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WO2024238359A2 - Ciblage d'arn associés à des tauopathies avec de petites molécules - Google Patents

Ciblage d'arn associés à des tauopathies avec de petites molécules Download PDF

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WO2024238359A2
WO2024238359A2 PCT/US2024/028867 US2024028867W WO2024238359A2 WO 2024238359 A2 WO2024238359 A2 WO 2024238359A2 US 2024028867 W US2024028867 W US 2024028867W WO 2024238359 A2 WO2024238359 A2 WO 2024238359A2
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optionally substituted
compound
pharmaceutically acceptable
hydrate
solvate
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WO2024238359A3 (fr
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Matthew D. Disney
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University of Florida
University of Florida Research Foundation Inc
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University of Florida Research Foundation Inc
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/76—Dibenzothiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the mechanistic underpinnings of disease-relevant alternative pre-mRNA splicing events can provide insights into the development of targeted therapeutics.
  • the aberrant alternative splicing of the microtubule-associated protein tau (MAPT) gene which encodes the protein tau, causes the genetically defined disease, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). 5
  • the gene comprises 16 exons, including alternatively spliced exons 2, 3, and 10, yielding six isoforms containing eight constitutive exons that affect the number of microtubule binding repeat (MTBR) domains at the carboxy-terminal.
  • MTBR microtubule binding repeat
  • the present disclosure provides compounds of Formula (I): or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, wherein R 1 , R 2 , and L are as defined herein.
  • the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein.
  • the present disclosure provides methods of preparing a compound of Formula (I-a-v): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R 1 , L, and R A are as defined herein.
  • the present disclosure provides kits comprising a provided compound or pharmaceutical composition disclosed herein and instructions for its use. [0017] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect.
  • FIGs.1A-1E show rational design of 2, which modulates alternative splicing of exon 10 by binding to an SRE present in MAPT pre-mRNA.
  • FIG.1A shows a schematic of alternative splicing of exons 9, 10, and 11 of MAPT pre-mRNA.
  • U1 snRNP binds and unfolds the MAPT SRE at the exon 10 ⁇ intron 10 junction, leading to exon 10 inclusion.
  • DDPAC MAPT a mutation associated with FTDP-17, has +14 C to U mutation that destabilizes the hairpin, promoting U1 snRNP binding and hence exon 10 inclusion, producing higher levels of 4R tau and an imbalance of the 4R/3R ratio.
  • the binding of small molecules to the A-bulge site within SRE stabilizes the hairpin, increasing exon 10 skipping and production of 3R tau.
  • FIG.1B shows a structure of parent compound 1, which was previously identified. 15 Compound 2 was rationally designed to form a base triple with a GC pair that closes the A-bulge, 1’s binding site.
  • FIG.1C shows secondary structures of various MAPT SRE RNAs used in the present disclosure.
  • FIGs.5A-5B show a comparison of Risdiplam and small molecule 2 of the present disclosure.
  • FIG.5A shows FDA-approved small molecule Risdiplam modulates alternative splicing of the SMN2 pre-mRNA by targeting RNA-protein complex as a treatment for SMA.
  • FIG.5B shows small molecule 2 in the present disclosure modulates alternative splicing of tau pre-mRNA by directly targeting its RNA structural motif and closing base pair.
  • FIG.6 shows structures of S1, 1, and the eight 2-aminopyridine analogs that were screened in cell-based luciferase assay.
  • S1 and 1 were previously described and designed by an iterative process of file mining, in vitro and cellular assays, and structure-based design.
  • 18 M1 was not pursued for derivatization since M1 has a low calculated binding energy (-6.39 kcal/mol, Table 1) due to its weak interactions (solely hydrogen bonds) with the A-bulge binding pocket.
  • FIG.7 shows the interaction network of first five structures, those with the lowest free energies, extracted from the NMR ensemble of the RNA-S1 complex (PDB:6VA2 18 ).
  • FIGs.12A-12C show percent spliced in index (PSI) values of MAPT exon 10 are downregulated by compounds.
  • PSI10 PSI of MAPT exon 10
  • PSI10 of tau ASO but not scrambled ASO was also downregulated in all cell lines.
  • FIGs.17A-17D show 1D NMR spectral analysis of 2 and WT Tau Duplex.
  • FIG.17A shows the secondary structure of the tau RNA duplex construct used for NMR studies.
  • FIG.17B shows a 1D 1 H NMR spectrum of 2 (300 ⁇ M) at 298 K focusing on the aromatic region.
  • FIG.17C shows a WaterLOGSY NMR spectrum for 2 alone (300 ⁇ M), acquired in 95% H2O and 5% D2O at 298 K (top) and for 2 (300 ⁇ M) and the WT tau duplex (10 ⁇ M), affording a compound:RNA ratio 20:1, showing the same aromatic region (bottom).
  • FIG.17D shows a 1D 1 H NMR spectrum of exchangeable imino protons in the WT tau duplex (50 ⁇ M), acquired at 10 ⁇ C in the presence and absence of varying equivalents of 2.
  • the imino proton spectrum in the absence of 2 shows base pairing of the RNA duplex in black and allows the assignment of the bases within the RNA duplex.
  • FIG.19B shows representative Sanger sequencing results to identify the nucleotide cross-linked to 3, indicated with an arrow; that is, where reverse transcription is halted (left). Secondary structure of the SRE annotated with the 2 binding site, including the G that participates in a base triple interaction and the nucleotide where cross-linking occurs and the corresponding RT stop (right).
  • FIGs.20A-20B show topology of the binding pocket induced by 2 (FIG.20A) and 1 (FIG. 20B). The binding pocket provided by the flipped-out A-bulge adopts a rod-shaped topology induced by 2 (FIG.20A) and sphere-like induced by 1 (FIG.20B).
  • FIG.21C shows plots of PSI of MAPT exons in FIG.21B. * P ⁇ 0.05 and ** P ⁇ 0.01 as determined by two-tailed Student t-test.
  • FIGs.22A-22B show Drug Metabolism and Pharmacokinetics (DMPK) analysis of 2 in C57BL/6 mice and the effect of 2 on the weight of WT and htau mice upon treatment.
  • C1-6 alkyl encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.
  • aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • 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 (“C 1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1–12 alkyl (such as unsubstituted C 1–6 alkyl, e.g., ⁇ CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)).
  • unsubstituted C 1–12 alkyl such as unsubstituted C 1–6 alkyl, e.g.
  • the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, – CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)).
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • Perhaloalkyl is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 20 carbon atoms (“C1–20 haloalkyl”).
  • the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10 haloalkyl”).
  • the haloalkyl moiety has 1 to 9 carbon atoms (“C1–9 haloalkyl”).
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1–7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1–4 haloalkyl”).
  • the haloalkyl moiety has 1 to 3 carbon atoms (“C1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1–2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group.
  • haloalkyl groups include –CHF2, ⁇ CH2F, ⁇ CF3, ⁇ CH2CF3, ⁇ CF 2 CF 3 , ⁇ CF 2 CF 2 CF 3 , ⁇ CCl 3 , ⁇ CFCl 2 , ⁇ CF 2 Cl, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–20 alkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–11 alkyl”). In some embodiments, a heteroalkyl group is a saturated group
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–9 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–8 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1–7 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroC1–12 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–12 alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2–12 alkenyl”).
  • an alkenyl group has 2 to 11 carbon atoms (“C2–11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2–4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl
  • alkenyl 12/131 U1202.70119WO00 12438115.1 (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C 2-20 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-20 alkenyl.
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • heteroatom e.g., 1, 2, 3, or 4 heteroatoms
  • a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–20 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–12 alkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–11 alkenyl”).
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2–9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–8 alkenyl”).
  • a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2–5 alkenyl”).
  • a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2–4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2–3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2–6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”).
  • an alkynyl group has 2 carbon atoms (“C2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like.
  • alkynyl examples include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-20 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2– 20 alkynyl”).
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2– 10 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–8 alkynyl”).
  • a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2–6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2–5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2–3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2–6 alkynyl”).
  • each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC2–20 alkynyl.
  • the heteroalkynyl group is a substituted heteroC2–20 alkynyl.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”).
  • a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”).
  • a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”).
  • a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, 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 (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
  • Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3-10 carbocyclyl groups include the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • Exemplary C 3-8 carbocyclyl groups include the aforementioned C 3-10 carbocyclyl groups as well as cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or
  • 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 carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 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”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 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 (C5) and cyclohexyl (C5).
  • 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 (C8).
  • 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 an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.
  • the term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-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 (“3–14 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 polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • heterocyclyl polycyclic 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
  • each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3–14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3–14 membered heterocyclyl.
  • the heterocyclyl is optionally substituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • 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. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6- membered heterocyclyl groups containing 3 heteroatoms include triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8- membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-
  • 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 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 pi electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl).
  • an aryl group has 14 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 unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is an unsubstituted C6-14 aryl.
  • the aryl group is a substituted C6-14 aryl.
  • “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi 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 (“5-14 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic 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 polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be
  • the heteroaryl is optionally substituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • the heteroaryl is optionally substituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
  • a heteroaryl group is a 5-10 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 (“5-10 membered heteroaryl”).
  • a heteroaryl group is a 5-8 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 (“5-8 membered heteroaryl”).
  • 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 unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl.
  • Exemplary 6- membered heteroaryl groups containing 1 heteroatom include pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl,
  • heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
  • the term “unsaturated bond” refers to a double or triple bond.
  • the term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond. [0068] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being optionally substituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which is optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted means that at least one hydrogen present on a group 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 and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present invention 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
  • each instance of R cc is, independently, selected from hydrogen, C 1–20 alkyl, C 1–20 perhaloalkyl, C 1–20 alkenyl, C 1–20 alkynyl, heteroC 1–20 alkyl, heteroC 1–20 alkenyl, heteroC 1–20 alkynyl, C 3-10 carbocyclyl, 3- 14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R dd is, independently, selected from
  • each carbon atom substituent is 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 carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, ⁇ OR aa , ⁇ SR aa , ⁇ N(R bb )2, – CN, –SCN, or –NO 2 , wherein R aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C 1–10 alkyl, 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, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyr
  • the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen,
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • a carbon atom substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms.
