), 5.84 (d, J = 13.5 Hz, 1H), 3.39 – 3.12 (m, 4H), 2.03 – 1.81 (m, 4H). Step 3: Preparation of 6-(trideuteriomethoxy)-1H-indole To a mixture of crude 1-[(E)-2-[2-nitro-4-(trideuteriomethoxy)phenyl]vinyl]pyrrolidine (93% purity, 5.30 g, 19.7 mmol) in EtOAc (70 mL) was added 10% Pd on carbon (0.403 g) under a blanket of N2. The mixture was then placed under an atmosphere of H2 (100 psi) and stirred for 19 h, then filtered through celite and the filter cake was washed with EtOAc (100 mL). The filtrate was washed with H2O (5 x 100 mL) and concentrated in vacuo and the crude material was purified by column chromatography on silica gel (EtOAc / hexane 1:9 to 3:7) to give crude product (2.75 g), which LCMS indicated was a ca.2:1 mixture of the desired product and an N- hydroxyindole intermediate. The impure material was taken up in AcOH (50 mL) and Zn powder (5.31 g, 81.2 mmol) was added in one portion. The suspension was heated to 60 °C and stirred for 3 h, then allowed to cool and poured into H2O (400 mL). The resulting solution was basified to pH ~8 with sodium bicarbonate and extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated in vacuo and the residue was taken up in hot n-hexane and the solution was separated from the dark oily residue. The hexane extract was concentrated in vacuo to afford the title compound (1.20 g, 49% over two steps) as a powdery solid. Retention time 1.53 min; m/z = [M+H]+ calculated for C9H6D3NO 151.0; found 151.2; 1H NMR (400 MHz, CDCl3) δ 8.01 (br. s, 1H), 7.50 (dt, J = 8.7, 0.7 Hz, 1H), 7.10 (dd, J = 3.3, 2.3 Hz, 1H), 6.89 (dt, J = 2.3, 0.7 Hz, 1H), 6.79 (dd, J = 8.6, 2.3 Hz, 1H), 6.48 (ddd, J = 3.2, 2.1, 1.0 Hz, 1H). Step 4: Preparation of 2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetyl chloride To a mixture of 6-(trideuteriomethoxy)-1H-indole (0.50 g, 3.33 mmol) in Et2O (15 mL) at 0 °C under an atmosphere of N2 was added oxalyl dichloride (0.42 mL, 4.99 mmol) dropwise. The mixture was warmed to 15 °C and stirred for 2 h, then concentrated in vacuo. The crude product was triturated with 1:1 Et2O-hexane, the solid was isolated by filtration and the filter cake was washed with 1:1 Et2O -hexane to give the title compound (0.68 g, 84%) as a solid.1H NMR (400 MHz, DMSO-d6) δ 12.12 (br. s, 1H), 8.26 (d, J = 3.2 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 8.4, 2.4 Hz, 1H). Step 5: Preparation of N,N-dimethyl-2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3- yl]acetamide To a mixture of Me2NH, 2M in THF (1.87 mL, 3.74 mmol) in DCM (5 mL) at 0 °C was added DIPEA (0.427 mL, 2.49 mmol), then a mixture of 2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3- yl]acetyl chloride (0.30 g, 1.25 mmol ) in THF (7.5 mL) was dropwise. The mixture was warmed to 15 °C and stirred for 2 h, then brine (30 mL) was added, and the mixture was stirred for 5 min. The mixture was extracted with DCM (3 x 50 mL) and the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (MeOH / DCM 1:99 to 1:9) to give the title compound (242 mg, 77%) as a solid. Retention time: 1.33 min; m/z = [M+H]+ calculated for C13H11D3N2O3 250.2; found 250.2; 1H NMR (400 MHz, DMSO-d6) δ 12.02 (br. s, 1H), 7.95 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 2.98 (s, 3H), 2.90 (s, 3H). Step 6: Preparation of 1,1,2,2-tetradeuterio-N,N-dimethyl-2-[6-(trideuteriomethoxy)-1H- indol-3-yl]ethanamine To a mixture of N,N-dimethyl-2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetamide (240 mg, 0.96 mmol) in THF (10 mL) in an ice-water bath was added LiAlD4 (242 mg, 5.76 mmol) under a stream of N2 with vigorous stirring. The mixture was heated to reflux and stirred for 7 h, then cooled and the mixture was poured slowly into ice-H2O. The resulting suspension was filtered through a pad of celite and the filter cake was rinsed with EtOAc (3 x 20 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (7N NH3 in MeOH / EtOAc 5:95) to give the title compound (186 mg, 85%) as a solid. Retention time 1.02 min; m/z = [M+H]+ calculated for C13H11D7N2O 226.3; found 226.3; 1H NMR (400 MHz, CDCl3) δ 7.87 (br. s, 1H), 7.46 (d, J = 8.4 Hz, 1H,), 6.89 (d, J = 2.4 Hz, 1H), 6.82 (m, 1H), 6.78 (dd, J = 8.4, 2.4 Hz, 1H), 2.32 (s, 6H). Example 6: Synthesis of 1,1,2,2-tetradeuterio-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]- N,N-bis(trideuteriomethyl)ethanamine (Compound 273)
Figure imgf000179_0001
Step 1: Preparation of N,N-di-(trideuteriomethyl)-2-oxo-2-[6-(trideuteriomethoxy)-1H- indol-3-yl]acetamide To a mixture of (CD3)2NH (230 mg, 2.63 mmol) in DCM (5 mL) at 0 °C was added DIPEA (0.64 mL, 3.74 mmol), followed by a dropwise addition of a mixture of 2-oxo-2-[6- (trideuteriomethoxy)-1H-indol-3-yl]acetyl chloride (0.30 g, 1.25 mmol) in THF (7.5 mL). The mixture was warmed to 15 °C and stirred for 2 h, then brine (30 mL) was added, the mixture was stirred for 5 min and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (MeOH / DCM 1:99 to 1:9) to give the title compound (190 mg, 49%) as a solid. Retention time: 1.32 min; m/z = [M+H]+ calculated for C13H5D9N2O3 256.2; found 256.2; 1H NMR (400 MHz, DMSO-d6) δ 12.02 (br. s, 1H), 7.95 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H). Step 2: Preparation of 1,1,2,2-tetradeuterio-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl)ethanamine To a vigorously stirred mixture of N,N-dimethyl-2-oxo-2-[6-(trideuteriomethoxy)-1H-indol-3- yl]acetamide (156 mg, 0.61 mmol) in anhydrous THF (10 mL) at 0 °C (ice-water bath) under an atmosphere of N2 was added LiAlD4 (154 mg, 3.67 mmol). The mixture was heated to reflux and stirred for 5 h, then cooled and poured slowly into a mixture of ice-H2O. The resulting suspension was extracted with EtOAc (3 x 20 mL and 3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (7N NH3 in MeOH / EtOAc 5:95) to give the title compound (94 mg, 66%) as a viscous oil. Retention time 1.01 min; m/z = [M+H]+ calculated for C13H5D13N2O 232.2; found 232.2; 1H NMR (400 MHz, CDCl3) δ 7.85 (br. s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 2.4, 0.4 Hz, 1H), 6.78 (dd, J = 8.4, 2.4 Hz, 1H). Example 7: Synthesis of 1,1-dideuterio-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl)ethanamine (Compound 274)
