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WO2025151874A1 - Agents antiplasmodiques alcaloïdes indoliques et leur préparation - Google Patents

Agents antiplasmodiques alcaloïdes indoliques et leur préparation

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Publication number
WO2025151874A1
WO2025151874A1 PCT/US2025/011410 US2025011410W WO2025151874A1 WO 2025151874 A1 WO2025151874 A1 WO 2025151874A1 US 2025011410 W US2025011410 W US 2025011410W WO 2025151874 A1 WO2025151874 A1 WO 2025151874A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
certain embodiments
stereoisomer
Prior art date
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PCT/US2025/011410
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English (en)
Inventor
Debopam Chakrabarti
Robert William HUIGENS, III
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University of Florida
University of Florida Research Foundation Inc
University of Central Florida Research Foundation Inc
Original Assignee
University of Florida
University of Florida Research Foundation Inc
University of Central Florida Research Foundation Inc
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Publication of WO2025151874A1 publication Critical patent/WO2025151874A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents

Definitions

  • CtD Complexity-to-Diversity
  • CtD offers an orthogonal discovery approach to diversity-oriented synthesis (DOS; simple materials utilized in complexitygenerating reactions to explore chemical space) 17 24 and biology-oriented synthesis (BIOS; generation of natural product-like molecules based on cheminformatic analysis of natural products and conserved proteins) 23 32 utilizing chemosei ective “ring distortion” reactions (e.g., ring cleavage, ring expansion reactions) to rapidly accesses diverse compounds through the dramatic architectural reorganization of stereochemically complex natural products.
  • ring distortion e.g., ring cleavage, ring expansion reactions
  • CtD platform delivering reengineered small molecules include the discovery of vincamine-derived V2a, which demonstrates antagonistic activity against hypocretin receptor 2 and inhibits morphine-seeking behaviors in mouse models, 16 and the identification of pleuromutilin-derived ferroptocide, a thioredoxin inhibitor that positively modulates the immune system in a murine model of breast cancer. 15
  • the present disclosure provides compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrug thereof, wherein the compounds are of Formula I:
  • the present disclosure provides compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrug thereof, wherein the compounds are of Formula II:
  • the provided compounds may be useful as anti-microbial agents.
  • the provided compounds are anti -parasitic agents.
  • the provided compounds are parasitostatic agents.
  • the provided compounds are antiplasmodial agents.
  • compositions comprising a provided compound and optionally a pharmaceutically acceptable excipient.
  • kits comprising a provided compound or pharmaceutical composition, and instructions for using the provided compound or pharmaceutical composition.
  • the present disclosure provides methods of treating a disease in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides use of a provided compound or pharmaceutical composition for the manufacture of a medicament for treating a disease in a subject in need thereof.
  • the present disclosure provides compounds and pharmaceutical compositions for use in treating a disease in a subject in need thereof.
  • the present disclosure provides methods of preventing a disease in a subject, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides use of a provided compound or pharmaceutical composition for the manufacture of a medicament for preventing a disease in a subject.
  • the present disclosure provides compounds and pharmaceutical compositions for use in preventing a disease in a subject.
  • the disease is an infection. In certain embodiments, the disease is a parasitic infection. In certain embodiments, the disease is malaria.
  • the present disclosure provides methods of inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue, the methods comprising administering to the subject or contacting the biological sample or tissue with an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides use of a provided compound or pharmaceutical composition for the manufacture of a medicament for inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue.
  • the present disclosure provides the provided compounds and pharmaceutical compositions for use in inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue.
  • the present disclosure provides in vitro methods of inhibiting the growth or reproduction of a microorganism or killing a microorganism in a biological sample or tissue or on a surface, the method comprising contacting the biological sample, tissue, or surface with an effective amount of a provided compound or pharmaceutical composition.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • the bond — is a single bond
  • the dashed line — is a single bond or absent
  • the bond — or — is a single or double bond.
  • a formula depicted herein includes compounds that do not include isotopically enriched atoms and also compounds that include isotopically enriched atoms.
  • Compounds that include isotopically enriched atoms may be useful as, for example, analytical tools, and/or probes in biological assays.
  • aliphatic includes both saturated and unsaturated, nonaromatic, straight chain (i.e., unbranched), branched, acyclic, and cyclic (i.e., carbocyclic) hydrocarbons.
  • an aliphatic group is optionally substituted with one or more functional groups (e.g., halo, such as fluorine).
  • halo such as fluorine
  • “aliphatic” is intended herein to include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • range When a range of values (“range”) is listed, it is intended to encompass each value and subrange within the range.
  • a range is inclusive of the values at the two ends of the range unless otherwise provided.
  • an integer between 1 and 4 refers to 1, 2, 3, and 4.
  • Ci-6 alkyl is intended to encompass, Ci, C2, C3, C4, Cs, Ce, C1-6, C1-5, Ci-4, C1-3, C1-2, C2-6, C2-5, C2 4, C2 3, C3 6, C3 5, C3 4, C4 6, C4 5, and Cs 6 alkyl.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (Cs), 3-pentanyl (C5), amyl (Cs), neopentyl (Cs), 3-methyl- 2-butanyl (Cs), tertiary amyl (Cs), and n-hexyl (Ce).
