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WO2025165908A1 - Bifunctional tead degraders - Google Patents

Bifunctional tead degraders

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Publication number
WO2025165908A1
WO2025165908A1 PCT/US2025/013644 US2025013644W WO2025165908A1 WO 2025165908 A1 WO2025165908 A1 WO 2025165908A1 US 2025013644 W US2025013644 W US 2025013644W WO 2025165908 A1 WO2025165908 A1 WO 2025165908A1
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Prior art keywords
optionally substituted
compound
alkyl
cancer
pharmaceutically acceptable
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PCT/US2025/013644
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French (fr)
Inventor
Hui Chen
Jyoti R. MISRA
Guangrong Zheng
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University of Florida
University of Texas System
University of Florida Research Foundation Inc
University of Texas at Austin
Original Assignee
University of Florida
University of Texas System
University of Florida Research Foundation Inc
University of Texas at Austin
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Publication of WO2025165908A1 publication Critical patent/WO2025165908A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Definitions

  • the Hippo signaling pathway plays a critical role in cell proliferation, survival, differentiation, and tissue homeostasis.
  • the pathway consists of a core kinase cascade that negatively regulates the paralogous oncogenic transcriptional coactivators, Yes Associated Protein (YAP) and Transcriptional Activator with PDZ-binding motif (TAZ).
  • YAP Yes Associated Protein
  • TEZ Transcriptional Activator with PDZ-binding motif
  • the kinase cascade consists of the serine threonine kinases MST1/2 and Large Tumor Suppressor 1/2 (LATS1/2), and their obligate adapters SAV and MOB1A/B respectively, where MST1/2 phosphorylates and activates LATS1/2, which in turn phosphorylates YAP/TAZ.
  • TEAD1-4 mediate the regulation of majority of the YAP-target genes, which encode various cytokines and matricellular proteins that promote cell proliferation and inhibit apoptosis.
  • the compounds of the present disclosure can recruit ubiquitin E3 ligase (e.g., VHL, CRBN, and lAPs) to the vicinity of TEAD proteins, triggering their polyubiquitination and subsequent proteasomal degradation.
  • ubiquitin E3 ligase e.g., VHL, CRBN, and lAPs
  • the compounds of the present disclosure may be useful in treating diseases and conditions associated with TEAD activation.
  • the present disclosure provides compounds of Formula (I): or pharmaceutically acceptable salts thereof, wherein E 1 , L 2 , and Y are as defined herein.
  • the present disclosure provides compounds of Formula (IV): or pharmaceutically acceptable salts thereof, wherein L 1 , L 2 , and Y are as defined herein.
  • the present disclosure provides compounds of Formula (V): or pharmaceutically acceptable salts thereof, wherein L 1 , L 2 , L 3 , L 4 , and X are as defined herein.
  • the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein.
  • the pharmaceutical composition comprises an excipient.
  • the present disclosure provides methods of degrading a TEAD protein in a subject or in a cell, tissue, or biological sample, the methods comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides methods of treating or preventing a disease in a subject in need thereof, the methods comprising administering to the subject in need thereof a therapeutically effective amount of a provided compound or pharmaceutical composition.
  • kits comprising a provided compound or pharmaceutical composition disclosed herein and instructions for its use.
  • kits comprising a provided compound or pharmaceutical composition disclosed herein and instructions for its use.
  • FIG. 1 shows anti-proliferation effects of representative TEAD degraders in NCI-H226 cells.
  • FIG. 2 shows that representative TEAD degraders destabilize multiple TEAD paralogues in NCI-H226 cells.
  • FIGs. 3A-3F show that HC242, HC278, and HC286 selectively degrade TEAD1 and TEAD3.
  • FIG. 3A shows a schematic of the pTRE-panTEAD plasmid showing TEAD 1-4 with FLAG, MYC, HA, and V5 tags interspersed with T2A, P2A, and E2A coding sequences to produce epitopetagged TEAD paralogs from a single transcript produced from the CMV promoter.
  • FIG. 3B shows Western blotting showing isolation of a stable cell clone that expresses FLAG-TEAD1, MYC- TEAD2, V5-TEAD3, and HA-TEAD4.
  • FIG. 3A shows a schematic of the pTRE-panTEAD plasmid showing TEAD 1-4 with FLAG, MYC, HA, and V5 tags interspersed with T2A, P2A, and E2A coding sequences to produce epitopetagged TEAD paralogs from a single transcript produced from the
  • FIGs. 3C shows chemical structures of HC242, HC278, and HC286.
  • FIGs. 3D-3F show representative Western blots (top) and histograms (bottom) showing dose-dependent degradation of TEAD by HC242, HC278, and HC286.
  • FIGs. 4A-4F show TEAD degrading PROTACs function in proteasome and CRBN-dependent manner.
  • FIGs. 4A-4C show representative Western Blots (top) and histograms (bottom) showing inhibition of HC242-induced TEAD degradation by MG132 and the warhead WH15 (FIG. 4A) or Ex. 29 (FIGs. 4B-4C).
  • FIG. 4D shows chemical structures of the negative controls HC278-Negl and HC278-Neg2.
  • FIGs. 4E-4F show HEK293 stable cells expressing epitope-tagged TEAD 1-4 were treated with indicated doses of HC278-Negl (FIG. 4E) or HC278-Neg2 (FIG. 4F) for 18 h and the level of TEAD1-4 was detected by Western blotting using antibodies against the corresponding epitope-tags. Actin was used as a control for loading and transfer.
  • FIGs. 5A-5C show HC278 induces ternary complex formation between TEAD1/3 and CRBN/DDB 1.
  • FIG. 5A shows a schematic illustration of the ternary complex formation assay using AlphaLISA assay.
  • FIGs. 6A-6F show proteomic and RNA-seq profiling of HC278 -mediated degradation.
  • FIG. 6A shows a scatterplot depicting the log2 (Fold Change) of relative protein abundance in NCI- H226 cells treated with HC278 (500 nM, 24 h) compared to those treated with DMSO in TMT proteomic profiling.
  • FIG. 6B shows a scatterplot depicting the log2 (Fold Change) of relative protein abundance in NCI-H226 cells treated with HC278 (500 nM, 24 h) compared to those treated with DMSO in RNA-seq profiling.
  • FIG. 6C shows top hits identified by TMT (FIG. 6A) proteomic profiling.
  • FIG. 6D shows top hits identified by RNA-seq profiling (FIG. 6B).
  • FIGs. 7A-7D show TEAD-degrading PROTACs inhibit YAP transcriptional activity.
  • FIG. 6E-6F show representative Western Blot (FIG. 6E) and Histograms (FIG. 6F) showing the effect of 100 nM and 500 nM HC278 on different TEAD paralogs and YAP in NCI-H226 cells treated for 18 h. Actin was used as the control for loading, transfer, and normalization. Histograms depict mean +
  • FIG. 7A shows a heatmap showing transcripts upregulated and downregulated in NCI-H226 cells treated with 500 nM of HC278 for 24 h.
  • FIG. 7B shows GSEA Enrichment plot of Differentially expressed genes in the MSigDB oncogenes data set.
  • FIG. 7C shows enrichment plot for Gene Set Enrichment Analysis for YAP signature gene set.
  • FIG. 9 shows chemical structures of control compounds HC278-Negl and HC278-Neg2, and warhead WH15 and Ex. 29.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • the bond is a single bond
  • the dashed line - is a single bond or absent
  • formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • range When a range of values (“range”) is listed, it encompasses each value and sub-range within the range.
  • a range is inclusive of the values at the two ends of the range unless otherwise provided.
  • C1-6 alkyl encompasses, C1, C2, C3, C4, C5, Ce, C1-6, C1-5, C1 ⁇ t, C1-3, C1-2, C2-6, C2-5, C2 4, C2-3, C3-6, C3-5, C s 4, C4-6, C4-5, and C5-6 alkyl.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1 ⁇ t alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) e.g., n-propyl, isopropyl), butyl (C4) (e.g., zz-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (Ce) (e.g., zr-hexyl).
  • alkyl groups include n- heptyl (C7), n-octyl (C 8 ), n-dodecyl (C12), and the like. Unless otherwise specified, 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 C1-12 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z'-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted zz-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z'-Bu)).
  • unsubstituted C1-6 alkyl e.g., -CH3 (Me), unsubstituted ethy
  • the alkyl group is a substituted C1-12 alkyl (such as substituted C1-6 alkyl, e.g., -CH2F, -CHF2, -CF3, - CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or benzyl (Bn)).
  • substituted C1-6 alkyl e.g., -CH2F, -CHF2, -CF3, - CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , or benzyl (Bn)
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”).
  • an alkenyl group has 1 to 12 carbon atoms (“C1-i 2 alkenyl”).
  • an alkenyl group has 1 to 11 carbon atoms (“C1-11 alkenyl”).
  • an alkenyl group has 1 to 10 carbon atoms (“C1-10 alkenyl”).
  • an alkenyl group has 1 to 9 carbon atoms (“C1-9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1-8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1 ⁇ t alkenyl”).
  • an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 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 C1 4 alkenyl groups include methylidenyl (C1), ethenyl (C 2 ), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • Examples of C1-6 alkenyl groups include the aforementioned C 2 -4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is an unsubstituted C1-20 alkenyl.
  • the alkenyl group is a substituted Cr 2 o alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1 -20 alkynyl”).
  • an alkynyl group has 1 to 10 carbon atoms (“C1-io alkynyl”).
  • an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”).
  • an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”).
  • an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”).
  • an alkynyl group has 1 carbon atom (“C1 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 C1-4 alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2- butynyl (C4), and the like.
  • C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl 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 C1-20 alkynyl.
  • the alkynyl group is a substituted C1-20 alkynyl.
  • the term “carbocyclyl” or “carbocyclic” 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”). In some embodiments, 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”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, 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 (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.
  • Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • Exemplary C3 8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11 ), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), 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 can contain one or more carbon-carbon double or triple bonds.
  • 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.
  • 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 C3-14 carbocyclyl.
  • 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”). In some embodiments, 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”).
  • 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). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).
  • C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C 8 ).
  • 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.
  • the cycloalkyl group is a substituted C3-14 cycloalkyl.
  • heterocyclyl or “heterocyclic” refers to a radical of a 3- to 14-membered nonaromatic 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”).
  • 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 continue to designate the number of ring members in the heterocyclyl ring system.
  • 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 substituted or unsubstituted, 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 - ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 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- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]di
  • 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 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“ C6-14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C1o aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu 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 Ce-i4 aryl.
  • the aryl group is a substituted C6-14 aryl.
  • 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 n 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 on either ring, e.g., either the ring bearing a heteroatom e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5 -indolyl).
  • the heteroaryl is substituted or unsubstituted, 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 substituted or unsubstituted, 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, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
  • 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
  • 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 substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
  • Optionally substituted refers to a group which is substituted or unsubstituted e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “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 disclosure contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the disclosure is not limited in any manner by the exemplary substituents described herein.
  • 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 -NO 2 .
  • each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1-10 alkyl, -OR 33 , -SR 33 , -N(R bb ) 2 , - CN, -SCN, or -NO 2 , wherein R 33 is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io 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-pyridine- s
  • R 33
  • halo or halogen refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
  • hydroxyl refers to the group -OH.
  • thiol refers to the group -SH.
  • amino refers to the group -NH 2 .
  • 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.
  • Nitrogen atoms can be substituted or unsubstituted 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.
  • each nitrogen protecting group 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, (iV’-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-nitrobutanamide
  • 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), l-(l-adamantyl)-l-methylethyl carb
  • 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, A’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, A-acctylmcthioninc derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthalimide, A-dithiasnccinimidc (Dts), A-2,3-diphcnylmalcimidc, A-2,5-dimcthy I pyrrole, N-l , 1 ,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohex
  • 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), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -meth
  • 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”).
  • Sulfur 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.
  • 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.
  • a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms.
  • 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.
  • 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", CP, Br , I"), NO 3 ", CIO4 , OH , H2PO4 , HCOf, HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5- sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, gluta
  • At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
  • 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.
  • Salts include 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 the present 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, persul
  • 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 the present 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.
  • 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
  • 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 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.
  • 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.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • a “subject” to which administration is contemplated 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.
  • the nonhuman 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.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a 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.
  • 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.
  • the compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 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 effect.
  • dose ranges as described herein provide guidance for the administration of provided 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.
  • 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 encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4).
  • a therapeutically effective amount is an amount sufficient for treating a cancer (e.g., a cancer associated with a TEAD protein (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer)).
  • a cancer associated with a TEAD protein e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer
  • a therapeutically effective amount is an amount sufficient for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) and treating a cancer (e.g., a cancer associated with a TEAD protein (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer)).
  • a cancer associated with a TEAD protein e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma,
  • a “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a prophylactically effective amount is an amount sufficient for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4).
  • a prophylactically effective amount is an amount sufficient for preventing a cancer (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer).
  • a cancer e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer.
  • a prophylactically effective amount is an amount sufficient for degrading a TEAD protein e.g., TEAD1, TEAD2, TEAD3, TEAD4) and preventing a cancer (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer).
  • a cancer e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer.
  • prevent 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 term “degrade” or “degradation” in the context of proteins refers to a reduction in the amount of the protein.
  • the term refers to a reduction of the amount of protein, e.g., a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4), to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of amount of the protein.
  • the term refers to a reduction of the amount of protein, e.g., a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4), to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of the amount of protein.
  • a TEAD protein e.g., TEAD1, TEAD2, TEAD3, TEAD4
  • X refers to a number or percentage that is between 99.5% and 100.5%, between 99% and 101%, between 98% and 102%, between 97% and 103%, between 96% and 104%, between 95% and 105%, between 92% and 108%, or between 90% and 110%, inclusive, of X.
  • a proliferative disease refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • angiogenesis refers to the physiological process through which new blood vessels form from pre-existing vessels.
  • Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development.
  • Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue.
  • angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer.
  • Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF).
  • angiogenic proteins such as growth factors (e.g., VEGF).
  • VEGF growth factors
  • “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and/or is associated with a disease.
  • neoplasm and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
  • a neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
  • a “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin.
  • a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.
  • Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
  • certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.”
  • An exemplary pre-malignant neoplasm is a teratoma.
  • a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.
  • the term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
  • a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
  • cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
  • Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocar
  • Wilms tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer
  • pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents.
  • biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon y), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g., HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)).
  • cytokines e.g., tumor necrosis factor, interferon a, inter
  • chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrclin and leuprolide), anti-androgens (e.g., flutamide and bicalutamide), photodynamic therapies (e.g., vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g., busulfan and treosulfan), tri-estrogens
  • a “protein,” “peptide,” or “polypeptide” comprises a polymer of amino acid residues linked together by peptide bonds.
  • the term refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein will be at least three amino acids long.
  • a protein may refer to an individual protein or a collection of proteins. Inventive proteins preferably contain only natural amino acids, although non-natural amino acids (z.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and/or amino acid analogs as are known in the art may alternatively be employed.
  • amino acids in a protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification.
  • a protein may also be a single molecule or may be a multi- molecular complex.
  • a protein may be a fragment of a naturally occurring protein or peptide.
  • a protein may be naturally occurring, recombinant, synthetic, or any combination of these.
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is hydrogen or optionally substituted alkyl; each instance of X is independently CH or N;
  • Y is a moiety capable of binding to an E3 ubiquitin ligase.
  • the present disclosure provides a compound of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein:
  • Y is of Formulae (II- a), (Il-b), or (II-c): wherein:
  • R 3 is hydrogen or optionally substituted alkyl
  • R 4 is optionally substituted alkyl or optionally substituted cycloalkyl
  • R 5 is optionally substituted alkyl or optionally substituted cycloalkyl.
  • R 1 is hydrogen or optionally substituted alkyl; each instance of X is independently CH or N;
  • L 3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
  • R 1 is hydrogen or optionally substituted alkyl.
  • R 1 is hydrogen
  • R 1 is optionally substituted alkyl.
  • R 1 is optionally substituted C1-12 alkyl, optionally substituted C1-11 alkyl, optionally substituted C1-10 alkyl, optionally substituted C1-9 alkyl, optionally substituted C1-8 alkyl, optionally substituted C1-7 alkyl, optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted C1-4 alkyl, optionally substituted Cm alkyl, or optionally substituted C1-2 alkyl.
  • R 1 is optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted C1-4 alkyl, optionally substituted Cm alkyl, or optionally substituted C1-2 alkyl.
  • R 1 is optionally substituted C1-12 alkyl. In some embodiments, R 1 is optionally substituted C1-11 alkyl. In some embodiments, R 1 is optionally substituted C1-10 alkyl. In some embodiments, R 1 is optionally substituted C1-9 alkyl. In some embodiments, R 1 is optionally substituted Cm alkyl. In some embodiments, R 1 is optionally substituted C1-7 alkyl. In some embodiments, R 1 is optionally substituted C1-6 alkyl. In some embodiments, R 1 is optionally substituted C1-5 alkyl. In some embodiments, R 1 is optionally substituted CM alkyl. In some embodiments, R 1 is optionally substituted C1-3 alkyl. In some embodiments, R 1 is optionally substituted C1-2 alkyl.
  • R 1 is substituted alkyl.
  • R 1 is substituted C1-12 alkyl, substituted C1-11 alkyl, substituted C1-10 alkyl, substituted C1-9 alkyl, substituted Cm alkyl, substituted C1-7 alkyl, substituted Cm alkyl, substituted Cm alkyl, substituted C1-4 alkyl, substituted Cm alkyl, or substituted Cm alkyl.
  • R 1 is substituted Cm alkyl, substituted Cm alkyl, substituted C1-4 alkyl, substituted Cm alkyl, or substituted Cm alkyl.
  • R 1 is substituted C1-12 alkyl. In some embodiments, R 1 is substituted C1-i i alkyl. In some embodiments, R 1 is substituted C1-io alkyl. In some embodiments, R 1 is substituted C1-9 alkyl. In some embodiments, R 1 is substituted C1-8 alkyl. In some embodiments, R 1 is substituted C1-7 alkyl. In some embodiments, R 1 is substituted C1-6 alkyl. In some embodiments, R 1 is substituted C1-5 alkyl. In some embodiments, R 1 is substituted C1-4 alkyl. In some embodiments, R 1 is substituted C1-3 alkyl. In some embodiments, R 1 is substituted C1-2 alkyl.
  • R 1 is unsubstituted alkyl. In some embodiments, R 1 is unsubstituted C1-i 2 alkyl, unsubstituted Cm alkyl, unsubstituted C1-10 alkyl, unsubstituted C1-9 alkyl, unsubstituted C1-8 alkyl, unsubstituted C1-7 alkyl, unsubstituted C1-6 alkyl, unsubstituted C1-5 alkyl, unsubstituted C1-4 alkyl, unsubstituted C1-3 alkyl, or unsubstituted C1-2 alkyl.
  • R 1 is unsubstituted C1-6 alkyl, unsubstituted C1-5 alkyl, unsubstituted C1-4 alkyl, unsubstituted C1-3 alkyl, or unsubstituted C1- 2 alkyl.
  • R 1 is unsubstituted Cm alkyl. In some embodiments, R 1 is unsubstituted Cm alkyl. In some embodiments, R 1 is unsubstituted C1-10 alkyl. In some embodiments, R 1 is unsubstituted C1-9 alkyl. In some embodiments, R 1 is unsubstituted C1-8 alkyl. In some embodiments, R 1 is unsubstituted C1-7 alkyl. In some embodiments, R 1 is unsubstituted C1-6 alkyl. In some embodiments, R 1 is unsubstituted C1-5 alkyl. In some embodiments, R 1 is unsubstituted CM alkyl. In some embodiments, R 1 is unsubstituted C1-3 alkyl. In some embodiments, R 1 is unsubstituted C1-2 alkyl.
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl, or /z-hcxyl.
  • R 1 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, or /z-hcxyl.
  • R 1 is methyl, ethyl, or n-propyl.
  • R 1 is methyl (-CH3).
  • each instance of X is independently CH or N.
  • At least one instance of X is CH. In some embodiments, at least one instance of X is N.
  • L 1 is of formula:
  • L 1 is of formula: formula:
  • L 1 is of formula:
  • L 1 is of formula: some embodiments, L 1 is of -6 alkyl. In some embodiments, L 1 is of formula: hydrogen or optionally substituted Cm alkyl. In some embodiments, L 1 is of formula: hydrogen or optionally substituted [0121] In some embodiments, L 1 is of formula:
  • L 1 is of formula: some embodiments, L 1 is of -6 alkyl. In some hydrogen or optionally substituted Cm alkyl. In some embodiments, L 1 is of formula: methyl. In some embodiments, L 1 is of formula: and R 1 is hydrogen or unsubstituted C1-6 alkyl. In some embodiments, L 1 is of formula: is hydrogen or methyl. substituted alkyl. In some embodiments, L 1 is of formula: optionally substituted alkyl. In some embodiments, L 1 is of alkyl. In some embodiments, L 1 is of formula: and R 1 is optionally substituted C1-3 alkyl. In some embodiments, L 1 is of formula: s optionally substituted methyl. In some unsubstituted C1-3 alkyl. In some embodiments, L 1 is of formula:
  • L 1 is of formula: and R 1 is hydrogen or optionally substituted C1-6 alkyl. In some embodiments, L 1 is of formula: hydrogen or optionally substituted methyl. In some embodiments, unsubstituted C1-6 alkyl. In some embodiments, L 1 is of formula: hydrogen or unsubstituted Cm alkyl. In some embodiments, L 1 is of embodiments,
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, -NR 2 -, — C(— O)— , or optionally substituted heterocyclylene.
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-. In some embodiments, L 2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with -O-. In some embodiments, L 2 comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with -O-. In some embodiments, L 2 comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with -O-.
  • L 2 comprises -O-. In some embodiments, L 2 comprises , wherein n is 1, 2, 3, 4, or 5; and p is 1, 2, 3, or 4. In some embodiments, L 2 comprises
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR 2 -. In some embodiments, L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-. In some embodiments, L 2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with -NR 2 -.
  • L 2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with -NH-.
  • L 2 comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with -NH-.
  • L 2 comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with -NH-.
  • L 2 comprises -NH-. In some embodiments, L 2 comprises
  • each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
  • L 2 comprises is independently CH or N; each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, or 5; and each p is independently 1, 2, 3, or 4. In some embodiments, L 2
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene. In some embodiments, L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 3-10 membered heterocyclylene. In some embodiments, L 2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with optionally substituted 3-10 membered heterocyclylene.
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene. In some embodiments, L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1- 20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms.
  • L 2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L 2 comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms.
  • L 2 comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms. [0139] In some embodiments, L 2 comprises
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are replaced with -O-, -NR 2 -, — C(— O)— , or optionally substituted heterocyclylene.
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-.
  • L 2 comprises
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR 2 -.
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-.
  • L 2 comprises wherein each wherein n is independently 1, 2, 3, 4, or 5, and each p is independently 1, 2, 3, or 4.
  • L 2 comprises
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene.
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -NR 2 -. In some embodiments, L 2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with
  • L 2 comprises wherein each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each n is independently 0, 1, 2, 3, 4, or 5. In some embodiments, L 2 comprises , , , , , 5, 6, 7,
  • L 2 comprises
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR 2 -, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene.
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene.
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1- 20 alkylene is replaced with -NH-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene.
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with
  • L 2 comprises O 0 , 0
  • L 2 is independently CH or N; and each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
  • L 2 comprises
  • L 2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L 2 comprises optionally substituted C1- 20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with optionally substituted 5-6 membered heterocyclylene. In some
  • L 2 comprises , wherein each instance of X is independently CH or N. In some embodiments,
  • L 2 comprises
  • L 2 comprises optionally substituted C1-20 alkylene and optionally substituted C2-20 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted C2-20 alkynylene are independently replaced with optionally substituted heterocyclylene.
  • L 2 comprises optionally substituted C1-20 alkylene and optionally substituted C2-20 alkynylene.
  • L 2 comprises optionally substituted C1-10 alkylene and optionally substituted C2-10 alkynylene.
  • L 2 comprises optionally substituted C1-6 alkylene and optionally substituted C2-6 alkynylene.
  • L 2 comprises optionally substituted C1-3 alkylene and optionally substituted C2-3 alkynylene.
  • L 2 comprises unsubstituted C1-20 alkylene and unsubstituted C2-20 alkynylene. In some embodiments, L 2 comprises unsubstituted C1-10 alkylene and unsubstituted C2-10 alkynylene. In some embodiments, L 2 comprises unsubstituted C1-6 alkylene and unsubstituted C2-6 alkynylene. In some embodiments, L 2 comprises unsubstituted C1-3 alkylene and unsubstituted C2-3 alkynylene. In some embodiments, L 2 comprises methylene, ethylene, or n-propylene; and ethynylene. In some embodiments, L 2 comprises methylene and ethynylene.