Figure imgf000180_0001
Step 1: Preparation of ethyl 2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetate To a stirred mixture of 6-(trideuteriomethoxy)-1H-indole (565 mg, 3.76 mmol) in DCM (20 mL) under an atmosphere of N2 was added copper(II) trifluoromethanesulfonate (68 mg, 0.19 mmol). The mixture was cooled to 0 °C, and ethyl diazoacetate, 87% in DCM (0.537 mL, 4.7 mmol) was added dropwise (CAUTION: vigorous gas evolution). After the addition was complete, the mixture was allowed to warm to rt and stirred for 1 h, then quenched with H2O (20 mL), the layers partitioned, and the aqueous layer was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (eluent: 5-50 % EtOAc in hexane gradient) to afford an inseparable mixture of C3-monoinsertion (the title compound, major) and C3, C2-diinsertion products (568 mg, 46%) as a viscous oil, which was used in the next step without further purification. Retention time: 1.606 min; m/z = [M+H]+ calculated for C13H12D3NO3237.1; found 237.0. Step 2: Preparation of 2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetic acid To a stirred mixture of isomers containing ethyl 2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetate as the major component (0.525g, 1.93 mmol) in THF (6 mL) at 0 °C was added 1M NaOH (5.79 mL, 5.8 mmol). The mixture was warmed to rt and stirred overnight, then concentrated in vacuo, the residue dissolved in H2O, cooled to 0 °C and acidified using 2N HCl. The emerging precipitate was filtered and the filter cake was washed H2O and dried under vacuum overnight to give the title compound (197 mg, 40%) as a solid. The filtrate from above was extracted with EtOAc (3 x 30 mL) and the combined organic layers were washed with brine (10 ml), dried over MgSO4, and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (eluent: 20-100 % EtOAc in hexane gradient) to afford the title compound (69 mg) as a solid. The two products were combined to give the title compound (266 mg, 57 %) as a solid. Retention time: 1.33 mins; m/z = [M+H]+ calculated for C11H8D3NO3 209.0; found 209.0; 1H NMR (DMSO-d6, 400 MHz) δ 12.01 (br. s, 1H), 10.63 (br. s, 1H), 7.35 (dd, J = 8.4 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.64 (dd, J = 8.6, 2.0 Hz, 1H), 3.58 (s, 2H). Step 3: Preparation of 2-[6-(trideuteriomethoxy)indolin-3-yl]-N,N- bis(trideuteriomethyl)acetamide To a 50 mL flask, under an atmosphere of N2 was added 2-[6-(trideuteriomethoxy)-1H-indol-3- yl]acetic acid (130 mg, 0.62 mmol), hydroxybenzotriazole monohydrate (115 mg, 0.75mmol) and DCM (5 mL) at rt to give a suspension.1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (144 mg, 0.75 mmol) was then added portion wise over 5 min and the mixture was stirred at rt for 2 h, then 1,1,1-trideuterio-N-(trideuteriomethyl)methanamine hydrochloride (109 mg, 1.25 mmol) was added portion wise, followed by DIPEA (0.214 mL, 1.25 mmol). The mixture was stirred at rt for 12 h, then quenched with 10% K2CO3 (10 mL) and stirred for 5 min. The layers were separated, and the aqueous layer extracted with DCM (10 mL x 2). The combined organic layers were washed with saturated brine (30 mL), dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (eluent: 20-100 % EtOAc in hexane gradient) to afford the title compound (102 mg, 67%) as a solid. Retention time: 1.34 min; m/z = [M+H]+ calculated for C13H7D9N2O2242.2; found 242.2; 1H NMR (DMSO-d6, 400 MHz) δ 12.01 (br. s, 1H), 10.63 (br. s, 1H), 7.35 (dd, J = 8.4 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.64 (dd, J = 8.6, 2.0 Hz, 1H), 3.58 (s, 2H). Step 4: Preparation of 1,1-dideuterio-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl) ethanamine To a 50 mL flask was added a stirrer bar and 2-[6-(trideuteriomethoxy)indolin-3-yl]-N,N- bis(trideuteriomethyl)acetamide (109 mg, 0.45 mmol). Ice-cold anhydrous THF (10 mL) was added under an atmosphere of N2, the mixture was cooled in an ice-batch and LiAlD4 (75.2 mg, 1.79 mmol) was added. The mixture was heated to reflux and stirred for 4 h, then poured carefully into a mixture of ice and H2O (10 mL of each). EtOAc (30 mL) was added and the suspension was stirred for 5 min, then filtered through a pad of celite, and the filter cake rinsed with EtOAc (3 x 30 mL). The combined filtrates were washed with brine (10 mL), dried (MgSO4) and evaporated in vacuo to afford the title compound (81 mg, 78%) as a solid. Retention time: 1.04 min; m/z = [M+H]+ calculated for C13H7D11N2O 230.2; found 230.2; 1H NMR (CDCl3, 400 MHz) δ 7.88 (br. s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 6.89 (t, J = 1.2 Hz, 1H), 6.83 (t, J = 1.6 Hz, 1H), 6.78 (dd, J = 8.6, 2.0 Hz, 1H), 2.89 (s, 2H). Example 8: Synthesis of 1,1-dideuterio-N,N-dimethyl-2-[6-(trideuteriomethoxy)-1H-indol- 3-yl]ethanamine (Compound 275)