  • Additional examples of alkyl groups include n- heptyl (C7), n-octyl (Cs) and the like.
  • an alkyl group is substituted with one or more halogens.
  • Perhaloalkyl is a substituted alkyl group as defined herein wherein all of the hydrogen atoms are independently replaced by a halogen, e.g, fluoro, bromo, chloro, or iodo.
  • the alkyl moiety has 1 to 8 carbon atoms (“C1-8 perhaloalkyl”).
  • the alkyl moiety has 1 to 6 carbon atoms (“Ci-6 perhaloalkyl”).
  • the alkyl moiety has 1 to 4 carbon atoms (“Ci-4 perhaloalkyl”).
  • the alkyl moiety has 1 to 3 carbon atoms (“C1-3 perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms (“C1-2 perhaloalkyl”). In some embodiments, all of the hydrogen atoms are replaced with fluoro. In some embodiments, all of the hydrogen atoms are replaced with chloro. Examples of perhaloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFCh, -CF2CI, and the like.
  • each instance of an alkenyl group is independently optionally substituted, e.g., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is unsubstituted C2-10 alkenyl.
  • the alkenyl group is substituted C2-10 alkenyl.
  • a C C double bond for which the stereochemistry is not specified e.g., -
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • C2-4 alkynyl groups include ethynyl (C2), 1- propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (Cs), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like.
  • each instance of an alkynyl group is independently optionally substituted, e.g., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
  • the alkynyl group is unsubstituted C2-10 alkynyl.
  • the alkynyl group is substituted C2-10 alkynyl.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”).
  • Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.
  • Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C3-10 carbocyclyl groups include the aforementioned C -8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-l/f-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged, or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”).
  • Carbocyclyl can be saturated, and saturated carbocyclyl is referred to as “cycloalkyl.”
  • carbocyclyl is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (Cs) and cyclohexyl (Cs). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C3-10 cycloalkyl.
  • the cycloalkyl group is substituted C3-10 cycloalkyl.
  • Carbocyclyl can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carb
  • each instance of a carbocyclyl group is independently optionally substituted, e.g., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C3-10 carbocyclyl.
  • the carbocyclyl group is a substituted C3-10 carbocyclyl.
  • the carbocyclyl is substituted or unsubstituted, 3- to 7-membered, and monocyclic.
  • the carbocyclyl is substituted or unsubstituted, 5- to 13-membered, and bicyclic.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”).
  • C5-6 cycloalkyl groups include cyclopentyl (Cs) and cyclohexyl (Cs).
  • C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C3-10 cycloalkyl.
  • the cycloalkyl group is substituted C3-10 cycloalkyl.
  • the carbocyclyl includes oxo substituted thereon.
  • Heterocyclyl refers to a radical of a 3- to 13-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-13 membered heterocyclyl”).
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”).
  • a heterocyclyl group can be saturated or can be partially unsaturated.
  • Heterocyclyl may include zero, one, or more (e. ., two, three, or four, as valency permits) double bonds in all the rings of the heterocyclic ring system that are not aromatic or heteroaromatic.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an “un substituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl.
  • the heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, and monocyclic.
  • the heterocyclyl is substituted or unsubstituted, 5- to 13-membered, and bicyclic.
  • the heterocyclyl includes oxo substituted thereon.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”).
  • an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently optionally substituted, e.g., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted Ce-14 aryl.
  • the aryl group is substituted Ce-14 aryl.
  • Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 K electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, e.g., unsubstituted (“un substituted heteroaryl”) or substituted (“substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is substituted 5-14 membered heteroaryl.
  • the heteroaryl group is 5-6 membered, monocyclic.
  • the heteroaryl group is 8-14 membered, bicyclic.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5- membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazol yl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl.
  • Partially unsaturated refers to a group that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as herein defined.
  • saturated refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the carbon atom substituents are independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -OR aa , -SR aa , -N(R bb ) 2 , -CN, -SCN, or -NO2.
  • each R bb is independently hydrogen, substituted (e.g, substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group.
  • Exemplary counterions which may be multivalent include CO3 2 , HPO4 2 , PO4 3 B4O7 2 , SO4 2 , S2O3 2 , carboxylate anions (e.g, tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • “Halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, - Br), or iodine (iodo, -1).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Sulfonamide nitrogen protecting groups include /Moluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6- trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),
  • a nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • FIG. 2 shows that exemplary X-ray crystal structures of yohimbine products supported NMR trends for stereochemical assignment.
  • FIG. 4 shows an exemplary free energy diagram for the ring cleavage pathway of yohimbine reacting with ethyl chloroformate and 2-iodobenzyl alcohol.
  • Optimized structure of Int-2B (33) is shown in the top right of the diagram. The arrow is pointing to the most accessible face of the (planar) electrophilic center for nucleophilic approach, rationalizing the stereochemical outcome for the reaction.
  • any two instances of the moiety may be the same or different from each other.
  • at least one instance is each instance.