  • L 2 comprises optionally substituted C2-20 alkynylene and optionally substituted heterocyclylene. In some embodiments, L 2 comprises optionally substituted C2 10 alkynylene and optionally substituted 3-6 membered heterocyclylene. In some embodiments, L 2 comprises optionally substituted C2-3 alkynylene and optionally substituted 5-6 membered heterocyclylene.
  • L 2 comprises unsubstituted C2-20 alkynylene and unsubstituted heterocyclylene. In some embodiments, L 2 comprises unsubstituted C2-10 alkynylene and unsubstituted 3-6 membered heterocyclylene. In some embodiments, L 2 comprises unsubstituted C2-3 alkynylene and unsubstituted 5-6 membered heterocyclylene. In some embodiments, L 2 comprises ethynylene; and piperidinylene or piperazinylene.
  • L 2 comprises optionally substituted C1-20 alkylene, optionally substituted C2-20 alkynylene, and optionally substituted heterocyclylene. In some embodiments, L 2 comprises optionally substituted C1-10 alkylene, optionally substituted C2-10 alkynylene, and optionally substituted 3-6 membered heterocyclylene. In some embodiments, L 2 comprises optionally substituted Cm alkylene, optionally substituted C2-3 alkynylene, and optionally substituted 5-6 membered heterocyclylene.
  • L 2 comprises unsubstituted C1-20 alkylene, unsubstituted C2-20 alkynylene, and unsubstituted heterocyclylene. In some embodiments, L 2 comprises unsubstituted C1- 10 alkylene, unsubstituted C2-10 alkynylene, and unsubstituted 3-6 membered heterocyclylene. In some embodiments, L 2 comprises unsubstituted Cm alkylene, unsubstituted C2-3 alkynylene, and unsubstituted 5-6 membered heterocyclylene. In some embodiments, L 2 comprises methylene, ethylene, or n-propylene; ethynylene; and piperidinylene or piperazinylene.
  • L 2 is of formula: 0 0 , 0 , wherein: each instance of X is independently CH or N; each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, or 5; and each p is independently 1, 2, 3, or 4.
  • At least one instance of R 2 is hydrogen.
  • At least one instance of R 2 is optionally substituted alkyl. In some embodiments, at least one instance of R 2 is optionally substituted C1-12 alkyl, optionally substituted C1 11 alkyl, optionally substituted C1-10 alkyl, optionally substituted C1-9 alkyl, optionally substituted C1-8 alkyl, optionally substituted C1-7 alkyl, optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted C1-4 alkyl, optionally substituted C1-3 alkyl, or optionally substituted C1-2 alkyl.
  • At least one instance of R 2 is optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted C1-4 alkyl, optionally substituted C1-3 alkyl, or optionally substituted C1-2 alkyl.
  • At least one instance of R 2 is optionally substituted C1-12 alkyl. In some embodiments, at least one instance of R 2 is optionally substituted Cm alkyl. In some embodiments, at least one instance of R 2 is optionally substituted C1-10 alkyl. In some embodiments, at least one instance of R 2 is optionally substituted C1-9 alkyl. In some embodiments, at least one instance of R 2 is optionally substituted C1-8 alkyl. In some embodiments, at least one instance of R 2 is optionally substituted C1-7 alkyl. In some embodiments, at least one instance of R 2 is optionally substituted C1-6 alkyl.
  • At least one instance of R 2 is optionally substituted C1-5 alkyl. In some embodiments, at least one instance of R 2 is optionally substituted C1-4 alkyl. In some embodiments, at least one instance of R 2 is optionally substituted Cm alkyl. In some embodiments, at least one instance of R 2 is optionally substituted C1-2 alkyl.
  • At least one instance of R 2 is substituted alkyl.
  • at least one instance of R 2 is substituted C1-12 alkyl, substituted Crn alkyl, substituted C1-10 alkyl, substituted C1-9 alkyl, substituted C1-8 alkyl, substituted C1-7 alkyl, substituted C1-6 alkyl, substituted Cm alkyl, substituted CM alkyl, substituted Cm alkyl, or substituted C1-2 alkyl.
  • at least one instance of R 2 is substituted C1-6 alkyl, substituted C1-5 alkyl, substituted C1-4 alkyl, substituted Cm alkyl, or substituted Cm alkyl.
  • At least one instance of R 2 is substituted Cm alkyl. In some embodiments, at least one instance of R 2 is substituted Cm alkyl. In some embodiments, at least one instance of R 2 is substituted C1-10 alkyl. In some embodiments, at least one instance of R 2 is substituted C1-9 alkyl. In some embodiments, at least one instance of R 2 is substituted Cm alkyl. In some embodiments, at least one instance of R 2 is substituted Cm alkyl. In some embodiments, at least one instance of R 2 is substituted Cm alkyl. In some embodiments, at least one instance of R 2 is substituted Cm alkyl. In some embodiments, at least one instance of R 2 is substituted Cm alkyl. In some embodiments, at least one instance of R 2 is substituted C1-4 alkyl. In some embodiments, at least one instance of R 2 is substituted Cm alkyl. In some embodiments, at least one instance of R 2 is substituted Cm alkyl.
  • At least one instance of R 2 is unsubstituted alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-C12 alkyl, unsubstituted C1-C 11 alkyl, unsubstituted C1-C10 alkyl, unsubstituted C1-C9 alkyl, unsubstituted C1-Cx alkyl, unsubstituted C1-C7 alkyl, unsubstituted C1-Ce alkyl, unsubstituted C1-C5 alkyl, unsubstituted C1-C4 alkyl, unsubstituted C1-C 3 alkyl, or unsubstituted C1-C2 alkyl.
  • At least one instance of R 2 is unsubstituted C1-Ce alkyl, unsubstituted C1-C5 alkyl, unsubstituted C1-C4 alkyl, unsubstituted C1-C 3 alkyl, or unsubstituted C1-C2 alkyl.
  • At least one instance of R 2 is unsubstituted C1-C12 alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-C11 alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-C10 alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-C9 alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-Cx alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-C7 alkyl.
  • At least one instance of R 2 is unsubstituted C1-Ce alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-C5 alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-C4 alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-C 3 alkyl. In some embodiments, at least one instance of R 2 is unsubstituted C1-C2 alkyl.
  • At least one instance of R 2 is methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertamyl, or //-hexyl.
  • at least one instance of R 2 is methyl, ethyl, n-propyl, //-butyl, //-pentyl, or //-hexyl.
  • at least one instance of R 2 is methyl, ethyl, or //-propyl.
  • at least one instance of R 2 is methyl (-CH3).
  • Y is a moiety capable of binding to an E3 ubiquitin ligase.
  • Y is a moiety capable of binding to an E3 ubiquitin ligase as described in Ishida T. and Ciulli A., SLAS Discov. 2021, 26(4), 484-502, doi: 10.1177/2472555220965528, or
  • Y is of Formula (Il-a): wherein R 3 is hydrogen or optionally substituted alkyl.
  • R 3 is hydrogen. In some embodiments, R 3 is optionally substituted C1-3 alkyl. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is hydrogen or -CH3.
  • Y is of Formula (Il-b): wherein R 4 is optionally substituted alkyl or optionally substituted cycloalkyl.
  • R 4 is optionally substituted Cm alkyl. In some embodiments, R 4 is - CH3. In some embodiments, R 4 is optionally substituted C3-4 cycloalkyl. In some embodiments, R 4 is cyclopropyl optionally substituted with halogen or -CN. In some embodiments, R 4 is cyclopropyl optionally substituted with -F or -CN. In some embodiments, R 4 is -CH3,
  • Y is of Formula (II-c): wherein R 5 is optionally substituted alkyl or optionally substituted cycloalkyl.
  • R 5 is optionally substituted Cm alkyl. In some embodiments, R 5 is - CH3. In some embodiments, R 5 is optionally substituted C3-4 cycloalkyl. In some embodiments, R 5 is cyclopropyl optionally substituted with halogen or -CN. In some embodiments, R 5 is cyclopropyl optionally substituted with -F or -CN. In some embodiments, R 5 is -CH3,
  • Y is of Formula (III): wherein:
  • X is CH or N
  • L 3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
  • X is CH. In some embodiments, X is N.
  • Y is of Formula (Ill-a):
  • Y is of Formula (Ill-b):
  • L 3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
  • L 3 is optionally substituted heterocyclylene. In some embodiments, L 3 is substituted heterocyclylene. In some embodiments, L 3 is optionally substituted heterocyclylene containing 1, 2, or 3 ring N atoms. In some embodiments, L 3 is optionally substituted heterocyclylene containing 1 ring N atom. In some embodiments, L 3 is optionally substituted heterocyclylene containing 2 ring N atom. In some embodiments, L 3 is substituted heterocyclylene containing 1, 2, or 3 ring N atoms. In some embodiments, L 3 is substituted heterocyclylene containing 1 ring N atom. In some embodiments, L 3 is optionally substituted arylene.
  • L 3 is optionally substituted phenylene. In some embodiments, L 3 is substituted phenylene. In some embodiments, L 3 is unsubstituted phenylene. In some embodiments, L 3 is optionally substituted heteroarylene. In some embodiments, L 3 is optionally substituted heteroarylene containing 1, 2, or 3 ring N atoms. In some embodiments, L 3 is optionally substituted heteroarylene containing 1 ring N atom. In some embodiments, L 3 is optionally substituted heteroarylene containing 2 ring N atoms.
  • Y is of Formulae (Il-a), (Il-b), (II-c), or (III). In some embodiments, Y is of Formulae (Il-a), (Il-b), (II-c), (Ill-a), or (Ill-b). In some embodiments, Y is of Formulae (Il-a), some embodiments, Y is of Formulae (Il-a), (Il-b), (II-c), (Ill-a), or
  • the compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formulae (I-a-1), (I-a-2), (I-a-3), or
  • R 3 is hydrogen or optionally substituted alkyl
  • R 4 is optionally substituted alkyl or optionally substituted cycloalkyl
  • R 5 is optionally substituted alkyl or optionally substituted cycloalkyl
  • X is CH or N
  • L 3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
  • the compound of Formula (I) is of Formulae (I-a-1). In some embodiments, the compound of Formula (I) is of Formulae (I-a-2). In some embodiments, the compound of Formula (I) is of Formulae (I-a-3). In some embodiments, the compound of Formula (I) is of Formulae (I-a-4).
  • the compound of Formula (I-a-4) is of Formulae (I-a-4-i) or (I-a-4-ii): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I-a-4) is of Formulae (I-a-4-i). In some embodiments, the compound of Formula (I-a-4) is of Formulae (I-a-4-ii).
  • the compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formulae (I-b-1), (I-b-2), (I-b-3), or
  • R 3 is hydrogen or optionally substituted alkyl
  • R 4 is optionally substituted alkyl or optionally substituted cycloalkyl
  • R 5 is optionally substituted alkyl or optionally substituted cycloalkyl
  • X is CH or N
  • L 3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
  • the compound of Formula (I) is of Formulae (I-b-1). In some embodiments, the compound of Formula (I) is of Formulae (I-b-2). In some embodiments, the compound of Formula (I) is of Formulae (I-b-3). In some embodiments, the compound of Formula (I) is of Formulae (I-b-4).
  • the compound of Formula (I-b-4) is of Formulae (I-b-4-i) or (I-b-4-ii): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I-b-4) is of Formulae (I-b-4-i). In some embodiments, the compound of Formula (I-b-4) is of Formulae (I-b-4-ii).
  • the compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formulae (I-c-1), (I-c-2), (I-c-3), or
  • R 3 is hydrogen or optionally substituted alkyl
  • R 4 is optionally substituted alkyl or optionally substituted cycloalkyl
  • R 5 is optionally substituted alkyl or optionally substituted cycloalkyl
  • X is CH or N
  • L 3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
  • the compound of Formula (I) is of Formulae (I-c-1). In some embodiments, the compound of Formula (I) is of Formulae (I-c-2). In some embodiments, the compound of Formula (I) is of Formulae (I-c-3). In some embodiments, the compound of Formula (I) is of Formulae (I-c-4).
  • the compound of Formula (I-c-4) is of Formulae (I-c-4-i) or (I-c-4-ii): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I-c-4) is of Formulae (I-c-4-i). In some embodiments, the compound of Formula (I-c-4) is of Formulae (I-c-4-ii).
  • the compound of Formula (I) is of Formula (I-d): or a pharmaceutically acceptable salt thereof.
  • R 3 is hydrogen or optionally substituted alkyl
  • R 4 is optionally substituted alkyl or optionally substituted cycloalkyl
  • R 5 is optionally substituted alkyl or optionally substituted cycloalkyl
  • X is CH or N
  • L 3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
  • the compound of Formula (I) is of Formulae (I-d-1). In some embodiments, the compound of Formula (I) is of Formulae (I-d-2). In some embodiments, the compound of Formula (I) is of Formulae (I-d-3). In some embodiments, the compound of Formula (I) is of Formulae (I-d-4).
  • the compound of Formula (I-d-4) is of Formulae (I-d-4-i) or (I-d-4-ii): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I-d-4) is of Formulae (I-d-4-i). In some embodiments, the compound of Formula (I-d-4) is of Formulae (I-d-4-ii).
  • the compound of Formula (I) is of Formula (I-e): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is of Formulae (I-e-1), (I-e-2), (I-e-3), or
  • R 3 is hydrogen or optionally substituted alkyl
  • R 4 is optionally substituted alkyl or optionally substituted cycloalkyl
  • R 5 is optionally substituted alkyl or optionally substituted cycloalkyl
  • X is CH or N
  • L 3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
  • the compound of Formula (I) is of Formulae (I-e-1). In some embodiments, the compound of Formula (I) is of Formulae (I-e-2). In some embodiments, the compound of Formula (I) is of Formulae (I-e-3). In some embodiments, the compound of Formula (I) is of Formulae (I-e-4).
  • the compound of Formula (I-e-4) is of Formulae (I-e-4-i) or (I-e-4-ii): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I-e-4) is of Formulae (I-e-4-i). In some embodiments, the compound of Formula (I-e-4) is of Formulae (I-e-4-ii).
  • the compound of Formula (IV) is of Formulae (IV-a), (IV-b), or (IV- c):
  • the compound of Formula (IV) is of Formula (IV-a). In some embodiments, the compound of Formula (IV) is of Formula (IV-b). In some embodiments, the compound of Formula (IV) is of Formula (IV-c).
  • the compound of Formula (I) is of Formula (IV). In some embodiments, the compound of Formula (I) is of Formulae (IV-a), (IV-b), or (IV-c). In some embodiments, the compound of Formula (I) is of Formula (IV-a). In some embodiments, the compound of Formula (I) is of Formula (IV-b). In some embodiments, the compound of Formula (I) is of Formula (IV-c).
  • the compound of Formula (V) is of Formulae (V-a) or (V-b): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (V) is of Formula (V-a). In some embodiments, the compound of Formula (V) is of Formula (V-b).
  • the compound of Formula (I) is of Formula (V). In some embodiments, the compound of Formula (I) is of Formulae (V-a) or (V-b). In some embodiments, the compound of Formula (I) is of Formula (V-a). In some embodiments, the compound of Formula (I) is of Formula (V-b).
  • the compound of Formula (I) is selected from those in Table 1, and pharmaceutically acceptable salts thereof.
  • a provided compound is any compound of the present disclosure (e.g., Formula (I)), or a pharmaceutically acceptable salt thereof. In some embodiments, a provided compound is any compound of the present disclosure (e.g., Formula (I)), or a salt thereof. In some embodiments, a provided compound is any compound of the present disclosure e.g., Formula (I)).
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition described herein comprises a compound of disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the compound described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof.
  • the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof.
  • the effective amount is an amount effective for treating a hematological disease in a subject in need thereof.
  • the effective amount is an amount effective for preventing a hematological disease in a subject in need thereof.
  • the effective amount is an amount effective for treating a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a in a painful condition subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a painful condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a psychiatric disorder in a subject in need thereof.
  • the effective amount is an amount effective for treating a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for degrading a TEAD protein e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject or cell.
  • a disease e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder
  • the subject is an animal.
  • the animal may be of either sex and may be at any stage of development.
  • the subject described herein is a human.
  • the subject is a non-human animal.
  • the subject is a mammal.
  • the subject is a non-human mammal.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • 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.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs).
  • the subject is a fish or reptile.
  • the cell is present in vitro. In certain embodiments, the cell is present in vivo.
  • the effective amount is an amount effective for degrading a protein 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%, or at least about 98%.
  • the effective amount is an amount effective for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%.
  • the effective amount is an amount effective for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.
  • compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, 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.
  • 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.
  • compositions 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 composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents or fillers, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents or fillers 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, starches (such as dry starch, cornstarch), sugars (such as powdered sugar), calcium trisulfate, carboxymethylcellulose calcium, dextrate, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium, maltitol, maltodextrin, maltose, sucrose, glucose, mannitol, silicic acid, xylitol, 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 (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • 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 carboxy vinyl polymer), carrageenan, cellulo
  • Exemplary disintegrating agents or disintegrants include agar, algin, alginic acid, sodium alginate, silicates, sodium carbonate, calcium carbonate, carboxymethylcellulose, cellulose, clay, colloidal silicon dioxide, croscarmellose sodium, crospovidone, rubber, magnesium silicate, methylcellulose, potassium krillin, hydroxypropylcellulose (e.g., low substituted Hydroxypropylcellulose), crosslinked polyvinylpyrrolidone, hydroxypropylcellulose, and starch (e.g., sodium glycolate starch, potato or tapioca starch).
  • hydroxypropylcellulose e.g., low substituted Hydroxypropylcellulose
  • starch e.g., sodium glycolate starch, potato or tapioca starch
  • Exemplary binding agents include starch (e.g., glycolate starch, 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, hydroxy ethylcellulose, 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,
  • 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 hydroxy anisole, 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
  • Exemplary 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.
  • 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 lubricating agents include agar, ethyl oleate, ethyl laurate, glycerin, blyceryl palmitostearate, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycol, sodium stearyl, sorbitol, zinc stearate, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • 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, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • 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, so
  • the oral 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.
  • 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.
  • the 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.
  • injectable preparations of the compositions disclosed herein are in the form of a ready-to-use (“RTU”) preparation that can be directly administered to a subject.
  • the RTU preparation is a suspension.
  • the RTU preparation is a solution.
  • the RTU preparation is an emulsion.
  • injectable preparations of the compositions disclosed herein are in the form of a solid that is reconstituted prior to administration.
  • the solid is a lyophilized solid.
  • injectable preparations of the compositions disclosed herein are in the form of a liquid or suspension that is diluted prior to administration.
  • the pharmaceutical compositions disclosed herein comprise a bulking agent.
  • Bulking agents can be used, e.g., to improve the appearance of a solid composition, to provide visible “bulk” to demonstrate product quality or to facilitate preparation, e.g., of a solid composition prepared for reconstitution prior to administration.
  • Bulking agents can be used for low dose (high potency) drugs that do not have the necessary bulk to support their own structure or provide a visible composition in a unit dosage form.
  • Bulking agents are used in lyophilized formulations. Bulking agents provide a desirable structure for a lyophilized cake comprising pores that provide the means for vapor to escape from the product during lyophilization cycles, and facilitate dissolution on reconstitution.
  • the bulking agent is mannitol, lactose, sucrose, dextran, trehalose, povidone, dextran, glycine, isoleucine, methionine, or a cyclodextrin (e.g., (2- hydroxypropyl) -P-cyclodextrin) .
  • 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 compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates 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 g
  • 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.
  • 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 polethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating agents which can be used include polymeric substances and waxes.
  • 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.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal 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 intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.
  • 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.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • 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 compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self- propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. 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 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 composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the 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).
  • 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, but not limited to, 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 described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • 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.
  • Such 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.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further 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 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.
  • compositions suitable for administration to humans are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • compositions described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment.
  • 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 compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, 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, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • mucosal nasal,
  • Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
  • direct administration e.g., direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, 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.
  • a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein. [0284] Dose ranges as described herein provide guidance for the administration of provided 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.
  • a compound or 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 compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
  • additional pharmaceutical agents e.g., therapeutically and/or prophylactically active agents.
  • additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy
  • a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
  • the additional pharmaceutical agent achieves a desired effect for the same disorder.
  • the additional pharmaceutical agent achieves different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophy tactically 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 or 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 e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder).
  • a disease e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder.
  • 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 composition described herein in a single dose or composition or administered separately in different doses or compositions.
  • 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.
  • it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in
  • 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 additional pharmaceutical agent is an antiproliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase.
  • the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HD AC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all- trans retinoic acids, and other agents that promote differentiation.
  • epigenetic or transcriptional modulators e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HD AC inhibitors), lysine methyltransferase inhibitors
  • antimitotic drugs e.g., taxanes and vinca
  • the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
  • an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.
  • Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.
  • drug compounds e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • the pharmaceutical composition further comprises an additional pharmaceutical agent (e.g., an anti-cancer agent (e.g., an alkylating agent, an anti-metabolite, an antitumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent)).
  • an anti-cancer agent e.g., an alkylating agent, an anti-metabolite, an antitumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent.
  • the anti-cancer agent is an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof.
  • the anti-cancer agent is an alkylating agent.
  • the anti-cancer agent is an anti-metabolite.
  • the anti-cancer agent is an anti-tumor antibiotic.
  • the anti-cancer agent is an anti-cytoskeletal agent.
  • the anti-cancer agent is a topoisomerase inhibitor.
  • the anti-cancer agent is an anti-hormonal agent.
  • the anti-cancer agent is a targeted therapeutic agent.
  • the anticancer agent is a photodynamic therapeutic agent.
  • kits e.g., pharmaceutical packs
  • the kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein.
  • the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
  • kits including a first container comprising a compound or pharmaceutical composition described herein.
  • the kits are useful for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof.
  • the kits are useful for preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof.
  • kits are useful for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof.
  • the kits are useful for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject or cell.
  • a kit described herein further includes instructions for using the kit.
  • a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
  • the information included in the kits is prescribing information.
  • kits and instructions provide for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof.
  • a disease e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder
  • the kits and instructions provide for preventing a disease e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof.
  • the kits and instructions provide for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof.
  • kits and instructions provide for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject or cell.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • the present disclosure provides a method of degrading a TEAD protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides a method of degrading a TEAD protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present disclosure provides a method of degrading a TEAD protein in a subject, the method comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides a method of degrading a TEAD protein in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present disclosure provides a method of degrading a TEAD protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition.
  • the present disclosure provides a method of degrading a TEAD protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the TEAD protein is TEAD1, TEAD2, TEAD3, and/or TEAD4. In some embodiments, the TEAD protein is TEAD1. In some embodiments, the TEAD protein is TEAD2. In some embodiments, the TEAD protein is TEAD3. In some embodiments, the TEAD protein is TEAD4. In some embodiments, the cell, tissue, or biological sample is in vitro. In some embodiments, the cell, tissue, or biological sample is in vivo. In some embodiments, the cell is a cancer cell.
  • the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a provided compound or pharmaceutical composition.
  • the method comprises administering to the subject a therapeutically effective amount of a provided compound.
  • the method comprises administering to the subject a therapeutically effective amount of a provided pharmaceutical composition.
  • the disease is a cancer (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer).
  • a cancer e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer.
  • the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (I).
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of Formula (I).
  • the disease is a cancer (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer).
  • a cancer e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer.
  • the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a provided compound or pharmaceutical composition.
  • the method comprises administering to the subject a therapeutically effective amount of a provided compound.
  • the method comprises administering to the subject a therapeutically effective amount of a provided pharmaceutical composition.
  • the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I).
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (I).
  • the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of Formula (I).
  • the cancer is associated with a TEAD protein (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer).
  • the cancer is associated with TEAD1, TEAD2, TEAD3, and/or TEAD4.
  • the cancer is associated with TEAD1.
  • the cancer is associated with TEAD2.
  • the cancer is associated with TEAD3.
  • the cancer is associated with TEAD4.
  • the cancer is esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, or bone cancer.
  • the cancer is esophageal cancer.
  • the cancer is liver cancer.
  • the cancer is glioma.
  • the cancer is glioblastoma.
  • the cancer is breast cancer.
  • the cancer is lung cancer.
  • the cancer is colorectal cancer. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is uveal melanoma. In some embodiments, the cancer is Ewing sarcoma. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is bone cancer.
  • the subject is an animal.
  • the animal may be of either sex and may be at any stage of development.
  • the subject described herein is a human.
  • the subject is a non-human animal.
  • the subject is a mammal.
  • the subject is a non-human mammal.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • 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.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs).
  • the subject is a fish or reptile.