Figure imgf000182_0001
Step 1: Preparation of N,N-dimethyl-2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetamide To a mixture of 2-[6-(trideuteriomethoxy)-1H-indol-3-yl]acetic acid (130 mg, 0.624 mmol), hydroxybenzotriazole monohydrate (0.115 g, 0.75 mmol) and DCM (10 mL) at rt under an atmosphere of N2 was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.144 g, 0.75 mmol) was added portion wise over 5 min. The mixture was stirred at rt for 2 h, then 2M Me2NH in THF (0.468 mL, 0.94 mmol) was added dropwise over 20 min. The resultant mixture was stirred at rt for 12 h, then quenched with 10% K2CO3 (10 mL) and stirred for 5 min. The aqueous and organic layers were separated, and the aqueous layer extracted with DCM (10 mL x 2). The combined organic layers were washed with saturated brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (eluent: 20-100 % EtOAc in hexane gradient) to afford the title compound (66 mg, 44%) as an oil. Retention time: 1.35 min; m/z = [M+H]+ calculated for C13H13D3N2O2236.2; found 236.2; 1H NMR (CDCl3, 400 MHz), δ 8.01 (br. s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 1.2 Hz, 1H), 6.83 (dd, J = 8.8, 1.6 Hz, 1H), 3.79 (s, 2H), 3.02 (s, 3H), 2.97 (s, 3H). Step 2: Preparation of 1,1-dideuterio-N,N-dimethyl-2-[6-(trideuteriomethoxy)-1H-indol-3- yl]ethanamine To a mixture of N,N-dimethyl-2-[6-(trideuteriomethoxy)indolin-3-yl]acetamide (66 mg, 1.07 mmol, 71% purity) and THF (5 mL) at 0 °C under an atmosphere of N2 was added LiAlD4 (46.7 mg, 1.1 mmol). The mixture was heated to reflux and stirred for 3 h, then cooled to 0 °C, and poured carefully into a mixture of ice-H2O (10 mL). EtOAc (20 mL) was added to the aqueous suspension and the mixture was stirred vigorously for 10 min, then filtered through a pad of celite, and the filter cake washed with EtOAc (2 x 20 mL). The aqueous and organic layers of the filtrate was partitioned and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 ml), dried (MgSO4) and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel (eluent: 1 – 100% [5% 7N methanolic ammonia in EtOAc] in EtOAc gradient) to afford the title compound (37 mg, 59%) as an oil. Retention time: 1.02 min; m/z = [M+H]+ calculated for m/z = [M+H]+ calculated for C13H13D5N2O 224.3; found 224.3; 1H NMR (CDCl3, 400 MHz) δ 7.82 (br. s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.90 (t, J = 1.2 Hz, 1H), 6.83 (dd, J = 2.2, 0.8 Hz, 1H), 6.78 (dd, J = 8.6 2.0 Hz, 1H), 2.89 (s, 2H), 2.33 (s, 6H). Example 9: Synthesis of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl- ethanamine (Compound 276)
Figure imgf000184_0001
Step 1: Preparation of 1-bromo-2-(2H3)-methoxy-5-methyl-4-nitrobenzene To a stirred solution of 2-bromo-4-methyl-5-nitrophenol (2.52 g, 10.9 mmol) in DMF (20 mL) was added Cs2CO3 (5.31 g, 16.3 mmol) followed by trideuterio(iodo)methane (0.811 mL, 13.0 mmol). The mixture was stirred at rt for 20 h, poured into H2O (200 mL) and extracted with Et2O (3 x 70 mL). The combined organc layers were washed with brine (3 x 50 mL), dried (MgSO4), filtered and the filtrate was concentrated in vacuo to afford the title compound (2.60 g, 96%) as a solid that was used without further purification. Retention time 4.07 min; ¹H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.54 (s, 1H), 2.54 (s, 3H). Step 2: Preparation of [2-(5-bromo-4-(2H3)-methoxy-2-nitrophenyl)ethenyl]dimethylamine A solution of 1-bromo-2-(2H3)-methoxy-5-methyl-4-nitrobenzene (1.60 g, 6.4 mmol) and DMF.DMA (3 mL, 25.5 mmol) in DMF (6 mL) was heated to 145 °C and stirred for 6 h. The mixture was cooled to rt, H2O (30 mL) added and the mixture was extracted with Et2O (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried (MgSO4), filtered and the filtrate was concentrated to a dark semi-solid (1.69 g) that was used immediately without further purification. Step 3: Preparation of 5-bromo-6-(2H3)methoxy-1H-indole To a stirred solution of [2-(5-bromo-4-(2H3)methoxy-2-nitrophenyl)ethenyl]dimethylamine (crude, 1.69 g) in AcOH (38 mL) and PhMe (64 mL) was added florisil (16.1 g) and Fe powder (6.44 g). The mixture was heated to reflux and stirred for 2 h, then cooled to rt and filtered through Celite, washing the filter cake with DCM (4 x 60 mL). H2O (200 mL) was added and the mixture was basified with NaHCO3. The organic layer was dried (MgSO4), filtered and the filtrate was concentrated to a residue that was purified by column chromatography on silica gel (eluent: 0 to 100% EtOAc / hexane) to afford the title compound (328 mg, 19%) as a solid. Retention time 3.487 min; m/z = [M+H]+ calculated for [C9H5BrD3NO]+ 229.0; found 229.0; ¹H NMR (400 MHz, CDCl3) δ 8.07 (br. s, 1H), 7.79 (s, 1H), 7.10 (dd, J = 3.2, 2.4 Hz, 1H), 6.91 (s, 1H), 6.43 – 6.42 (m, 1H). Step 4: Preparation of 6-(2H3)-Methoxy-(5-2H)-1H-indole A suspension of 5-bromo-6-(2H3)methoxy-1H-indole (328 mg, 1.43 mmol) and 10% Pd/C (122 mg) with iPr2NEt (0.3 mL, 1.72 mmol) in CD3OD (5 ml) was stirred in a pressure vessel under D2 (initially 20 psi) for a total of 23 h. The mixture was filtered through Celite, and the filter cake was washed with DCM (3 x 5mL). The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (eluent: 0 to 100% EtOAc / hexane) to afford the title compound (72 mg, 33%) as a light brown solid. Retention time 2.839 min; m/z = [M+H]+ calculated for [C9H5D4NO]+ 152.0: found 152.2; ¹H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.50 (s, 1H), 7.09 (dd, J = 3.3, 2.3 Hz, 1H), 6.88 (s, 1H), 6.48 (ddd, J = 3.1, 2.0, 0.9 Hz, 1H). Step 5: Preparation of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-2-oxo-acetyl chloride To a mixture of 5-deuterio-6-(trideuteriomethoxy)-1H-indole (72 mg, 0.48 mmol) in dry Et2O (2 mL) at 0 °C under an atmosphere of N2 was added oxalyl dichloride (0.060 mL, 0.71 mmol) dropwise. The mixture was warmed to 15 °C and stirred for 2 h, then concentrated to obtain the title compound (109 mg, 94%) as a solid.1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.28 (d, J = 3.