  • halo or halogen refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • hydroxyl or “hydroxy” refers to the group ⁇ OH.
  • thiol refers to the group –SH.
  • amino refers to the group ⁇ NH2.
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from ⁇ N(R bb ) 3 and ⁇ N(R bb ) 3 + X ⁇ , wherein R bb and X ⁇ are as defined herein.
  • sulfonyl refers to a group selected from –SO 2 N(R bb ) 2 , –SO 2 R aa , and –SO 2 OR aa , wherein R aa and R bb are as defined herein.
  • acyl groups include aldehydes ( ⁇ CHO), carboxylic acids ( ⁇ CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
  • sil refers to the group –Si(R aa ) 3 , wherein R aa is as defined herein.
  • phosphino refers to the group –P(R cc ) 2 , wherein R cc is as defined herein.
  • Nitrogen atoms can be optionally substituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.
  • the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”).
  • 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.
  • U1202.70119WO00 12438115.1 together with the nitrogen atom to which the nitrogen protecting group is attached is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3- methyl-3-nitrobutan
  • each nitrogen protecting group is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate
  • each nitrogen protecting group is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms),
  • Ts p-toluenesulfonamide
  • each nitrogen protecting group is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzy
  • two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine.
  • at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group.
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
  • Oxygen 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.
  • each oxygen protecting group is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),
  • At least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
  • each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
  • the molecular weight of a substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, a substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors. [0105] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (e.g., including one formal negative charge).
  • An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ), NO 3 – , ClO 4 – , OH – , H 2 PO 4 – , HCO 3 ⁇ , HSO 4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate,
  • Exemplary counterions which may be multivalent include CO3 2 ⁇ , HPO 4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 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.
  • 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
  • carboranes e.g., tartrate, citrate, fumarate, maleate, mal
  • LG is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501–502).
  • Suitable leaving groups include, but are not limited to, halogen alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates.
  • the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • phosphineoxide e.g., formed during a Mitsunobu reaction
  • Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper
  • non-hydrogen group refers to any group that is defined for a particular variable that is not hydrogen.
  • salt refers to any and all salts and encompasses pharmaceutically acceptable salts.
  • salt refers to ionic compounds that result from the neutralization reaction of an acid and a base.
  • a salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this disclosure include those derived from inorganic and organic acids and bases.
  • acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, per
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C1–4 alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1–4 alkyl)4- salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H2O) and hexahydrates (R ⁇ 6 H2O)).
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition.
  • crystal refers to a crystalline structure comprising at least two different components (e.g., a compound and an acid), wherein each of the components is independently an
  • a co-crystal of a compound and an acid is different from a salt formed from a compound and the acid.
  • a compound is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound easily occurs at room temperature.
  • a compound is complexed with the acid in a way that proton transfer from the acid to a herein does not easily occur at room temperature.
  • co-crystal in certain embodiments, there is substantially no proton transfer from the acid to a compound. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound.
  • tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • Tautomerizations i.e., the reaction providing a tautomeric pair
  • exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • isotopically labeled compound refers to a derivative of a compound that only structurally differs from the compound in that at least one atom of the derivative includes at least one isotope enriched above (e.g., enriched 3-, 10-, 30-, 100-, 300-, 1,000-, 3,000- or 10,000-fold above) its natural abundance, whereas each atom of the compound includes isotopes at their natural abundances.
  • the isotope enriched above its natural abundance is 2 H.
  • the isotope enriched above its natural abundance is 13 C, 15 N, or 18 O.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are
  • 35/131 U1202.70119WO00 12438115.1 pharmaceutically active in vivo Such examples include choline ester derivatives and the like, N- alkylmorpholine esters and the like.
  • Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a optionally substituted amine, or acid anhydrides, or mixed anhydrides.
  • composition refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • a human i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non- human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • patient refers to a human subject in need of treatment of a disease.
  • tissue sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection) or samples of cells obtained by microdissection
  • samples of whole organisms such as samples of yeasts or bacteria
  • cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • administered refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutical composition thereof, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen).
  • Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • the term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease.
  • the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.
  • the subject is at risk of developing a disease or condition due to environmental factors (e.g., exposure to the sun).
  • an “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term “therapeutically effective amount” can
  • a therapeutically effective amount is an amount sufficient for treating a disease or disorder associated with an RNA target in a subject in need thereof.
  • a therapeutically effective amount is an amount sufficient for treating a disease or disorder associated with microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • MTT microtubule-associated protein Tau
  • a therapeutically effective amount is an amount effective for treating a disease or disorder associated with microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • MTT microtubule-associated protein Tau
  • a therapeutically effective amount is an amount effective for stabilizing microtubule-associated protein Tau (MAPT) pre-mRNA in a subject in need thereof or in a cell, tissue, or biological sample (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%).
  • MAPST microtubule-associated protein Tau
  • a therapeutically effective amount is an amount effective for decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%).
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a condition, or one or more signs and/or symptoms associated with the condition or prevent its recurrence.
  • the prophylactically effective amount is an amount that improves overall prophylaxis and/or enhances the prophylactic efficacy of another prophylactic agent.
  • a prophylactically effective amount is an amount effective for preventing a disease or disorder associated with an RNA target in a subject in need thereof.
  • a prophylactically effective amount is an amount effective for preventing a disease or disorder associated with microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • MTT microtubule-associated protein Tau
  • a prophylactically effective amount is an amount effective for reducing the risk of developing a disease or disorder associated with microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • a prophylactically effective amount is an amount effective for stabilizing microtubule-associated protein Tau (MAPT) pre-mRNA in a subject in need thereof or in a cell, tissue, or biological sample (e.g., by at least about
  • a prophylactically effective amount is an amount effective for decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%).
  • the term “gene” refers to a nucleic acid fragment that expresses a protein, including regulatory sequences preceding (5’ non-coding sequences) and following (3’ non-coding sequences) the coding sequence.
  • “Native gene” refers to a gene as found in nature with its own regulatory sequences.
  • “Chimeric gene” or “chimeric construct” refers to any gene or a construct, not a native gene, comprising regulatory and coding sequences that are not found together in nature. Accordingly, a chimeric gene or chimeric construct may comprise regulatory sequences and coding sequences that are derived from different sources, or regulatory sequences and coding sequences derived from the same source, but arranged in a manner different than that found in nature.
  • “Endogenous gene” refers to a native gene in its natural location in the genome of an organism.
  • a “foreign” gene refers to a gene not normally found in the host organism, but which is introduced into the host organism by gene transfer.
  • Foreign genes can comprise native genes inserted into a non-native organism, or chimeric genes.
  • a “transgene” is a gene that has been introduced into the genome by a transformation procedure.
  • the terms “polynucleotide”, “nucleotide sequence”, “nucleic acid”, “nucleic acid molecule”, “nucleic acid sequence”, and “oligonucleotide” refer to a series of nucleotide bases (also called “nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides.
  • the polynucleotides can be chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded.
  • the oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, its hybridization parameters, etc.
  • the antisense oligonuculeotide may comprise a modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5- carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluracil, dihydrouracil, beta- D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2- dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5- methylcytosine,
  • a nucleotide sequence typically carries genetic information, including the information used by cellular machinery to make proteins and enzymes. These terms include double- or single- stranded genomic and cDNA, RNA, any synthetic and genetically manipulated polynucleotide, and both sense and antisense polynucleotides. This includes single- and double-stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA-RNA hybrids, as well as “protein nucleic acids” (PNAs) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing carbohydrate or lipids.
  • PNAs protein nucleic acids
  • Exemplary DNAs include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA.
  • RNAs include single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and viral satellite RNA
  • Polynucleotides described herein may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as those that are commercially available from Biosearch, Applied Biosystems, etc.).
  • an automated DNA synthesizer such as those that are commercially available from Biosearch, Applied Biosystems, etc.
  • phosphorothioate oligonucleotides may be synthesized by the method of Stein et al., Nucl. Acids Res., 16, 3209, (1988)
  • methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., Proc. Natl. Acad. Sci. U.S.A.85, 7448-7451, (1988)).
  • antisense molecules can be injected directly into the tissue site, or modified antisense molecules, designed to target the desired cells (antisense linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface) can be administered systemically.
  • RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences may be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
  • antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines.
  • a preferred approach utilizes a recombinant DNA construct in which the antisense oligonucleotide is placed under the control of a strong promoter. The use of such a construct to transfect target cells in the patient will
  • a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of an antisense RNA.
  • a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA.
  • Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in mammalian cells.
  • Expression of the sequence encoding the antisense RNA can be by any promoter known in the art to act in mammalian, preferably human, cells. Such promoters can be inducible or constitutive. Any type of plasmid, cosmid, yeast artificial chromosome, or viral vector can be used to prepare the recombinant DNA construct that can be introduced directly into the tissue site.
  • the polynucleotides may be flanked by natural regulatory (expression control) sequences or may be associated with heterologous sequences, including promoters, internal ribosome entry sites (IRES) and other ribosome binding site sequences, enhancers, response elements, suppressors, signal sequences, polyadenylation sequences, introns, 5 ⁇ - and 3 ⁇ -non-coding regions, and the like.
  • the nucleic acids may also be modified by many means known in the art.
  • Non-limiting examples of such modifications include methylation, “caps”, substitution of one or more of the naturally occurring nucleotides with an analog, and internucleotide modifications, such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.).
  • uncharged linkages e.g., methyl phosphonates, phosphotriesters, phosphoroamidates, carbamates, etc.
  • charged linkages e.g., phosphorothioates, phosphorodithioates, etc.
  • Polynucleotides may contain one or more additional covalently linked moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, oxidative metals, etc.), and alkylators.