  • Step 1 Synthesis of 5-hydroxy-2-naphthoic acid.
  • tetrabutylammonium hydroxide 100 mL, 40% in H2O
  • deionized water 50 mL
  • Step 2 Synthesis of methyl 5-hydroxy-2-naphthoate.
  • 5-hydroxy-2- naphthoic acid 7.49 g, 39.80 mmol
  • MeOH 150 mL
  • SOCI2 47.35 g, 398.02 mmol
  • the resulting mixture was stirred at 70 °C for 2 h.
  • the mixture was concentrated directly and extracted with EtOAc. The combined organic layers were washed with brine, then dried over Na2SO_i. filtered, and then concentrated.
  • Step 3 Synthesis of methyl 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate.
  • methyl 5-hydroxy-2-naphthoate (3.00 g, 14.84 mmol) and l-bromo-4-(trifluoromethyl)benzene (4.01 g, 17.80 mmol) in toluene (60 mL) was added Pd(OAc)2 (0.16 g, 0.74 mmol), tBuXPhos (0.44 g, 1.04 mmol), and K3PO4 (6.30 g, 29.67 mmol).
  • Pd(OAc)2 (0.16 g, 0.74 mmol
  • tBuXPhos 0.44 g, 1.04 mmol
  • K3PO4 6.30 g, 29.67 mmol
  • Step 4 Synthesis of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid.
  • MeOH methyl 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate (2.80 g, 8.09 mmol) in MeOH (30 mL) and THF (10 mL) was added 2 N NaOH (30 mL). The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was acidified to pH 3-4 with con. HC1. The mixture was extracted with EtOAc.
  • Step 5 Synthesis of tert-butyl ((l-(5-(4-(trifluoromethyl)phenoxy)-2-naphthoyl)azetidin- 3-yl)methyl)carbamate.
  • Step 6 Synthesis of (3-(aminomethyl)azetidin-l-yl)(5-(4-(trifluoromethyl)phenoxy) naphthalen-2-yl)methanone (IW-I).
  • Step 1 Synthesis of methyl 2-(3-cyanophenyl)acetate.
  • methyl 2-(3- bromophenyl) acetate (2.50 g, 10.91 mmol) and Zn(CN)2 (0.83 g, 7.09 mmol) in DMF (30 mL) was added Pd(PPh3)4 (0.63 g, 0.55 mmol).
  • Pd(PPh3)4 (0.63 g, 0.55 mmol).
  • the resulting mixture was stirred at 90 °C for 4 h under N2 atmosphere. After completion of the reaction, the mixture was quenched by adding aqueous 2 N ammonia and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated.
  • Step 2 Synthesis of methyl-3-(aminomethyl)phenylacetate hydrochloride.
  • MeOH MeOH
  • 4 M HC1 dioxane
  • Pd/C 10% Pd/C
  • the resulting mixture was stirred at room temperature overnight under H2 atmosphere.
  • the mixture was filtered over Celite and concentration of the filtrate, the resulting crystals were taken with EtOAc to give methyl-3- (aminomethyl)phenylacetate hydrochloride (0.61 g, 35% yield) as a gray solid.
  • Step 3 Synthesis of methyl 2-(3-((5-(4-(trifluoromethyl)phenoxy)-2- naphthamido)methyl)phenyl)acetate.
  • DIEA 3-((5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid)
  • HATU hydroxy-3-(aminomethyl)phenylacetate hydrochloride
  • Step 4 Synthesis of 2-(3-((5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)methyl) phenyl)acetic acid (IW-II).
  • MeOH MeOH
  • THF 4 mL
  • 2 N NaOH 3 mL
  • the resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was acidified to pH 3-4 with con. HC1. The mixture was extracted with EtOAc.
  • Step 1 Synthesis of tert- butyl (3-((5-(4-(trifluoromethyl)phenoxy)-2- naphthamido)methyl)benzyl) carbamate.
  • DIEA 350.08 mg, 2.71 mmol
  • HATU HATU
  • tert-butyl 3-(aminomethyl)benzyl)carbamate
  • Step 2 Synthesis of N-(3-(aminomethyl)benzyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (IW-III).
  • Step 1 Synthesis of 3-(aminomethyl) benzaldehyde hydrochloride.
  • a solution of tert-butyl tert-butyl (3-formylbenzyl)carbamate (156.00 mg, 0.66 mmol) in 4 M HC1 in dioxane (10 mL) was stirred at room temperature for 1 h. The mixture was concentrated to afford 3- (aminomethyl)benzaldehyde hydrochloride as the crude product, which was used directly without purification.
  • Step 2 Synthesis of N-(3-formylbenzyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (IW-IV).
  • DIEA 388.97 mg, 3.01 mmol
  • HATU 397.53 mg, 0.78 mmol
  • 3- (aminomethyl) benzaldehyde hydrochloride 114.00 mg, 0.66 mmol
  • Step 1 Synthesis of (S)-N-(l-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2- sulfinamide.
  • l-(6-bromopyridin-2-yl)ethan-l-one 4.00 g, 20.00 mmol
  • Ti(OEt)4 9.12 g, 39.99 mmol
  • S)-2-methylpropane-2-sulfinamide 4.85 g, 39.99 mmol.
  • the reaction mixture was heated to reflux overnight, whereupon it was allowed to cool to room temperature and stirred for 30 min.
  • reaction was cooled to -30 °C and NaBm (1.51 g, 39.99 mmol) was added.
  • the reaction mixture was stirred at 0-5 °C for 2 h and then quenched by drop-wise addition of water.
  • the mixture was filtered through Celite, and the solids were washed with EtOAc.
  • the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Synthesis of tert-butyl (S)-(l-(6-bromopyridin-2-yl)ethyl)carbamate.
  • (S)-N-((S)-l-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.40 g, 7.86 mmol) in MeOH (12 mL) was added 4 M HC1 in dioxane (12 mL). The mixture was stirred at room temperature for 1 h.
  • Step 3 Synthesis of tert-butyl (S)-(l-(6-cyanopyridin-2-yl)ethyl)carbamate.
  • tert-butyl (S)-(l-(6-bromopyridin-2-yl)ethyl)carbamate 1.5 g, 4.98 mmol
  • DMF 20 mL
  • Zn(CN)2 0.88 g, 7.47 mmol
  • Pd(PPh3)4 0.57 g, 0.49 mmol
  • Step 4 Synthesis of tert-butyl (S)-(l-(6-formylpyridin-2-yl)ethyl)carbamate.
  • tert-butyl (S)-(l-(6-cyanopyridin-2-yl)ethyl)carbamate (1.05 g, 4.25 mmol) in DCM (20 mL) was added DIBAL-H solution (5.31 mL, 6.37 mmol, 1.2 M in toluene) by dropwise at -78 °C under N2 atmosphere.
  • the reaction mixture was stirred at -78 °C under N2 atmosphere for 2 h.
  • Step 5 Synthesis of (S)-N-(l-(6-formylpyridin-2-yl)ethyl)-5-(4-
  • Step 1 Synthesis of Benzyl (S)-4-(6-(l-((tert-butoxycarbonyl)amino)ethyl)pyridin-2- yl)piperazine-l-carboxylate.
  • Step 2 Tert-butyl (S)-(l-(6-(piperazin-l-yl)pyridin-2-yl)ethyl)carbamate.
  • benzyl (S)-4-(6-( 1 -((tert-butoxycarbonyl)amino)ethyl)pyridin-2-yl)piperazine- 1 -carboxylate 210.00 mg, 0.48 mmol
  • MeOH MeOH
  • 10% Pd/C 40.00 mg
  • Step 3 Tert-butyl ((lS)-l-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazin-l-yl)pyridin-2-yl)ethyl)carbamate.
  • Step 4 N-((lS)-l-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l- yl)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.
  • NCI-H226 cells were seeded in triplicates at a density of 800 cells per well in a white 96-well dish. The following day, cells were treated with serial dilutions of degrader ranging logarithmically from 10 4 to 10 pM and incubated for five days. Viability was assessed using the CellTiter-Glo® 2.0 Cell Viability Assay (Promega), following the manufacturer’s instructions. Luminescence data was recorded on a Promega Gio-Max Navigator instrument. Representative normalized values were plotted as percent viability after the five day treatment (FIG. 1).
  • NCI-H226 cells plated at a density of 2 x 10 5 cells per well of a 6-well dish were harvested by trypsinization after treatment.
  • Cell pellets were lysed in 100 pL of RIPA buffer on ice for 30 minutes and sonicated at 50% amplitude for 5 seconds.
  • Samples were centrifuged at 18213 x g for 20 minutes at 4 °C to remove cell debris.
  • Supernatants were diluted 2X Laemmli buffer, boiled at 98°C for 5 minutes, and resolved by SDS-PAGE. Gels were transferred to nitrocellulose membranes using a Bio-RAD Trans-Blot Turbo semi-dry transfer system.
  • blots were stained at 4°C with antibodies to TEAD1 (D9X2L, Cell Signaling #12292, 1:750), TEAD2 (C-10, Santa Cruz # sc- 518181, 1:1000), TEAD3 (Abeam #ab 138246 1:1000), and TEAD4 (5H3, Abeam #ab58310 1:5000), then with appropriate secondary antibodies before development on a Li-COR Odyssey CLx system (FIG. 2).
  • TEAD1 D9X2L, Cell Signaling #12292, 1:750
  • TEAD2 C-10, Santa Cruz # sc- 518181, 1:1000
  • TEAD3 Abeam #ab 138246 1:1000
  • TEAD4 5H3, Abeam #ab58310 1:5000
  • Overexpressed TEAD in HEK293-pTRE-puro-pan-TEAD was conducted as previously described, except that cells were seeded at 1.2- 1.5 x 10 5 cells per well of a 24-well dish and paralogues detected by antibodies to FLAG, Myc, V5, and HA tags.
  • HEK293 ATCC, (RRID: CVCL_0045), NCI-H226 (NCI, (RRID: CVCL_1544) and NCI-H28 (NCI, (RRID: CVCL_1555)
  • DMEM Dulbecco's modified Eagle's Medium
  • HI FBS heat- inactivated fetal bovine serum
  • GibcoTM antibiotic/antimycotic
  • HEK293-PanTEAD cells were created by stable transfection of HEK293 cells with lentivirus containing pTRE-Puro-PanTEAD construct and were maintained in DMEM supplemented with 10 % FBS, 1 % antibiotic/antimycotic, and 2.5 pg ml of puromycin.
  • cDNAs for full-length TEAD1/2/3/4 were PCR amplified with forward primers containing sequences for FLAG, Myc, HA, and V5 epitope tags and sequences for T2A, P2A and E2A and cloned simultaneously into the BamHI and Xbal site in pCDNA3.1 using NEBuilder® HiFi DNA Assembly Kit (New England Biolabs Cat. #E2621).
  • the entire cassette containing all the TEAD was amplified from pCDNA3.1-pan-TEAD and cloned between Mlul and Agel in pTRE by NEBuilder® HiFi DNA Assembly.
  • telomere sequences for YBD of TEAD1-4 were PCR amplified from pCMX-GAL4-TEADl (Addgene #33108), pCMX-GAL4-TEAD2 (Addgene #33107), pCMX-GAL4-TEAD3 (Addgene #33106), pCMX-GAL4-TEAD4 (Addgene #33105), pRK5-Myc-TEAD4 (Addgene #24638), as two overlapping fragments with the mutations introduced in the primers for amplifying them, and cloned into the BamHl site in PGEX-3X plasmid by NEBuilder® HiFi DNA Assembly.
  • HEK293 cells were seeded in antibiotic-free medium at a density of 5 x 10 5 cells per well of a 6- well dish and allowed to attach overnight. Cells were transfected with packaging plasmids psPAX2 and pMD2. G along with the transfer plasmid pTRE-puro-pan-TEAD. After 48 h virus supernatants were collected and filtered through a 0.45 pm syringe filter.
  • 4x lentivirusmaity concentration solution (40 % w/v PEG-8000, 1.2 M NaCl in lx PBS, pH 7.4) was added at a 1:4 to the filtered supernatant and the mixture was rotated end-over-end overnight at 4 °C. The following day, the virus was precipitated by centrifugation at 1600xg for 60 min at 4 °C and diluted in lx PBS. Virus aliquots were stored at -80 °C.
  • Stable cell line generation Lentiviral particles were used to transduce HEK293 cells. 8 pg/mL polybrene was added to antibiotic-free medium containing the viruses to enhance transduction efficiency. Stable clones were established by selection with 2.5 pg/mL puromycin starting 48 h after transduction until distinct colonies formed. Colonies were isolated and screened for expression of epitope-tagged TEAD paralogues by western blotting.
  • Clonogenic assay Clonogenic assays were done as previously described. Briefly, an equal number NCI-H226 cells were plated in triplicate and were treated with DMSO or different doses of HC278 for two weeks, following which they were fixed with 4 % PFA and stained with 0.5 % crystal violet dissolved in methanol. The images were acquired using Gelcount (Oxford Optronix) mammalian-cell colony, spheroid, and organoid counter, and the colony areas were quantified using FIJI.
  • blots were incubated overnight at 4 °C with primary antibodies against TEAD1 (D9X2L, Cell Signaling Technology #12292, 1:750), TEAD2 (C-10, Santa Cruz # sc-518181, 1:1000), TEAD3 (Abeam #ab 138246 1:1000), and TEAD4 (5H3, Abeam #ab58310 1:5000), following which, they were washed thrice with TBST buffer and incubated with appropriate IR Dye 680 or IR Dye 780 conjugated secondary antibodies at room temperature for 2 h.
  • TEAD1 D9X2L, Cell Signaling Technology #12292, 1:750
  • TEAD2 C-10, Santa Cruz # sc-518181, 1:1000
  • TEAD3 Abeam #ab 138246 1:1000
  • TEAD4 5H3, Abeam #ab58310 1:5000
  • blots were washed thrice with TBST and scanned with a Li-COR Odyssey CLx imager.
  • Overexpressed TEAD in HEK293-pTRE-puro-pan-TEAD was conducted as previously described, except that cells were seeded at 1.2- 1.5 x 10 5 cells per well of a 24-well dish and paralogues detected by antibodies against FLAG (1:5000), Myc (1: 5000), HA (1:2000), V5 (1:5000) tags.
  • RNA extraction and RT-qPCR MDA-MB-231 cells were seeded at ⁇ 50 % confluence in 6 well dishes and allowed to attach overnight. Cells were then treated with DMSO or different doses of HC278 (500 nM and 1 pM) for 24 h. Total RNA was extracted with TRIzol reagent (Invitrogen), following the manufacturer's protocol. 1 pg of total RNA was reverse transcribed to cDNA using the iScriptTM gDNA Clear cDNA synthesis kit (Bio-RAD). qPCR was performed with Applied Biosystems Fast SYBR Green master mix on an Applied Biosystems QuantStudio 6 Flex system. Target genes were normalized to GAPDH mRNA levels and relative fold changes were calculated as
  • Cells were collected by centrifuging at 8000 rpm for 10 min and were resuspended in ice-cold lysis buffer (50 mM TRIS pH 7.4, 1 mM EDTA, 150 mM NaCl, 1 mM DTT) supplemented with protease inhibitor cocktail, 0.1 % triton X 100 and Lysozyme, and lysed using sonication and a homogenizer.
  • the soluble fraction was separated by centrifuging at 20,000 rpm for 30 min at 4°C and was incubated with Glutathione Sepharose 4B affinity resin for 2 h. After thorough washing, the protein was eluted with 10 mM glutathione and dialyzed overnight. The purity was verified with SDS-PAGE and Coomassie Brilliant Blue staining.
  • AlphaLISA assay for evaluating the ternary complex formation.
  • AlphaLISA assay was used to evaluate the in vitro ternary complex formation between potential target proteins (GST-tagged TEAD1-4), PROTAC, and CRBN/DDB1 complex (His-tagged CRBN/DDB1 complex). Assays were performed at room temperature. All reagents were diluted in an assay buffer of 50 mM HEPES, pH 7.5, 150 mM NaCl, 0.1 % BSA, and 0.005 % Tween 80.
  • the resulting mixture was transferred to two adjacent wells (17 pL each) of a 384-well white OptiPlate (Cat. No. 6008280, PerkinElmer), and incubated for an additional 18 h in the dark.
  • the luminescence signal was detected on a Biotek's Synergy Neo 2 multimode plate reader installed with an AphaScreen filter cube. Intensity values were plotted in GraphPad Prism with PROTAC concentration values represented on a log 10 scale.
  • NCI-H226 cells were treated in triplicate with either DMSO or 500 nM HC278 for 24 h, following which, the cells were trypsinized and collected by centrifugation.
  • the cell pellets were lysed in RIPA buffer and 15 pL of each sample was diluted to 50 pL with 5 % SDS, 100 mM triethylammonium bicarbonate (TEAB). 2 pL of 500 mM (tris(2-carboxyethyl) phosphine) (TCEP) was added to reduce disulfide bonds and samples were incubated at 56 °C for 30 min.
  • TEAB triethylammonium bicarbonate
  • a high-pH reverse-phase fractionation spin column (Pierce) was used according to the manufacturer's directions to fractionate the sample into 8 fractions.
  • the fractions were dried in a SpeedVac and reconstituted in a 2 % acetonitrile, 0.1 % TFA buffer.
  • Peptides were analyzed on a Thermo Orbitrap Eclipse MS system coupled to an Ultimate 3000 RSLC-Nano liquid chromatography system. Samples were injected onto a 75 pm i. d., 75-cm long EasySpray column (Thermo) and eluted with a gradient from 0 to 28 % buffer B over 180 min at a flow rate of 250 nL/min. Buffer A contained 2 % (v/v) ACN and 0.1 % formic acid in water, and buffer B contained 80 % (v/v) ACN, 10 % (v/v) trifluoroethanol, and 0.1 % formic acid in water, at a flow rate of 250 nL/min.
  • Buffer A contained 2 % (v/v) ACN and 0.1 % formic acid in water
  • buffer B contained 80 % (v/v) ACN, 10 % (v/v) trifluoroethanol, and 0.1 % formic acid in water, at a flow
  • Spectra were continuously acquired in a data-dependent manner throughout the gradient, acquiring a full scan in the Orbitrap (at 120,000 resolution with a standard AGC target) followed by MS/MS scans on the most abundant ions in 2.5 s in the ion trap (turbo scan type with an intensity threshold of 5,000, CID collision energy of 35 %, standard AGC target, maximum injection time of 35 ms and isolation width of 0.7 m/z). Charge states from 2 to 6 were included. Dynamic exclusion was enabled with a repeat count of 1 , an exclusion duration of 25 s and an exclusion mass width of ⁇ 10 ppm.
  • RNA-seq experiment NCI-H226 cells were treated in triplicate with either DMSO or 500 nM HC278 for 24 h, following which, the cells were trypsinized and collected by centrifugation. Total RNA was extracted with TRIzol reagent (Invitrogen) with on-column DNA removal.
  • the RNA sequencing library was prepared using Illumina Stranded mRNA prep kit (20040532) according to Manufacturer's protocol. This protocol requires input RNA with RIN (RNA integrity number) > 7 RNA and concentration range between 25 ng and 1000 ng. Illumina UMI barcodes were used to multiplex the libraries as per the Manufacturer's instructions.
  • each sequencing final library was assessed using Agilent 2100 BioAnalyzer system (Agilent, CA, USA). A total of 10 nM Picogreen measured library were pooled for 1.3 pM loading on the sequencer. The pooled libraries were sequenced on Illumina NexSeq platform in SE75 (75 bp single end) run with the NextSeq reagent kit v2.5 for 75 cycles. About 30-40 Million sequencing reads were generated per sample for the transcriptome analysis. Single end demultiplexed fastq files were generated using bcl2fastq2 (Illumina, v2.17), from NextSeq 550 v2.5 reagent's bcl files.
  • a platform was developed for screening the TEAD degrading activities of the PROTACs (FIG. 3A).
  • the TEAD transcription factors exist in four different paralogs, making it important to determine whether a PROTAC can degrade all four of them or only specific paralogs.
  • a major obstacle is that no single cell line naturally expresses all four TEAD paralogs in detectable amounts, which creates a challenge to assess PROTACs’ ability to selectively degrade specific paralogs using available pan-TEAD antibodies.
  • the commercially available antibodies against different TEAD paralogs are not equally specific.
  • This allows translation of the four different proteins from a single transcript produced under the control of a single promoter, thus eliminating variability due to differing strengths of promoters.
  • This construct successfully produces individually tagged TEAD 1-4.
  • a stable cell line was established harboring this construct, with one of the stable cell clones expressing all four TEAD paralogs, that can be readily detected by commercially available antibodies against the different epitope tags (FIG. 3B).
  • the designed PROTACs were screened at concentrations of 0.1 pM.
  • the TEAD-degrading PROTACs potently degrade TEAD1 and TEAD3. Based on the screening results of all these fourteen compounds, three PROTACs, HC242, HC278, and HC286 were selected for further characterization (FIG. 3). To evaluate the potency of these PROTACs, a dose-response analysis was performed. The cells were treated with varying concentrations of the PROTACs, and the effect on all four TEAD paralogs was assessed by Western blotting, using antibodies against the respective epitope tags.
  • TEAD degrading PROTACs function in a proteasome and CRBN-dependent manner.
  • the HEK293-pan-TEAD cells were treated with 500 nM HC242, HC278, and HC286 for different time periods and TEAD degradation assessed by Western blotting. TEAD1/3 degradation could be detected as early as 2 h after PROTAC treatment and continued to increase over time.
  • HC278-Negl in which the TEAD binding warhead is the enantiomer of the one in HC278, exhibited a much weaker degradative effect (FIGs. 4D-4E).
  • Another negative control, HC278-Neg2 uses the same warhead as in HC278 but contains an altered CRBN ligand that cannot engage with CRBN, failed to induce degradation of the TEAD proteins (FIGs. 4D- 4F). This confirms that the activity of these PROTACs is CRBN-dependent.
  • HC278 can form ternary complex with TEAD1/3 and CRBN/DDB1.
  • TEAD1/3 and CRBN/DDB1 To gain more understanding of HC278-induced isoform selective degradation of TEAD proteins, the in vitro formation of ternary complexes between CRBN/DDB1, HC278, and TEAD 1-4 was measured using the cell-free AlphaLISA assay. For this, GST-tagged TEAD proteins and His-tagged CRBN/DDB1 were used (FIG. 5A). Since recombinant TEAD purified from E. coli is normally bound to palmitic acid, which would prevent binding of the PROTAC to TEAD, the TEAD proteins were purified with the conserved cysteine mutated to alanine.
  • HC278 can form stable ternary complexes with TEAD1 and CRBN/DDB1 complex, which is consistent with the Western blotting data (FIG. 5B).
  • HC278-Negl generated a weak Alpha signal due to its reduced binding affinity to TEAD.
  • HC278-Neg2 which cannot bind to CRBN, also failed to form a stable ternary complex (FIG. 5B).
  • TEAD1 and TEAD3 could form stable ternary complexes with HC278 and CRBN/DDB1
  • TEAD2 and TEAD4 weakly formed ternary complex (FIG. 5C).
  • HC278 selectively depletes TEAD1/3 in the whole proteome.
  • an unbiased global proteomic analysis was performed. NCI-H226 cells were treated with either DMSO or 500 nM of HC278 for 24 h, total protein extracted, and the proteins up or downregulated by HC278 treatment identified. There was significant downregulation of TEAD1 and TEAD3 (FIGs. 6A-6B), while TEAD2 was not detectable, presumably because it is not expressed in these cells.
  • RNA-Seq RNA Sequencing
  • HC278 downregulates TEAD/Y AP-regulated transcriptome. Given that HC278 depletes TEAD1 and TEAD3 and degrades TEAD4 to some extent, it was predicted that it would inhibit TEAD/YAP transcriptional activity. To address this possibility, the RNA-Seq data was compared with published YAP signature data sets. Overall, a small set of genes was found to be downregulated or upregulated by > 2 fold (p ⁇ 0.05) in cells treated with HC278 compared to those treated with DMSO (FIG. 7A). Gene Set Enrichment Analysis (GSEA) of the differentially expressed genes revealed that several gene sets in the MSigDB oncogene dataset were highly enriched (FIG. 7B).
  • GSEA Gene Set Enrichment Analysis
  • the Cordonensi YAP signature gene set is highly downregulated in the differentially expressed genes in cells treated with HC278 (FIGs. 7B-7C). Consistently, a significant number of YAP-target genes such as CTGF, CYR61, and ANKRD1 were significantly downregulated (FIG. 7A). To further verify the RNA-Seq results, transcript levels were examined for well-known YAP target genes such as CTGF, CYR61, and ANKRD1 by quantitative RT-PCR.