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 2.3, 8.7 Hz, 1H). Step 6: Preparation of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl- 2-oxo-acetamide To a solution of Me2NH, 2M solution in THF (0.31 mL, 0.62 mmol) in THF (2 mL) was added iPr2NEt (0.071 mL, 0.41 mmol) at 0 °C.2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-2- oxo-acetyl chloride (50 mg, 2.1 mmol) in suspension in THF (7.5 mL) was added at 0 °C. The mixture was warmed to 15 °C and stirred for 2 h, then brine (30 mL) was added, and the mixture was stirred for 5 min. The aqueous phase was extracted with DCM (50 mL x 3) and the combined organic layers were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: 1 -10% MeOH in DCM) to afford the title compound (33 mg, 63%) as a solid. Retention time 1.33 min; m/z = [M+H]+ calculated for [C13H10D4N2O3]+ 251.2: found 251.2; 1H NMR (400 MHz, CDCl3) δ 9.30 (br. s, 1H), 8.18 (s, 1H), 7.74 (d, J = 3.2 Hz, 1H), 6.84 (s, 1H), 3.09 (s, 3H), 3.05 (s, 3H). Step 7: Preparation of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl- ethanamine LiAlH4 (33 mg, 0.86 mmol) was taken up in anhydrous THF (3 mL) at 0 °C under an atmosphere of N2 and 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl-2-oxo-acetamide (0.036 g, 0.144 mmol) was added portion-wise with stirring at 0 °C. The mixture was heated to reflux and stirred for 3 h, then cooled and the mixture was poured carefully onto a mixture of ice/H2O (10 mL). To the suspension thus obtained was added EtOAc (20 mL) with vigorous stirring. The suspension was filtered and the precipitate washed with EtOAc (4 x 10 mL). The combined organic filtrates were washed with brine (2 x 30 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: 5% [7N ammonia in MeOH] in EtOAc) to afford the title compound (19 mg, 59%) as a solid. Retention time 1.05 mins; m/z = [M+H]+ calculated for [C13H14D4N2O]+ 223.3; Found 223.2; 1H NMR (CDCl3, 400 MHz,) δ 7.84 (br. s, 1H), 7.47 (s, 1H), 6.90 (dd, J = 2.0, 0.8 Hz, 1H), 6.83 (s, 1H), 2.93 – 2.89 (m, 2H), 2.66 – 2.62 (m, 2H), 2.45 – 2.24 (m, 2H), 2.34 (s, 6H). Example 10: Synthesis of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl)ethanamine (Compound 277)
Figure imgf000186_0001
Step 1: Preparation of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-2-oxo-N,N- bis(trideuteriomethyl) acetamide To a solution of 1,1,1-trideuterio-N-(trideuteriomethyl)methanamine HCl (27.2 mg, 0.31 mmol) in DCM (2 mL) was added iPr2NEt (0.106 mL, 0.62 mmol) at 0 °C.2-[5-deuterio-6- (trideuteriomethoxy)-1H-indol-3-yl]-2-oxo-acetyl chloride (0.050 g, 0.21 mmol) in suspension in THF (3 mL) was added at 0 °C. The mixture was warmed to 15 °C and stirred for 2 h, then brine (30 mL) was added, and the mixture was stirred for 5 min. The aqueous phase was extracted with DCM (3 x 50 mL) and the combined organic layers were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: 1-10% MeOH in DCM) to afford the title compound (37 mg, 69%) as a solid. Retention time 1.33 mins; m/z = [M+H]+ calculated for [C13H4D10N2O3]+ 257.2: found 257.2; 1H NMR (400 MHz, CDCl3) δ 9.53 (br. s, 1H), 8.17 (s, 1H), 7.70 (d, J = 3.2 Hz, 1H), 6.81 (d, J = 0.4 Hz, 1H). Step 2: Preparation of 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl)ethanamine LiAlH4 (33 mg, 0.86 mmol) was taken up in anhydrous THF (3 mL) at 0 °C under an atmosphere of N2 and 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-2-oxo-N,N- bis(trideuteriomethyl)acetamide (36 mg, 0.144 mmol) was added portion-wise with stirring at 0°C. The mixture was heated to reflux and stirred for 3 h, then cooled and the mixture was added dropwise to a mixture of ice/H2O (10 mL). To the suspension thus obtained was added EtOAc (20 mL) with vigorous stirring. The suspension was filtered and the precipitate washed with EtOAc (100 mL). The combined organic filtrates and washings were washed with brine (2 x 30 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: 5% [7N ammonia in MeOH] in EtOAc) to afford the title compound (10 mg, 30%) as a solid. Retention time 1.05 min; m/z = [M+H]+ calculated for [C13H8D10N2O]+ 229.3; found 229.2; 1H NMR (CDCl3, 400 MHz,) δ 7.84 (br. s, 1H), 7.47 (s, 1H), 6.91-6.90 (m,1H), 6.84 (s, 1H), 2.93-2.87 (m, 2H), 2.65 – 2.61 (m, 2H), 2.45 – 2.24 (m, 2H). Example 11: Synthesis of 1,1,2,2-tetradeuterio-2-[5-deuterio-6-(trideuteriomethoxy)-1H- indol-3-yl]-N,N-dimethyl-ethanamine (Compound 278)
Figure imgf000187_0001