  • R 1 is substituted or unsubstituted alkyl.
  • R 1 is substituted or unsubstituted, Ci-6 alkyl.
  • R 1 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen.
  • R 1 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro.
  • R 1 is unsubstituted Ci-4 alkyl.
  • R 1 is Me.
  • R 1 is Et.
  • R 1 is zz-Pr or z-Pr.
  • R 1 is - CH2-(3 -mono-substituted phenyl). In certain embodiments, R 1 is -CH 2 -(2 -mono-substituted phenyl). In certain embodiments, R 1 is -CH2-(di-substituted phenyl).
  • R 1 is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl).
  • an oxygen protecting group e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • R 2 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl).
  • R 2 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.
  • R 2 is saturated heterocyclyl.
  • R 2 is substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, R 2 is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R 2 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.
  • R 2 is a sulfur protecting group (e.g., acetamidomethyl, Z-Bu, 3-nitro- 2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.
  • a sulfur protecting group e.g., acetamidomethyl, Z-Bu, 3-nitro- 2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl
  • At least one instance of R 3 is -CH2-(3-mono-substituted phenyl). In certain embodiments, at least one instance of R 3 is -CH2-(2-mono-substituted phenyl). In certain embodiments, at least one instance of R 3 is -CH2-(di-substituted phenyl).
  • At least one instance of R 3 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R 3 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R 3 is saturated heterocyclyl. In certain embodiments, at least one instance of R 3 is partially unsaturated heterocyclyl (e.g, comprising only
  • At least one instance of R 3 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R 3 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R 3 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl.
  • At least one instance of R A is a sulfur protecting group (e.g., acetamidomethyl, Z-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.
  • a sulfur protecting group e.g., acetamidomethyl, Z-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl
  • two instances of R A attached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl).
  • two instances of R A attached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).
  • R 4 is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, R 4 is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R 4 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.
  • R 5 is hydrogen. In certain embodiments, R 3 is halogen.
  • R 5 is -CH2-(4-mono-substituted phenyl). In certain embodiments, R 5 is -CH2-(3-mono-substituted phenyl). In certain embodiments, R 3 is -CH2-(2-mono-substituted phenyl). In certain embodiments, R 5 is -CH2-(di-substituted phenyl).
  • R 5 is substituted or unsubstituted aryl. In certain embodiments, R 5 is substituted or unsubstituted phenyl. In certain embodiments, R 5 is unsubstituted phenyl. In certain embodiments, R 3 is 4-mono-substituted phenyl. In certain embodiments, R 3 is 3-mono-substituted phenyl. In certain embodiments, R 5 is 2-mono-substituted phenyl. In certain embodiments, R 5 is disubstituted phenyl. In certain embodiments, R 5 is substituted or unsubstituted naphthyl.
  • R 5 is substituted or unsubstituted heteroaryl. In certain embodiments, R 5 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R 3 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl.
  • R 5 is substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl).
  • R 3 is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl.
  • R 3 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.
  • R 6 is hydrogen. In certain embodiments, R 6 is halogen.
  • R 6 is substituted or unsubstituted alkyl. In certain embodiments, R 6 is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, R 6 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, R 6 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro. In certain embodiments, R 6 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of substituted or unsubstituted phenyl. In certain embodiments, R 6 is unsubstituted Ci-4 alkyl.
  • R 6 is Me. In certain embodiments, R 6 is Et. In certain embodiments, R 6 is zz-Pr or z-Pr. In certain embodiments, R 6 is zz-Bu, z-Bu, or sec-Bu. In certain embodiments, R 6 is Z-Bu. In certain embodiments, R 6 is fluorinated methyl. In certain embodiments, R 6 is fluorinated ethyl. In certain embodiments, R 6 is chlorinated methyl. In certain embodiments, R 6 is chlorinated ethyl. In certain embodiments, R 6 is -CH2-( substituted or unsubstituted phenyl). In certain embodiments, R 6 is Bn.
  • R 6 is -CH2-(4-mono-substituted phenyl). In certain embodiments, R 6 is -CH2-(3-mono-substituted phenyl). In certain embodiments, R 6 is -CH2-(2 -mono-substituted phenyl). In certain embodiments, R 6 is -CH2-(di-substituted phenyl).
  • R 6 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl).
  • R 6 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.
  • R 6 is saturated heterocyclyl.
  • R 6 is substituted or unsubstituted aryl. In certain embodiments, R 6 is substituted or unsubstituted phenyl. In certain embodiments, R 6 is unsubstituted phenyl. In certain embodiments, R 6 is 4-mono-substituted phenyl. In certain embodiments, R 6 is 3-mono-substituted phenyl. In certain embodiments, R 6 is 2-mono-substituted phenyl. In certain embodiments, R 6 is disubstituted phenyl. In certain embodiments, R 6 is substituted or unsubstituted naphthyl.
  • R 7 is hydrogen. In certain embodiments, R 7 is halogen.
  • At least one instance of R B is hydrogen. In certain embodiments, each instance of R B is hydrogen. In certain embodiments, at least one instance of R B is not hydrogen. In certain embodiments, no instance of R B is hydrogen.