  • TEAD-degrading PROTACs inhibit growth of NCI-H226 cells. Inhibition of YAP transcriptional activity by HC278 suggested that it can potentially inhibit the proliferation of YAP- driven cancer cells. HCNCI-HC226 mesothelioma cells harbor deletions in NF2, causing activation of YAP. Genetic studies have established that they exhibit vulnerability to loss of YAP/TEAD activity. Furthermore, several TEAD palmitoylation inhibitors are known to inhibit the proliferation of these cells.
  • the oncogenic transcriptional activators YAP/TAZ function as the terminal effectors of the Hippo signaling pathway and are frequently hyperactivated in many human cancers. Thus, they provide a critical point for therapeutic intervention in cancers. YAP/TAZ exert their oncogenic activity by regulating gene expression by associating primarily with the TEAD transcription factors. Thus, YAP activity can be impaired by inhibiting TEAD.
  • the TEAD transcription factors exist as four different paralogs TEAD 1-4, which are highly similar in sequence and structure. A unique feature of TEAD proteins is that they get autopalmitoylated, and inhibiting this posttranslational modification interferes with their function. Therefore, several TEAD palmitoylation inhibitors have been developed over the last few years.
  • TEAD degraders that can potently degrade TEAD1 and TEAD3 at low nanomolar concentrations while degrading TEAD2 and 4 only at higher doses were developed and characterized. These molecules degrade TEAD in a proteasome and CRBN-dependent manner and inhibit YAP transcriptional response. Consistently they exhibit antiproliferative effects on the YAP-dependent mesothelioma cells. This has important biological and clinical implications for treatment of disease conditions that are primarily dependent on TEAD1 and TEAD3. Investigations will be required to determine if the TEAD degraders have an advantage over the autopalmitoylation inhibitors with respect to the development of resistance.
  • PROTACs developed from non-selective ligands can degrade specific paralogs depending on the linker length, type, and geometry of orientation, which together can affect stable ternary complex formation. Further studies are needed to elucidate the structural basis that governs the ternary complex formation.
  • HC278 specifically degrades TEAD1 and TEAD3, and several other proteins were downregulated with HC278 treatment.
  • transcriptome analysis revealed that these proteins were transcriptionally regulated by TEAD.
  • GSEA revealed that the YAP signature gene set was specifically downregulated upon HC278 treatment, indicating that HC278 specifically inhibits YAP transcriptional activities.
  • the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claims that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features.

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Abstract

The present disclosure provides compounds of the formulae herein (e.g., Formula (I), Formula (IV), Formula (V)), and pharmaceutically acceptable salts thereof, and compositions and kits comprising the compounds, or pharmaceutically acceptable salts thereof, which are useful for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4). The present disclosure also provides methods of treating or preventing diseases (e.g., diseases associated with a TEAD protein) by administering the compounds, or pharmaceutically acceptable salts thereof, or compositions thereof, to a subject in need thereof.

Description

BIFUNCTIONAL TEAD DEGRADERS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63/626,113, filed January 29, 2024, titled BIFUNCTIONAL TEAD DEGRADERS, the contents of which are incorporated herewith by reference in their entirety.
GOVERNMENT SUPPORT
[0002] This invention was made with government support under Grant Numbers CA242003 and CA1241191 awarded by the National Institutes of Health. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION
[0003] The Hippo signaling pathway plays a critical role in cell proliferation, survival, differentiation, and tissue homeostasis. The pathway consists of a core kinase cascade that negatively regulates the paralogous oncogenic transcriptional coactivators, Yes Associated Protein (YAP) and Transcriptional Activator with PDZ-binding motif (TAZ). The kinase cascade consists of the serine threonine kinases MST1/2 and Large Tumor Suppressor 1/2 (LATS1/2), and their obligate adapters SAV and MOB1A/B respectively, where MST1/2 phosphorylates and activates LATS1/2, which in turn phosphorylates YAP/TAZ. Phosphorylated YAP/TAZ gets sequestered in the cytoplasm and gets ubiquitinated and degraded. Inactivation of the Hippo pathway leads to hypo/dephosphorylation of YAP/TAZ and translocation into the nucleus, where it associates with transcription factors such as TEAD1-4, SMAD3 and RUNX. Of these transcription factors, TEAD1-4 mediate the regulation of majority of the YAP-target genes, which encode various cytokines and matricellular proteins that promote cell proliferation and inhibit apoptosis.
SUMMARY OF THE INVENTION
[0004] The compounds of the present disclosure can recruit ubiquitin E3 ligase (e.g., VHL, CRBN, and lAPs) to the vicinity of TEAD proteins, triggering their polyubiquitination and subsequent proteasomal degradation. Thus, the compounds of the present disclosure may be useful in treating diseases and conditions associated with TEAD activation. [0005] In one aspect, the present disclosure provides compounds of Formula (I): or pharmaceutically acceptable salts thereof, wherein E1, L2, and Y are as defined herein.
[0006] In another aspect, the present disclosure provides compounds of Formula (IV): or pharmaceutically acceptable salts thereof, wherein L1, L2, and Y are as defined herein.
[0007] In another aspect, the present disclosure provides compounds of Formula (V): or pharmaceutically acceptable salts thereof, wherein L1, L2, L3, L4, and X are as defined herein. [0008] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein. In some embodiments, the pharmaceutical composition comprises an excipient.
[0009] In another aspect, the present disclosure provides methods of degrading a TEAD protein in a subject or in a cell, tissue, or biological sample, the methods comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition.
[0010] In another aspect, the present disclosure provides methods of treating or preventing a disease in a subject in need thereof, the methods comprising administering to the subject in need thereof a therapeutically effective amount of a provided compound or pharmaceutical composition.
[0011] In another aspect, the present disclosure provides kits comprising a provided compound or pharmaceutical composition disclosed herein and instructions for its use. [0012] 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. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows anti-proliferation effects of representative TEAD degraders in NCI-H226 cells. [0014] FIG. 2 shows that representative TEAD degraders destabilize multiple TEAD paralogues in NCI-H226 cells.
[0015] FIGs. 3A-3F show that HC242, HC278, and HC286 selectively degrade TEAD1 and TEAD3. FIG. 3A shows a schematic of the pTRE-panTEAD plasmid showing TEAD 1-4 with FLAG, MYC, HA, and V5 tags interspersed with T2A, P2A, and E2A coding sequences to produce epitopetagged TEAD paralogs from a single transcript produced from the CMV promoter. FIG. 3B shows Western blotting showing isolation of a stable cell clone that expresses FLAG-TEAD1, MYC- TEAD2, V5-TEAD3, and HA-TEAD4. FIG. 3C shows chemical structures of HC242, HC278, and HC286. FIGs. 3D-3F show representative Western blots (top) and histograms (bottom) showing dose-dependent degradation of TEAD by HC242, HC278, and HC286. HEK293 stable cells expressing epitope-tagged TEAD 1-4, were treated with indicated doses of HC242, HC278, and HC286 for 18 h, and the level of TEAD1-4 was detected by Western blotting using antibodies against the corresponding epitope tags. Actin was used as a control for loading, transfer, and normalization. Histograms show mean + SEM (n = 3). *: p < 0.05.
[0016] FIGs. 4A-4F show TEAD degrading PROTACs function in proteasome and CRBN- dependent manner. FIGs. 4A-4C show representative Western Blots (top) and histograms (bottom) showing inhibition of HC242-induced TEAD degradation by MG132 and the warhead WH15 (FIG. 4A) or Ex. 29 (FIGs. 4B-4C). HEK293 stable cells expressing epitope-tagged TEAD1-4, treated with DMSO, or 500 nM HC242 (FIG. 4A), HC278 (FIG. 4B) or HC286 (FIG. 4C) without or with 1 pM MG132 or 500 nM WH15 or Ex. 29 for 18 h, and the level of TEAD1-4 was detected by Western blotting using antibodies against the corresponding epitope tags. Actin was used as a control for loading and transfer. Histograms show mean + SEM (n = 3). FIG. 4D shows chemical structures of the negative controls HC278-Negl and HC278-Neg2. FIGs. 4E-4F show HEK293 stable cells expressing epitope-tagged TEAD 1-4 were treated with indicated doses of HC278-Negl (FIG. 4E) or HC278-Neg2 (FIG. 4F) for 18 h and the level of TEAD1-4 was detected by Western blotting using antibodies against the corresponding epitope-tags. Actin was used as a control for loading and transfer.
[0017] FIGs. 5A-5C show HC278 induces ternary complex formation between TEAD1/3 and CRBN/DDB 1. FIG. 5A shows a schematic illustration of the ternary complex formation assay using AlphaLISA assay. FIGs. 5B-5C show ternary complex formation between the CRBN/DDB1, compounds, and TEAD1 (FIG. 5B) or TEAD1-4 (FIG. 5C) based on in vitro AlphaLISA assay. Data are shown as mean + SEM (n = 3).
[0018] FIGs. 6A-6F show proteomic and RNA-seq profiling of HC278 -mediated degradation. FIG. 6A shows a scatterplot depicting the log2 (Fold Change) of relative protein abundance in NCI- H226 cells treated with HC278 (500 nM, 24 h) compared to those treated with DMSO in TMT proteomic profiling. FIG. 6B shows a scatterplot depicting the log2 (Fold Change) of relative protein abundance in NCI-H226 cells treated with HC278 (500 nM, 24 h) compared to those treated with DMSO in RNA-seq profiling. FIG. 6C shows top hits identified by TMT (FIG. 6A) proteomic profiling. FIG. 6D shows top hits identified by RNA-seq profiling (FIG. 6B). FIGs. 6E-6F show representative Western Blot (FIG. 6E) and Histograms (FIG. 6F) showing the effect of 100 nM and 500 nM HC278 on different TEAD paralogs and YAP in NCI-H226 cells treated for 18 h. Actin was used as the control for loading, transfer, and normalization. Histograms depict mean + SEM (n = 3). [0019] FIGs. 7A-7D show TEAD-degrading PROTACs inhibit YAP transcriptional activity. FIG. 7A shows a heatmap showing transcripts upregulated and downregulated in NCI-H226 cells treated with 500 nM of HC278 for 24 h. FIG. 7B shows GSEA Enrichment plot of Differentially expressed genes in the MSigDB oncogenes data set. FIG. 7C shows enrichment plot for Gene Set Enrichment Analysis for YAP signature gene set. FIG. 7D shows histograms showing relative expression of CTGF, CYR61, and ANKRD1 mRNA levels in NCI-H226 cells treated with DMSO or indicated doses of HC278. Data are shown as mean + SEM (n = 3). * = p < 0.05.
[0020] FIGs. 8A-8F show TEAD-degrading PROTACs inhibit the colony forming ability of NCI- H226 cells through representative images and histograms showing colony formation assay for NCIH226 (FIGs. 8A-8C) or NCI-H28 (FIGs. 8D-8F) control cells, treated with DMSO or indicated doses of HC242 (FIGs. 8A, 8D), HC278 (FIGs. 8B, 8E) or HC286 (FIGs. 8C, 8F). Histograms show normalized colony area for DMSO and HC242 treated NCI-H226 and NCI-H28 cells, (n = 3). *: p < 0.05, ns: Not significant.
[0021] FIG. 9 shows chemical structures of control compounds HC278-Negl and HC278-Neg2, and warhead WH15 and Ex. 29.
DEFINITIONS
[0022] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’ s Advanced Organic Chemistry, 7th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.
[0023] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
[0024] In a formula, the bond is a single bond, the dashed line - is a single bond or absent, and the bond =-= or = is a single or double bond.
[0025] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19F with 18F, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
[0026] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6 alkyl” encompasses, C1, C2, C3, C4, C5, Ce, C1-6, C1-5, C1^t, C1-3, C1-2, C2-6, C2-5, C2 4, C2-3, C3-6, C3-5, C s 4, C4-6, C4-5, and C5-6 alkyl.
[0027] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1^t alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) e.g., n-propyl, isopropyl), butyl (C4) (e.g., zz-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (Ce) (e.g., zr-hexyl). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, 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). In certain embodiments, the alkyl group is an unsubstituted C1-12 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z'-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted zz-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z'-Bu)). In certain embodiments, 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)).
[0028] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 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 1 to 20 carbon atoms (“C1-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“C1-i2 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“C1-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“C1-10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1-9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1-8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“C1-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“C1^t alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“C1 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 C1 4 alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), 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 C1-20 alkenyl. In certain embodiments, the alkenyl group is a substituted Cr2o alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 or may be in the (E)- or
(Z)-configuration.
[0029] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 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 1 to 10 carbon atoms (“C1-io alkynyl”). In some embodiments, an alkynyl group has 1 to 9 carbon atoms (“C1-9 alkynyl”). In some embodiments, an alkynyl group has 1 to 8 carbon atoms (“C1-8 alkynyl”). In some embodiments, an alkynyl group has 1 to 7 carbon atoms (“C1-7 alkynyl”). In some embodiments, an alkynyl group has 1 to 6 carbon atoms (“C1-6 alkynyl”). In some embodiments, an alkynyl group has 1 to 5 carbon atoms (“C1-5 alkynyl”). In some embodiments, an alkynyl group has 1 to 4 carbon atoms (“C1-4 alkynyl”). In some embodiments, an alkynyl group has 1 to 3 carbon atoms (“C1-3 alkynyl”). In some embodiments, an alkynyl group has 1 to 2 carbon atoms (“C1-2 alkynyl”). In some embodiments, an alkynyl group has 1 carbon atom (“C1 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 C1-4 alkynyl groups include, without limitation, methylidynyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2- butynyl (C4), and the like. Examples of C1-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl 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 C1-20 alkynyl. In certain embodiments, the alkynyl group is a substituted C1-20 alkynyl. [0030] The term “carbocyclyl” or “carbocyclic” 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. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3 -14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3 -13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, 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”). In some embodiments, 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 (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- IH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3 8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, 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 can contain one or more carbon-carbon double or triple bonds. “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. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.
[0031] In some embodiments, “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”). In some embodiments, 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). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits. [0032] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered nonaromatic 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”). In 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 continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 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.
[0033] In some embodiments, 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”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 - ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, 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”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 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.
[0034] 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- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1,4,5 ,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H- furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo- [2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.
[0035] The term “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 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“ C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C1o aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu 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. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-i4 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.
[0036] The term “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 n 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”). In heteroaryl groups that contain one or more nitrogen atoms, 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 on either ring, e.g., either the ring bearing a heteroatom e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5 -indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.
[0037] In some embodiments, 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”). In some embodiments, 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”). In some embodiments, 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”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
[0038] 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, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
[0039] The term “unsaturated bond” refers to a double or triple bond.
[0040] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
[0041] 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.
[0042] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.
[0043] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “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. Unless otherwise indicated, 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. The term “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 disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.
[0044] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3 +X-, -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3 -C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3 +X-, -P(ORCC)3 +X’, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3 +X’, -OP(ORCC)2, -OP(ORCC)3 +X-, -OP(RCC)4, -OP(ORcc)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), C1 20 alkyl, C1 20 perhaloalkyl, C1 20 alkenyl, C1-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X- is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; wherein: each instance of Raa is, independently, selected from C1-20 alkyl, C1-20 perhaloalkyl, C1-2o alkenyl, C1-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5- 14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rbb is, independently, selected from hydrogen, -OH, -OR311, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, CI 20 alkyl, C1 20 perhaloalkyl, C1-2o alkenyl, C1-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5- 14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rcc is, independently, selected from hydrogen, C1-20 alkyl, C1-20 perhaloalkyl, C1-20 alkenyl, C1-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, G> 14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3 +X-, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-10 alkyl, C1-10 perhaloalkyl, C1-10 alkenyl, C1-10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, G> 10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents are joined to form =0 or =S; wherein X- is a counterion; each instance of Ree is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, 10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C1-10 alkenyl, C1-10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce 10 aryl, and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each X- is a counterion.
[0045] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SR311, -N(Rbb)2, -CN, -SCN, -NO2, -C(=0)R33, -CO2R33, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCChR33, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -C(=O)Raa, -CChR33, -C(=O)N(Rbb)2, -0C(=0)R33, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raa is hydrogen, substituted e.g., substituted with one or more halogen) or unsubstituted C1-io 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-pyridine- sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, or -NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1-10 alkyl, -OR33, -SR33, -N(Rbb)2, - CN, -SCN, or -NO2, wherein R33 is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io 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-pyridine- sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). [0046] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
[0047] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxy,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=O)SRaa, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=O)Raa, -OSO2Raa, -OSi(Raa)3, -OP(RCC)2, -OP(RCC)3 +X-, -OP(ORCC)2, -OP(ORCC)3 +X-, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, and -OP(=O)(N(Rbb))2, wherein X-, Raa, Rbb, and Rcc are as defined herein.
[0048] The term “thiol” or “thio” refers to the group -SH. The term “substituted thiol” or “substituted thio,” by extension, refers to a thiol group wherein the sulfur atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from - SRaa, -S=SRCC, -SC(=S)SRaa, -SC(=S)ORaa, -SC(=S) N(Rbb)2, -SC(=O)SRaa, -SC(=O)ORaa, - SC(=O)N(Rbb)2, and -SC(=O)Raa, wherein Raa and Rcc are as defined herein.
[0049] The term “amino” refers to the group -NH2. The term “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. [0050] The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=O)Raa, -NHCO2Raa, -NHC(=O)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, -NHSO2Raa, -NHP(=O)(ORCC)2, and -NHP(=O)(N(Rbb)2)2, wherein Raa, Rbb and Rcc are as defined herein, and wherein Rbb of the group -NH(Rbb) is not hydrogen.
[0051] The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbb C(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbSO2Raa, -NRbbP(=O)(ORcc)2, and -NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rcc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
[0052] The term “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(Rbb)3 and -N(Rbb)3 +X-, wherein Rbb and X- are as defined herein.
[0053] The term “carbonyl” refers to a group wherein the carbon directly attached to the parent molecule is sp2 hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (-C(=O)Raa), carboxylic acids (-CO2H), aldehydes (-CHO), esters (-CO^,- C(=O)SRaa, -C(=S)SRaa), amides (-C(=O)N(Rbb)2, -C(=O)NRbbSO2Raa, -C(=S)N(Rbb)2), and imines (-C(=NRbb)Raa, -C(=NRbb)ORaa), -C(=NRbb)N(Rbb)2), wherein Raa and Rbb are as defined herein. [0054] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOFT. -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(ORCC)2, -P(=O)(Raa)2, -P(=O)(N(RCC)2)2, CI 2O alkyl, C i-2o perhaloalkyl, C1-20 alkenyl, C1-2o alkynyl, hetero C1-20 alkyl, hetero C1-20 alkenyl, hetero C1- 20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -14 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein R“ Rbb, Rcc and Rdd are as defined above.
[0055] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, or a nitrogen protecting group. In certain embodiments, 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. [0056] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOFT. -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C1-2o alkenyl, C1-20 alkynyl, hetero C1-2o alkyl, hetero C1-2o alkenyl, hetero C1-20 alkynyl, C3 10 carbocyclyl, 3-14 membered heterocyclyl, Ce 14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein. 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[0057] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, 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, (iV’-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-nitrobutanamide, o-nitrocinnamide, acctylmcthioninc derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.
[0058] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -C(=O)ORaa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, 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), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'~ and 4'-pyridy l)cthy 1 carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cy anoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m- nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6- nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(A,iV-dimethylcarboxamido)benzyl carbamate, 1 , 1 -dimethyl-3-(iV,iV- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate, 1 -methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, 1 -methyl- 1- (3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l- phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0059] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that include the nitrogen atom to which the nitrogen protecting groups (e.g., -S(=O)2Raa) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, 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), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4/,8/-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
[0060] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, A’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, A-benzoylphenylalanyl derivatives, A-acctylmcthioninc derivatives, 4,5-diphenyl-3-oxazolin-2-one, A-phthalimide, A-dithiasnccinimidc (Dts), A-2,3-diphcnylmalcimidc, A-2,5-dimcthy I pyrrole, N-l , 1 ,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1, 3 -dibenzyl- 1,3,5 - triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, A-methylamine, A-allylamine, A-[2- (trimethylsilyl)ethoxy]methylamine (SEM), A-3-acetoxypropylamine, A-(l-isopropyl-4-nitro-2-oxo- 3-pyroolin-3-yl)amine, quaternary ammonium salts, A-benzylamine, A-di(4- methoxyphenyl)methylamine, A-5-dibenzosuberylamine, A-triphenylmethylamine (Tr), A-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), A-9-phenylfluorenylamine (PhF), A-2,7-dichloro-9- fluorenylmethyleneamine, N- ferrocenyl ethyl amino (Fem), A-2-picolylamino N ’-ox ide, A- 1,1- dimethylthiomethyleneamine, A-benzylideneamine, A-p-methoxybenzylideneamine, A- diphenylmethyleneamine, A-[(2-pyridyl)mesityl]methyleneamine, A-(A’,A’- dime thylaminome thy lene) amine, A-p-nitrobenzylideneamine, A-salicylideneamine, A-5- chlorosalicylideneamine, A-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, A- cyclohexylideneamine, AH5,5-dimcthyl-3-oxo- l -cyclohexenyl)amine, A-borane derivatives, N- diphenylborinic acid derivatives, A-[phenyl(pentaacylchromium- or tungsten)acyl]amine, X-coppcr chelate, A-zinc chelate, A-nitroamine, A-nitrosoamine, amine iV-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2- nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’ -isopropylidenediamine.
[0061] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
[0062] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, -C(=O)Raa, -CC>2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CC>2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, or a nitrogen protecting group. In certain embodiments, 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. [0063] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3 +X’, -P(ORCC)2, -P(ORCC)3 +X-, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein X-, Raa, Rbb, and Rcc are as defined herein. 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[0064] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, 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), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxy cyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl .S',.S'-dioxidc, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8- trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1 -methyl- 1- methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, benzyl (Bn),p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3- methyl-2-picolyl tV-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4'-dimethoxytrityl (4,4'-dimethoxytriphenylmethyl or DMT), a- naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p- methoxyphenyl)methyl, 4-(4’ -bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5- dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4, 4', 4"- tris(benzoyloxyphenyl)methyl, 4,4’-Dimethoxy-3"‘-[N-(imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4’-Dimethoxy-3"‘-[N-(imidazolylethyl)carbamoyl]trityl Ether (lETr-OR), 1 ,l-bis(4- methoxyphenyl)-r-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri- p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxy acetate, triphenylmethoxy acetate, phenoxy acetate, p-chlorophenoxy acetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o- nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6- dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l , 1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4- bis(l,l-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl X-phcnylcarbamatc, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). [0065] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.
[0066] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-io alkyl, or a nitrogen protecting group. In certain embodiments, 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. [0067] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CC>2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X-, -P(ORCC)2, -P(ORCC)3 +X-, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein Raa, Rbb, and Rcc are as defined herein. Sulfur 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[0068] In certain embodiments, 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. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms. In certain embodiments, 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.
[0069] 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", CP, Br , I"), NO3", CIO4 , OH , H2PO4 , HCOf, HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5- sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
[0070] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
[0071] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.
[0072] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the above exemplary listing of substituents.
[0073] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include 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 the present disclosure include those derived from inorganic and organic acids and bases. Examples of 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 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. 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. [0074] The term “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 the present 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, 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. 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 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.
[0075] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. [0076] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. 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. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [0077] The terms “composition” and “formulation” are used interchangeably.
[0078] A “subject” to which administration is contemplated 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. In certain embodiments, the nonhuman 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)). In certain embodiments, 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. The term “patient” refers to a human subject in need of treatment of a disease. [0079] The term “biological 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). Other examples of 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.
[0080] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
[0081] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, 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.
[0082] The terms “condition,” “disease,” and “disorder” are used interchangeably.
[0083] 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. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, 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. In certain embodiments, 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).
[0084] In certain embodiments, 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.
[0085] In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 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 effect.
[0086] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided 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.
[0087] 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 encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4). In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a cancer (e.g., a cancer associated with a TEAD protein (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer)). In certain embodiments, a therapeutically effective amount is an amount sufficient for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) and treating a cancer (e.g., a cancer associated with a TEAD protein (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer)).
[0088] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4). In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a cancer (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer). In certain embodiments, a prophylactically effective amount is an amount sufficient for degrading a TEAD protein e.g., TEAD1, TEAD2, TEAD3, TEAD4) and preventing a cancer (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer).
[0089] 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. In certain embodiments, 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.
[0090] As used herein, the term “degrade” or “degradation” in the context of proteins, for example, in the context of degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4), refers to a reduction in the amount of the protein. In some embodiments, the term refers to a reduction of the amount of protein, e.g., a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4), to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of amount of the protein. In some embodiments, the term refers to a reduction of the amount of protein, e.g., a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4), to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of the amount of protein.