LiAlD4 (92 mg, 2.2 mmol) was taken up in anhydrous THF (3 mL) at 0 °C under a atmosphere of N2 and 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl-2-oxo-acetamide (92 mg, 0.37 mmol) was added portion-wise with stirring at 0 °C. The mixture was heated to reflux and stirred for 3 h, then cooled and the reaction was poured carefully onto a mixture of ice/H2O (10 mL). To the suspension thus obtained was added EtOAc (20 mL) with vigorous stirring. The suspension was filtered, and the precipitate washed with EtOAc (4 x 10 mL). The combined organic filtrate and washings were washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: 5% [7N ammonia in MeOH] in EtOAc) to afford the title compound (61 mg, 73%) as a solid. Retention time 1.045 min; m/z = [M+H]+ calculated for [C13H10D8N2O]+ 227.3; Found 227.2; 1H NMR (CDCl3, 400 MHz,) δ 7.84 (br. S, 1H), 7.47 (t, J = 4.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.83 (s, 1H), 2.32 (s, 6H). Example 12: Synthesis of 1,1,2,2-tetradeuterio-2-[5-deuterio-6-(trideuteriomethoxy)-1H- indol-3-yl]-N,N-bis(trideuteriomethyl)ethanamine (Compound 279)
Figure imgf000188_0001
LiAlD4 (72 mg, 1.73 mmol) was taken up in anhydrous THF (7 mL) at 0 °C under an atmosphere of N2 and 2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-2-oxo-N,N- bis(trideuteriomethyl)acetamide (74 mg, 0.29 mmol) was added portion-wise with stirring at 0°C. The reaction mixture was heated to reflux and stirred for 3 h, then cooled, and the reaction was added dropwise to a mixture of ice/H2O (10 mL). To the suspension thus obtained was added EtOAc (20 mL) with vigorous stirring. The suspension was filtered, and the precipitate washed with EtOAc (100 mL). The combined organic filtrate and washings were washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: 5% [7N ammonia in MeOH] in EtOAc) to afford the title compound (31 mg, 46%) as a solid. Retention time 1.05 min; m/z = [M+H]+ calculated for [C13H4D14N2O]+ 233.; found 233.2; 1H NMR (400 MHz, CDCl3) δ 7.87 (br. s, 1H), 7.46 (s, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.83 (s, 1H). Example 13: Evaluation of Metabolic Stability in Human Liver Microsomes The test compound at 1.0 µM in singlet or positive controls including Testosterone (CYP3A4 substrate), Propafenone (CYP2D6 substrate) or Diclofenac (CYP2C9 substrate) were incubated with the liver microsomes at 0.5 mg/mL, respectively. The mixture was warmed up at 37 °C for 10 minutes and the reactions were initiated by the addition of a NADPH regenerating system (~1.0 mM). The test compound incubated with the liver microsomes at 37 °C without the NADPH regenerating system served as the negative control reaction. The reaction samples were removed at multiple time points (such as 0, 5, 15, 30, 45 and 60 minutes) and the sample without NADPH (NCF) was removed at 60 minutes. All the samples were immediately mixed with cold acetonitrile containing internal standard (IS) to stop the reaction. Samples were analyzed by LC/MS/MS and the disappearance of test compound was assessed based on peak area ratios of analyte/IS (no standard curve). The microsomal intrinsic clearance and T1/2 values were calculated using the following equation:
Figure imgf000189_0001
The microsomal intrinsic clearance and T1/2 values were calculated using the following equation:
Figure imgf000189_0002
The mg microsomal protein / g liver weight was 45 for 5 species The liver weight values used 40 g/kg, 30 g/kg, 32 g/kg, 20 g/kg and 88 g/kg for rat, monkey, dog, human and mouse, respectively. The liver clearance was calculated using CLint(mic) with,
Figure imgf000189_0003
In these experiments the comparator compound may be a suitable reference standard. In one embodiment the comparator compound was 2-(6-methoxy-1H-indol-3-yl)-N,N- dimethylethanamine (6-MeO-DMT). Table 2. Metabolic stability in human liver microsomes of representative deuterated compounds
Figure imgf000190_0001
Figure imgf000191_0001
T1/2: half life CLint(mic): intrinsic clearance CLint(mic) = 0.693/T1/2/mg microsome protein per mL CLint(liver) = CLint(mic) * mg microsomal protein/g liver weight * g liver weight/kg body weight Based on the results in Table 2, Compounds 267, 269, 270, 271, 272, 273, 274, 275, 276, 278 and 279 all exhibit significant differences in half-life and intrinsic clearance compared to 2- (6-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine (6-MeO-DMT). Compound 1,1,2,2- Tetradeuterio-2-[5-deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N-dimethyl-ethanamine (compound 278) and Compound 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl)ethanamine (compound 269) exhibit the largest differences in half-life and intrinsic clearance compared to 2-(6-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine (6-MeO- DMT). Example 14: Behavioral Despair Test in the rat The method, which detects antidepressant activity, follows that described by Porsolt et al (Eur. J. Pharmacol., 47, 379-391, 1978). Rats forced to swim in a situation from which they cannot escape rapidly become immobile. Antidepressants decrease the duration of immobility. Animal conditions The experiment used 39 (including 3 spare) Male Wistar (Han) rats, 180 - 280 g (max. range per experiment = 50 g). Rats were delivered to the laboratory at least 5 days before the experiments during which time they was acclimatized to laboratory conditions. Rats were identified with indelible marker on the tail. Rats were housed grouped in macrolon cages (no more than 6 animals per cage) on wood litter. Environmental enrichment (such as tunnel, gnawing material, nesting material) was provided. The animal house was maintained under artificial lighting (12 hours) between 7:00 and 19:00 in a controlled ambient temperature of 22 ± 2°C, and relative humidity between 30-70%. All animals had free access to food and water. The batches of diet and wood litter are analyzed by the suppliers for composition and contaminant levels. Bacterial