  • the polynucleotides may be derivatized by formation of a methyl or ethyl phosphotriester or an alkyl phosphoramidate linkage.
  • RNA transcript refers to the product resulting from RNA polymerase-catalyzed transcription of a DNA sequence.
  • RNA transcript refers to the product resulting from RNA polymerase-catalyzed transcription of a DNA sequence.
  • the primary transcript or it may be an RNA sequence derived from post- transcriptional processing of the primary transcript and is referred to as the mature RNA.
  • RNA essential RNA
  • cRNA refers to complementary RNA, transcribed from a recombinant cDNA template.
  • cDNA refers to DNA that is complementary to and derived from an mRNA template. The cDNA can be single-stranded or converted to double-stranded form using, for example, the Klenow fragment of DNA polymerase I.
  • a sequence “complementary” to a portion of an RNA refers to a sequence having sufficient complementarity to be able to hybridize with the RNA, forming a stable duplex; in the case of double- stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed.
  • the ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the longer the hybridizing nucleic acid, the more base mismatches with an RNA it may contain and still form a stable duplex (or triplex, as the case may be).
  • nucleic acid or “nucleic acid sequence”, “nucleic acid molecule”, “nucleic acid fragment” or “polynucleotide” may be used interchangeably with “gene”, “mRNA encoded by a gene” and “cDNA”.
  • mRNA or “mRNA molecule” refers to messenger RNA, or the RNA that serves as a template for protein synthesis in a cell. The sequence of a strand of mRNA is based on the sequence of a complementary strand of DNA comprising a sequence coding for the protein to be synthesized.
  • siRNA refers to small inhibitory RNA duplexes that induce the RNA interference (RNAi) pathway, where the siRNA interferes with the expression of specific genes with a complementary nucleotide sequence.
  • siRNA molecules can vary in length (e.g., between 18-30 or 20-25 basepairs, inclusive) and contain varying degrees of complementarity to their target mRNA in the antisense strand. Some siRNA have unpaired overhanging bases on the 5′ or 3′ end of the sense strand and/or the antisense strand.
  • siRNA includes duplexes of two separate strands, as well as single strands that can form hairpin structures comprising a duplex region.
  • microRNAs refers to small non-coding RNAs that are transcribed as primary transcripts that are processed first in the nucleus by a first nuclease to liberate the precursor miRNA, and then in the cytoplasm by a second nuclease to produce the mature miRNA.
  • microRNAs or “miRNA” refers to small non-coding RNAs that are transcribed as primary transcripts that are processed first in the nucleus by Drosha to liberate the precursor miRNA, and then in the cytoplasm by Dicer to produce the mature miRNA.
  • linker refers to a bond or a divalent chemical moiety that is bonded to (i.e., that connects) two separate monovalent chemical moieties (e.g., the moieties N and R 2 in Formula (I)).
  • linker refers to a bond or a divalent chemical moiety that is bonded to (i.e., that connects) two separate monovalent chemical moieties (e.g., the moieties N and R 2 in Formula (I)).
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: L is a linker; R 1 is hydrogen or optionally substituted alkyl; and R 2 is optionally substituted heteroaryl.
  • R 1 is hydrogen.
  • R 1 is optionally substituted alkyl.
  • R 1 is optionally substituted C1-12 alkyl.
  • R 1 is optionally substituted C1-6 alkyl.
  • R 1 is unsubstituted C1-6 alkyl. In certain embodiments, R 1 is substituted C1-6 alkyl. In certain embodiments, R 1 is optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2- butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl.
  • R 1 is substituted methyl, substituted ethyl, substituted n-propyl, substituted isopropyl, substituted n- butyl, substituted tert-butyl, substituted sec-butyl, substituted isobutyl, substituted n-pentyl, substituted 3-pentanyl, substituted amyl, substituted neopentyl, substituted 3-methyl-2-butanyl, substituted tert-amyl, or substituted n-hexyl.
  • R 1 is unsubstituted methyl, unsubstituted ethyl, unsubstituted n-propyl, unsubstituted isopropyl, unsubstituted n-butyl, unsubstituted tert-butyl, unsubstituted sec-butyl, unsubstituted isobutyl, unsubstituted n-pentyl, unsubstituted 3-pentanyl, unsubstituted amyl, unsubstituted neopentyl, unsubstituted 3-methyl-2- butanyl, unsubstituted tert-amyl, or unsubstituted n-hexyl.
  • R 1 is –CH 3 .
  • R 2 is optionally substituted heteroaryl. In certain embodiments, R 2 is optionally substituted 5–14 membered heteroaryl. In certain embodiments, R 2 is optionally substituted monocyclic heteroaryl. In certain embodiments, R 2 is optionally substituted 5- to 6-membered, monocyclic heteroaryl.
  • R 2 is optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted isothiazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, or optionally substituted tetrazolyl.
  • R 2 is optionally substituted pyridinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted tetrazinyl, optionally substituted oxepinyl, or optionally substituted thiepinyl.
  • R 2 is optionally substituted bicyclic heteroaryl (e.g. optionally substituted bicyclic, 9- or 10-membered heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur).
  • R 2 is optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzotriazolyl, optionally substituted benzothiophenyl, optionally substituted isobenzothiophenyl, optionally substituted benzofuranyl, optionally substituted benzoisofuranyl, optionally substituted benzimidazolyl, optionally substituted benzoxazolyl, optionally substituted benzisoxazolyl, optionally substituted benzoxadiazolyl, optionally substituted benzthiazolyl, optionally substituted benzisothiazolyl, optionally substituted benzthiadiazolyl, optionally substituted indolizinyl, optionally substituted purinyl.
  • R 2 is optionally substituted naphthyridinyl, optionally substituted pteridinyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted cinnolinyl, optionally substituted quinoxalinyl, optionally substituted phthalazinyl, or optionally substituted quinazolinyl.
  • R 2 is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted indolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted pyrrolyl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted benzimidazolyl, or optionally substituted indazolyl.
  • R 2 is heteroaryl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –OR A , –
  • R 2 is optionally substituted pyridyl.
  • R 2 is pyridyl substituted with one or more of halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –OR A , – [0148]
  • each of R 2A , R 2B , R 2C , and R 2D is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl
  • R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to
  • the compound of Formula (I-a-i) is of Formula (I-a-ii): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound of Formula (I-a-i) is of Formula (I-a-iii): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound of Formula (I-a-i) is of Formula (I-a-iv): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • R 2A is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN,
  • R 2B is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, [0155]
  • R 2C is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN,
  • R 2D is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, [0157] In certain embodiments, at least one of R 2A , R 2B , R 2C , and R 2D is hydrogen, –OR A , or –N(R A )2.
  • each of R 2A , R 2B , R 2C , and R 2D is independently hydrogen, –OR A , or –N(R A )2. In certain embodiments, at least one of R 2A , R 2B , R 2C , and R 2D is hydrogen. In certain embodiments, R 2A is hydrogen. In certain embodiments, R 2B is hydrogen. In certain embodiments, R 2C is hydrogen. In certain embodiments, R 2D is hydrogen. In certain embodiments, R 2B is hydrogen and R 2D is hydrogen.
  • R 2A is hydrogen, –OR A , or –N(R A )2, R 2B is hydrogen, R 2C is hydrogen, –OR A , or –N(R A )2, and R 2D is hydrogen.
  • R 2A is –OR A or –N(R A )2, R 2B is hydrogen, R 2C is –OR A or –N(R A ) 2 , and R 2D is hydrogen.
  • R 2A is –OR A
  • R 2B is hydrogen
  • R 2C is –OR A or –N(R A ) 2
  • R 2D is hydrogen.
  • R 2A is –OR A or –N(R A ) 2
  • R 2B is hydrogen
  • R 2C is –N(R A ) 2
  • R 2D is hydrogen
  • R 2A is – OR A
  • R 2B is hydrogen
  • R 2C is –N(R A ) 2
  • R 2D is hydrogen.
  • at least one of R 2A , R 2B , R 2C , and R 2D is –OR A .
  • R 2A is –OR A .
  • R 2B is –OR A .
  • R 2C is – OR A .
  • R 2D is –OR A .
  • R 2A is –OR A
  • R 2B is hydrogen, — OR A , or –N(R A ) 2
  • R 2C is hydrogen, –OR A , or –N(R A ) 2
  • R 2D is hydrogen, –OR A , or –N(R A ) 2 .
  • R 2A is –OR A
  • R 2B is hydrogen, R 2C is hydrogen, –OR A , or –N(R A ) 2
  • R 2D is hydrogen, –OR A , or –N(R A ) 2 .
  • R 2A is –OR A
  • R 2B is hydrogen, –OR A , or –
  • R 2C is –OR A or –N(R A ) 2
  • R 2D is hydrogen, –OR A , or –N(R A ) 2
  • R 2A is –OR A
  • R 2B is hydrogen, –OR A , or –N(R A ) 2
  • R 2C is –N(R A ) 2
  • R 2D is hydrogen, –OR A , or – N(R A ) 2 .
  • R 2A is –OR A
  • R 2B is hydrogen, –OR A , or –N(R A ) 2
  • R 2C is hydrogen, – OR A , or –N(R A ) 2
  • R 2D is hydrogen.
  • R 2A is –OR A
  • R 2B is hydrogen
  • R 2C is hydrogen, –OR A , or –N(R A )2
  • R 2D is hydrogen.
  • R 2A is –OR A
  • R 2B is hydrogen
  • R 2C is –OR A or –N(R A ) 2
  • R 2D is hydrogen.
  • R 2A , R 2B , R 2C , and R 2D is –N(R A ) 2 .
  • R 2A is –N(R A )2.
  • R 2B is –N(R A )2.
  • R 2C is –N(R A )2.
  • R 2D is –N(R A )2.
  • R 2A is hydrogen, –OR A , or –N(R A )2, R 2B is hydrogen, —OR A , or –N(R A )2, R 2C is –N(R A )2, and R 2D is hydrogen, –OR A , or –N(R A )2.