[0091] The term “about X,” where X is a number or percentage, refers to a number or percentage that is between 99.5% and 100.5%, between 99% and 101%, between 98% and 102%, between 97% and 103%, between 96% and 104%, between 95% and 105%, between 92% and 108%, or between 90% and 110%, inclusive, of X.
[0092] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
[0093] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and/or is associated with a disease.
[0094] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
[0095] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and nonHodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (z.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T- cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).
[0096] Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. [0097] Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon a, interferon y), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g., HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)).
[0098] Exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrclin and leuprolide), anti-androgens (e.g., flutamide and bicalutamide), photodynamic therapies (e.g., vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g., busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide), platinum containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g., paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., ’2’ -paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5 -fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., l-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycin (e.g., actinomycin D, dactinomycin), bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca2+ ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI- 272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF- 02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ- 26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM- 121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,, aminopterin, and hexamethyl melamine.
[0099] A “protein,” “peptide,” or “polypeptide” comprises a polymer of amino acid residues linked together by peptide bonds. The term refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein will be at least three amino acids long. A protein may refer to an individual protein or a collection of proteins. Inventive proteins preferably contain only natural amino acids, although non-natural amino acids (z.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and/or amino acid analogs as are known in the art may alternatively be employed. Also, one or more of the amino acids in a protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification. A protein may also be a single molecule or may be a multi- molecular complex. A protein may be a fragment of a naturally occurring protein or peptide. A protein may be naturally occurring, recombinant, synthetic, or any combination of these.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0100] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. Compounds
[0101] In one aspect, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen or optionally substituted alkyl; each instance of X is independently CH or N;
L2 is optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R2 is independently hydrogen or optionally substituted alkyl; and
Y is a moiety capable of binding to an E3 ubiquitin ligase.
[0102] In another aspect, the present disclosure provides a compound of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen or optionally substituted alkyl; each instance of X is independently CH or N; L2 is optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R2 is independently hydrogen or optionally substituted alkyl; and
Y is of Formulae (II- a), (Il-b), or (II-c): wherein:
R3 is hydrogen or optionally substituted alkyl;
R4 is optionally substituted alkyl or optionally substituted cycloalkyl; and
R5 is optionally substituted alkyl or optionally substituted cycloalkyl.
[0103] In another aspect, the present disclosure provides a compound of Formula (V):
R1 is hydrogen or optionally substituted alkyl; each instance of X is independently CH or N;
L2 is optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R2 is independently hydrogen or optionally substituted alkyl;
L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; and
L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof.
R1, X, and L1
[0104] As generally described herein, R1 is hydrogen or optionally substituted alkyl.
[0105] In some embodiments, R1 is hydrogen.
[0106] In some embodiments, R1 is optionally substituted alkyl. In some embodiments, R1 is optionally substituted C1-12 alkyl, optionally substituted C1-11 alkyl, optionally substituted C1-10 alkyl, optionally substituted C1-9 alkyl, optionally substituted C1-8 alkyl, optionally substituted C1-7 alkyl, optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted C1-4 alkyl, optionally substituted Cm alkyl, or optionally substituted C1-2 alkyl. In some embodiments, R1 is optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted C1-4 alkyl, optionally substituted Cm alkyl, or optionally substituted C1-2 alkyl.
[0107] In some embodiments, R1 is optionally substituted C1-12 alkyl. In some embodiments, R1 is optionally substituted C1-11 alkyl. In some embodiments, R1 is optionally substituted C1-10 alkyl. In some embodiments, R1 is optionally substituted C1-9 alkyl. In some embodiments, R1 is optionally substituted Cm alkyl. In some embodiments, R1 is optionally substituted C1-7 alkyl. In some embodiments, R1 is optionally substituted C1-6 alkyl. In some embodiments, R1 is optionally substituted C1-5 alkyl. In some embodiments, R1 is optionally substituted CM alkyl. In some embodiments, R1 is optionally substituted C1-3 alkyl. In some embodiments, R1 is optionally substituted C1-2 alkyl.
[0108] In some embodiments, R1 is substituted alkyl. In some embodiments, R1 is substituted C1-12 alkyl, substituted C1-11 alkyl, substituted C1-10 alkyl, substituted C1-9 alkyl, substituted Cm alkyl, substituted C1-7 alkyl, substituted Cm alkyl, substituted Cm alkyl, substituted C1-4 alkyl, substituted Cm alkyl, or substituted Cm alkyl. In some embodiments, R1 is substituted Cm alkyl, substituted Cm alkyl, substituted C1-4 alkyl, substituted Cm alkyl, or substituted Cm alkyl.
[0109] In some embodiments, R1 is substituted C1-12 alkyl. In some embodiments, R1 is substituted C1-i i alkyl. In some embodiments, R1 is substituted C1-io alkyl. In some embodiments, R1 is substituted C1-9 alkyl. In some embodiments, R1 is substituted C1-8 alkyl. In some embodiments, R1 is substituted C1-7 alkyl. In some embodiments, R1 is substituted C1-6 alkyl. In some embodiments, R1 is substituted C1-5 alkyl. In some embodiments, R1 is substituted C1-4 alkyl. In some embodiments, R1 is substituted C1-3 alkyl. In some embodiments, R1 is substituted C1-2 alkyl.
[0110] In some embodiments, R1 is C1-6 alkyl, C1-5 alkyl, CM alkyl, C1-3 alkyl, or C1-2 alkyl substituted with halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -ORA, -SCN, -SRA, -SSRA, -N3, - NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, -C(=NRA)RA, - C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, - S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, - OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, - OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, - OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, - NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, - NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, - NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, - NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, - OSi(RA)(ORA)2, -OSi(ORA)a, and/or -B(ORA)2, wherein each instance of RA is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, 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 instances of RA are joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
[0111] In some embodiments, R1 is unsubstituted alkyl. In some embodiments, R1 is unsubstituted C1-i2 alkyl, unsubstituted Cm alkyl, unsubstituted C1-10 alkyl, unsubstituted C1-9 alkyl, unsubstituted C1-8 alkyl, unsubstituted C1-7 alkyl, unsubstituted C1-6 alkyl, unsubstituted C1-5 alkyl, unsubstituted C1-4 alkyl, unsubstituted C1-3 alkyl, or unsubstituted C1-2 alkyl. In some embodiments, R1 is unsubstituted C1-6 alkyl, unsubstituted C1-5 alkyl, unsubstituted C1-4 alkyl, unsubstituted C1-3 alkyl, or unsubstituted C1-2 alkyl.
[0112] In some embodiments, R1 is unsubstituted Cm alkyl. In some embodiments, R1 is unsubstituted Cm alkyl. In some embodiments, R1 is unsubstituted C1-10 alkyl. In some embodiments, R1 is unsubstituted C1-9 alkyl. In some embodiments, R1 is unsubstituted C1-8 alkyl. In some embodiments, R1 is unsubstituted C1-7 alkyl. In some embodiments, R1 is unsubstituted C1-6 alkyl. In some embodiments, R1 is unsubstituted C1-5 alkyl. In some embodiments, R1 is unsubstituted CM alkyl. In some embodiments, R1 is unsubstituted C1-3 alkyl. In some embodiments, R1 is unsubstituted C1-2 alkyl.
[0113] In some embodiments, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl, or /z-hcxyl. In some embodiments, R1 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, or /z-hcxyl. In some embodiments, R1 is methyl, ethyl, or n-propyl. In some embodiments, R1 is methyl (-CH3).
[0114] As generally described herein, each instance of X is independently CH or N.
[0115] In some embodiments, at least one instance of X is CH. In some embodiments, at least one instance of X is N.
[0116] As generally described herein, L1 is of formula:
In some embodiments, L1 is of formula: formula:
[0119] In some embodiments, L1 is of formula:
In some embodiments, L1 is of formula: some embodiments, L1 is of -6 alkyl. In some embodiments, L1 is of formula: hydrogen or optionally substituted Cm alkyl. In some embodiments, L1 is of formula: hydrogen or optionally substituted [0121] In some embodiments, L1 is of formula:
In some embodiments, L1 is of formula: some embodiments, L1 is of -6 alkyl. In some hydrogen or optionally substituted Cm alkyl. In some embodiments, L1 is of formula: methyl. In some embodiments, L1 is of formula: and R1 is hydrogen or unsubstituted C1-6 alkyl. In some embodiments, L1 is of formula: is hydrogen or methyl. substituted alkyl. In some embodiments, L1 is of formula: optionally substituted alkyl. In some embodiments, L1 is of alkyl. In some embodiments, L1 is of formula: and R1 is optionally substituted C1-3 alkyl. In some embodiments, L1 is of formula: s optionally substituted methyl. In some unsubstituted C1-3 alkyl. In some embodiments, L1 is of formula:
[0125] In some embodiments, L1 is of formula: and R1 is hydrogen or optionally substituted C1-6 alkyl. In some embodiments, L1 is of formula: hydrogen or optionally substituted methyl. In some embodiments, unsubstituted C1-6 alkyl. In some embodiments, L1 is of formula: hydrogen or unsubstituted Cm alkyl. In some embodiments, L1 is of embodiments,
L2 and R2
[0128] As generally described herein, L2 is optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. [0129] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-, -NR2-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene.
[0130] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, -NR2-, — C(— O)— , or optionally substituted heterocyclylene.
[0131] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-. In some embodiments, L2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with -O-. In some embodiments, L2 comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with -O-. In some embodiments, L2 comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with -O-.
[0132] In some embodiments, L2 comprises -O-. In some embodiments, L2 comprises , wherein n is 1, 2, 3, 4, or 5; and p is 1, 2, 3, or 4. In some embodiments, L2 comprises
[0133] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR2-. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-. In some embodiments, L2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with -NR2-. In some embodiments, L2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with -NH-.In some embodiments, L2 comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with -NH-.In some embodiments, L2 comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with -NH-.
[0134] In some embodiments, L2 comprises -NH-. In some embodiments, L2 comprises
[0135] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-. In some embodiments, L2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with — C(=O)— . In some embodiments, L2 comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with — C(=O)— . In some embodiments, L2 comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with -C(=O)-.
[0136] In some embodiments, L2 comprises -C(=O)-. In some embodiments, L2 comprises
O or O , wherein each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
In some embodiments, L2 comprises is independently CH or N; each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, or 5; and each p is independently 1, 2, 3, or 4. In some embodiments, L2
[0138] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 3-10 membered heterocyclylene. In some embodiments, L2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with optionally substituted 3-10 membered heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1- 20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2 comprises optionally substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted straight-chain C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2 comprises substituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the substituted straight-chain C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms. In some embodiments, L2 comprises unsubstituted straight-chain C1-20 alkylene, wherein at least one backbone carbon atom in the unsubstituted straight-chain C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms. [0139] In some embodiments, L2 comprises
[0140] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are replaced with -O-, -NR2-, — C(— O)— , or optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-. In some embodiments, L2 comprises
[0141] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR2-. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-. In some
[0142] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-. In some embodiments, L2 comprises wherein each wherein n is independently 1, 2, 3, 4, or 5, and each p is independently 1, 2, 3, or 4. In some embodiments, L2 comprises
[0144] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -O-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene.
[0145] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -NR2-. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with
-NH-. In some embodiments, L2 comprises wherein each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and each n is independently 0, 1, 2, 3, 4, or 5. In some embodiments, L2 comprises , , , , , 5, 6, 7,
8, 9, 10, 11, or 12; and each n is independently 0, 1, 2, 3, 4, or 5. In some embodiments, L2 comprises
[0146] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR2-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-. In some is independently CH or N; each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, or 5; and each p is independently 1, 2, 3, or 4. In some embodiments, L2 [0147] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NR2-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -NH-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1- 20 alkylene is replaced with -NH-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene. In some
[0148] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with
— C(— O)— . In some embodiments, L2 comprises O 0 , 0
wherein each instance of X is independently CH or N; each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1,2, 3, 4, or 5; and each p is independently 1, 2, 3, or 4. In some embodiments, L2 comprises O 0 , 0 0 , 0 O , [0149] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with -C(=O)-, and at least one backbone carbon atom in the optionally substituted C1-20 alkylene is replaced with optionally substituted 5-6 membered heterocyclylene. In some embodiments, L2 is independently CH or N; and each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, L2 comprises
[0150] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C1- 20 alkylene, wherein at least two backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with optionally substituted 5-6 membered heterocyclylene. In some
[0151] In some embodiments, L2 comprises optionally substituted C2-20 alkenylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkenylene are independently replaced with -O-, -NR2-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2 comprises optionally substituted C2-20 alkenylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkenylene are independently replaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene. [0152] In some embodiments, L2 comprises optionally substituted C2-20 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkynylene are independently replaced with -O-, -NR2-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2 comprises optionally substituted C2-20 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkynylene are independently replaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene.
[0153] In some embodiments, L2 comprises , wherein each instance of X is independently CH or N. In some embodiments,
[0154] In some embodiments, L2 comprises optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, -S-, -S(=O)-, -S(=O)2- -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
[0155] In some embodiments, L2 comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR2-, -S-, - S(=O)-, -S(=O)2- — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2 comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted 5-6 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted 5-6 membered heterocyclylene are independently replaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted 5-6 membered heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene.
[0156] In some embodiments, L2 comprises
[0157] In some embodiments, L2 comprises optionally substituted C1-20 alkylene and optionally substituted C2-20 alkenylene, optionally substituted C1-20 alkylene and optionally substituted C2-20 alkynylene, optionally substituted C1-20 alkylene and optionally substituted heterocyclylene, optionally substituted C2-20 alkenylene and optionally substituted C2-20 alkynylene, optionally substituted C2-20 alkenylene and optionally substituted heterocyclylene, or optionally substituted C2-20 alkynylene and optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2- — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
[0158] In some embodiments, L2 comprises optionally substituted C1-20 alkylene and optionally substituted C2-20 alkynylene, optionally substituted C1-20 alkylene and optionally substituted heterocyclylene, or optionally substituted C2-20 alkynylene and optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
[0159] In some embodiments, L2 comprises optionally substituted C1-20 alkylene and optionally substituted C2-20 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted C2-20 alkynylene are independently replaced with — O— , -NR2-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene and optionally substituted C2-20 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted C2-20 alkynylene are independently replaced with optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene and optionally substituted C2-20 alkynylene. In some embodiments, L2 comprises optionally substituted C1-10 alkylene and optionally substituted C2-10 alkynylene. In some embodiments, L2 comprises optionally substituted C1-6 alkylene and optionally substituted C2-6 alkynylene. In some embodiments, L2 comprises optionally substituted C1-3 alkylene and optionally substituted C2-3 alkynylene.
[0160] In some embodiments, L2 comprises unsubstituted C1-20 alkylene and unsubstituted C2-20 alkynylene. In some embodiments, L2 comprises unsubstituted C1-10 alkylene and unsubstituted C2-10 alkynylene. In some embodiments, L2 comprises unsubstituted C1-6 alkylene and unsubstituted C2-6 alkynylene. In some embodiments, L2 comprises unsubstituted C1-3 alkylene and unsubstituted C2-3 alkynylene. In some embodiments, L2 comprises methylene, ethylene, or n-propylene; and ethynylene. In some embodiments, L2 comprises methylene and ethynylene.
[0161] In some embodiments, L2 comprises optionally substituted C1-20 alkylene and optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with — O— , -NR2-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene and optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene.
[0162] In some embodiments, L2 comprises optionally substituted C1-10 alkylene and optionally substituted 3-10 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-10 alkylene or optionally substituted 3-10 membered heterocyclylene are independently replaced with -0-, -NR2-, -C(=0)-, or optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-io alkylene and optionally substituted 3-6 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-io alkylene or optionally substituted 3-6 membered heterocyclylene are independently replaced with -O-, -NH-, -C(=O)-, or optionally substituted heterocyclylene.
[0163] In some embodiments, L2 comprises optionally substituted C10-20 alkylene and optionally substituted 3-10 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C 10-20 alkylene or optionally substituted 3-10 membered heterocyclylene are independently replaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C10-20 alkylene and optionally substituted 3-6 membered heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C10-20 alkylene or optionally substituted 3-6 membered heterocyclylene are independently replaced with -O-, -NH-, -C(=O)-, or optionally substituted heterocyclylene.
[0164] In some embodiments, L2 comprises optionally substituted C2-20 alkynylene and optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkynylene or optionally substituted heterocyclylene are independently replaced with — O— , -NR2-, =N-, -N=, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2 comprises optionally substituted C2-20 alkynylene and optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C2 10 alkynylene and optionally substituted 3-6 membered heterocyclylene. In some embodiments, L2 comprises optionally substituted C2-3 alkynylene and optionally substituted 5-6 membered heterocyclylene.
[0165] In some embodiments, L2 comprises unsubstituted C2-20 alkynylene and unsubstituted heterocyclylene. In some embodiments, L2 comprises unsubstituted C2-10 alkynylene and unsubstituted 3-6 membered heterocyclylene. In some embodiments, L2 comprises unsubstituted C2-3 alkynylene and unsubstituted 5-6 membered heterocyclylene. In some embodiments, L2 comprises ethynylene; and piperidinylene or piperazinylene.
[0166] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, and optionally substituted C2-20 alkynylene; optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, and optionally substituted heterocyclylene; optionally substituted C1-20 alkylene, optionally substituted C2-20 alkynylene, and optionally substituted heterocyclylene; or optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, and optionally substituted heterocyclylene; optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
[0167] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, optionally substituted C2-20 alkynylene, and optionally substituted heterocyclylene; optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, - C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene. In some embodiments, L2 comprises optionally substituted C1-20 alkylene, optionally substituted C2-20 alkynylene, and optionally substituted heterocyclylene. In some embodiments, L2 comprises optionally substituted C1-10 alkylene, optionally substituted C2-10 alkynylene, and optionally substituted 3-6 membered heterocyclylene. In some embodiments, L2 comprises optionally substituted Cm alkylene, optionally substituted C2-3 alkynylene, and optionally substituted 5-6 membered heterocyclylene.
[0168] In some embodiments, L2 comprises unsubstituted C1-20 alkylene, unsubstituted C2-20 alkynylene, and unsubstituted heterocyclylene. In some embodiments, L2 comprises unsubstituted C1- 10 alkylene, unsubstituted C2-10 alkynylene, and unsubstituted 3-6 membered heterocyclylene. In some embodiments, L2 comprises unsubstituted Cm alkylene, unsubstituted C2-3 alkynylene, and unsubstituted 5-6 membered heterocyclylene. In some embodiments, L2 comprises methylene, ethylene, or n-propylene; ethynylene; and piperidinylene or piperazinylene.
[0169] In some embodiments, L2 comprises optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, and optionally substituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
[0170] In some embodiments, L2 is of formula: 0 0 , 0 , wherein: each instance of X is independently CH or N; each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, or 5; and each p is independently 1, 2, 3, or 4.
substituted alkyl.
[0173] In some embodiments, at least one instance of R2 is hydrogen.
[0174] In some embodiments, at least one instance of R2 is optionally substituted alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-12 alkyl, optionally substituted C1 11 alkyl, optionally substituted C1-10 alkyl, optionally substituted C1-9 alkyl, optionally substituted C1-8 alkyl, optionally substituted C1-7 alkyl, optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted C1-4 alkyl, optionally substituted C1-3 alkyl, or optionally substituted C1-2 alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-6 alkyl, optionally substituted C1-5 alkyl, optionally substituted C1-4 alkyl, optionally substituted C1-3 alkyl, or optionally substituted C1-2 alkyl.
[0175] In some embodiments, at least one instance of R2 is optionally substituted C1-12 alkyl. In some embodiments, at least one instance of R2 is optionally substituted Cm alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-10 alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-9 alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-8 alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-7 alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-6 alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-5 alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-4 alkyl. In some embodiments, at least one instance of R2 is optionally substituted Cm alkyl. In some embodiments, at least one instance of R2 is optionally substituted C1-2 alkyl.
[0176] In some embodiments, at least one instance of R2 is substituted alkyl. In some embodiments, at least one instance of R2 is substituted C1-12 alkyl, substituted Crn alkyl, substituted C1-10 alkyl, substituted C1-9 alkyl, substituted C1-8 alkyl, substituted C1-7 alkyl, substituted C1-6 alkyl, substituted Cm alkyl, substituted CM alkyl, substituted Cm alkyl, or substituted C1-2 alkyl. In some embodiments, at least one instance of R2 is substituted C1-6 alkyl, substituted C1-5 alkyl, substituted C1-4 alkyl, substituted Cm alkyl, or substituted Cm alkyl.
[0177] In some embodiments, at least one instance of R2 is substituted Cm alkyl. In some embodiments, at least one instance of R2 is substituted Cm alkyl. In some embodiments, at least one instance of R2 is substituted C1-10 alkyl. In some embodiments, at least one instance of R2 is substituted C1-9 alkyl. In some embodiments, at least one instance of R2 is substituted Cm alkyl. In some embodiments, at least one instance of R2 is substituted Cm alkyl. In some embodiments, at least one instance of R2 is substituted Cm alkyl. In some embodiments, at least one instance of R2 is substituted Cm alkyl. In some embodiments, at least one instance of R2 is substituted C1-4 alkyl. In some embodiments, at least one instance of R2 is substituted Cm alkyl. In some embodiments, at least one instance of R2 is substituted Cm alkyl.
[0178] In some embodiments, at least one instance of R2 is Cm alkyl, Cm alkyl, C1-4 alkyl, Cm alkyl, or Cm alkyl substituted with halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, =0, =S, -CN, -ORA, -SCN, -SRA, - SSRA, -N3, -NO, -N(RA)2, -NO2, -C(=O)RA, -C(=O)ORA, -C(=O)SRA, -C(=O)N(RA)2, - C(=NRA)RA, -C(=NRA)ORA, -C(=NRA)SRA, -C(=NRA)N(RA)2, -S(=O)RA, -S(=O)ORA, -S(=O)SRA, -S(=O)N(RA)2, -S(=O)2RA, -S(=O)2ORA, -S(=O)2SRA, -S(=O)2N(RA)2, -OC(=O)RA, -OC(=O)ORA, -OC(=O)SRA, -OC(=O)N(RA)2, -OC(=NRA)RA, -OC(=NRA)ORA, -OC(=NRA)SRA, - OC(=NRA)N(RA)2, -OS(=O)RA, -OS(=O)ORA, -OS(=O)SRA, -OS(=O)N(RA)2, -OS(=O)2RA, - OS(=O)2ORA, -OS(=O)2SRA, -OS(=O)2N(RA)2, -ON(RA)2, -SC(=O)RA, -SC(=O)ORA, -SC(=O)SRA, -SC(=O)N(RA)2, -SC(=NRA)RA, -SC(=NRA)ORA, -SC(=NRA)SRA, -SC(=NRA)N(RA)2, - NRAC(=O)RA, -NRAC(=O)ORA, -NRAC(=O)SRA, -NRAC(=O)N(RA)2, -NRAC(=NRA)RA, - NRAC(=NRA)ORA, -NRAC(=NRA)SRA, -NRAC(=NRA)N(RA)2, -NRAS(=O)RA, -NRAS(=O)ORA, - NRAS(=O)SRA, -NRAS(=O)N(RA)2, -NRAS(=O)2RA, -NRAS(=O)2ORA, -NRAS(=O)2SRA, - NRAS(=O)2N(RA)2, -Si(RA)3, -Si(RA)2ORA, -Si(RA)(ORA)2, -Si(ORA)3, -OSi(RA)3, -OSi(RA)2ORA, - OSi(RA)(ORA)2, -OSi(ORA)3, and/or -B(ORA)2, wherein each instance of RA is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, 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 instances of RA are joined together with their intervening atom(s) to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring.
[0179] In some embodiments, at least one instance of R2 is unsubstituted alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-C12 alkyl, unsubstituted C1-C11 alkyl, unsubstituted C1-C10 alkyl, unsubstituted C1-C9 alkyl, unsubstituted C1-Cx alkyl, unsubstituted C1-C7 alkyl, unsubstituted C1-Ce alkyl, unsubstituted C1-C5 alkyl, unsubstituted C1-C4 alkyl, unsubstituted C1-C3 alkyl, or unsubstituted C1-C2 alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-Ce alkyl, unsubstituted C1-C5 alkyl, unsubstituted C1-C4 alkyl, unsubstituted C1-C3 alkyl, or unsubstituted C1-C2 alkyl.
[0180] In some embodiments, at least one instance of R2 is unsubstituted C1-C12 alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-C11 alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-C10 alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-C9 alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-Cx alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-C7 alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-Ce alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-C5 alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-C4 alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-C3 alkyl. In some embodiments, at least one instance of R2 is unsubstituted C1-C2 alkyl.