and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrates by-products). Dosage forms preparation 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl) ethanamine HCl (HCl salt of Compound 269) was first dissolved in physiological saline for solubility check. Around 10 mg of Vial 7 (for Group 5) was used for this. If soluble, physiological saline was used as vehicle. If insoluble, for each dose, amount of compound in each vial was first dissolved in DMSO (10% final volume) and then diluted in water (90% final volume). Doses was prepared W/V (stock), no serial dilutions. The dosages administered are summarized in Table 3. Route and duration of administration The test, reference or vehicle formulations was administered intraperitoneally 3 times: 24 hours (after Session 1), 4 hours and 30 minutes before the test session (Session 2). Protocol Rats are individually placed in a cylinder (height = 40 cm; diameter = 20 cm) containing 13 cm water (25°C) for 15 minutes on the first day of the experiment (Session 1) and are then put back in the water 24 hours later for a 5 minute test (Session 2). The duration of immobility during the 5-minute test is measured. Data analysis Data with 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl) ethanamine was analyzed by comparing treated groups with vehicle control using one-way ANOVA followed by post-hoc Dunnett’s tests. Data with the reference substance (imipramine) was analyzed separately using unpaired Student's t tests. Treatment schedule 6 rats are studied per group and the test is performed blind.1,1,2,2-tetradeuterio-2-(6- methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl) ethanamine HCl (HCl salt of Compound 269) was evaluated at 4 doses, administered intraperitoneally (i.p.) 3 times: 24 hours, 4 hours and 30 minutes before the test (Session 2), and compared with a vehicle control group. Imipramine (32 mg/kg i.p.), administered under the same experimental conditions, was used as reference substance. Table 3.
Figure imgf000193_0001
Results 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl) ethanamine HCl (HCl salt of Compound 269) (1, 5, 10 and 30 mg/kg), administered i.p.24 hours, 4 hours and 30 minutes before the test, significantly decreased the duration of immobility over the 5-minute testing period at 10 and 30 mg/kg, as compared with vehicle controls (-17%, NS; -11%, NS; -31%, p < 0.01 and -24%, p < 0.05, at the 4 doses respectively). In the same experiment, Imipramine (32 mg/kg), administered i.p.30 minutes before the test, significantly decreased the duration of immobility, as compared with vehicle controls (-70%, p < 0.001). These results suggest the presence of antidepressant-like activity for 1,1,2,2-tetradeuterio- 2-(6-methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl) ethanamine HCl (HCl salt of Compound 269) over the dose range 10 – 30 mg/kg i.p. in the Behavioral Despair Test in the rat. Imipramine exhibited antidepressant-like activity at 32 mg/kg i.p. in the same experimental conditions. Discussion The data shows that 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl) ethanamine significantly reduced immobility on the forced swim test (FIG.1). Additionally this was dose dependent with lower subtherapeutic dosages having no effect. This shows that 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl) ethanamine has an anti-depressant effect and supports the development of the deuterated compounds in Table 1 and Table 2 for the treatment of depression. Additionally, anxiolytic drugs such as alprazolam and buspirone show significant reductions in the forced swim test (Flugy, Anna, et al. "Antidepressant and anxiolytic effects of alprazolam versus the conventional. antidepressant desipramine and the anxiolytic diazepam in the forced swim test in rats." European journal of pharmacology 214.2-3 (1992): 233-238). This data also supports that 1,1,2,2-tetradeuterio-2-(6-methoxy-1H-indol-3-yl)-N,N-bis(trideuteriomethyl) ethanamine is both an antidepressant and an anxiolytic therapeutic. This data supports that the following deuterated compounds would have antidepressant and anxiolytic activity and would be effective in the treatment of depression and anxiety and related disorders 1,1,2,2-Tetradeuterio-2-(6- methoxy-1H-indol-3-yl)-N,N-dimethyl-ethanamine; 1,1,2,2-tetradeuterio-2-(6-methoxy-1H- indol-3-yl)-N,N-bis(trideuteriomethyl)ethanamine; 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)- N,N-dimethyl-ethanamine; 1,1-dideuterio-2-(6-methoxy-1H-indol-3-yl)-N,N- bis(trideuteriomethyl)ethanamine; 1,1,2,2-tetradeuterio-N,N,-dimethyl-2-[6- (trideuteriomethoxy)-1H-indol-3-yl]ethanamine; 1,1,2,2-tetradeuterio-2-[6-(trideuteriomethoxy)- 1H-indol-3-yl]-N,N-bis(trideuteriomethyl)ethanamine; 1,1-dideuterio-2-[6-(trideuteriomethoxy)- 1H-indol-3-yl]-N,N-bis(trideuteriomethyl)ethanamine; 1,1-dideuterio-N,N-dimethyl-2-[6- (trideuteriomethoxy)-1H-indol-3-yl]ethanamine; 2-[5-Deuterio-6-(trideuteriomethoxy)-1H-indol- 3-yl]-N,N-dimethyl-ethanamine; 2-[5-Deuterio-6-(trideuteriomethoxy)-1H-indol-3-yl]-N,N- bis(trideuteriomethyl)ethanamine; 1,1,2,2-Tetradeuterio-2-[5-deuterio-6-(trideuteriomethoxy)- 1H-indol-3-yl]-N,N-dimethyl-ethanamine; and 1,1,2,2-Tetradeuterio-2-[5-deuterio-6- (trideuteriomethoxy)-1H-indol-3-yl]-N,N-bis(trideuteriomethyl)ethanamine. In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

CLAIMS What is claimed is: 1. A compound of Formula (I):
Figure imgf000196_0001