  • R 2A is –OR A or –N(R A )2, R 2B is hydrogen, –OR A , or –N(R A )2, R 2C is –N(R A )2, and R 2D is hydrogen, –OR A , or –N(R A )2.
  • R 2A is –OR A
  • R 2B is hydrogen, – OR A , or –N(R A )2
  • R 2C is –N(R A )2
  • R 2D is hydrogen, –OR A , or –N(R A )2.
  • R 2A is hydrogen, –OR A , or –N(R A )2
  • R 2B is hydrogen
  • R 2C is –N(R A )2
  • R 2D is hydrogen, –OR A , or – N(R A )2.
  • R 2A is hydrogen, –OR A , or –N(R A )2, R 2B is hydrogen, —OR A , or – N(R A )2, R 2C is –N(R A )2, and R 2D is hydrogen.
  • R 2A is hydrogen, –OR A , or – N(R A )2, R 2B is hydrogen, R 2C is –N(R A )2, and R 2D is hydrogen.
  • R 2A is –OR A or –N(R A )2, R 2B is hydrogen, R 2C is –N(R A )2, and R 2D is hydrogen.
  • R 2A is –OR A , and R A is hydrogen or optionally substituted alkyl. In certain embodiments, R 2A is –OR A , and R A is hydrogen. In certain embodiments, R 2A is –OH. In certain embodiments, R 2A is –OR A , and R A is optionally substituted alkyl. In certain embodiments, R 2A is –O(optionally substituted alkyl). In certain embodiments, R 2A is –O(optionally substituted C1-12 alkyl). In certain embodiments, R 2A is –O(optionally substituted C1-6 alkyl). In certain embodiments, R 2A is –O(unsubstituted C1-6 alkyl).
  • R 2A is –O(substituted C1-6 alkyl). In certain embodiments, R 2A is –O(optionally substituted methyl), –O(optionally substituted ethyl), – O(optionally substituted n-propyl), –O(optionally substituted isopropyl), –O(optionally substituted n- butyl), –O(optionally substituted tert-butyl), –O(optionally substituted sec-butyl), –O(optionally substituted isobutyl), –O(optionally substituted n-pentyl), –O(optionally substituted 3-pentanyl), – O(optionally substituted amyl), –O(optionally substituted neopentyl), –O(optionally substituted 3- methyl-2-butanyl), –O(optionally substituted tert-amyl), or –O(optionally substituted n-hexyl).
  • R 2A is –O(substituted methyl), –O(substituted ethyl), –O(substituted n-propyl), –O(substituted isopropyl), –O(substituted n-butyl), –O(substituted tert-butyl), –O(substituted sec- butyl), –O(substituted isobutyl), –O(substituted n-pentyl), –O(substituted 3-pentanyl), –O(substituted amyl), –O(substituted neopentyl), –O(substituted 3-methyl-2-butanyl), –O(substituted tert-amyl), or – O(substituted n-hexyl).
  • R 2A is –O(unsubstituted methyl), –O(unsubstituted ethyl), –O(unsubstituted n-propyl), –O(unsubstituted isopropyl), –O(unsubstituted n-butyl), – O(unsubstituted tert-butyl), –O(unsubstituted sec-butyl), –O(unsubstituted isobutyl), –O(unsubstituted
  • R 2A is –O(optionally substituted methyl), –O(optionally substituted ethyl), – O(optionally substituted n-propyl), –O(optionally substituted n-butyl), –O(optionally substituted n- pentyl), or –O(optionally substituted n-hexyl).
  • R 2A is –O(substituted methyl), –O(substituted ethyl), –O(substituted n-propyl), –O(substituted n-butyl), –O(substituted n-pentyl), or –O(substituted n-hexyl).
  • R 2A is –O(unsubstituted methyl), –O(unsubstituted ethyl), –O(unsubstituted n-propyl), –O(unsubstituted n-butyl), –O(unsubstituted n-pentyl), or – O(unsubstituted n-hexyl).
  • R 2A is –O(optionally substituted methyl).
  • R 2A is –O(substituted methyl).
  • R 2A is –O(unsubstituted methyl).
  • R 2A is –OCH3.
  • R 2C is –N(R A )2, and each occurrence of R A is independently hydrogen or optionally substituted alkyl. In certain embodiments, R 2C is –N(R A )2, and each occurrence of R A is independently hydrogen. In certain embodiments, R 2C is –NH2. In certain embodiments, R 2C is –NHR A , and R A is optionally substituted alkyl. In certain embodiments, R 2C is –NH(optionally substituted alkyl). In certain embodiments, R 2C is –NH(optionally substituted C1-12 alkyl). In certain embodiments, R 2C is –NH(optionally substituted C1-6 alkyl).
  • R 2C is — NH(unsubstituted C1-6 alkyl). In certain embodiments, R 2C is —NH(substituted C1-6 alkyl). In certain embodiments, R 2C is —NH(optionally substituted methyl), –NH(optionally substituted ethyl), – NH(optionally substituted n-propyl), –NH(optionally substituted isopropyl), –NH(optionally substituted n-butyl), –NH(optionally substituted tert-butyl), –NH(optionally substituted sec-butyl), – NH(optionally substituted isobutyl), –NH(optionally substituted n-pentyl), –NH(optionally substituted 3-pentanyl), –NH(optionally substituted amyl), –NH(optionally substituted neopentyl), – NH(optionally substituted 3-methyl-2-butanyl), –NH(optionally substituted methyl
  • R 2C is —NH(substituted methyl), – NH(substituted ethyl), –NH(substituted n-propyl), –NH(substituted isopropyl), –NH(substituted n- butyl), –NH(substituted tert-butyl), –NH(substituted sec-butyl), –NH(substituted isobutyl), – NH(substituted n-pentyl), –NH(substituted 3-pentanyl), –NH(substituted amyl), –NH(substituted neopentyl), –NH(substituted 3-methyl-2-butanyl), –NH(substituted tert-amyl), or —NH(substituted n- hexyl).
  • R 2C is —NH(unsubstituted methyl), –NH(unsubstituted ethyl), – NH(unsubstituted n-propyl), –NH(unsubstituted isopropyl), –NH(unsubstituted n-butyl), – NH(unsubstituted tert-butyl), –NH(unsubstituted sec-butyl), –NH(unsubstituted isobutyl), – NH(unsubstituted n-pentyl), –NH(unsubstituted 3-pentanyl), –NH(unsubstituted amyl), – NH(unsubstituted neopentyl), –NH(unsubstituted 3-methyl-2-butanyl), –NH(unsubstituted tert-amyl), or —NH(unsubstituted
  • R 2C is —NH(optionally substituted methyl), – NH(optionally substituted ethyl), –NH(optionally substituted n-propyl), –NH(optionally substituted n- butyl), –NH(optionally substituted n-pentyl), or –NH(optionally substituted n-hexyl).
  • R 2C is —NH(substituted methyl), –NH(substituted ethyl), –NH(substituted n-propyl), – NH(substituted n-butyl), –NH(substituted n-pentyl), or –NH(substituted n-hexyl).
  • R 2C is —NH(unsubstituted methyl), –NH(unsubstituted ethyl), –NH(unsubstituted n- propyl), –NH(unsubstituted n-butyl), –NH(unsubstituted n-pentyl), or –NH(unsubstituted n-hexyl).
  • R 2C is —NH(optionally substituted methyl).
  • R 2C is – NH(substituted methyl).
  • R 2C is –NH(unsubstituted methyl).
  • R 2C is –NHCH 3 .
  • R 2A is –O(optionally substituted alkyl), and R 2C is —NH2. In certain embodiments, R 2A is –O(optionally substituted alkyl), and R 2C is —NH(optionally substituted alkyl). In certain embodiments, R 2A is –O(optionally substituted alkyl), and R 2C is —NH(optionally substituted C1-6 alkyl). In certain embodiments, R 2A is –O(optionally substituted alkyl), and R 2C is –NH(optionally substituted methyl). In certain embodiments, R 2A is –O(optionally substituted alkyl), and R 2C is – NHCH3.
  • R 2A is – O(optionally substituted alkyl), and R 2C is —NH2 or – NHCH3. In certain embodiments, R 2A is –O(optionally substituted C1-6 alkyl), and R 2C is –NH2. In certain embodiments, R 2A is –O(optionally substituted C1-6 alkyl), and R 2C is —NH(optionally substituted alkyl). In certain embodiments, R 2A is –O(optionally substituted C1-6 alkyl), and R 2C is – NH(optionally substituted C1-6 alkyl). In certain embodiments, R 2A is –O(optionally substituted C1-6 alkyl), and R 2C is –NH(optionally substituted methyl).
  • R 2A is –O(optionally substituted C1-6 alkyl), and R 2C is —NHCH3.
  • R 2A is – O(optionally substituted C1-6 alkyl), and R 2C is –NH2 or –NHCH3.
  • R 2A is –O(optionally substituted methyl), and R 2C is –NH2.
  • R 2A is –O(optionally substituted methyl), and R 2C is –NH(optionally substituted alkyl).
  • R 2A is –O(optionally substituted methyl), and R 2C is —NH(optionally substituted C1-6 alkyl).
  • R 2A is – O(optionally substituted methyl), and R 2C is —NH(optionally substituted methyl). In certain embodiments, R 2A is –O(optionally substituted methyl), and R 2C is —NHCH3. In certain embodiments, R 2A is – O(optionally substituted methyl), and R 2C is –NH2 or –NHCH3. In certain embodiments, R 2A is –OCH3, and R 2C is –NH2. In certain embodiments, R 2A is –OCH3, and R 2C is –NH(optionally substituted alkyl). In certain embodiments, R 2A is –OCH 3 , and R 2C is —NH(optionally substituted C 1-6 alkyl).
  • R 2A is –OCH 3
  • R 2C is —NH(optionally substituted methyl).
  • R 2A is –OCH 3
  • R 2C is —NHCH 3
  • R 2A is –OCH 3
  • R 2C is —NH 2 or –NHCH 3
  • R 2A is –O(optionally substituted alkyl)
  • R 2B is hydrogen
  • R 2C is —NH 2
  • R 2D is hydrogen.