[0181] In some embodiments, at least one instance of R2 is methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertamyl, or //-hexyl. In some embodiments, at least one instance of R2 is methyl, ethyl, n-propyl, //-butyl, //-pentyl, or //-hexyl. In some embodiments, at least one instance of R2 is methyl, ethyl, or //-propyl. In some embodiments, at least one instance of R2 is methyl (-CH3).
Y, R3, R4, and R5
[0182] As generally described herein, Y is a moiety capable of binding to an E3 ubiquitin ligase.
[0183] In some embodiments, Y is a moiety capable of binding to an E3 ubiquitin ligase as described in Ishida T. and Ciulli A., SLAS Discov. 2021, 26(4), 484-502, doi: 10.1177/2472555220965528, or
Bricelj, A. et al., Front. Chem. 2021, 9, Article 707317, doi: 10.3389/fchem.2021.707317, the contents of each of which are incorporated by reference.
[0184] In some embodiments, Y is of Formula (Il-a): wherein R3 is hydrogen or optionally substituted alkyl.
[0185] In some embodiments, R3 is hydrogen. In some embodiments, R3 is optionally substituted C1-3 alkyl. In some embodiments, R3 is -CH3. In some embodiments, R3 is hydrogen or -CH3.
[0186] In some embodiments, Y is of Formula (Il-b): wherein R4 is optionally substituted alkyl or optionally substituted cycloalkyl.
[0187] In some embodiments, R4 is optionally substituted Cm alkyl. In some embodiments, R4 is - CH3. In some embodiments, R4 is optionally substituted C3-4 cycloalkyl. In some embodiments, R4 is cyclopropyl optionally substituted with halogen or -CN. In some embodiments, R4 is cyclopropyl optionally substituted with -F or -CN. In some embodiments, R4 is -CH3,
[0188] In some embodiments, Y is of Formula (II-c): wherein R5 is optionally substituted alkyl or optionally substituted cycloalkyl.
[0189] In some embodiments, R5 is optionally substituted Cm alkyl. In some embodiments, R5 is - CH3. In some embodiments, R5 is optionally substituted C3-4 cycloalkyl. In some embodiments, R5 is cyclopropyl optionally substituted with halogen or -CN. In some embodiments, R5 is cyclopropyl optionally substituted with -F or -CN. In some embodiments, R5 is -CH3,
[0191] In some embodiments, Y is of Formula (III): wherein:
X is CH or N;
L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof; and each instance of R2 is independently hydrogen or optionally substituted alkyl.
[0192] In some embodiments, X is CH. In some embodiments, X is N.
[0193] In some embodiments, Y is of Formula (Ill-a):
[0194] In some embodiments, Y is of Formula (Ill-b):
[0195] As generally described herein, L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
[0196] In some embodiments, L3 is optionally substituted heterocyclylene. In some embodiments, L3 is substituted heterocyclylene. In some embodiments, L3 is optionally substituted heterocyclylene containing 1, 2, or 3 ring N atoms. In some embodiments, L3 is optionally substituted heterocyclylene containing 1 ring N atom. In some embodiments, L3 is optionally substituted heterocyclylene containing 2 ring N atom. In some embodiments, L3 is substituted heterocyclylene containing 1, 2, or 3 ring N atoms. In some embodiments, L3 is substituted heterocyclylene containing 1 ring N atom. In some embodiments, L3 is optionally substituted arylene. In some embodiments, L3 is optionally substituted phenylene. In some embodiments, L3 is substituted phenylene. In some embodiments, L3 is unsubstituted phenylene. In some embodiments, L3 is optionally substituted heteroarylene. In some embodiments, L3 is optionally substituted heteroarylene containing 1, 2, or 3 ring N atoms. In some embodiments, L3 is optionally substituted heteroarylene containing 1 ring N atom. In some embodiments, L3 is optionally substituted heteroarylene containing 2 ring N atoms.
[0198] As generally described herein, L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof; and each instance of R2 is independently hydrogen or optionally substituted alkyl.
[0199] In some embodiments, L4 is a bond. In some embodiments, L4 is -C(R2)2- In some embodiments, L4 is -CHR2-. In some embodiments, L4 is -CH2-. In some embodiments, L4 is -NR2-. In some embodiments, L4 is -NH-. In some embodiments, L4 is -C(=O)-. In some embodiments, L4 is -C(=O)NR2-. In some embodiments, L4 is -C(=O)NH-.
[0201] In some embodiments, Y is of Formulae (Il-a), (Il-b), (II-c), or (III). In some embodiments, Y is of Formulae (Il-a), (Il-b), (II-c), (Ill-a), or (Ill-b). In some embodiments, Y is of Formulae (Il-a), some embodiments, Y is of Formulae (Il-a), (Il-b), (II-c), (Ill-a), or
Subgeneric Embodiments
[0203] In some embodiments, the compound of Formula (I) is of Formula (I-a): or a pharmaceutically acceptable salt thereof.
[0204] In some embodiments, the compound of Formula (I) is of Formulae (I-a-1), (I-a-2), (I-a-3), or
(I-a-4):
or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen or optionally substituted alkyl;
R4 is optionally substituted alkyl or optionally substituted cycloalkyl;
R5 is optionally substituted alkyl or optionally substituted cycloalkyl;
X is CH or N;
L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof; and each instance of R2 is independently hydrogen or optionally substituted alkyl.
[0205] In some embodiments, the compound of Formula (I) is of Formulae (I-a-1). In some embodiments, the compound of Formula (I) is of Formulae (I-a-2). In some embodiments, the compound of Formula (I) is of Formulae (I-a-3). In some embodiments, the compound of Formula (I) is of Formulae (I-a-4).
[0206] In some embodiments, the compound of Formula (I-a-4) is of Formulae (I-a-4-i) or (I-a-4-ii): or a pharmaceutically acceptable salt thereof.
[0207] In some embodiments, the compound of Formula (I-a-4) is of Formulae (I-a-4-i). In some embodiments, the compound of Formula (I-a-4) is of Formulae (I-a-4-ii).
[0208] In some embodiments, the compound of Formula (I) is of Formula (I-b): or a pharmaceutically acceptable salt thereof.
[0209] In some embodiments, the compound of Formula (I) is of Formulae (I-b-1), (I-b-2), (I-b-3), or
(I-b-4):
or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen or optionally substituted alkyl;
R4 is optionally substituted alkyl or optionally substituted cycloalkyl;
R5 is optionally substituted alkyl or optionally substituted cycloalkyl;
X is CH or N;
L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof; and each instance of R2 is independently hydrogen or optionally substituted alkyl.
[0210] In some embodiments, the compound of Formula (I) is of Formulae (I-b-1). In some embodiments, the compound of Formula (I) is of Formulae (I-b-2). In some embodiments, the compound of Formula (I) is of Formulae (I-b-3). In some embodiments, the compound of Formula (I) is of Formulae (I-b-4).
[0211] In some embodiments, the compound of Formula (I-b-4) is of Formulae (I-b-4-i) or (I-b-4-ii): or a pharmaceutically acceptable salt thereof.
[0212] In some embodiments, the compound of Formula (I-b-4) is of Formulae (I-b-4-i). In some embodiments, the compound of Formula (I-b-4) is of Formulae (I-b-4-ii).
[0213] In some embodiments, the compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt thereof.
[0214] In some embodiments, the compound of Formula (I) is of Formulae (I-c-1), (I-c-2), (I-c-3), or
(I-c-4):
or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen or optionally substituted alkyl;
R4 is optionally substituted alkyl or optionally substituted cycloalkyl;
R5 is optionally substituted alkyl or optionally substituted cycloalkyl;
X is CH or N;
L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof; and each instance of R2 is independently hydrogen or optionally substituted alkyl.
[0215] In some embodiments, the compound of Formula (I) is of Formulae (I-c-1). In some embodiments, the compound of Formula (I) is of Formulae (I-c-2). In some embodiments, the compound of Formula (I) is of Formulae (I-c-3). In some embodiments, the compound of Formula (I) is of Formulae (I-c-4).
[0216] In some embodiments, the compound of Formula (I-c-4) is of Formulae (I-c-4-i) or (I-c-4-ii): or a pharmaceutically acceptable salt thereof.
[0217] In some embodiments, the compound of Formula (I-c-4) is of Formulae (I-c-4-i). In some embodiments, the compound of Formula (I-c-4) is of Formulae (I-c-4-ii).
[0218] In some embodiments, the compound of Formula (I) is of Formula (I-d): or a pharmaceutically acceptable salt thereof.
[0219] In some embodiments, the compound of Formula (I) is of Formulae (I-d-1), (I-d-2), (I-d-3), or
(I-d-4):
or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen or optionally substituted alkyl;
R4 is optionally substituted alkyl or optionally substituted cycloalkyl;
R5 is optionally substituted alkyl or optionally substituted cycloalkyl;
X is CH or N;
L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof; and each instance of R2 is independently hydrogen or optionally substituted alkyl.
[0220] In some embodiments, the compound of Formula (I) is of Formulae (I-d-1). In some embodiments, the compound of Formula (I) is of Formulae (I-d-2). In some embodiments, the compound of Formula (I) is of Formulae (I-d-3). In some embodiments, the compound of Formula (I) is of Formulae (I-d-4).
[0221] In some embodiments, the compound of Formula (I-d-4) is of Formulae (I-d-4-i) or (I-d-4-ii): or a pharmaceutically acceptable salt thereof.
[0222] In some embodiments, the compound of Formula (I-d-4) is of Formulae (I-d-4-i). In some embodiments, the compound of Formula (I-d-4) is of Formulae (I-d-4-ii).
[0223] In some embodiments, the compound of Formula (I) is of Formula (I-e): or a pharmaceutically acceptable salt thereof.
[0224] In some embodiments, the compound of Formula (I) is of Formulae (I-e-1), (I-e-2), (I-e-3), or
(I-e-4):
or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen or optionally substituted alkyl;
R4 is optionally substituted alkyl or optionally substituted cycloalkyl;
R5 is optionally substituted alkyl or optionally substituted cycloalkyl;
X is CH or N;
L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof; and each instance of R2 is independently hydrogen or optionally substituted alkyl.
[0225] In some embodiments, the compound of Formula (I) is of Formulae (I-e-1). In some embodiments, the compound of Formula (I) is of Formulae (I-e-2). In some embodiments, the compound of Formula (I) is of Formulae (I-e-3). In some embodiments, the compound of Formula (I) is of Formulae (I-e-4).
[0226] In some embodiments, the compound of Formula (I-e-4) is of Formulae (I-e-4-i) or (I-e-4-ii): or a pharmaceutically acceptable salt thereof.
[0227] In some embodiments, the compound of Formula (I-e-4) is of Formulae (I-e-4-i). In some embodiments, the compound of Formula (I-e-4) is of Formulae (I-e-4-ii).
[0228] In some embodiments, the compound of Formula (IV) is of Formulae (IV-a), (IV-b), or (IV- c):
or a pharmaceutically acceptable salt thereof.
[0229] In some embodiments, the compound of Formula (IV) is of Formula (IV-a). In some embodiments, the compound of Formula (IV) is of Formula (IV-b). In some embodiments, the compound of Formula (IV) is of Formula (IV-c).
[0230] In some embodiments, the compound of Formula (I) is of Formula (IV). In some embodiments, the compound of Formula (I) is of Formulae (IV-a), (IV-b), or (IV-c). In some embodiments, the compound of Formula (I) is of Formula (IV-a). In some embodiments, the compound of Formula (I) is of Formula (IV-b). In some embodiments, the compound of Formula (I) is of Formula (IV-c).
[0231] In some embodiments, the compound of Formula (V) is of Formulae (V-a) or (V-b): or a pharmaceutically acceptable salt thereof.
[0232] In some embodiments, the compound of Formula (V) is of Formula (V-a). In some embodiments, the compound of Formula (V) is of Formula (V-b).
[0233] In some embodiments, the compound of Formula (I) is of Formula (V). In some embodiments, the compound of Formula (I) is of Formulae (V-a) or (V-b). In some embodiments, the compound of Formula (I) is of Formula (V-a). In some embodiments, the compound of Formula (I) is of Formula (V-b).
[0234] In some embodiments, the compound of Formula (I) is selected from those in Table 1, and pharmaceutically acceptable salts thereof.
[0235] In some embodiments, a provided compound is any compound of the present disclosure (e.g., Formula (I)), or a pharmaceutically acceptable salt thereof. In some embodiments, a provided compound is any compound of the present disclosure (e.g., Formula (I)), or a salt thereof. In some embodiments, a provided compound is any compound of the present disclosure e.g., Formula (I)).
Pharmaceutical Compositions and Kits
[0236] The present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0237] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a in a painful condition subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a painful condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for degrading a TEAD protein e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject or cell.
[0238] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. 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. In certain embodiments, 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.
[0239] In certain embodiments, the cell is present in vitro. In certain embodiments, the cell is present in vivo.
[0240] In certain embodiments, the effective amount is an amount effective for degrading a protein 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%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.
[0241] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, 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.
[0242] 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.
[0243] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, 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 composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.
[0244] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents or fillers, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
[0245] Exemplary diluents or fillers 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, starches (such as dry starch, cornstarch), sugars (such as powdered sugar), calcium trisulfate, carboxymethylcellulose calcium, dextrate, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium, maltitol, maltodextrin, maltose, sucrose, glucose, mannitol, silicic acid, xylitol, and mixtures thereof.
[0246] 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 (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
[0247] 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 carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly (vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
[0248] Exemplary disintegrating agents or disintegrants include agar, algin, alginic acid, sodium alginate, silicates, sodium carbonate, calcium carbonate, carboxymethylcellulose, cellulose, clay, colloidal silicon dioxide, croscarmellose sodium, crospovidone, rubber, magnesium silicate, methylcellulose, potassium krillin, hydroxypropylcellulose (e.g., low substituted Hydroxypropylcellulose), crosslinked polyvinylpyrrolidone, hydroxypropylcellulose, and starch (e.g., sodium glycolate starch, potato or tapioca starch).
[0249] Exemplary binding agents include starch (e.g., glycolate starch, 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, hydroxy ethylcellulose, 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, and/or mixtures thereof.
[0250] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent. [0251] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. [0252] 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.
[0253] Exemplary 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. [0254] 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.
[0255] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[0256] 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.
[0257] 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, NeoIone®, Kathon®, and Euxyl®.
[0258] 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, Ringer’s solution, ethyl alcohol, and mixtures thereof.
[0259] Exemplary lubricating agents include agar, ethyl oleate, ethyl laurate, glycerin, blyceryl palmitostearate, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycol, sodium stearyl, sorbitol, zinc stearate, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
[0260] 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, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. 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.
[0261] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, 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. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
[0262] 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. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[0263] In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a ready-to-use (“RTU”) preparation that can be directly administered to a subject. In some embodiments, the RTU preparation is a suspension. In some embodiments, the RTU preparation is a solution. In some embodiments, the RTU preparation is an emulsion. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a solid that is reconstituted prior to administration. In some embodiments, the solid is a lyophilized solid. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a liquid or suspension that is diluted prior to administration.
[0264] In some embodiments, the pharmaceutical compositions disclosed herein comprise a bulking agent. Bulking agents can be used, e.g., to improve the appearance of a solid composition, to provide visible “bulk” to demonstrate product quality or to facilitate preparation, e.g., of a solid composition prepared for reconstitution prior to administration. Bulking agents can be used for low dose (high potency) drugs that do not have the necessary bulk to support their own structure or provide a visible composition in a unit dosage form. Bulking agents are used in lyophilized formulations. Bulking agents provide a desirable structure for a lyophilized cake comprising pores that provide the means for vapor to escape from the product during lyophilization cycles, and facilitate dissolution on reconstitution. In some embodiments, the bulking agent is mannitol, lactose, sucrose, dextran, trehalose, povidone, dextran, glycine, isoleucine, methionine, or a cyclodextrin (e.g., (2- hydroxypropyl) -P-cyclodextrin) .
[0265] 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 compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[0266] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.
[0267] 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.
[0268] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.
[0269] 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. Examples of encapsulating compositions which can be used include polymeric substances and waxes. 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 polethylene glycols and the like.
[0270] 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 admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, 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. Examples of encapsulating agents which can be used include polymeric substances and waxes.
[0271] 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. Generally, 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. Additionally, 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. Alternatively or additionally, 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. [0272] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal 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 intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.
[0273] 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.
[0274] 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 compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self- propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. 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 compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
[0275] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the 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).
[0276] 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, but not limited to, 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.
[0277] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
[0278] 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. Such 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. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
[0279] 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.
[0280] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
[0281] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. 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.
[0282] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, 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. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
[0283] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, 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. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein. [0284] Dose ranges as described herein provide guidance for the administration of provided 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.
[0285] A compound or 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 compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.
[0286] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophy tactically 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. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder). 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 composition described herein in a single dose or composition or administered separately in different doses or compositions. 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. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
[0287] 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. In certain embodiments, the additional pharmaceutical agent is an antiproliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HD AC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all- trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells. [0288] In some embodiments, the pharmaceutical composition further comprises an additional pharmaceutical agent (e.g., an anti-cancer agent (e.g., an alkylating agent, an anti-metabolite, an antitumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent)). In some embodiments, the additional pharmaceutical agent is an anti-cancer agent (e.g., an alkylating agent, an anti-metabolite, an antitumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent). In some embodiments, the anti-cancer agent is an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof. In some embodiments, the anti-cancer agent is an alkylating agent. In some embodiments, the anti-cancer agent is an anti-metabolite. In some embodiments, the anti-cancer agent is an anti-tumor antibiotic. In some embodiments, the anti-cancer agent is an anti-cytoskeletal agent. In some embodiments, the anti-cancer agent is a topoisomerase inhibitor. In some embodiments, the anti-cancer agent is an anti-hormonal agent. In some embodiments, the anti-cancer agent is a targeted therapeutic agent. In some embodiments, the anticancer agent is a photodynamic therapeutic agent.
[0289] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
[0290] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject or cell. [0291] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for degrading a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
Methods of Degrading a TEAD Protein and Methods of Treatment or Prevention
[0292] In another aspect, the present disclosure provides a method of degrading a TEAD protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a method of degrading a TEAD protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [0293] In another aspect, the present disclosure provides a method of degrading a TEAD protein in a subject, the method comprising administering to the subject an effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a method of degrading a TEAD protein in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
[0294] In another aspect, the present disclosure provides a method of degrading a TEAD protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a provided compound or pharmaceutical composition. In another aspect, the present disclosure provides a method of degrading a TEAD protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
[0295] In some embodiments, the TEAD protein is TEAD1, TEAD2, TEAD3, and/or TEAD4. In some embodiments, the TEAD protein is TEAD1. In some embodiments, the TEAD protein is TEAD2. In some embodiments, the TEAD protein is TEAD3. In some embodiments, the TEAD protein is TEAD4. In some embodiments, the cell, tissue, or biological sample is in vitro. In some embodiments, the cell, tissue, or biological sample is in vivo. In some embodiments, the cell is a cancer cell.
[0296] In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a provided compound or pharmaceutical composition. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a provided compound. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a provided pharmaceutical composition. In some embodiments, the disease is a cancer (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer).
[0297] In another aspect, the present disclosure provides a method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (I). In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of Formula (I). In some embodiments, the disease is a cancer (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer).
[0298] In another aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a provided compound or pharmaceutical composition. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a provided compound. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a provided pharmaceutical composition.
[0299] In another aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (I). In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of Formula (I).
[0300] In some embodiments, the cancer is associated with a TEAD protein (e.g., esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, bone cancer). In some embodiments, the cancer is associated with TEAD1, TEAD2, TEAD3, and/or TEAD4. In some embodiments, the cancer is associated with TEAD1. In some embodiments, the cancer is associated with TEAD2. In some embodiments, the cancer is associated with TEAD3. In some embodiments, the cancer is associated with TEAD4.
[0301] In some embodiments, the cancer is esophageal cancer, liver cancer, glioma, glioblastoma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, or bone cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is glioma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is uveal melanoma. In some embodiments, the cancer is Ewing sarcoma. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is bone cancer.
[0302] In some embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In some embodiments, the subject described herein is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In some embodiments, the subject is a companion animal, such as a dog or cat. In some embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In some 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 some embodiments, the animal is a genetically engineered animal. In some embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In some embodiments, the subject is a fish or reptile.
EXAMPLES
[0303] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope.
[0304] The reagents (chemicals) were purchased from commercial sources and used without further purification unless otherwise specified. Thin layer chromatography (TLC) was performed on precoated plates and visualized by fluorescence quenching under UV light. Column chromatography was performed on silica gel. ’H NMR spectra were recorded on a Bruker spectrometer at ambient temperature. ’H NMR spectra are internally referenced to residual solvent signals (CDCh, 87.26; DMSO-oC 8 2.50). Data for ’H NMR is reported as follows: chemical shift (8 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), integration. Mass spectra were acquired on LCMS systems using electrospray ionization methods. Other substrates were purchased from commercial sources and used without further purification unless otherwise noted.
Example 1: Preparation of Intermediates
[0305] The intermediate compounds described herein are useful in the preparation of conjugates of Formula (I). [0306] Preparation of intermediate (3-(aminomethyl)azetidin-l-yl)(5-(4-(trifluoromethyl) phenoxy)naphthalene-2-yl)methanone (I W -I)
[0307] Step 1: Synthesis of 5-hydroxy-2-naphthoic acid. To a solution of 5-bromo-2-naphthoic acid (10.00 g, 39.83 mmol) in tetrabutylammonium hydroxide (100 mL, 40% in H2O) and deionized water (50 mL) was added CU2O (0.85 g, 5.97 mmol) and 4,7-dihydroxy-l,r-phenanthroline (1.94 g,
9.16 mmol). The resulting mixture was stirred at 100 °C overnight under N2 atmosphere. After completion of the reaction, the mixture was acidified to pH 2-3 with 2 N HC1 after cooling to room temperature. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, then dried over Na2SC>4, filtered, and concentrated. The resulting residue was used directly without purification.
[0308] Step 2: Synthesis of methyl 5-hydroxy-2-naphthoate. To a solution of 5-hydroxy-2- naphthoic acid (7.49 g, 39.80 mmol) in MeOH (150 mL) was added SOCI2 (47.35 g, 398.02 mmol). The resulting mixture was stirred at 70 °C for 2 h. After completion of the reaction, the mixture was concentrated directly and extracted with EtOAc. The combined organic layers were washed with brine, then dried over Na2SO_i. filtered, and then concentrated. The residue was purified by flash column chromatography (0% to 20% of EtOAc in hexanes) to afford methyl 5-hydroxy-2-naphthoate (3.83 g, 48% yield for two steps) as a colorless oil. ’H NMR (600 MHz, DMS0-7J 5 10.37 (s, 1H), 8.52 (d, 7 = 1.7 Hz, 1H), 8.24 - 8.20 (m, 1H), 7.91 (dd, 7= 8.8, 1.7 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.41 (t, 7= 7.9 Hz, 1H), 7.01 (dd, 7 = 7.6, 1.0 Hz, 1H), 3.91 (s, 3H).
[0309] Step 3: Synthesis of methyl 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate. To a solution of methyl 5-hydroxy-2-naphthoate (3.00 g, 14.84 mmol) and l-bromo-4-(trifluoromethyl)benzene (4.01 g, 17.80 mmol) in toluene (60 mL) was added Pd(OAc)2 (0.16 g, 0.74 mmol), tBuXPhos (0.44 g, 1.04 mmol), and K3PO4 (6.30 g, 29.67 mmol). The resulting mixture was stirred at 110 °C overnight under N2 atmosphere. After completion of the reaction, the mixture was filtered and concentrated. The residue was purified by flash column chromatography (0% to 5% of EtOAc in hexanes) to afford methyl 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate (3.82 g, 74% yield) as a colorless oil. ’H NMR (600 MHz, Chloroform-7) 5 8.66 (d, 7= 1.6 Hz, 1H), 8.13 (d, 7= 8.8 Hz, 1H), 8.07 (dd, 7 = 8.8, 1.6 Hz, 1H), 7.82 (d, 7= 8.2 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.51 (t, 7= 7.9 Hz, 1H),
7.17 (dd, 7 = 7.6, 1.0 Hz, 1H), 7.08 (d, 7= 8.6 Hz, 2H), 4.00 (s, 3H). [0310] Step 4: Synthesis of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid. To a solution of methyl 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate (2.80 g, 8.09 mmol) in MeOH (30 mL) and THF (10 mL) was added 2 N NaOH (30 mL). The resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was acidified to pH 3-4 with con. HC1. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, then dried over Na2SC>4, filtered, and concentrated to afford 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (2.50 g, 93% yield) as a white solid. >H NMR (600 MHz, DMSO-76) 5 13.21 (s, 1H), 8.71 (d, J= 1.6 Hz, 1H), 8.08 - 8.00 (m, 3H), 7.77 - 7.71 (m, 2H), 7.64 (t, 7= 7.9 Hz, 1H), 7.37 (dd, 7 = 7.6, 1.0 Hz, 1H), 7.17 (d, 7= 8.6 Hz, 2H).