(I), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy; R2 is hydrogen, -C(O)OR3, -C(O)R4, -CH(R5)OR6, -C(O)OCH(R5)OC(O)R6, - C(O)OCH(R5)OC(O)OR6, -C(O)NHCH(R5)OC(O)R6, -CH(R5)C(O)R6, -S(O)2OR7, - P(O)OR8[N(R9)R10], -C(O)N(R9)R10, -P(O)OR11(OR12), -CH(R4)OP(O)OR8[N(R9)R10], or -CH(R4)OP(O)OR11(OR12); each of R3, R6, R7, and R8 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, each of R4 and R5, is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA,each of R9 and R10 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R9 and R10 together with the atom to which they are attached form a heterocyclylalkyl ring or a heteroaryl ring that is unsubstituted or substituted with one or more RA; each of R11 and R12 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R11 and R12 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RA; each RA is independently alkyl, heteroalkyl, oxo, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, an amino acid side chain, -OR13, -N(R18)R19, -NHC(=NH)NH2, -C(O)OR13, - N(R13)C(O)OR14, -N(R13)C(O)R14, -C(O)R14, -OC(O)R15, -OC(O)OR16, - OP(O)OR17[N(R18)R19], -C(O)N(R18)R19, -OC(O)N(R18)R19, -SR13, -SO2R13, or - OP(O)OR20(OR21), wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with alkyl, aryl, halogen, -OR13, -N(R18)R19, - C(O)R14, -OC(O)R15, -OC(O)OR16, or -OC(O)N(R18)R19; each of R13, R14, R15, R16, or R17 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is unsubstituted or substituted with one or more RB; each of R18 and R19 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one or more RB; each of R20 and R21 is independently alkyl, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB, or R20 and R21 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RB; and each RB is independently halogen, amino, cyano, hydroxyl, alkoxy, benzyl, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, -C(O)CH3, -CO2H, -C(O)Ph, or heteroarylalkyl, wherein cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more halogen, amino, cyano, hydroxyl, alkyl, acetyl, or benzoyl; provided that when R2 is hydrogen, the molecule is isotopically enriched.
2. The compound of claim 1, wherein the compound is enriched in deuterium.
3. The compound of claim 1 or claim 2, wherein R1 is alkoxy or deuterated alkoxy.
4. The compound of claim 1 or claim 2, wherein the compound has Formula (Ia):
Figure imgf000198_0001
wherein R1 is alkoxy or deuterated alkoxy, and R3 is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl.
5. The compound of claim 3, wherein the compound has Formula (Ib)
Figure imgf000198_0002
wherein each of RA1, RA2, RA3, and RA4 is independently hydrogen or alkyl; and RA5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR13, -N(R13)C(O)OR14, - N(R13)C(O)R14, -C(O)R14, -OC(O)R15, or -OC(O)OR16.
6. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (Ic):
Figure imgf000198_0003
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy or deuterated alkoxy; each of R18 and R19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring.
7. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (Id):
Figure imgf000199_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy or deuterated alkoxy; R5 is hydrogen, alkyl, or cycloalkyl; and RA6 is hydrogen or alkyl.
8. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (Ie):
Figure imgf000199_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy or deuterated alkoxy, such as methoxy or deuterated methoxy, and R5 is hydrogen, alkyl, or cycloalkyl.
9. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (If):
Figure imgf000200_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy; and each of R9 and R10 is independently alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl.
10. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (Ig):
Figure imgf000200_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy or deuterated alkoxy; each of RA1, RA2, RA3, and RA4 is independently hydrogen or alkyl; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and RA5 is heteroalkyl, heterocyclylalkyl, heteroaryl, or -C(O)OR13, -N(R13)C(O)OR14, - N(R13)C(O)R14, -C(O)R14, -OC(O)R15, or -OC(O)OR16.
11. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (Ih):
Figure imgf000201_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy or deuterated alkoxy; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and each of R18 and R19 is independently hydrogen, alkyl, cycloalkyl, or heteroalkyl; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring.
12. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (Ii):
Figure imgf000201_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy or deuterated alkoxy; R5 is hydrogen, alkyl, or cycloalkyl; R10 is hydrogen, alkyl, heteroalkyl, or cycloalkyl; and RA6 is hydrogen or alkyl.
13. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (Ij):
Figure imgf000202_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy or deuterated alkoxy; and R5 is hydrogen or alkyl.
14. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (Ik):
Figure imgf000202_0002
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxy or deuterated alkoxy; and R4 is alkyl, heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl.
15. The compound of claim 1 or claim 2, wherein the compound has the structure of Formula (Il):
Figure imgf000202_0003
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is alkoxy or deuterated alkoxy; R5 is hydrogen alkyl, or cycloalkyl; and R6 is alkyl, cycloalkyl, heterocyclylalkyl, or heteroalkyl.