  • At least one instance of R B is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R B is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R B is saturated heterocyclyl. In certain embodiments, at least one instance of R B is partially unsaturated heterocyclyl (e.g., comprising
  • At least one instance of R B is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl.
  • at least one instance of R B is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl).
  • At least one instance of R B is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom.
  • at least one instance of R B is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, TUP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom.
  • At least one instance of R B is a sulfur protecting group (e.g., acetamidomethyl, Z-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.
  • a sulfur protecting group e.g., acetamidomethyl, Z-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl
  • two instances of R B attached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl).
  • two instances of R B attached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).
  • Formula I is of Formula 1-2: optionally wherein R 1 and R 2 are as shown in Table 2: Table 2
  • Formula I is of Formula 1-3: optionally wherein R 1 and R 2 are as shown in Table 3: Table 3
  • Formula I is of Formula 1-4: optionally wherein R 1 and R 2 are as shown in Table 4: Table 4
  • Formula I is of Formula 1-5: optionally wherein R 1 and R 2 are as shown in Table 5: Table 5
  • Formula I is of Formula 1-6: optionally wherein R 1 and R 2 are as shown in Table 6: Table 6
  • Formula I is of Formula 1-7: optionally wherein R 1 and R 2 are as shown in Table 7:
  • Formula I is of Formula 1-8: optionally wherein R 1 and R 2 are as shown in Table 8: Table 8 In certain embodiments, Formula I is of Formula 1-9: optionally wherein R 1 and R 2 are as shown in Table 9: Table 9 In certain embodiments, Formula I is of Formula 1-10:
  • Formula I is of Formula 1-11 : optionally wherein R 1 and R 2 are as shown in Table 11 : Table 11
  • Formula I is of Formula 1-12: optionally wherein R 1 and R 2 are as shown in Table 12: Table 12
  • Formula I is of Formula 1-13: optionally wherein R 1 and R 2 are as shown in Table 13: Table 13
  • Formula I is of Formula 1-14: optionally wherein R 1 and R 2 are as shown in Table 14: Table 14
  • Formula I is of Formula 1-15: optionally wherein R 1 and R 2 are as shown in Table 15: Table 15
  • Formula I is of Formula 1-16:
  • the present disclosure provides compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrug thereof, wherein: the compounds are of Formula II:
  • R 11 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group;
  • X 11 is oxygen or sulfur
  • R 12 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; ni l is 0; or: nl 1 is 1, 2, 3, or 4; each instance of R 13 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or un substituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,
  • R 19 is substituted or unsubstituted alkyl or hydrogen.
  • any two instances of the moiety may be the same or different from each other.
  • at least one instance is each instance.
  • R 11 is substituted or unsubstituted alkyl.
  • R 11 is substituted or unsubstituted, Ci-6 alkyl.
  • R 11 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen.
  • R 11 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro.
  • R 11 is unsubstituted Ci-4 alkyl.
  • R 11 is Me.
  • R 11 is Et.
  • R 11 is zz-Pr or z-Pr.
  • R 11 is zz-Bu, z-Bu, or sec-Bu. In certain embodiments, R 11 is /-Bu. In certain embodiments, R 11 is fluorinated methyl. In certain embodiments, R 11 is fluorinated ethyl. In certain embodiments, R 11 is chlorinated methyl. In certain embodiments, R 11 is chlorinated ethyl. In certain embodiments, R 11 is -CH2CCI3. In certain embodiments, R 11 is -CH2-(substituted or unsubstituted phenyl). In certain embodiments, R 11 is Bn. In certain embodiments, R 11 is -CH2-(4-mono-substituted phenyl).
  • R 11 is - CH2-(3 -mono-substituted phenyl). In certain embodiments, R 11 is -CH2-(2-mono-substituted phenyl). In certain embodiments, R 11 is -CH2-(di-substituted phenyl).
  • R 11 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl).
  • R 11 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.
  • R 11 is saturated heterocyclyl.
  • R 11 is substituted or unsubstituted heteroaryl. In certain embodiments, R 11 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R 11 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl.
  • R 11 is substituted or unsubstituted pyridinyl (e.g, 2-, 3-, or 4-pyridinyl). In certain embodiments, R 11 is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R 11 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.
  • X 11 is oxygen. In certain embodiments, X 11 is sulfur.
  • R 12 is substituted or unsubstituted aryl. In certain embodiments, R 12 is substituted or unsubstituted phenyl. In certain embodiments, R 12 is unsubstituted phenyl. In certain embodiments, R 12 is 4-m ono-substituted phenyl. In certain embodiments, R 12 is 3-mono-substituted phenyl. In certain embodiments, R 12 is 2-mono-substituted phenyl. In certain embodiments, R 12 is disubstituted phenyl. In certain embodiments, R 12 is substituted or unsubstituted naphthyl.
  • R 12 is substituted or unsubstituted heteroaryl. In certain embodiments, R 12 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, R 12 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl.
  • R 12 is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom.
  • an oxygen protecting group e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, Z-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl
  • At least one instance of R 13 is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R 13 is substituted or unsubstituted, Ci-6 alkyl. In certain embodiments, at least one instance of R 13 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen. In certain embodiments, at least one instance of R 13 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro.