[0311] Step 5: Synthesis of tert-butyl ((l-(5-(4-(trifluoromethyl)phenoxy)-2-naphthoyl)azetidin- 3-yl)methyl)carbamate. To a solution of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (450.00 mg, 1.35 mmol) in DMF (8 mL) was added DIEA (612.63 mg, 4.74 mmol), HATU (669.43 mg, 1.76 mmol), and tert-butyl (azetidin-3-ylmethyl)carbamate hydrochloride (392.10 mg, 1.76 mmol), successively. The resulting mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, then dried over Na^SO-i. filtered, and concentrated. The residue was purified by flash column chromatography (0% to 50% of EtOAc in hexanes) to afford tert-butyl ((l-(5-(4- (trifluoromethyl)phenoxy)-2-naphthoyl)azetidin-3-yl)methyl)carbamate (597.00 mg, 88% yield) as a white solid. >H NMR (600 MHz, Chloroform-7) 5 8.18 (d, 7= 1.6 Hz, 1H), 8.09 (d, 7= 8.7 Hz, 1H), 7.75 (d, 7= 8.3 Hz, 1H), 7.70 (dd, 7= 8.7, 1.6 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.49 (t, 7= 7.9 Hz, 1H), 7.13 (dd, 7 = 7.5, 1.0 Hz, 1H), 7.06 (d, 7= 8.6 Hz, 2H), 4.72 (s, 1H), 4.46 - 4.27 (m, 2H), 4.08 (s, 1H), 3.98 - 3.90 (m, 1H), 3.40 (t, 7= 6.5 Hz, 2H), 2.93 - 2.82 (m, 1H), 1.43 (s, 9H). LC/MS (ESI) m/z 501.2 [M+H]+.
[0312] Step 6: Synthesis of (3-(aminomethyl)azetidin-l-yl)(5-(4-(trifluoromethyl)phenoxy) naphthalen-2-yl)methanone (IW-I). To a solution of tert-butyl ((l-(5-(4-(trifluoromethyl)phenoxy)- 2-naphthoyl)azetidin-3-yl)methyl)carbamate (330.00 mg, 0.66 mmol) in DCM (4 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was quenched by adding aqueous sat. NaHCCL and extracted with DCM. The combined organic layers were washed with brine, then dried over Na2SC>4, filtered, and concentrated to afford (3-(aminomethyl)azetidin- 1 -yl)(5-(4-(trifluoromethyl)phenoxy) naphthalen-2-yl)methanone (IW-I) (261.00 mg, 99% yield) as a white solid. ’H NMR (600 MHz, Chloroform-7) 5 8.20 (d, 7= 1.6 Hz, 1H), 8.09 (d, 7= 8.7 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.61 - 7.55 (m, 2H), 7.49 (t, 7= 7.9 Hz, 1H), 7.13 (dd, 7 = 7.5, 1.0 Hz, 1H), 7.06 (d, 7= 8.6 Hz, 2H), 4.52 - 4.24 (m, 2H), 4.13 - 3.86 (m, 2H), 3.07 - 2.90 (m, 2H), 2.80 - 2.66 (m, 1H). LC/MS (ESI) m/z 401.0 [M+H]+ [0313] Preparation of intermediate 2-(3-((5-(4-(trifluoromethyl)phenoxy)-2-naphthamido) methyl)phenyl)acetic acid (IW-II)
[0314] Step 1: Synthesis of methyl 2-(3-cyanophenyl)acetate. To a solution of methyl 2-(3- bromophenyl) acetate (2.50 g, 10.91 mmol) and Zn(CN)2 (0.83 g, 7.09 mmol) in DMF (30 mL) was added Pd(PPh3)4 (0.63 g, 0.55 mmol). The resulting mixture was stirred at 90 °C for 4 h under N2 atmosphere. After completion of the reaction, the mixture was quenched by adding aqueous 2 N ammonia and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 15% of EtOAc in hexanes) to afford methyl 2-(3-cyanophenyl)acetate (1.50 g, 79% yield) as a white solid. ’H NMR (600 MHz, Chloroform-^/) 5 7.60 - 7.55 (m, 2H), 7.52 (dt, J = 7.9, 1.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 3.71 (s, 3H), 3.66 (s, 2H).
[0315] Step 2: Synthesis of methyl-3-(aminomethyl)phenylacetate hydrochloride. To a solution of methyl 2-(3-cyanophenyl)acetate (1.40 g, 7.99 mmol) in MeOH (18 mL) and 4 M HC1 in dioxane (3 mL) was added 10% Pd/C (0.14 g). The resulting mixture was stirred at room temperature overnight under H2 atmosphere. After completion of the reaction, the mixture was filtered over Celite and concentration of the filtrate, the resulting crystals were taken with EtOAc to give methyl-3- (aminomethyl)phenylacetate hydrochloride (0.61 g, 35% yield) as a gray solid. ’H NMR (600 MHz, Methanol-^) 5 7.44 - 7.33 (m, 4H), 4.11 (s, 2H), 3.71 (s, 2H), 3.69 (s, 3H). LC/MS (ESI) m/z 180.0 [M+H]+.
[0316] Step 3: Synthesis of methyl 2-(3-((5-(4-(trifluoromethyl)phenoxy)-2- naphthamido)methyl)phenyl)acetate. To a solution of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (240.00 mg, 0.72 mmol) in DMF (5 mL) was added DIEA (373.41 mg, 2.89 mmol), HATU (357.03 mg, 0.94 mmol), and methyl-3-(aminomethyl)phenylacetate hydrochloride (156.00 mg, 0.72 mmol), successively. The resulting mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 30% of EtOAc in hexanes) to afford methyl 2-(3-((5-(4-(trifluoromethyl)phenoxy)-2- naphthamido)methyl)phenyl)acetate (290.00 mg, 81% yield) as a white solid. ’H NMR (600 MHz, Chloroform-7) 5 8.38 (d, J = 1.7 Hz, 1H), 8.15 - 8.10 (m, 1H), 7.85 (dd, J = 8.8, 1.8 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.62 - 7.55 (m, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.37 - 7.29 (m, 3H), 7.23 (dt, J= 7.3, 1.7 Hz, 1H), 7.14 (dd, J = 7.6, 0.9 Hz, 1H), 7.09 - 7.05 (m, 2H), 6.58 (t, J = 5.7 Hz, 1H), 4.70 (d, J= 5.6 Hz, 2H), 3.70 (s, 3H), 3.64 (s, 2H). LC/MS (ESI) m/z 494.1 [M+H]+.
[0317] Step 4: Synthesis of 2-(3-((5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)methyl) phenyl)acetic acid (IW-II). To a solution of methyl 2-(3-((5-(4-(trifluoromethyl)phenoxy)-2- naphthamido)methyl)phenyl)acetate (275.00 mg, 0.56 mmol) in MeOH (12 mL) and THF (4 mL) was added 2 N NaOH (3 mL). The resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was acidified to pH 3-4 with con. HC1. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, then dried over Na2SC>4, filtered, and concentrated to afford 2-(3-((5-(4-(trifluoromethyl)phenoxy)-2- naphthamido)methyl)phenyl)acetic acid (IW-II) (264.00 mg, 99% yield) as a white solid. ’H NMR (600 MHz, DMSO-76) 5 12.30 (s, 1H), 9.26 (t, J= 6.0 Hz, 1H), 8.61 (t, J = 1.2 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.96 (d, J = 8.2 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.63 (t, 7= 7.9 Hz, 1H), 7.33 (dd, J = 7.6, 1.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.26 - 7.21 (m, 2H), 7.19 - 7.13 (m, 3H), 4.53 (d, J = 5.9 Hz, 2H), 3.55 (s, 2H). LC/MS (ESI) m/z 480.1 [M+H]+.
[0318] Preparation of intermediate N-(3-(aminomethyl)benzyl)-5-(4-(trifluoromethyl)phenoxy)- 2-naphthamide (IW-III)
[0319] Step 1: Synthesis of tert- butyl (3-((5-(4-(trifluoromethyl)phenoxy)-2- naphthamido)methyl)benzyl) carbamate. To a solution of 5-(4-(trifluoromethyl)phenoxy)-2- naphthoic acid (300.00 mg, 0.90 mmol) in DMF (5 mL) was added DIEA (350.08 mg, 2.71 mmol), HATU (446.29 mg, 1.17 mmol), and tert-butyl (3-(aminomethyl)benzyl)carbamate (234.69 mg, 0.99 mmol), successively. The resulting mixture was stirred at room temperature for 2 h. The mixture was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 40% of EtOAc in hexanes) to afford tert-butyl (3-((5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)methyl)benzyl)carbamate (490.00 mg, 98% yield) as a white solid. ’H NMR (600 MHz, Chloroform-7) 5 8.38 (d, J = 1.8 Hz, 1H), 8.12 (d, J= 8.7 Hz, 1H), 7.85 (dd, J= 8.8, 1.8 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.61 - 7.55 (m, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.30 - 7.27 (m, 2H), 7.23 (d, J = 7.5 Hz, 1H), 7.14 (dd, J= 7.6, 1.0 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.60 (t, J = 5.7 Hz, 1H), 4.88 (s, 1H), 4.69 (d, 7= 5.6 Hz, 2H), 4.32 (d, J= 6.0 Hz, 2H), 1.44 (s, 9H). LC/MS (ESI) m/z 551.3 [M+H]+.
[0320] Step 2: Synthesis of N-(3-(aminomethyl)benzyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (IW-III). A solution of tert-butyl (3-((5-(4-(trifluoromethyl)phenoxy)-2- naphthamido)methyl)benzyl)carbamate (450.00 mg, 0.82 mmol) in 4 M HC1 in dioxane (8 mL) was stirred at room temperature for 2 h. After completion of the reaction by checking the thin layer chromatography, the mixture was filtered, and the concentration of the filtrate to afford N-(3- (aminomethyl)benzyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (IW-III) (360.00 mg, 90% yield) as a white solid.
[0321] Preparation of intermediate N-(3-formylbenzyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide (IW-IV)
[0322] Step 1: Synthesis of 3-(aminomethyl) benzaldehyde hydrochloride. A solution of tert-butyl tert-butyl (3-formylbenzyl)carbamate (156.00 mg, 0.66 mmol) in 4 M HC1 in dioxane (10 mL) was stirred at room temperature for 1 h. The mixture was concentrated to afford 3- (aminomethyl)benzaldehyde hydrochloride as the crude product, which was used directly without purification.
[0323] Step 2: Synthesis of N-(3-formylbenzyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (IW-IV). To a solution of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (200.00 mg, 0.60 mmol) in DMF (5 mL) was added DIEA (388.97 mg, 3.01 mmol), HATU (297.53 mg, 0.78 mmol), and 3- (aminomethyl) benzaldehyde hydrochloride (114.00 mg, 0.66 mmol), successively. The resulting mixture was stirred at room temperature for 2 h. The mixture was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 30% of EtOAc in hexanes) to afford N-(3-formylbenzyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (IW-IV) (241.00 mg, 89% yield for two steps) as a white solid. 'H NMR (600 MHz, Chloroform-7) 5 10.02 (s, 1H), 8.40 (d, J= 1.7 Hz, 1H), 8.14 (d, J= 8.7 Hz, 1H), 7.90 (t, 7= 1.8 Hz, 1H), 7.85 (dd, 7= 8.8, 1.8 Hz, 1H), 7.82 (dt, 7 = 7.6, 1.4 Hz, 1H), 7.78 (d, 7= 8.2 Hz, 1H), 7.69 (dt, 7 = 7.7, 1.4 Hz, 1H), 7.59 (d, 7= 8.7 Hz, 2H), 7.54 (t, 7 = 7.6 Hz, 1H), 7.51 (t, 7 = 7.9 Hz, 1H), 7.14 (dd, 7= 7.6, 1.0 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.73 (t, 7 = 6.0 Hz, 1H), 4.80 (d, 7= 5.9 Hz, 2H). [0324] Preparation of intermediate (S)-N-(l-(6-formylpyridin-2-yl)ethyl)-5-(4-(trifluoromethyl) phenoxy)-2-naphthamide (IW-V)
[0325] Step 1: Synthesis of (S)-N-(l-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2- sulfinamide. To a solution of l-(6-bromopyridin-2-yl)ethan-l-one (4.00 g, 20.00 mmol) in THF (40 mL) was added Ti(OEt)4 (9.12 g, 39.99 mmol) and (S)-2-methylpropane-2-sulfinamide (4.85 g, 39.99 mmol). The reaction mixture was heated to reflux overnight, whereupon it was allowed to cool to room temperature and stirred for 30 min. The reaction was cooled to -30 °C and NaBm (1.51 g, 39.99 mmol) was added. The reaction mixture was stirred at 0-5 °C for 2 h and then quenched by drop-wise addition of water. The mixture was filtered through Celite, and the solids were washed with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0% to 70% of EtOAc in hexanes) to afford (S)-N-((S)-l-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (5.55 g, 91% yield) as a brown solid. ’H NMR (600 MHz, Chloroform-7) 5 7.51 (t, J = 7.7 Hz, 1H), 7.36 (dd, J = 7.9, 0.8 Hz, 1H), 7.28 (dd, 7 = 7.6, 0.9 Hz, 1H), 4.58 - 4.52 (m, 1H), 4.49 (d, 7 = 6.3 Hz, 1H), 1.51 (d, 7 = 6.7 Hz, 3H), 1.25 (s, 9H). LC/MS (ESI) m/z 305.0 [M+H]+.
[0326] Step 2: Synthesis of tert-butyl (S)-(l-(6-bromopyridin-2-yl)ethyl)carbamate. To a solution of (S)-N-((S)-l-(6-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.40 g, 7.86 mmol) in MeOH (12 mL) was added 4 M HC1 in dioxane (12 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated to afford tert-butyl (S)-(l-(6-bromopyridin-2- yl)ethyl)carbamate hydrochloride as the crude product, which was used directly without purification. To a solution of the above crude in DCM (30 mL) was added DIEA (3.05 g, 23.57 mmol) and di-tert- butyl decarbonate (2.57 g, 11.79 mmol). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was extracted with DCM. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 20% of EtOAc in hexanes) to afford tert-butyl (S)-(l-(6-bromopyridin-2-yl)ethyl)carbamate (2.22 g, 94% yield) as a white solid. ’H NMR (600 MHz, Chloroform-7) 5 7.49 (t, 7 = 7.7 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 5.45 (d, J = 7.5 Hz, 1H), 4.90 - 4.72 (m, 1H), 1.47
- 1.38 (m, 12H). LC/MS (ESI) m/z 201.1 [M+H]+.
[0327] Step 3: Synthesis of tert-butyl (S)-(l-(6-cyanopyridin-2-yl)ethyl)carbamate. To a solution of tert-butyl (S)-(l-(6-bromopyridin-2-yl)ethyl)carbamate (1.5 g, 4.98 mmol) in DMF (20 mL) was added Zn(CN)2 (0.88 g, 7.47 mmol) and Pd(PPh3)4 (0.57 g, 0.49 mmol). The reaction mixture was stirred for 12 h at 100 °C and then cooled to room temperature. The mixture was filtered through a plug of celite and concentrated. The residue was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 25% of EtOAc in hexanes) to afford tert-butyl (S)-(l-(6-cyanopyridin-2- yl)ethyl)carbamate (1.10 g, 89% yield) as a white solid. ’H NMR (600 MHz, Chloroform-7) 5 7.79 (t, J = 7.8 Hz, 1H), 7.58 (dd, 7= 7.7, 1.0 Hz, 1H), 7.48 (d, 7 = 8.0 Hz, 1H), 5.57 - 5.39 (m, 1H), 4.97 - 4.83 (m, 1H), 1.48 - 1.41 (m, 12H).
[0328] Step 4: Synthesis of tert-butyl (S)-(l-(6-formylpyridin-2-yl)ethyl)carbamate. To a solution of tert-butyl (S)-(l-(6-cyanopyridin-2-yl)ethyl)carbamate (1.05 g, 4.25 mmol) in DCM (20 mL) was added DIBAL-H solution (5.31 mL, 6.37 mmol, 1.2 M in toluene) by dropwise at -78 °C under N2 atmosphere. The reaction mixture was stirred at -78 °C under N2 atmosphere for 2 h. After completion of the reaction by checking the thin layer chromatography, the mixture was quenched by adding water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 25% of EtOAc in hexanes) to afford tert-butyl (S)-(l-(6-formylpyridin-2-yl)ethyl)carbamate (260 mg, 25% yield) as a light yellow solid. ’H NMR (600 MHz, Chloroform-7) 5 10.07 (s, 1H), 7.87 - 7.80 (m, 2H), 7.48 (dd, 7= 6.6, 2.2 Hz, 1H), 5.72 - 5.57 (m, 1H), 5.02 - 4.88 (m, 1H), 1.50 (d, 7= 6.9 Hz, 3H), 1.45 (s, 9H).
[0329] Step 5: Synthesis of (S)-N-(l-(6-formylpyridin-2-yl)ethyl)-5-(4-
(trifluoromethyl)phenoxy)-2-naphthamide (IW-V). A solution of tert-butyl (S)-(l-(6- formylpyridin-2-yl)ethyl)carbamate (150.66 mg, 0.60 mmol) in DCM (1 mL) and 4 M HC1 in dioxane (2 mL) was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated to give (S)-6-(l-aminoethyl)picolinaldehyde hydrochloride as the crude product, which was used directly without purification. To a solution of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (200.00 mg, 0.60 mmol) in DMF (5 mL) was added DIEA (388.97 mg, 3.01 mmol), HATU (297.53 mg, 0.78 mmol), and (S)-6-(l-aminoethyl)picolinaldehyde hydrochloride (112.00 mg, 0.60 mmol), successively. The resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 30% of EtOAc in hexanes) to afford (S)-N-(l-(6-formylpyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenoxy)-2-naphthamide (IW-V) (210.00 mg, 75% yield) as a white solid. ’H NMR (600 MHz, Chloroform-7) 5 10.12 (s, 1H), 8.45 (d, 7 = 1.7 Hz, 1H), 8.15 (d, 7= 8.7 Hz, 1H), 7.93 - 7.89 (m, 3H), 7.82 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.61 - 7.55 (m, 3H), 7.52 (t, J = 7.9 Hz, 1H), 7.15 (dd, 7= 7.6, 1.0 Hz, 1H), 7.07 (d, 7= 8.7 Hz, 2H), 5.60 - 5.46 (m, 1H), 1.68 (d, 7= 6.8 Hz, 3H). LC/MS (ESI) m/z 465.2 [M+H]+.
[0330] Preparation of intermediate (R)-N-(l-(6-formylpyridin-2-yl)ethyl)-5-(4-(trifluoromethyl) phenoxy)-2-naphthamide (IW-VI)
[0331] IW-VI was prepared using procedure similarly to the preparation of IW-V. ’H NMR (600 MHz, Chloroform-7) 5 10.12 (s, 1H), 8.45 (d, 7= 1.7 Hz, 1H), 8.19 - 8.13 (m, 1H), 7.93 - 7.89 (m, 3H), 7.85 - 7.80 (m, 1H), 7.77 (d, 7 = 7.4 Hz, 1H), 7.62 - 7.56 (m, 3H), 7.55 - 7.49 (m, 1H), 7.15 (dd, 7 = 7.6, 1.0 Hz, 1H), 7.10 - 7.05 (m, 2H), 5.57 - 5.50 (m, 1H), 1.68 (d, 7= 6.9 Hz, 3H).
Example 2: Preparation of Compounds of the Present Disclosure
[0332] General Procedure 1: To a solution of an appropriate E3 ligase ligand with a terminal carboxylic acid group containing linker attached (1.0 equiv.) in DMF was added DIEA (4.0 equiv.), HATU (1.3 equiv.), and intermediate IW-I, IW-II, or IW-III (1.1 equiv.), successively. The resulting mixture was stirred at room temperature. After completion of the reaction (monitored by TLC), the mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 7% of MeOH in DCM) to afford the corresponding final product.
[0333] The following Examples were prepared according to General Procedure 1:
[0334] General Procedure 2: To a solution of an appropriate E3 ligase ligand with a terminal amino group containing linker attached (1.0 equiv.) in MeOH was added KO Ac (3.0 equiv.), AcOH (75.0 equiv.), IW-IV/IW-V/IW-VI (1.0 equiv.), and NaBH iCN (30.0 equiv.), successively. The resulting mixture was stirred at room temperature. After completion of the reaction (monitored by TLC), the mixture was quenched by adding water and extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography
(0% to 30% of MeOH in DCM) to afford the corresponding final product.
[0335] The following Examples were prepared according to General Procedure 2: [0336] General Procedure 3: Synthesis of Example 71 (N-((lS)-l-(6-(4-(2-(2,6-dioxopiperidin-3- yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2- naphthamide)
[0337] Step 1: Synthesis of Benzyl (S)-4-(6-(l-((tert-butoxycarbonyl)amino)ethyl)pyridin-2- yl)piperazine-l-carboxylate. To a solution of tert-butyl (S)-(l-(6-bromopyridin-2-yl)ethyl)carbamate (200.00 mg, 0.66 mmol) and benzyl piperazine- 1 -carboxylate (219.41 mg, 1.00 mmol) in 1,4-dioxane (3 mL) was added Pd2(dba)3 (60.00 mg, 0.066 mmol), XPhos (63.31 mg, 0.132 mmol), and CS2CO3 (432.72 mg, 1.33 mmol). The resulting mixture was stirred at 100 °C for 6 h under N2 atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 30% of EtOAc in Hexanes) to afford benzyl (S)-4-(6-( 1 -((tert-butoxycarbonyl)amino)ethyl)pyridin-2-yl)piperazine- 1 -carboxylate (226 mg, 77% yield) as a white solid. ’H NMR (600 MHz, Chloroform-7) 57.45 (dd, J = 8.4, 7.3 Hz, 1H), 7.40 - 7.36 (m, 4H), 7.35 - 7.30 (m, 1H), 6.58 (d, 7 = 7.3 Hz, 1H), 6.51 (d, 7= 8.4 Hz, 1H), 5.50 (d, 7= 8.0 Hz, 1H), 5.17 (s, 2H), 4.79 - 4.65 (m, 1H), 3.68 - 3.60 (m, 4H), 3.59 - 3.53 (m, 4H), 1.45 (s, 9H), 1.40 (d, 7= 6.8 Hz, 3H).
[0338] Step 2: Tert-butyl (S)-(l-(6-(piperazin-l-yl)pyridin-2-yl)ethyl)carbamate. To a solution of benzyl (S)-4-(6-( 1 -((tert-butoxycarbonyl)amino)ethyl)pyridin-2-yl)piperazine- 1 -carboxylate (210.00 mg, 0.48 mmol) in MeOH (5 mL) was added 10% Pd/C (40.00 mg). The resulting mixture was stirred at room temperature for 4 h under H2 atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was filtered over Celite and concentration of the filtrate to give tert-butyl (S)-(l-(6-(piperazin-l-yl)pyridin-2-yl)ethyl)carbamate (145 mg, 99% yield) as a colorless oil. LC/MS (ESI) m/z 307.1 [M+H]+.
[0339] Step 3: Tert-butyl ((lS)-l-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazin-l-yl)pyridin-2-yl)ethyl)carbamate. To a solution of 3-(5-bromo-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (70.00 mg, 0.22 mmol) and tert-butyl (S)-(l-(6-(piperazin-l-yl)pyridin-2- yl)ethyl)carbamate (80.00 mg, 0.26 mmol) in 1,4-dioxane (1.5 mL) was added Pd-PEPPSI-IPent (17.00 mg, 0.021 mmol), and CS2CO3 (141.16 mg, 0.43 mmol). The resulting mixture was stirred at 90 °C overnight under N2 atmosphere. After completion of the reaction by checking the thin layer chromatography, the mixture was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 5% of MeOH in EtOAc) to afford tert-butyl ((lS)-l-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)piperazin-l-yl)pyridin-2-yl)ethyl)carbamate (28.00 mg, 24% yield) as a gray solid. >H NMR (600 MHz, Chloroform-7) 57.97 (s, 1H), 7.77 (d, J= 8.5 Hz, 1H), 7.48 (dd, J= 8.4, 7.3 Hz, 1H), 7.04 (dd, J= 8.6, 2.1 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.63 - 6.58 (m, 1H), 6.57 - 6.53 (m, 1H), 5.55 (d, 7 = 7.9 Hz, 1H), 5.21 (dd, J= 13.3, 5.1 Hz, 1H), 4.78 - 4.70 (m, 1H), 4.44 (d, 7= 15.5 Hz, 1H), 4.28 (d, 7= 15.5 Hz, 1H), 3.79 - 3.71 (m, 4H), 3.48 - 3.44 (m, 4H), 2.95 - 2.88 (m, 1H), 2.87 - 2.78 (m, 1H), 2.38 - 2.30 (m, 1H), 2.24 - 2.19 (m, 1H), 1.46 (s, 9H), 1.43 (d, 7= 6.8 Hz, 3H). LC/MS (ESI) m/z 549.3 [M+H]+.