16. The compound of any one of claims 1 – 15, wherein R1 is alkoxy or deuterated alkoxy.
17. The compound of any one of claims 1 – 15, wherein the compound is an isotopically labeled analog.
18. The compound of claim 1, wherein the compound has the structure of Formula (Iv):
Figure imgf000203_0001
(Iv), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3; R2 is hydrogen, -C(O)OR3, -C(O)R4, -CH(R5)OR6, -C(O)OCH(R5)OC(O)R6, - C(O)OCH(R5)OC(O)OR6, -C(O)NHCH(R5)OC(O)R6, -CH(R5)C(O)R6, -S(O)2OR7, - P(O)OR8[N(R9)R10], -C(O)N(R9)R10, -P(O)OR11(OR12), -CH(R4)OP(O)OR8[N(R9)R10], or -CH(R4)OP(O)OR11(OR12); each of R3, R6, R7, and R8 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, each of R4 and R5, is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, each of R9 and R10 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R9 and R10 together with the atom to which they are attached form a heterocyclylalkyl ring or a heteroaryl ring that is unsubstituted or substituted with one or more RA; each of R11 and R12 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RA, or R11 and R12 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RA; each RA is independently alkyl, heteroalkyl, oxo, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, an amino acid side chain, -OR13, -N(R18)R19, -NHC(=NH)NH2, -C(O)OR13, - N(R13)C(O)OR14, -N(R13)C(O)R14, -C(O)R14, -OC(O)R15, -OC(O)OR16, - OP(O)OR17[N(R18)R19], -C(O)N(R18)R19, -OC(O)N(R18)R19, -SR13, -SO2R13, or - OP(O)OR20(OR21), wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with alkyl, aryl, halogen, -OR13, -N(R18)R19, - C(O)R14, -OC(O)R15, -OC(O)OR16, or -OC(O)N(R18)R19; each of R13, R14, R15, R16, or R17 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is unsubstituted or substituted with one or more RB; each of R18 and R19 is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB; or R18 and R19 together with the atom to which they are attached form a heterocyclylalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one or more RB; each of R20 and R21 is independently alkyl, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more RB, or R20 and R21 together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more RB; and each RB is independently halogen, amino, cyano, hydroxyl, alkoxy, benzyl, -CO2H, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, -C(O)CH3, - C(O)Ph, or heteroarylalkyl, wherein cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more halogen, amino, cyano, hydroxyl, alkyl, acetyl, or benzoyl; provided that when R2 is hydrogen, the molecule is isotopically enriched.
19. The compound of claim 18, wherein at least one of R1, L1, L2, L3, L4, L5, L6 and L7 is deuterium.
20. The compound of claim 18, wherein R1 is -OCH3, -OCH2D, -OCHD2, or -OCD3; and at least one of L1, L2, L3, L4, L5, L6 and L7 is deuterium.
21. The compound of claim 18, wherein L6 is -CH3; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L7 is deuterium.
22. The compound of claim 18, wherein L6 is -CH3; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L7 is deuterium.
23. The compound of claim 18, wherein L7 is -CH3; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L6 is deuterium.
24. The compound of claim 18, wherein L7 is -CH3; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L6 is deuterium.
25. The compound of claim 18, wherein L6 is -CD3; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L7 is deuterium.
26. The compound of claim 18, wherein L6 is -CD3; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L7 is deuterium.
27. The compound of claim 18, wherein L7 is -CD3; R1 is -OCH3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L6 is deuterium.
28. The compound of claim 18, wherein L7 is -CD3; R1 is -OCD3; R2 is hydrogen; and at least one of L1, L2, L3, L4, L5, and L6 is deuterium.
29. The compound of claim 18, wherein L6 is -CH3; R1 is -OCH3 or -OCD3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L7 is selected from -CH3, -CH2D, -CHD2, and -CD3.
30. The compound of claim 18, wherein L7 is -CH3; R1 is -OCH3 or -OCD3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 is selected from -CH3, -CH2D, -CHD2, and -CD3.
31. The compound of claim 18, wherein L6 is -CD3; R1 is -OCH3 or -OCD3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L7 is selected from -CH3, -CH2D, -CHD2, and -CD3.
32. The compound of claim 18, wherein L7 is -CD3; R1 is -OCH3 or -OCD3; R2 is hydrogen; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 is selected from -CH3, -CH2D, -CHD2, and -CD3.
33. The compound of claim 18, wherein R2 is hydrogen and the compound has the structure of Formula (Iv-1):
Figure imgf000206_0001
(Iv-1), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, deuterium, alkoxy, or deuterated alkoxy; L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
34. The compound of claim 18, wherein R1 is -OCH3, R2 is hydrogen, and the compound has the structure of Formula (Iv-2):
Figure imgf000207_0001
(Iv-2), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
35. The compound of claim 18, wherein R1 is -OCD3, R2 is hydrogen, and the compound has the structure of Formula (Iv-3):
Figure imgf000207_0002
(Iv-3), or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof, wherein: L1, L2, L3, L4, and L5 are each independently selected from hydrogen and deuterium; and L6 and L7 are each independently selected from -CH3, -CH2D, -CHD2, and -CD3.
36. The compound of claim 18, wherein the compound is selected from a compound depicted in Table 1, or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof.
37. The compound of claim 36, wherein the compound is
Figure imgf000208_0001
; or
Figure imgf000208_0002
Figure imgf000209_0001
or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof.
38. The compound of any one of claims 1 – 36, wherein the compound is in the form of a pharmaceutically acceptable salt.
39. The compound of any one of claims 1 – 38, wherein the compound is in the form of a solvate.
40. A pharmaceutical composition comprising a compound of any one of claims 1 – 39.
41. A method for method for increasing neuronal plasticity, comprising contacting a neuron with an effective amount of a compound according to any one of claims 1 – 39 or a pharmaceutical composition of claim 40.
42. The method of claim 41, wherein contacting comprises administering the compound to a subject.
43. A method for treating a neurological disorder or a psychiatric disorder, or both, comprising contacting a subject having the neurological disorder, psychiatric disorder or both with an effective amount of a compound according to any one of claims 1 – 39 or a pharmaceutical composition of claim 40.
44. The method of claim 43, wherein the neurological disorder is a neurodegenerative disorder.
45. The method of claim 43, wherein the neurological disorder or psychiatric disorder, or both, comprises depression, addiction, anxiety, or a post-traumatic stress disorder.
46. The method of claim 43, wherein the neurological disorder or psychiatric disorder, or both, comprises treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.
47. The method of claim 43, wherein the neurological disorder or psychiatric disorder, or both, comprises stroke, traumatic brain injury, or a combination thereof.
48. The method of claim 43, further comprising administering to the subject an effective amount of an empathogenic agent.
49. The method of claim 48, wherein the empathogenic agent is MDMA.
50. The method of claim 43, further comprising administering a 5-HT2A antagonist to the subject.
51. The method of claim 50, wherein the 5-HT2A antagonist is selected from MDL- 11,939, eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, volinanserin (MDL-100,907), olanzapine, risperidone, pimavanserin, nelotanserin and lorcaserin.
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