  • At least one instance of R 13 is -CH2-(3-mono- substituted phenyl). In certain embodiments, at least one instance of R 13 is -CH2-(2-mono- substituted phenyl). In certain embodiments, at least one instance of R 13 is -CH2-(di- substituted phenyl).
  • At least one instance of R 13 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R 13 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R 13 is substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl.
  • At least one instance of R 13 is -OR C . In certain embodiments, at least one instance of R 13 is - ⁇ (substituted or unsubstituted alkyl). In certain embodiments, at least one instance of R 13 is - ⁇ (substituted or unsubstituted, Ci-6 alkyl). In certain embodiments, at least one instance of R 13 is - ⁇ (unsubstituted Ci-6 alkyl). In certain embodiments, at least one instance of R 13 is - ⁇ Me. In certain embodiments, at least one instance of R 13 is -O(Ci-6 alkyl substituted with one or more instances of halogen).
  • At least one instance of R c is substituted alkyl (e.g, alkyl substituted with one or more instances of halogen (e.g, F)). In certain embodiments, at least one instance of R c is unsubstituted alkyl. In certain embodiments, at least one instance of R c is unsubstituted Ci-6 alkyl. In certain embodiments, at least one instance of R c is Me. In certain embodiments, at least one instance of R c is Et, Pr, or Bu. In certain embodiments, at least one instance of R c is substituted Ci-6 alkyl. In certain embodiments, at least one instance of R c is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R c is substituted ethyl, substituted propyl, or substituted butyl.
  • halogen e.g, F
  • at least one instance of R c is unsubstituted alkyl.
  • At least one instance of R c is a sulfur protecting group (e.g., acetamidomethyl, /-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom.
  • a sulfur protecting group e.g., acetamidomethyl, /-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl
  • At least one instance of R 18 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R 18 is substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R 18 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl.
  • At least one instance of R D is substituted or unsubstituted pyridinyl (e.g., 2-, 3-, or 4-pyridinyl). In certain embodiments, at least one instance of R D is substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R D is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl.
  • At least one instance of R D is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom.
  • at least one instance of R D is an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom.
  • two instances of R D attached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl).
  • two instances of R D attached to the same intervening atom are joined together with the intervening atom to form substituted or unsubstituted, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl).
  • R 19 is substituted or unsubstituted alkyl.
  • R 19 is substituted or unsubstituted, Ci-6 alkyl.
  • R 19 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of halogen.
  • R 19 is unsubstituted Ci-6 alkyl or Ci-6 alkyl substituted with at least one instance of fluoro or chloro.
  • R 19 is unsubstituted C1-4 alkyl.
  • R 19 is Me.
  • R 19 is Et.
  • R 19 is zz-Pr or z-Pr.
  • R 19 is - CH2-(3 -mono-substituted phenyl). In certain embodiments, R 19 is -CH2-(2-mono-substituted phenyl). In certain embodiments, R 19 is -CH2-(di- substituted phenyl). In certain embodiments, R 19 is hydrogen.
  • Formula II is of Formula II-l : optionally wherein R 1 and R 2 are as shown in Table 25:
  • Formula II is of Formula II-2:
  • Formula II is of Formula II-4: optionally wherein R 1 and R 2 are as shown in Table 28: Table 28 In certain embodiments, Formula II is of any one of the formulae:
  • a provided compound (a compound provided herein or a compound of the present disclosure) is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof.
  • a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
  • a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a provided compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a provided compound (a compound provided herein or a compound of the present disclosure) is a compound of Formula II, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof.
  • a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
  • a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt thereof.
  • a provided compound is a compound of Formula II, or a pharmaceutically acceptable salt thereof.
  • the molecular weight of a compound of Formula I is lower than 400, between 400 and 500, between 500 and 600, between 600 and 800, between 800 and 1000, between 1000 and 1200, between 1200 and 1500, or between 1500 and 2000, inclusive, g/mol.
  • the molecular weight of a compound of Formula II is lower than 400, between 400 and 500, between 500 and 600, between 600 and 800, between 800 and 1000, between 1000 and 1200, between 1200 and 1500, or between 1500 and 2000, inclusive, g/mol.
  • compositions comprising a provided compound and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the provided compound. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is an amount effective for treating a disease in a subject in need thereof. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, an effective amount is an amount effective for preventing a disease in a subject. In certain embodiments, an effective amount is an amount effective for inhibiting the growth or reproduction of a microorganism or killing a microorganism in a subject in need thereof, biological sample, or tissue. In certain embodiments, an effective amount is an amount effective for inhibiting the growth or reproduction of a microorganism or killing a microorganism in a biological sample or tissue or on a surface.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • the subject is a genetically engineered animal.
  • the subject is a transgenic animal (e.g., transgenic mice, transgenic pigs).
  • the subject is a fish or reptile.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one- third of such a dosage.
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulos
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g, sodium edetate, di sodium edetate, trisodium edetate, calcium di sodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g, sodium edetate, di sodium edetate, trisodium edetate, calcium di sodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid monohydrate
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the oral pharmaceutical compositions can 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.