  • R 2A is –O(optionally substituted alkyl)
  • R 2B is hydrogen
  • R 2C is –NH(optionally substituted alkyl)
  • R 2D is hydrogen.
  • R 2A is –O(optionally substituted alkyl)
  • R 2B is hydrogen
  • R 2C is —NH(optionally substituted C 1-6 alkyl)
  • R 2D is hydrogen.
  • R 2A is –O(optionally substituted alkyl)
  • R 2B is hydrogen
  • R 2C is —NH(optionally substituted methyl)
  • R 2D is hydrogen.
  • R 2A is –
  • R 2B is hydrogen, R 2C is –NHCH 3 , and R 2D is hydrogen.
  • R 2A is – O(optionally substituted alkyl)
  • R 2B is hydrogen, R 2C is –NH 2 or –NHCH 3
  • R 2D is hydrogen.
  • R 2A is –O(optionally substituted C 1-6 alkyl)
  • R 2B is hydrogen, R 2C is –NH 2
  • R 2D is hydrogen.
  • R 2A is –O(optionally substituted C1-6 alkyl), R 2B is hydrogen, R 2C is —NH(optionally substituted alkyl), and R 2D is hydrogen.
  • R 2A is –O(optionally substituted C 1-6 alkyl)
  • R 2B is hydrogen
  • R 2C is —NH(optionally substituted C 1-6 alkyl)
  • R 2D is hydrogen.
  • R 2A is –O(optionally substituted C1-6 alkyl)
  • R 2B is hydrogen
  • R 2C is –NH(optionally substituted methyl
  • R 2D is hydrogen.
  • R 2A is –O(optionally substituted C1-6 alkyl), R 2B is hydrogen, R 2C is —NHCH3, and R 2D is hydrogen. In certain embodiments, R 2A is – O(optionally substituted C1-6 alkyl), R 2B is hydrogen, R 2C is –NH2 or –NHCH3, and R 2D is hydrogen. In certain embodiments, R 2A is – O(optionally substituted methyl), R 2B is hydrogen, R 2C is –NH2, and R 2D is hydrogen. In certain embodiments, R 2A is –O(optionally substituted methyl), R 2B is hydrogen, R 2C is –NH(optionally substituted alkyl), and R 2D is hydrogen.
  • R 2A is –O(optionally substituted methyl), R 2B is hydrogen, R 2C is —NH(optionally substituted C1-6 alkyl), and R 2D is hydrogen.
  • R 2A is –O(optionally substituted methyl)
  • R 2B is hydrogen
  • R 2C is —NH(optionally substituted methyl)
  • R 2D is hydrogen.
  • R 2A is –O(optionally substituted methyl)
  • R 2B is hydrogen
  • R 2C is –NHCH3, and R 2D is hydrogen.
  • R 2A is – O(optionally substituted methyl)
  • R 2B is hydrogen, R 2C is –NH2 or –NHCH3, and R 2D is hydrogen.
  • R 2A is –OCH3, R 2B is hydrogen, R 2C is –NH2, and R 2D is hydrogen.
  • R 2A is –OCH3, R 2B is hydrogen, R 2C is —NH(optionally substituted alkyl), and R 2D is hydrogen.
  • R 2A is –OCH3, R 2B is hydrogen, R 2C is —NH(optionally substituted C1-6 alkyl), and R 2D is hydrogen.
  • R 2A is –OCH3, R 2B is hydrogen, R 2C is –NH(optionally substituted methyl), and R 2D is hydrogen.
  • R 2A is – OCH3, R 2B is hydrogen, R 2C is —NHCH3, and R 2D is hydrogen.
  • R 2A is –OCH3, R 2B is hydrogen, R 2C is –NH2 or –NHCH3, and R 2D is hydrogen.
  • the compound of Formula (I-a-i) is of Formula (I-a-v): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound of Formula (I-a-i) is of Formula (I-a-vi):
  • the compound of Formula (I-a-i) is of Formula (I-a-vii): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • L is a linker.
  • L is a bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted heterocyclylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or a combination thereof.
  • L is a bond.
  • L is optionally substituted alkylene.
  • L is optionally substituted alkenylene.
  • L is optionally substituted alkynylene.
  • L is optionally substituted heteroalkylene.
  • L is optionally substituted heteroalkenylene. In certain embodiments, L is optionally substituted heteroalkynylene. In certain embodiments, L is optionally substituted heterocyclylene. In certain embodiments, L is optionally substituted carbocyclylene. In certain embodiments, L is optionally substituted arylene. In certain embodiments, L is optionally substituted heteroarylene. [0168] In certain embodiments, L is optionally substituted alkylene. In certain embodiments, L is optionally substituted C1-12 alkylene. In certain embodiments, L is optionally substituted C1-6 alkylene. In certain embodiments, L is unsubstituted C1-6 alkylene. In certain embodiments, L is substituted C1-6 alkylene.
  • L is optionally substituted methylene, optionally substituted ethylene, optionally substituted n-propylene, optionally substituted isopropylene, optionally substituted n-butylene, optionally substituted tert-butylene, optionally substituted sec-butylene, optionally substituted isobutylene, optionally substituted n-pentylene, optionally substituted 3- pentanylene, optionally substituted amylene, optionally substituted neopentylene, optionally substituted 3-methylene-2-butanylene, optionally substituted tert-amylene, or optionally substituted n- hexylene.
  • L is substituted methylene, substituted ethylene, substituted n-
  • L is unsubstituted methylene, unsubstituted ethylene, unsubstituted n-propylene, unsubstituted isopropylene, unsubstituted n-butylene, unsubstituted tert- butylene, unsubstituted sec-butylene, unsubstituted isobutylene, unsubstituted n-pentylene, unsubstituted 3-pentanylene, unsubstituted amylene, unsubstituted neopentylene, unsubstituted 3- methylene-2-butanylene, unsubstituted tert-amylene, or unsubstituted n-hexylene.
  • L is optionally substituted methylene, optionally substituted ethylene, optionally substituted n-propylene, optionally substituted n-butylene, optionally substituted n-pentylene, or optionally substituted n-hexylene. In certain embodiments, L is substituted methylene, substituted ethylene, substituted n-propylene, substituted n-butylene, substituted n-pentylene, or substituted n- hexylene.
  • L is unsubstituted methylene, unsubstituted ethylene, unsubstituted n-propylene, unsubstituted n-butylene, unsubstituted n-pentylene, or unsubstituted n-hexylene.
  • L is optionally substituted n-propylene.
  • L is substituted n-propylene.
  • L is unsubstituted n-propylene.
  • L is , wherein n is 1, 2, 3, 4, or 5.
  • L is .
  • L is .
  • L is .
  • L is .
  • L is . In certain embodiments, L is . [0170] in certain embodiments, the compound of Formula (I) is of Formula (I-b-i): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: each of R 2A , R 2B , R 2C , and R 2D is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, –CN, –OR A , –SCN, –SR A , –SSR A , –N3, –NO,
  • each occurrence of R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of R A are joined together with their intervening atom or atoms to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; and n is 1, 2, 3, 4, or 5.
  • n is 1, 2, 3, 4, or 5. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. [0172] In certain embodiments, the compound of Formula (I-b-i) is of Formula (I-b-ii): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound of Formula (I-b-i) is of Formula (I-b-iii): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound of Formula (I-b-i) is of Formula (I-b-iv): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound of Formula (I-b-i) is of Formula (I-b-v): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound of Formula (I-b-i) is of Formula (I-b-vi): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound of Formula (I-b-i) is of Formula (I-b-vii): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • the compound of Formula (I-b-i) is of Formula (I-b-viii):
  • each occurrence of R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of R A are joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
  • At least one occurrence of R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two occurrences of R A are joined together with their intervening atom to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
  • At least one occurrence of R A is hydrogen. In certain embodiments, at least one occurrence of R A is optionally substituted acyl. In certain embodiments, at least one occurrence of R A is optionally substituted C 1-12 alkyl. In certain embodiments, at least one occurrence of R A is optionally substituted C 1-6 alkyl. In certain embodiments, at least one occurrence of R A is unsubstituted C 1-6 alkyl. In certain embodiments, at least one occurrence of R A is substituted C 1-6 alkyl.
  • At least one occurrence of R A is optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted isopropyl, optionally substituted n-butyl, optionally substituted tert-butyl, optionally substituted sec-butyl, optionally substituted isobutyl, optionally substituted n-pentyl, optionally substituted 3-pentanyl, optionally substituted amyl, optionally substituted neopentyl, optionally substituted 3-methyl-2- butanyl, optionally substituted tert-amyl, or optionally substituted n-hexyl.
  • at least one occurrence of R A is optionally substituted C 2-12 alkenyl.
  • at least one occurrence of R A is optionally substituted C 2-6 alkenyl.
  • R A is optionally substituted ethenyl, optionally substituted 1–propenyl, optionally substituted 2–propenyl, optionally substituted 1–butenyl, optionally substituted 2–butenyl, optionally substituted butadienyl, optionally substituted pentenyl, optionally substituted pentadienyl, or optionally substituted hexenyl.
  • at least one occurrence of R A is optionally substituted C2-12 alkynyl.
  • at least one occurrence of R A is optionally substituted C 2-6 alkynyl.
  • At least one occurrence of R A is optionally substituted ethynyl, optionally substituted 1–propynyl, optionally substituted 2–propynyl, optionally substituted 1–butynyl, optionally substituted 2–butynyl, optionally substituted pentynyl, or optionally substituted hexynyl.
  • at least one occurrence of R A is optionally substituted heteroC1–12 alkyl.
  • at least one occurrence of R A is optionally substituted heteroC1–6 alkyl.
  • at least one occurrence of R A is optionally substituted heteroC1–12 alkenyl.
  • At least one occurrence of R A is optionally substituted heteroC1–6 alkenyl. In certain embodiments, at least one occurrence of R A is optionally substituted heteroC1–12 alkynyl. In certain embodiments, at least one occurrence of R A is optionally substituted heteroC1–6 alkynyl. In certain embodiments, at least one occurrence of R A is optionally substituted C3– 14 cycloalkyl. In certain embodiments, at least one occurrence of R A is optionally substituted 5–10 membered heterocyclyl. In certain embodiments, at least one occurrence of R A is optionally substituted 6–14 membered aryl.
  • At least one occurrence of R A is optionally substituted 5–14 membered heteroaryl.
  • at least one occurrence of R A is a nitrogen protecting group when attached to a nitrogen atom.
  • at least one occurrence of R A is an oxygen protecting group when attached to an oxygen atom.
  • at least one occurrence of R A is a sulfur protecting group when attached to a sulfur atom.
  • at least two occurrences of R A are joined together with their intervening atom to form an optionally substituted 5–10 membered heterocyclic ring.
  • at least two occurrences of R A are joined together with their intervening atom to form an optionally substituted 5–14 membered heteroaryl ring.
  • the present disclosure provides a compound of formula: or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound (a compound described herein, a compound of the present disclosure) is a compound of any of the formulae herein (e.g., Formula (I)) or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
  • a provided compound is a compound of any of the formulae herein (e.g., Formula (I)), or a pharmaceutically acceptable salt or tautomer thereof.
  • a provided compound is a compound of any of the formulae herein (e.g., Formula (I)), or a pharmaceutically acceptable salt thereof.
  • a provided compound is a compound of any of the formulae herein (e.g., Formula (I)), or a salt thereof.
  • the present disclosure provides pharmaceutical compositions comprising a provided compound.
  • the pharmaceutical composition comprises one or more excipients.
  • the pharmaceutical compositions described herein comprise a provided compound and an excipient.
  • the pharmaceutical composition comprises an effective amount of the provided compound.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the effective amount is an amount effective for stabilizing an RNA target in a subject in need thereof or in a cell, tissue, or biological sample.
  • the RNA target is microtubule-associated protein Tau (MAPT) pre-mRNA.
  • the effective amount is an amount effective for decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform in a subject in need thereof or in a cell, tissue, or biological sample.
  • the effective amount is an amount effective for treating a disease or disorder associated with microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • a disease or disorder associated with microtubule-associated protein Tau (MAPT) pre-mRNA e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease
  • the effective amount is an amount effective for preventing a disease or disorder associated with MAPT pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • the effective amount is an amount effective for reducing the risk of developing a disease or disorder associated with MAPT pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • the subject is an animal.
  • the subject is a human. In certain embodiments, the subject is a human aged 18 years or older. In certain embodiments, the subject is a human aged 12-18 years, exclusive. In certain embodiments, the subject is a human aged 2-12 years, inclusive. In certain embodiments, the subject is a human younger than 2 years. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.
  • the effective amount is an amount effective for decreasing an amount of microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least 95%, at least 98%, at least 99%, or at least about 100%).
  • the effective amount is an amount effective for decreasing an amount of MAPT pre-mRNA by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.
  • the pharmaceutical composition is for use in treating a disease or disorder associated with microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • a disease or disorder associated with MAPT pre- mRNA e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease
  • FTDP-17 frontotemporal dementia and parkinsonism linked to chromosome 17
  • the pharmaceutical composition is for use in stabilizing an RNA target in a subject in need thereof or in a cell, tissue, or biological sample. In certain embodiments, the pharmaceutical composition is for use in decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform in a subject in need thereof or in a cell, tissue, or biological sample.
  • a provided compound or pharmaceutical composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active 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 or disorder associated with microtubule- associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof, in preventing a disease or disorder associated with MAPT pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof, and/or in reducing the risk of developing a disease or disorder associated with MAPT pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17),
  • a pharmaceutical composition described herein including a provided compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the provided compounds and the additional pharmaceutical agent, but
  • the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.
  • the provided compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound or pharmaceutical composition and may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • CFR Code of Federal Regulations
  • proteins proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides, synthetic proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • CFR Code of Federal Regulations
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease or disorder associated with microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)).
  • MTT microtubule-associated protein Tau
  • FTDP-17 frontotemporal dementia and parkinsonism linked to chromosome 17
  • 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 the compound or pharmaceutical composition described herein 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 compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • 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, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol- lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti–pyretics, hormones, and prostaglandins.
  • the provided compound or pharmaceutical composition is a solid.
  • the provided compound or pharmaceutical composition is a powder.
  • the provided compound or pharmaceutical composition can be dissolved in a liquid to
  • the provided compound or pharmaceutical composition is dissolved in water to make an aqueous solution.
  • the pharmaceutical composition is a liquid for parental injection.
  • the pharmaceutical composition is a liquid for oral administration (e.g., ingestion).
  • the pharmaceutical composition is a liquid (e.g., aqueous solution) for intravenous injection.
  • the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection.
  • compositions comprising a provided compound (i.e., the “active ingredient”) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • a provided compound i.e., the “active ingredient”
  • Pharmaceutical 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.
  • Relative amounts of the provided compound, pharmaceutically acceptable excipient, agent, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the pharmaceutical composition is to be administered.
  • the pharmaceutical composition may comprise between 0.1% and 100% (w/w) agent, inclusive.
  • compositions used in manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
  • Excipients and accessory ingredients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents, may also be present in the pharmaceutical composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose
  • 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, cell
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol,
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include alpha tocopherol, ascorbic acid, ascorbyl 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, disodium edetate, trisodium edetate, calcium disodium 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, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ® Plus, Phenonip ® , methylparaben, Germall ® 115, Germaben ® II, Neolone ® , Kathon ® , and Euxyl ® .
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange
  • 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 liquid dosage forms may comprise 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 (e.g., cottonseed, groundnut, corn, 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 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 described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • injectable preparations for example, 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 for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein 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) fillers 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 monostearate, (h) absorbents such as kaolin and bentonite clay, and (a) fillers or
  • the dosage form may include a buffering agent.
  • Solid 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 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 compositions which can be used include polymeric substances and waxes.
  • 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. In such solid dosage forms the active ingredient can be
  • the 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 composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • Suitable devices for use in delivering injectable pharmaceutical compositions described herein include short needle devices. Injectable pharmaceutical compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of administration. Jet injection devices which deliver liquid formulations via a liquid jet injector and/or via a needle. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form are suitable.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • 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
  • 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. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder pharmaceutical compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the pharmaceutical composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically- administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the provided compounds and pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarticular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intraarticular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/
  • contemplated routes are intraarticular administration, 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.
  • intraarticular administration e.g., oral administration
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., systemic intravenous injection
  • direct administration e.g., systemic intravenous injection
  • an affected site e.g., systemic intravenous injection
  • the most appropriate route of administration will depend
  • any two doses of the multiple doses include different or substantially the same amounts of an agent described herein.
  • a pharmaceutical composition comprising a provided compound is administered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration).
  • the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
  • the desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • the pharmaceutical composition described herein is administered at a dose that is below the dose at which the agent causes non- specific effects. [0235] In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical composition is administered at a dose of about 0.01 mg to
  • the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.
  • Dose ranges as described herein provide guidance for the administration of provided compounds or pharmaceutical compositions to an adult. 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. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell may be, in non-limiting examples, 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, or even slow dose controlled delivery over a selected period of time using a drug delivery device.
  • 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, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • kits e.g., pharmaceutical packs.
  • the kit comprises a provided compound or pharmaceutical composition described herein, and instructions for using the compound or pharmaceutical composition.
  • the kit comprises a first container, wherein the first container includes the 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 compound or pharmaceutical composition).
  • the second container includes an additional pharmaceutical agent.
  • the kit further comprises a third container. In certain embodiments, 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.
  • the provided compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are
  • each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler.
  • the instructions are for administering the provided compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease described herein).
  • the instructions are for contacting a biological sample or cell with the provided compound or pharmaceutical composition.
  • the instructions comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA).
  • kits and instructions provide for treating a disease or disorder associated with microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • a disease or disorder associated with MAPT pre-mRNA e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)
  • FTDP-17 frontotemporal dementia and parkinsonism linked to chromosome 17
  • kits and instructions provide for reducing the risk of developing a disease or disorder associated with MAPT pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)) in a subject in need thereof.
  • a disease or disorder associated with MAPT pre-mRNA e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)
  • the kits and instructions provide for stabilizing an RNA target in a subject in need thereof or in a cell, tissue, or biological sample.
  • the kits and instructions provide for decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform in a subject in need thereof or in a cell, tissue, or biological sample.
  • kits described herein may include one or more additional pharmaceutical agents described herein as a separate pharmaceutical composition.
  • Another object of the present disclosure is the use of a compound as described herein in the manufacture of a medicament for use in the treatment of a disorder or disease described herein.
  • Another object of the present disclosure is the use of a compound as described herein for use in the treatment of a disorder or disease described herein.
  • Methods of Treatment and Prevention [0243] In another aspect, the present disclosure provides methods of treating or preventing a disease in a subject in need thereof, comprising administering to the subject in need thereof a provided compound or pharmaceutical composition.
  • the present disclosure provides methods of treating a disease in a subject in need thereof, comprising administering to the subject in need thereof a provided compound or pharmaceutical composition. In certain embodiments, the present disclosure provides methods of preventing a disease in a subject in need thereof, comprising
  • the disease is associated with microtubule-associated protein Tau (MAPT) pre- mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)).
  • MTT microtubule-associated protein Tau
  • FTDP-17 frontotemporal dementia and parkinsonism linked to chromosome 17
  • the present disclosure provides a provided compound or pharmaceutical composition for use in treating or preventing a disease in a subject in need thereof.
  • the present disclosure provides a provided compound or pharmaceutical composition for use in treating a disease in a subject in need thereof.
  • the present disclosure provides a provided compound or pharmaceutical composition for use in preventing a disease in a subject in need thereof.
  • the disease is associated with microtubule-associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)).