  • the conjugates are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the 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 pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates 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 ingredient.
  • 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 ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fdlers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as 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,
  • Solid pharmaceutical compositions of a similar type can 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 art of pharmacology. They may optionally comprise opacifying agents and can be of a pharmaceutical composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating pharmaceutical compositions which can be used include polymeric substances and waxes.
  • Solid pharmaceutical compositions of a similar type can be employed as fdlers in soft and hard-fdled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in a 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 ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may 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 comprise buffering agents. They may optionally comprise opacifying agents and can be of a pharmaceutical composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating agents which can be used include polymeric substances and waxes.
  • Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • Such pharmaceutical compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
  • direct administration e.g., direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • the provided compound or pharmaceutical composition is suitable for topical administration to the eye of a subject.
  • any two doses of the multiple doses include different or substantially the same amounts of a provided compound.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is one dose per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is two doses per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • a dose (e.g., a single dose, or any dose of multiple doses) includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a provided compound.
  • a dose includes independently between 1 mg and 3 mg, inclusive, of a provided compound.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • the pharmaceutical composition further comprises an additional pharmaceutical agent.
  • the additional pharmaceutical agent is different from the provided compound.
  • the additional pharmaceutical agent is an additional therapeutically active agent.
  • the additional pharmaceutical agent is an additional prophylactically active agent.
  • a provided compound or pharmaceutical composition can be administered in combination with one or more additional pharmaceutical agents.
  • the provided compounds or pharmaceutical compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, biological sample, or cell.
  • a pharmaceutical composition including a provided compound and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the provided compound and the additional pharmaceutical agent, but not both.
  • the provided compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g, combination therapies.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease or premalignant condition.
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with a provided compound or pharmaceutical composition in a single dose or administered separately in different doses.
  • the particular combination to employ in a regimen will take into account compatibility of the provided compound with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the additional pharmaceutical agents include, but are not limited to, cytotoxic chemotherapeutic agents, epigenetic modifiers, glucocorticoids, immunotherapeutic agents, antiproliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-microbial agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof
  • at least one additional pharmaceutical agent is a microbicidal agent.
  • at least one additional pharmaceutical agent is an anti-bacterial agent.
  • at least one additional pharmaceutical agent is an anti-viral agent.
  • At least one additional pharmaceutical agent is an anti-parasitic agent. In certain embodiments, at least one additional pharmaceutical agent is a parasitocidal agent. In certain embodiments, at least one additional pharmaceutical agent is a rapid malaria-parasite killing agent. In certain embodiments, at least one additional pharmaceutical agent is a parasitostatic agent. In certain embodiments, at least one additional pharmaceutical agent is an antiplasmodial agent.
  • the additional pharmaceutical agent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, or a DNA damage inducer.
  • the additional pharmaceutical agent is a binder or inhibitor of a kinase (e.g., tyrosine kinase).
  • the additional pharmaceutical agent is an antibody or a fragment thereof (e.g., monoclonal antibody).
  • the additional therapy is an immunotherapy (e.g., an immunotherapeutic monoclonal antibody).
  • the additional pharmaceutical agent is an immunosuppressor.
  • the additional pharmaceutical agent is an immunoactivator.
  • the additional pharmaceutical agent is an immune checkpoint inhibitor.
  • the additional pharmaceutical agent is a programmed cell death 1 protein (PD-1) inhibitor.
  • the additional pharmaceutical agent is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor.
  • the additional pharmaceutical agent is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor.
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • the additional pharmaceutical agent is a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor, lymphocyte activation gene-3 (LAG3) inhibitor, V-set domain-containing T-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, cluster of differentiation 276 (CD276 or B7-H3) inhibitor, B and T lymphocyte attenuator (BTLA) inhibitor, galectin-9 (GAL9) inhibitor, checkpoint kinase 1 (Chkl) inhibitor, adenosine A2A receptor (A2AR) inhibitor, indoleamine 2,3-dioxygenase (IDO) inhibitor, killer-cell immunoglobulin-like receptor (KIR) inhibitor, or V-domain Ig suppressor of T cell activation (VISTA) inhibitor.
  • TIM3 T-cell immunoglobulin domain and mucin domain 3
  • LAG3 lymphocyte activation gene-3
  • VTCN1 or B7-H4 inhibitor V-set domain-containing T-cell activation inhibitor 1
  • kits comprising a provided compound or pharmaceutical composition, and instructions for using the provided compound or pharmaceutical composition.
  • the kit comprises a first container, wherein the first container comprises the provided compound or pharmaceutical composition.
  • the kit further comprises a second container.
  • the second container includes an excipient (e.g., an excipient for dilution or suspension of the provided compound or pharmaceutical composition).
  • the second container includes an additional pharmaceutical agent.
  • the kit further comprises a third container.
  • the third container includes an additional pharmaceutical agent.
  • the provided compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form.
  • Formula I the methods comprising reacting under suitable conditions a mixture comprising: a compound of Formula LA: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula I-B: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula I-C: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and a base.
  • a compound of Formula LA or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof
  • a compound of Formula I-B or a salt,
  • the present disclosure provides methods of preparing the compounds of Formula II, the methods comprising reacting under suitable conditions a mixture comprising: a compound of Formula II-A: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula ILB: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; a compound of Formula ILC: or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and a base.
  • the base is an inorganic base. In certain embodiments, the base is an alkali metal hydroxide. In certain embodiments, the base is LiOH, NaOH, or KOH. In certain embodiments, the base is an alkali metal carbonate. In certain embodiments, the base is Li2COs, Na2CO3, or K2CO3. In certain embodiments, the base is Na2CO3. In certain embodiments, the base is an alkali metal bicarbonate. In certain embodiments, the base is LiHCCh, NaHCOs, or KHCO3. In certain embodiments, the base is ammonia, ammonium carbonate, or ammonium hydroxide.
  • the base is an organic base (e.g, mono-, di-, or tri-(unsubstituted C1-6 alkyl) amine, cyclic non-aromatic amine, or aromatic amine (e.g., pyridine)).
  • the pK a at about 25 °C and about 1 atm of the conjugate acid of the base is between 4 and 6, between 6 and 8, between 8 and 10, between 10 and 12, or between 12 and 14, inclusive.
  • the mixture further comprises a solvent.
  • the solvent is an organic solvent.
  • the solvent of is one single solvent.
  • the solvent is a mixture of two or more (e.g., three) solvents.
  • the solvent is an aprotic solvent.
  • the solvent is a chlorinated hydrocarbon solvent.
  • the solvent is dichloromethane, chloroform, or a mixture thereof.
  • the solvent is dichloromethane.
  • the solvent is chloroform.
  • the solvent is 1,2-di chloroethane.
  • the solvent is an ether solvent.
  • the solvent is a di(unsubstituted Ci-4 alkyl) ether.
  • the solvent is diethyl ether, methyl te/7-butyl ether, tetrahydrofuran, or 2- methyltetrahydrofuran.
  • the solvent is a ketone solvent.
  • the solvent is acetone, acetonitrile, dichloromethane, or ethyl acetate.
  • the solvent is an alkane solvent.
  • the solvent is pentane, hexane, or heptane, or a mixture thereof.
  • the boiling point of the solvent at about 1 atm is between 30 and 50, between 50 and 70, between 70 and 100, or between 100 and 130 °C, inclusive.
  • the reaction temperature is between 0 and 20, between 20 and 30, between 30 and 40, or between 40 and 50 °C, inclusive, and the reaction pressure is between 0.5 and 1.1 atm, inclusive. In certain embodiments, the reaction temperature is between 50 and 60, between 60 and 70, or between 70 and 80 °C, inclusive, and the reaction pressure is between 0.5 and 1.1 atm, inclusive. In certain embodiments, the reaction temperature is between 60 and 80 °C, between 80 and 100 °C, or between 100 and 120 °C, inclusive, and the reaction pressure is between 1. 1 and 5, between 5 and 10, or between 10 and 20 atm, inclusive. In certain embodiments, the reaction temperature is substantially constant over the reaction time. In certain embodiments, the reaction temperature is variable temperature over at least part of the reaction time.
  • the suitable conditions further comprise microwave irradiation. In certain embodiments, the suitable conditions does not comprise microwave irradiation.
  • the reaction time is between 1 and 3 hours, between 3 and 6 hours, between 6 and 12 hours, between 12 and 24 hours, between 1 and 3 days, between 3 and 7 days, or between 7 and 14 days, inclusive.
  • the method further comprises isolating the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the step of isolating comprises liquid-liquid phase separation, drying, filtration, concentration, chromatography, decolorization, or recrystallization, or a combination thereof.
  • the step of isolating comprises liquid-liquid phase separation, drying, filtration, concentration, decolorization, or recrystallization, or a combination thereof.
  • the liquid-liquid phase separation is a separation of an organic phase and an aqueous phase.
  • the drying is drying an organic phase over a solid drying agent (e.g., anhydrous Na2SO4, anhydrous MgSCU, anhydrous CaSCU, anhydrous CaCh, or activated molecular sieves).
  • a solid drying agent e.g., anhydrous Na2SO4, anhydrous MgSCU, anhydrous CaSCU, anhydrous CaCh, or activated molecular sieves.
  • the filtration is a filtration of a mixture of an organic phase and a solid drying agent to remove the solid drying agent and hydrates thereof.
  • the concentration is concentration of an organic phase to remove part or substantially all of the volatiles (e.g., organic solvents).
  • the concentration is performed under a pressure lower than 1 atm (e.g., between 0.001 and 0.01, between 0.01 and 0.1, or between 0.1 and 1 atm, inclusive).
  • the concentration is performed under a temperature of between 0 and 10, between 10 and 20, between 20 and 25, between 25 and 35, between 35 and 50, or between 50 and 80 °C, inclusive.
  • the chromatography is flash chromatography (e.g., normal-phase flash chromatography (e.g., over silica gel)).
  • the step of isolating does not comprise chromatography.
  • the chromatography is high-performance liquid chromatography.
  • the chromatography is chiral chromatography.