  • MTT microtubule-associated protein Tau
  • FTDP-17 frontotemporal dementia and parkinsonism linked to chromosome 17
  • the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for treatment or prevention of a disease in a subject in need thereof.
  • the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for treatment of a disease in a subject in need thereof.
  • the present disclosure provides a provided compound or pharmaceutical composition for use in the manufacture of a medicament for prevention of a disease in a subject in need thereof.
  • the disease is associated with microtubule- associated protein Tau (MAPT) pre-mRNA (e.g., a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease)).
  • FTDP-17 frontotemporal dementia and parkinsonism linked to chromosome 17
  • AD microtubule-associated protein Tau
  • the disease is a neurodegenerative disease (e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Alzheimer’s disease).
  • the neurodegenerative disease is frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
  • the neurodegenerative disease is Alzheimer’s disease.
  • the method comprises mitigating pathologies relative to Tauopathy.
  • the method comprises correcting aberrant behavior phenotypes associated with the disease.
  • the present disclosure provides methods of stabilizing an RNA target in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or composition.
  • the present disclosure provides methods of stabilizing an RNA target in a subject in need thereof, comprising administering to the
  • the present disclosure provides methods of stabilizing an RNA target in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or composition.
  • the present disclosure provides a provided compound or composition for use in stabilizing an RNA target in a subject in need thereof or in a cell, tissue, or biological sample.
  • the present disclosure provides a provided compound or composition for use in the manufacture of a medicament for stabilizing an RNA target in a subject in need thereof or in a cell, tissue, or biological sample.
  • the RNA target is microtubule-associated protein Tau (MAPT) pre- mRNA.
  • MPT microtubule-associated protein Tau
  • stabilizing the RNA target comprises intercalating to an A bulge site of the MAPT pre-MRNA.
  • stabilizing the RNA target comprises forming a base triple with a GC pair of the MAPT pre-MRNA.
  • stabilizing the RNA target comprises inducing exon 10 skipping.
  • the present disclosure provides methods of decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform in a subject in need thereof or in a cell, tissue, or biological sample, comprising administering to the subject in need thereof or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or composition.
  • the present disclosure provides methods of decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a provided compound or composition.
  • the present disclosure provides methods of decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform in a cell, tissue, or biological sample, comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or composition.
  • the present disclosure provides a provided compound or composition for use in decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform in a subject in need thereof or in a cell, tissue, or biological sample.
  • the present disclosure provides a provided compound or composition for use in the manufacture of a medicament for decreasing a ratio of an amount of a first mRNA isoform to an amount of a second mRNA isoform in a subject in need thereof or in a cell, tissue, or biological sample.
  • the method comprises decreasing the amount of the first mRNA isoform (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%).
  • the first mRNA isoform is four-repeat Tau mRNA (4R-Tau mRNA).
  • the second mRNA isoform is three-repeat Tau mRNA (3R-Tau mRNA).
  • the method comprises decreasing a ratio of an amount of a first protein isoform to an amount of a second protein isoform. In certain embodiments, the method comprises decreasing the amount of the first protein isoform (e.g., by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 100%). In certain embodiments, the first protein isoform is four-repeat Tau (4R-Tau).
  • the second protein isoform is three-repeat Tau (3R-Tau).
  • the cell, tissue, or biological sample is in vivo. In certain embodiments, the cell, tissue, or biological sample is in vitro.
  • the present disclosure provides methods of preparing a compound of Formula (I-a-v): or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, comprising reacting a compound of Formula (II): or a salt thereof, with a compound of Formula (III): or a salt thereof, wherein: R 1 is hydrogen or optionally substituted alkyl; L is linker; and each occurrence of R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally
  • the compound of Formula (II) is of Formula (II-a): or salt thereof.
  • the compound of Formula (II) is of Formula (II-b): or salt thereof.
  • the compound of Formula (III) is of Formula (III-a): or a salt thereof, wherein R A is a nitrogen protecting group.
  • the method further comprises deprotecting the nitrogen protecting group.
  • the nitrogen protecting group is Boc (tert-butyloxycarbonyl).
  • the eight conjugates (five for S1 and three for 1) were screened in a cellular MAPT exon 10 splicing mini-gene reporter assay.
  • the mini-gene comprises MAPT exons 9 – 11 with truncated introns and expresses firefly luciferase in-frame with
  • RT-qPCR was employed to measure the amount of each isoform using primers specific for 3R and 4R MAPT.
  • a previously reported Vivo-Morpholino ASO (Gene Tools; uses an arginine-rich peptide to facilitate uptake) complementary to the SRE RNA that directs splicing to the 3R isoform was named as tau ASO and served as a positive control.
  • 10 A scrambled ASO served as a negative control. Both 1 (10 ⁇ M) and 2 (1.5 ⁇ M) reduced the ratio 4R/3R in HeLa cells transfected with WT or DDPAC mini-genes.
  • PSI10 PSI of MAPT exon 10
  • PSI of MAPT exon 10 was downregulated by for 1 and for 2 compared to vehicle in LAN5 cells as well as HeLa cells transfected by WT and DDPAC mini-gene but not WT I17T or DDPAC I17T mutant (FIGs.12A-12C).
  • affinities of 1 and 2 for the WT and DDPAC MAPT SRE were measured by monitoring the change in the inherent fluorescence of the small molecules as a function of RNA concentration.
  • the ellipticine core of 2 displaced the A-bulge from the co-axial helical axis and stacked on G7 (one of the A-bulge’s closing base pairs) and the closing base pair formed by C5-G17A-bulge. Although 1 stacked on C5-G17 base pair, it did not form stacking interactions with G7.
  • the H5/H6 proton of 2 lies in the A-bulge, consistent with its observed NOE with G17H1′.
  • the 2-aminopyridine group in 2 forms two hydrogen bonds with the backbone and a hydrogen bond with C14. These additional interactions stabilize the 2-RNA complex more than the 1-RNA complex.
  • RNA-seq experiment demonstrates 2’s selectivity across the transcriptome.
  • sagittal brain sections were assessed for tau phosphorylation by immunohistochemistry (IHC) using AT8 antibody which detects S202/T205 phosphorylation events.
  • IHC immunohistochemistry
  • 34 Treatment of 2 reduced antibody immunoreactivity throughout the cortex, indicative of decreased pathological tau burden with a lower 4R/3R ratio (FIG.4B).
  • NeuN a neuron-specific protein, was used as a marker to quantify neuron viability, which was enhanced in 2-treated mice (FIG.4B).
  • One of behavioral deficits observed in htau mice is impaired nesting behavior, 35-36 which can be quantified based on published criteria (FIG.4C). 37 From Day 1 to Day 20, mice were individually housed and nesting material from the previous day was removed.
  • the nestlet score is 2; a score of 3 is assigned when 50-90% of the nestlet is torn but spread around the cage and no identifiable nest site is found (Medium; FIG.4C). When more than 90% of the nestlet is torn and the nest is identifiable but flat, the nestlet score is 4. When a near perfect nest is built and the wall is higher than the mouse’s body, it is assigned a nestlet score of 5 (Good; FIG.4C). [0287] WT mice showed no significant difference in nesting behavior without or with 2-treatment after 20 days, and the average nest score was consistent over time, ranging from 4.0 – 4.4 and 3.7 – 4.3, respectively.
  • SMN2 pre- mRNA splicing outcome could be directed to include exon 7, then SMN2 could substitute functionally for the loss of SMN1 and hence as a treatment for SMA.
  • the first approved modalities were oligonucleotide-based medicines such as nusinersen (Spinraza) that affect SMN pre-mRNA splicing by targeting an intronic splicing silencer downstream of the 5′ splice site of exon 7. 41-42 Small molecules were discovered from phenotypic screening and later optimized, including risdiplam (FIG.5A).
  • RNA-binding pockets have a complex mode of action that includes the stabilization of an RNA-macromolecular complex including protein.
  • 2 has a simpler mode of action where it binds the MAPT SRE and thermally stabilizes its structure to impede U1 snRNA binding as designed (FIG.5B).
  • the design principles outlined in the present disclosure emphasize the importance of shape complementarity of the binding pocket beyond the scope of the topological properties as an approach to increase the favorable interactions and hence potency of a small molecule.
  • T-shaped small molecules grown vertically, can have sub-micromolar binding affinity.
  • T-shaped geomorphic compound design principles could be a general strategy to generate small molecules targeting RNA with favorable physicochemical properties, bio-distribution, and oral bioavailability as exemplified in the present disclosure.
  • the shape distribution of compounds in DrugBank has a high enrichment of the rod-like molecules with thinner distribution for disk-like or sphere-like molecules (FIG.24). Very few T- shaped molecules are observed, which is a restraint imposed by the binding pocket topology of proteins which prevents longitudinal growth. This suggests that a T-shape topology could be a general strategy for targeting RNAs specifically over proteins.
  • Targeting RNAs using a base-triple-formation strategy is an area of ongoing investigation in the peptide-nucleic acid space. 21, 48-51 Emerging datasets described here could provide additional modules that could be appended to small molecule RNA binders as a means to increase in affinity and specificity.
  • Cieply, B.; Carstens, R. P. Functional roles of alternative splicing factors in human disease. Wiley Interdiscip Rev RNA 2015, 6 (3), 311-26. 5. Ingram, E. M.; Spillantini, M. G., Tau gene mutations: dissecting the pathogenesis of FTDP- 17. Trends Mol Med 2002, 8 (12), 555-62. 6. Goedert, M.; Spillantini, M. G.; Jakes, R.; Rutherford, D.; Crowther, R. A., Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease.
  • a Vivo-Morpholino antisense oligonucleotide (ASO) targeting the MAPT exon-10-intron junction hairpin (4R-to-3R tau ASO: 5’- TGAAGGTACTCACACTGCCGC-3’(SEQ ID NO: 1)) and a scrambled ASO (5’- CTGTCTGACGTTCTTTGT-3’(SEQ ID NO: 2)) were purchased from Gene Tools, LLC. The stock
  • RNA oligonucleotide concentrations were determined by their absorbance at 260 nm at 90 °C using a Beckman Coulter DU800 UV/vis spectrophotometer and the corresponding extinction coefficient provided by the manufacturer.
  • RNA oligonucleotides were combined in 400 ⁇ L of NMR Buffer [10 mM KH2PO4/K2HPO4, pH 6.0 and 0.5 mM EDTA] in H2O or 100% D2O with a final RNA duplex concentration of 15 ⁇ M for WaterLOGSY experiments, 100 ⁇ M for 1D 1 400 ⁇ M for 2D 1 D2O was added to 5% (v/v) to provide a lock signal.
  • RNA samples were annealed by heating to 95 °C for 3 min, followed by slow cooling to room temperature before being added to Shigemi NMR tubes (Shigemi, Inc.).
  • NMR Spectroscopy NMR Spectroscopy. NMR spectra were acquired on Bruker Avance III 600 and 700 MHz spectrometers equipped with cryoprobes. WaterLOGSY spectra were acquired at 298 K, 1D NMR spectra of samples in 95% H2O/5% D2O were acquired at 283 K, and 2D NOESY spectra in 100% D2O were acquired at 308 K. For 1D spectra of samples in 95% H2O/5% D2O, an excitation sculpting sequence during acquisition suppressed the water signal.
  • mice were orally administered vehicle (5/5/90 DMSO/Tween-80/H 2 O) or 100 mg/kg of 2 in the same formulation every other day (q.o.d.).
  • nesting activity was assessed, as describe in Nesting Activity below.
  • the mice were euthanized (in accordance with guidelines provided by the American Veterinarian Medical Association), and the brain was harvested for analysis. One hemisphere of the brain was frozen at -80 °C for RT-qPCR analyses while the other was used for histological studies.
  • Nesting Activity From Day 1 to Day 20, mice were individually housed and nesting material from the previous day was removed. An intact 3.0 g nestlet was placed within each cage.
  • nesting is scored on a rating scale of 1–5 where if the nestlet is over 90% intact, it is given a nestlet score is 1 (Poor; FIG.4C). When the nestlet is partially torn but >50% remains, the nestlet score is 2; a score of 3 is assigned when 50-90% of the nestlet is torn but spread around the cage and no identifiable nest site is found (Medium; FIG.4C). When more than 90% of the nestlet is torn and the nest is identifiable but flat, the nestlet score is 4.
  • FIG.4C Brain Tissue Histology. Left brain hemispheres of htau mice were harvested for total RNA. Right brain hemispheres (unfrozen) of htau mice were stored in 10% neutral buffered formalin (VWR) for 48 h. Tissue processing, embedding, and sectioning were performed and generated by the Scripps Florida Histology Core. Briefly, tissue was embedded in paraffin using a Sakura Tissue-Tek VIP5 paraffin processor, sectioned at 4 ⁇ m, and then mounted on positively charged slides for further immunostaining.
  • This intermediate was added into 3,3- diethoxypropan-1-amine (20 mL), and the mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. To this mixture, H 2 O (20 mL) was added, and the mixture was filtered to give 3-(3,3-diethoxypropyl)-3,5-dihydro-4H-pyrimido[5,4- b]indol-4-one (A3) (6.00 g, 89% (2 steps)). The material was used in the next reaction without further purification.
  • A4 3-(3,3-diethoxypropyl)-5-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (A4): To a solution of A3 (6.00 g, 19.0 mmol) in DMF (60.0 mL), NaH (1142 mg, 28.5 mmol) was added at 0 °C and the mixture was stirred at 0 °C for 10 min. MeI (3.53 mL, 38.1 mmol) was then added at 0 °C.
  • reaction mixture was stirred at 0 °C for 25 min, then H2O (100 mL) was added, and the mixture was extracted with MeOH/DCM (1/9, 3 x 100 mL) and concentrated in vacuo.
  • the reaction mixture was purified by column chromatography (Agela Technologies, Silica, 20 g, 10% - 30% ethylacetate in hexane) to afford 3-(3,3-diethoxypropyl)-5-methyl-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (A4) (4.98 g, 79 %).
  • tert-butyl (5-iodo-4-methoxypyridin-2-yl)carbamate (A7) To a solution of 4- methoxypyridin-2-amine (A5) (25.0 g, 201 mmol) in DMF (400 mL), NIS (54.4 g, 225 mmol) was added at 0 °C. The mixture was stirred at room temperature overnight. The reaction was then concentrated in vacuo. Then, DCM/ saturated NaHCO3 (v/v, 400 mL) was added, and the resultant solids were separated by filtration. The resultant DCM/ saturated NaHCO3 mixture was extracted with DCM (400 mL ⁇ 3) and concentrated in vacuo.
  • tert-butyl (4-methoxy-5-(3-(methylamino)propyl)pyridin-2-yl)carbamate (A9) A mixture of A7 (3.00 g, 8.57 mmol), PdCl 2 (103 mg, 0.343 mmol), PPh 3 (180 mg, 0.685 mmol), CuI (131 mg, 0.685 mmol), NEt 3 (8.44 mL, 60.6 mmol) and N-methylprop-2-yn-1-amine (1.78 g, 25.7 mmol) in DMF (45 mL) was stirred at 50 °C for 1 h. After cooling to room temperature, saturated NaHCO3 (100
  • the crude material was purified by reverse-phase column chromatography (C18 column, 120 g, 2% - 100% MeOH + 0.1%TFA/H2O + 0.1%TFA, 80 ml/min). The fractions were collected and neutralized with saturated NaHCO3 and extracted with DCM (3 ⁇ 50 mL). The resultant organic layer was dried over MgSO4 and concentrated in vacuo. The material was then purified by column chromatography (Biotage SNAP cartridge, KP-NH, 28g, 100% ethyl acetate, 5 CV, 80 ml/min then
  • tert-butyl (4-methoxy-5-(3-(amino)propyl)pyridin-2-yl)carbamate (A12): A mixture of Ar-iodide A7 (1.50 g, 4.28 mmol), PdCl2 (40.0 mg, 0.214 mmol, 5 mol %), PPh3 (112 mg, 0.428 mmol, 10 mol %), CuI (81.6 mg, 0.428 mmol, 10 mol %), and propargylamine (823 mL, 12.9 mmol, 3 equiv.) in THF/DMF/Et3N (10:3:3, 16 mL) was stirred at 50 °C for 2 h.
  • tert-butyl (5-(3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)propyl)-4-methoxypyridin- 2-yl)carbamate) (A15): Dess-Martin periodinane (325 mg, 0.768 mmol) was added to a solution of A13 (70.0 mg, 0.427 mmol) in DCM (5 mL), and the mixture was stirred for 1 h. The reaction mixture was quenched by 10% aqueous Na 2 S 2 O 3 (3 mL) and saturated NaHCO 3 solution (3 mL).
  • the organic layer was extracted by DCM (10 mL ⁇ 2), dried over Na 2 SO 4 , and concentrated in vacuo.
  • the crude aldehyde A14 was used without further purification.
  • AcOH (30.5 mL, 0.533 mmol, 1.5 equiv.) was added to a mixture of crude A14 and amine A12 (100 mg, 0.355 mmol) in MeOH, and the mixture was stirred for 30 min.
  • NaBH 3 CN (67.0 mg, 1.07 mmol, 3 equiv.) was added, the reaction mixture was stirred for 2 d.
  • sat. aqueous NaHCO 3 was added, and the organic layer was extracted with DCM, dried over Na 2 SO 4 , and concentrated in vacuo.
  • tert-butyl (5-(3-((2-((tert-butoxycarbonyl)amino)ethyl)(3-(5-methyl-4-oxo-4,5-dihydro- 3H-pyrimido[5,4-b]indol-3-yl)propyl)amino)propyl)-4-methoxypyridin-2-yl)carbamate (A16): AcOH (1 uL, 17 mmol, 0.1 equiv.) was added to a mixture of the crude aldehyde A10 and amine A15 (85.4 mg, 0.201 mmol), and the mixture was stirred at room temperature for 30 min.
  • Diazirine carboxylic acid (6.6 mg, 43 ⁇ mol) was pre-activated with HATU (18.6 mg, 49 ⁇ mol) and DIEA (15.7 mL, 98 ⁇ mol) in DMF (450 ⁇ L).
  • HATU 18.6 mg, 49 ⁇ mol
  • DIEA 15.7 mL, 98 ⁇ mol
  • DMF 450 ⁇ L
  • To a solution of the crude amine and DIEA (6.5 mL, 41 ⁇ mol) in DMF (150 ⁇ L) the pre-activated solution (150 ⁇ L) was added, and the mixture was stirred for 4 h. An additional portion of pre-activated solution (50 ⁇ L) was added to the mixture, and the mixture was stirred overnight.

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Abstract

La présente divulgation propose des composés représentés par les formules (par exemple, la formule (I)), et des sels, des solvates, des hydrates, des polymorphes, des cocristaux, des tautomères, des stéréoisomères, des composés marqués isotopiquement et promédicaments pharmaceutiquement acceptables de ceux-ci, qui stabilisent une cible d'ARN. La présente divulgation propose également des compositions pharmaceutiques et des kits comprenant les composés, ou des sels, des solvates, des hydrates, des polymorphes, des cocristaux, des tautomères, des stéréoisomères, des composés marqués isotopiquement ou des promédicaments pharmaceutiquement acceptables de ceux-ci, ainsi que des procédés de traitement ou de prévention de maladies par l'administration à un sujet en ayant besoin des composés, ou des sels, des solvates, des hydrates, des polymorphes, des cocristaux, des tautomères, des stéréoisomères, des composés marqués isotopiquement ou promédicaments pharmaceutiquement acceptables de ceux-ci, ou des compositions pharmaceutiques de ceux-ci.
PCT/US2024/028867 2023-05-12 2024-05-10 Ciblage d'arn associés à des tauopathies avec de petites molécules Pending WO2024238359A2 (fr)

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