  • the decolorization comprises redissolving in an organic solvent, decolorization, and concentration.
  • the decolorization comprises contacting with a solid decolorization agent (e.g., activated charcoal).
  • a solid decolorization agent e.g., activated charcoal
  • the recrystallization is preferential recrystallization.
  • the recrystallization is a single- solvent recrystallization.
  • the recrystallization is a multi-solvent (e.g., bi-solvent or tri-solvent) recrystallization.
  • the recrystallization is a hot filtrationrecrystallization.
  • the step of isolating further comprises removing part or substantially all of the volatiles (e.g., organic solvents) by decreasing the pressure (e.g., to a pressure of lower than 1 atm (e.g., between 0.001 and 0.01, between 0.01 and 0.1, or between 0.1 and 1 atm, inclusive) and/or increasing the temperature (e.g., to a temperature between 25 and 35, between 35 and 50, or between 50 and 80 °C, inclusive).
  • the pressure e.g., to a pressure of lower than 1 atm (e.g., between 0.001 and 0.01, between 0.01 and 0.1, or between 0.1 and 1 atm, inclusive) and/or increasing the temperature (e.g., to a temperature between 25 and 35, between 35 and 50, or between 50 and 80 °C, inclusive).
  • the step of isolating comprises chiral separation.
  • the chiral separation comprises chiral chromatography, preferential recrystallization, or a combination thereof.
  • the enantiomeric excess or diastereomeric excess, respectively, of the compounds of Formula I or II, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, before or in the absence of chiral separation is between 2% and 10%, between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 60%, between 60% and 80%, or between 80% and 99%, inclusive.
  • the present disclosure also provides methods of using the provided compounds and pharmaceutical compositions.
  • the present disclosure provides methods of treating a disease in a subject in need thereof, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides compounds and pharmaceutical compositions for use in treating a disease in a subject in need thereof.
  • the present disclosure provides methods of preventing a disease in a subject, the methods comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the disease is a disease described herein. In certain embodiments, the disease is an infection. In certain embodiments, the disease is a parasitic infection, bacterial infection, biofilm infection, mycosis, prion diseases, sepsis, or viral infection. In certain embodiments, the disease is a parasitic infection. In certain embodiments, the disease is a protozoal infection, ascariasis, heartwater, helminthiasis, ichthyophoniasis, microsporidiosis, mite infestation, parasitemia, parasitic ectoparasitic infectious disease, taeniasis, trichinosis, or trichuriasis. In certain embodiments, the disease is a protozoal infection.
  • the present disclosure provides in vitro methods of inhibiting the growth or reproduction of a microorganism or killing a microorganism in a biological sample or tissue or on a surface, the method comprising contacting the biological sample, tissue, or surface with an effective amount of a provided compound or pharmaceutical composition.
  • Ring cleavage reactions with apovincamine 25 involved harsh conditions (100 °C via microwave for one hour, or in a sealed tube for days) and typically gave low yields with significant amounts of starting material following the end of the reaction (with up to 76% starting material recovered following reaction). For these reactions, di chloromethane was found to be superior to chloroform as a solvent. Despite low yields, all ring cleavage reactions with 25 and 28 produced a single diastereomeric product which we characterize as the inversion product based on the X-ray of derivative 27 (FIG. 3).
  • nucleophiles such as 2-iodobenzyl alcohol
  • smaller nucleophiles e.g., methanol
  • ring-cleaved carbamates with larger groups e.g., phenyl
  • ring-cleaved carbamates with smaller groups e.g., ethyl

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Abstract

La présente divulgation concerne des composés de formule (I) ou (II). Les composés selon l'invention peuvent être utiles en tant qu'agents antimicrobiens (par exemple, agents antiplasmodiques). La présente invention concerne également des compositions pharmaceutiques comprenant les composés selon l'invention ; des kits comprenant les composés fournis ou des compositions pharmaceutiques ; et des procédés d'utilisation des composés et des compositions pharmaceutiques selon l'invention (par exemple, pour le traitement ou la prévention d'une maladie).
PCT/US2025/011410 2024-01-12 2025-01-13 Agents antiplasmodiques alcaloïdes indoliques et leur préparation Pending WO2025151874A1 (fr)

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem 26 October 2006 (2006-10-26), ANONYMOUS: "7-Methyl-3-phenyl-7,17-diazatricyclo[8.7.0.011,16]heptadeca-1(10),11,13,15-tetraene ", XP093337311, Database accession no. C22H26N2 | CID 11674133 *
DATABASE PubChem 6 December 2019 (2019-12-06), ANONYMOUS: "11-Ethyl-9,9-dimethyl-15-nitro-19-azatetracyclo[10.7.0.03,8.013,18]nonadeca-1(12),3,5,7,13(18),14,16-heptaene ", XP093337241, Database accession no. | C22H24N2O2 | CID 141999003 *
MITAINE-OFFER ET AL.: "Antiplasmodial activity of Aspidosperma indole alkaloids", PHYTOMEDICINE, vol. 9, 2002, pages 142 - 145, XP004956833, DOI: 10.1078/0944-7113-00094 *

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