[0340] Step 4: N-((lS)-l-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l- yl)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. A solution of tert-butyl (( 1 S)- 1 -(6-(4-(2-(2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-5-yl)piperazin- 1 -yl)pyridin-2- yl)ethyl)carbamate (13.21 mg, 0.024 mmol) in DCM (1 mL) and 4 M HC1 in dioxane (1 mL) was stirred at room temperature for 1 h. After completion of the reaction by checking the thin layer chromatography, the mixture was concentrated to give 3-(5-(4-(6-((S)-l-aminoethyl)pyridin-2- yl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride as the crude product, which was used directly without purification. To a solution of 5-(4-(trifluoromethyl)phenoxy)-2- naphthoic acid (8.00 mg, 0.024 mmol) in DMF (0.5 mL) was added DIEA (15.56 mg, 0.12 mmol), HATU (11.90 mg, 0.31 mmol), and 3-(5-(4-(6-((S)-l-aminoethyl)pyridin-2-yl)piperazin-l-yl)-l- oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride, successively. The resulting mixture was stirred at room temperature for 1 h. After completion of the reaction by checking the thin layer chromatography, the mixture was extracted with EtOAc. The combined organic layers were washed with brine and then concentrated. The residue was purified by flash column chromatography (0% to 5% of MeOH in EtOAc) to afford N-((lS)-l-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperazin-l-yl)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (8.00 mg, 44% yield) as a white solid. ’H NMR (600 MHz, Chloroform-7) 5 8.44 (t, 7= 1.9 Hz, 1H), 8.15 (d, 7= 8.7 Hz, 1H), 8.05 (s, 1H), 7.88 (dd, 7= 8.8, 1.7 Hz, 1H), 7.81 - 7.73 (m, 3H), 7.62 - 7.57 (m, 2H), 7.57 - 7.53 (m, 1H), 7.51 (t, 7= 7.9 Hz, 1H), 7.14 (dd, 7 = 7.6, 0.9 Hz, 1H), 7.08 (d, 7= 8.5 Hz, 2H), 7.03 (dd, 7 = 8.6, 2.2 Hz, 1H), 6.92 (t, 7 = 2.1 Hz, 1H), 6.71 (d, 7 = 7.3 Hz, 1H), 6.63 (d, 7 = 8.4 Hz, 1H), 5.33 - 5.25 (m, 1H), 5.24 - 5.17 (m, 1H), 4.42 (d, 7= 15.6 Hz, 1H), 4.27 (dd, 7= 15.6, 4.3 Hz, 1H), 3.87 - 3.73 (m, 4H), 3.48 (t, 7 = 5.3 Hz, 4H), 2.94 - 2.88 (m, 1H), 2.87 - 2.80 (m, 1H), 2.37 - 2.28 (m, 1H), 2.23 - 2.18 (m, 1H), 1.61 (d, 7= 6.7 Hz, 3H). LC/MS (ESI) m/z 763.3 [M+H]+. [0341] The following Examples were prepared according to General Procedure 3:
Example 3: Cell Viability Assay
[0342] NCI-H226 cells were seeded in triplicates at a density of 800 cells per well in a white 96-well dish. The following day, cells were treated with serial dilutions of degrader ranging logarithmically from 104 to 10 pM and incubated for five days. Viability was assessed using the CellTiter-Glo® 2.0 Cell Viability Assay (Promega), following the manufacturer’s instructions. Luminescence data was recorded on a Promega Gio-Max Navigator instrument. Representative normalized values were plotted as percent viability after the five day treatment (FIG. 1).
Example 4: Protein-Degradation Assay
[0343] For detection of endogenous TEAD in cells, NCI-H226 cells plated at a density of 2 x 105 cells per well of a 6-well dish were harvested by trypsinization after treatment. Cell pellets were lysed in 100 pL of RIPA buffer on ice for 30 minutes and sonicated at 50% amplitude for 5 seconds. Samples were centrifuged at 18213 x g for 20 minutes at 4 °C to remove cell debris. Supernatants were diluted 2X Laemmli buffer, boiled at 98°C for 5 minutes, and resolved by SDS-PAGE. Gels were transferred to nitrocellulose membranes using a Bio-RAD Trans-Blot Turbo semi-dry transfer system. After blocking with protein-free blocking buffer (Li-COR), blots were stained at 4°C with antibodies to TEAD1 (D9X2L, Cell Signaling #12292, 1:750), TEAD2 (C-10, Santa Cruz # sc- 518181, 1:1000), TEAD3 (Abeam #ab 138246 1:1000), and TEAD4 (5H3, Abeam #ab58310 1:5000), then with appropriate secondary antibodies before development on a Li-COR Odyssey CLx system (FIG. 2). Overexpressed TEAD in HEK293-pTRE-puro-pan-TEAD was conducted as previously described, except that cells were seeded at 1.2- 1.5 x 105 cells per well of a 24-well dish and paralogues detected by antibodies to FLAG, Myc, V5, and HA tags.
Example 5: Additional Experimental Procedures
[0344] Additional procedures were performed as described in Chen, Hui et al., Heliyon, Volume 10, Issue 18, e37829.
[0345] Cell lines and cell line culture. HEK293 (ATCC, (RRID: CVCL_0045), NCI-H226 (NCI, (RRID: CVCL_1544) and NCI-H28 (NCI, (RRID: CVCL_1555), cells were cultured in Dulbecco's modified Eagle's Medium (DMEM, Corning Cat. #10-013-CV) supplemented with 10 % heat- inactivated fetal bovine serum (HI FBS, Gibco™ Cat. #10438026) and 1 % antibiotic/antimycotic (Gibco™). All cell lines were tested to be mycoplasma free. All cells were cultured in a humidified incubator at 37 °C with 5 % CO2. HEK293-PanTEAD cells were created by stable transfection of HEK293 cells with lentivirus containing pTRE-Puro-PanTEAD construct and were maintained in DMEM supplemented with 10 % FBS, 1 % antibiotic/antimycotic, and 2.5 pg ml of puromycin.
[0346] Molecular biology. To make pCDNA3.1-pan-TEAD, cDNAs for full-length TEAD1/2/3/4 were PCR amplified with forward primers containing sequences for FLAG, Myc, HA, and V5 epitope tags and sequences for T2A, P2A and E2A and cloned simultaneously into the BamHI and Xbal site in pCDNA3.1 using NEBuilder® HiFi DNA Assembly Kit (New England Biolabs Cat. #E2621). To make pTRE-Puro-pan-TEAD, the entire cassette containing all the TEAD was amplified from pCDNA3.1-pan-TEAD and cloned between Mlul and Agel in pTRE by NEBuilder® HiFi DNA Assembly. To make pGEX-3X-TEADl-YBD-C359A, pGEX-3X-TEAD2-YBD-C380A, pGEX-3X- TEAD3-YBD-C368A, pGEX-3X-TEAD4-YBD-C367A, the coding sequences for YBD of TEAD1-4 were PCR amplified from pCMX-GAL4-TEADl (Addgene #33108), pCMX-GAL4-TEAD2 (Addgene #33107), pCMX-GAL4-TEAD3 (Addgene #33106), pCMX-GAL4-TEAD4 (Addgene #33105), pRK5-Myc-TEAD4 (Addgene #24638), as two overlapping fragments with the mutations introduced in the primers for amplifying them, and cloned into the BamHl site in PGEX-3X plasmid by NEBuilder® HiFi DNA Assembly.
[0347] Lentivirus production. HEK293 cells were seeded in antibiotic-free medium at a density of 5 x 105 cells per well of a 6- well dish and allowed to attach overnight. Cells were transfected with packaging plasmids psPAX2 and pMD2. G along with the transfer plasmid pTRE-puro-pan-TEAD. After 48 h virus supernatants were collected and filtered through a 0.45 pm syringe filter. 4x lentivirusmaity concentration solution (40 % w/v PEG-8000, 1.2 M NaCl in lx PBS, pH 7.4) was added at a 1:4 to the filtered supernatant and the mixture was rotated end-over-end overnight at 4 °C. The following day, the virus was precipitated by centrifugation at 1600xg for 60 min at 4 °C and diluted in lx PBS. Virus aliquots were stored at -80 °C.
[0348] Stable cell line generation. Lentiviral particles were used to transduce HEK293 cells. 8 pg/mL polybrene was added to antibiotic-free medium containing the viruses to enhance transduction efficiency. Stable clones were established by selection with 2.5 pg/mL puromycin starting 48 h after transduction until distinct colonies formed. Colonies were isolated and screened for expression of epitope-tagged TEAD paralogues by western blotting.
[0349] Clonogenic assay. Clonogenic assays were done as previously described. Briefly, an equal number NCI-H226 cells were plated in triplicate and were treated with DMSO or different doses of HC278 for two weeks, following which they were fixed with 4 % PFA and stained with 0.5 % crystal violet dissolved in methanol. The images were acquired using Gelcount (Oxford Optronix) mammalian-cell colony, spheroid, and organoid counter, and the colony areas were quantified using FIJI.
[0350] Western blotting. For detection of endogenous TEAD in cells, NCI-H226 cells plated at a density of 2 x 105 cells per well of a 6-well dish were harvested by trypsinization after treatment. Cell pellets were lysed in 100 pL of RIPA buffer on ice for 30 min and sonicated at 50 % amplitude for 5 s. Samples were centrifuged at 18213xg for 20 min at 4 °C to remove cell debris. Supernatants were diluted 2x Laemmli buffer, boiled at 98 °C for 5 min, and resolved by SDS-PAGE. Gels were transferred to nitrocellulose membranes using a Bio-RAD Trans-Blot Turbo semi-dry transfer system. After blocking with protein-free blocking buffer (Li-COR), blots were incubated overnight at 4 °C with primary antibodies against TEAD1 (D9X2L, Cell Signaling Technology #12292, 1:750), TEAD2 (C-10, Santa Cruz # sc-518181, 1:1000), TEAD3 (Abeam #ab 138246 1:1000), and TEAD4 (5H3, Abeam #ab58310 1:5000), following which, they were washed thrice with TBST buffer and incubated with appropriate IR Dye 680 or IR Dye 780 conjugated secondary antibodies at room temperature for 2 h. Subsequently, the blots were washed thrice with TBST and scanned with a Li-COR Odyssey CLx imager. Overexpressed TEAD in HEK293-pTRE-puro-pan-TEAD was conducted as previously described, except that cells were seeded at 1.2- 1.5 x 105 cells per well of a 24-well dish and paralogues detected by antibodies against FLAG (1:5000), Myc (1: 5000), HA (1:2000), V5 (1:5000) tags.
[0351] RNA extraction and RT-qPCR. MDA-MB-231 cells were seeded at ~50 % confluence in 6 well dishes and allowed to attach overnight. Cells were then treated with DMSO or different doses of HC278 (500 nM and 1 pM) for 24 h. Total RNA was extracted with TRIzol reagent (Invitrogen), following the manufacturer's protocol. 1 pg of total RNA was reverse transcribed to cDNA using the iScript™ gDNA Clear cDNA synthesis kit (Bio-RAD). qPCR was performed with Applied Biosystems Fast SYBR Green master mix on an Applied Biosystems QuantStudio 6 Flex system. Target genes were normalized to GAPDH mRNA levels and relative fold changes were calculated as
[0352] Protein purification. Recombinant GST-tagged TEAD1-4 YBD with the conserved cysteine mutated to alanine (CS mutants) were purified from E. coli. BL-21(DE3) cells were transformed with pGEX-3X-TEADl-YBD, pGEX-3X-TEAD2-YBD, pGEX-3X-TEAD3-YBD, pGEX-3X-TEAD4- YBD plasmids. Cultures were grown to 0.6 OD 600 nm and protein production was induced by 300 pM IPTG, at 16 °C overnight. Cells were collected by centrifuging at 8000 rpm for 10 min and were resuspended in ice-cold lysis buffer (50 mM TRIS pH 7.4, 1 mM EDTA, 150 mM NaCl, 1 mM DTT) supplemented with protease inhibitor cocktail, 0.1 % triton X 100 and Lysozyme, and lysed using sonication and a homogenizer. The soluble fraction was separated by centrifuging at 20,000 rpm for 30 min at 4°C and was incubated with Glutathione Sepharose 4B affinity resin for 2 h. After thorough washing, the protein was eluted with 10 mM glutathione and dialyzed overnight. The purity was verified with SDS-PAGE and Coomassie Brilliant Blue staining.
[0353] AlphaLISA assay for evaluating the ternary complex formation. AlphaLISA assay was used to evaluate the in vitro ternary complex formation between potential target proteins (GST-tagged TEAD1-4), PROTAC, and CRBN/DDB1 complex (His-tagged CRBN/DDB1 complex). Assays were performed at room temperature. All reagents were diluted in an assay buffer of 50 mM HEPES, pH 7.5, 150 mM NaCl, 0.1 % BSA, and 0.005 % Tween 80. To a 96-well PCR plate were added 10 pL of 6 x His-tagged protein (CRBN/DDB1, 100 nM), 10 pL of the serially diluted compound solution (4 x dilution), and 10 pL of GST-TEAD1-4 (100 nM). After incubating at room temperature for 60 min, 5 pL of alpha glutathione donor beads (160 pg/mL, Cat. No. 6765300, PerkinElmer) and 5 pL of anti-6 x His acceptor beads (160 pg/mL, Cat. No. AL 128 A, PerkinElmer) were added to each well under subdued light, successively. Then, the resulting mixture was transferred to two adjacent wells (17 pL each) of a 384-well white OptiPlate (Cat. No. 6008280, PerkinElmer), and incubated for an additional 18 h in the dark. The luminescence signal was detected on a Biotek's Synergy Neo 2 multimode plate reader installed with an AphaScreen filter cube. Intensity values were plotted in GraphPad Prism with PROTAC concentration values represented on a log 10 scale.
[0354] Proteomic analysis. NCI-H226 cells were treated in triplicate with either DMSO or 500 nM HC278 for 24 h, following which, the cells were trypsinized and collected by centrifugation. The cell pellets were lysed in RIPA buffer and 15 pL of each sample was diluted to 50 pL with 5 % SDS, 100 mM triethylammonium bicarbonate (TEAB). 2 pL of 500 mM (tris(2-carboxyethyl) phosphine) (TCEP) was added to reduce disulfide bonds and samples were incubated at 56 °C for 30 min. After cooling, 2 pL of 500 mM iodoacetamide (IAA) was added to alkylate the free cysteine thiols, and samples were incubated for 30 min at room temperature in the dark. Samples were then digested overnight with trypsin at 37 °C using an S-Trap (Protifi). Following digestion, the peptides were eluted from the S-Trap, dried, and reconstituted in 75 pL of 50 mM TEAB was added. The samples were labeled with TMT-6 plex reagents, quenched with 5 % hydroxylamine, and combined. A high-pH reverse-phase fractionation spin column (Pierce) was used according to the manufacturer's directions to fractionate the sample into 8 fractions. The fractions were dried in a SpeedVac and reconstituted in a 2 % acetonitrile, 0.1 % TFA buffer.
[0355] Peptides were analyzed on a Thermo Orbitrap Eclipse MS system coupled to an Ultimate 3000 RSLC-Nano liquid chromatography system. Samples were injected onto a 75 pm i. d., 75-cm long EasySpray column (Thermo) and eluted with a gradient from 0 to 28 % buffer B over 180 min at a flow rate of 250 nL/min. Buffer A contained 2 % (v/v) ACN and 0.1 % formic acid in water, and buffer B contained 80 % (v/v) ACN, 10 % (v/v) trifluoroethanol, and 0.1 % formic acid in water, at a flow rate of 250 nL/min. Spectra were continuously acquired in a data-dependent manner throughout the gradient, acquiring a full scan in the Orbitrap (at 120,000 resolution with a standard AGC target) followed by MS/MS scans on the most abundant ions in 2.5 s in the ion trap (turbo scan type with an intensity threshold of 5,000, CID collision energy of 35 %, standard AGC target, maximum injection time of 35 ms and isolation width of 0.7 m/z). Charge states from 2 to 6 were included. Dynamic exclusion was enabled with a repeat count of 1 , an exclusion duration of 25 s and an exclusion mass width of ±10 ppm. Real-time search was used for selection of peaks for SPS-MS3 analysis, with searched performed against the human reviewed protein database from UniProt, Up to 1 missed tryptic cleavage was allowed, with carbamidomethylation (+57.0215) of cysteine and TMT reagent (+229.1629) modification of lysine and peptide N-termini used as static modifications, and oxidation (+15.9949) of methionine used as a variable modification. MS3 data were collected for up to 10 MS2 peaks which matched to fragments from the real-time peptide search identification, in the orbitrap at a resolution of 50,000, HCD collision energy of 65 % and a scan range of 100-500.
[0356] Protein identification and quantification were done using Proteome Discoverer v.3.0 SP1 (Thermo). Raw MS data files were analyzed against the human reviewed protein database from UniProt. Both Comet and Sequest HT with INFERYS Rescoring were used, with carbamidomethylation (+57.0215) of cysteine and TMT reagent (+229.1629) of lysine and peptide N- termini used as static modifications and oxidation (+15.9949) of methionine used as a variable modification. Reporter ion intensities were reported, with further normalization performed by using the total intensity in each channel to correct discrepancies in sample amount in each channel. The false-discovery rate (FDR) cutoff was 1 % for all peptides.
[0357] RNA-seq experiment. NCI-H226 cells were treated in triplicate with either DMSO or 500 nM HC278 for 24 h, following which, the cells were trypsinized and collected by centrifugation. Total RNA was extracted with TRIzol reagent (Invitrogen) with on-column DNA removal. The RNA sequencing library was prepared using Illumina Stranded mRNA prep kit (20040532) according to Manufacturer's protocol. This protocol requires input RNA with RIN (RNA integrity number) > 7 RNA and concentration range between 25 ng and 1000 ng. Illumina UMI barcodes were used to multiplex the libraries as per the Manufacturer's instructions. The quality and quantity of each sequencing final library were assessed using Agilent 2100 BioAnalyzer system (Agilent, CA, USA). A total of 10 nM Picogreen measured library were pooled for 1.3 pM loading on the sequencer. The pooled libraries were sequenced on Illumina NexSeq platform in SE75 (75 bp single end) run with the NextSeq reagent kit v2.5 for 75 cycles. About 30-40 Million sequencing reads were generated per sample for the transcriptome analysis. Single end demultiplexed fastq files were generated using bcl2fastq2 (Illumina, v2.17), from NextSeq 550 v2.5 reagent's bcl files. Initial quality control was performed using FastQC v0.11.8 and multiqc vl.7. Fastq files were imported batch wise, trimmed for adapter sequences followed by quality trimming using CLC Genomics Workbench (CLC Bio, v23.0.3). The imported high-quality reads were mapped against gene regions and transcripts annotated by ENSEMBL v99 hg38 using the RNA-Seq Analysis tool v2.7 (CLC Genomics Workbench), only matches to the reverse strand of the genes were accepted (using the strand-specific reverse option). Differential gene expression analysis between the sample groups was done using the Differential Expression for RNA-seq tool v2.8, where the normalization method was set as TMM. Differential expression between the groups was tested using a control group, outliers were downweighed, and filter on average expression for FDR correction was enabled.
[0358] Quantification and statistical analysis. Results were recorded and sorted in Microsoft Excel and all statistical analyses were performed using GraphPad Prism (San Diego, CA). Histograms show the mean plus Standard Error of Mean (SEM). For pairwise comparisons two-tailed Student's t-test was used for parametric distributions and a Mann- Whitney test was used for non-parametric distributions.
Example 6: Additional Results
[0359] A platform was developed for screening the TEAD degrading activities of the PROTACs (FIG. 3A). The TEAD transcription factors exist in four different paralogs, making it important to determine whether a PROTAC can degrade all four of them or only specific paralogs. However, a major obstacle is that no single cell line naturally expresses all four TEAD paralogs in detectable amounts, which creates a challenge to assess PROTACs’ ability to selectively degrade specific paralogs using available pan-TEAD antibodies. Further, the commercially available antibodies against different TEAD paralogs are not equally specific. To address this challenge, a construct encoding FLAG-tagged TEAD1, Myc-tagged TEAD2, V5-tagged TEAD3, and HA-tagged TEAD4, was engineered, interspersed with viral 2A-like peptides in between (FIG. 3A). This allows translation of the four different proteins from a single transcript produced under the control of a single promoter, thus eliminating variability due to differing strengths of promoters. This construct successfully produces individually tagged TEAD 1-4. Subsequently, a stable cell line was established harboring this construct, with one of the stable cell clones expressing all four TEAD paralogs, that can be readily detected by commercially available antibodies against the different epitope tags (FIG. 3B). Using this cell line, the designed PROTACs were screened at concentrations of 0.1 pM. [0360] The TEAD-degrading PROTACs potently degrade TEAD1 and TEAD3. Based on the screening results of all these fourteen compounds, three PROTACs, HC242, HC278, and HC286 were selected for further characterization (FIG. 3). To evaluate the potency of these PROTACs, a dose-response analysis was performed. The cells were treated with varying concentrations of the PROTACs, and the effect on all four TEAD paralogs was assessed by Western blotting, using antibodies against the respective epitope tags. These experiments revealed that while all three PROTACs HC242, HC278, and HC286 can degrade TEAD1 and TEAD3 even at 50 nM, they have little effect on TEAD2 and had only a weak degrading effect on TEAD4 at 500 nM, indicating that these PROTACs are more specific for TEAD1 and TEAD3 (FIGs. 3D-3F) at low doses. Since these PROTACs can cause more than 50 % degradation at 50 nM, their degradative effect on TEAD1 and TEAD3 at lower concentrations was examined. These experiments revealed that HC242, HC278, and HC286 can degrade TEAD1 and TEAD3 at low nanomolar concentrations. [0361] TEAD degrading PROTACs function in a proteasome and CRBN-dependent manner. To determine the kinetics of degradation by the PROTACs, the HEK293-pan-TEAD cells were treated with 500 nM HC242, HC278, and HC286 for different time periods and TEAD degradation assessed by Western blotting. TEAD1/3 degradation could be detected as early as 2 h after PROTAC treatment and continued to increase over time. Rescue experiments to investigate whether HC242, HC278, and HC286 are bona fide PROTAC degraders showed that when cells are co-treated with these PROTACs and the proteasomal inhibitor MG132, the degradation of TEAD proteins was completely blocked, suggesting that these compounds degrade TEAD proteins in a proteasomal-dependent manner (FIGs. 4A-4C). Similarly, co-treatment of the cells with the warheads, WH15 and Ex. 29 also inhibited the degradation activity of the PROTACs on TEAD proteins, suggesting that the warhead of the PROTACs engaged with the TEAD proteins (FIGs. 4A- 4C). Furthermore, the negative control HC278-Negl, in which the TEAD binding warhead is the enantiomer of the one in HC278, exhibited a much weaker degradative effect (FIGs. 4D-4E). Another negative control, HC278-Neg2, uses the same warhead as in HC278 but contains an altered CRBN ligand that cannot engage with CRBN, failed to induce degradation of the TEAD proteins (FIGs. 4D- 4F). This confirms that the activity of these PROTACs is CRBN-dependent. Taken together, these experiments revealed that HC242, HC278, and HC286 are bona fide PROTAC degraders of TEAD1 and TEAD3.
[0362] HC278 can form ternary complex with TEAD1/3 and CRBN/DDB1. To gain more understanding of HC278-induced isoform selective degradation of TEAD proteins, the in vitro formation of ternary complexes between CRBN/DDB1, HC278, and TEAD 1-4 was measured using the cell-free AlphaLISA assay. For this, GST-tagged TEAD proteins and His-tagged CRBN/DDB1 were used (FIG. 5A). Since recombinant TEAD purified from E. coli is normally bound to palmitic acid, which would prevent binding of the PROTAC to TEAD, the TEAD proteins were purified with the conserved cysteine mutated to alanine. HC278 can form stable ternary complexes with TEAD1 and CRBN/DDB1 complex, which is consistent with the Western blotting data (FIG. 5B). In contrast, HC278-Negl generated a weak Alpha signal due to its reduced binding affinity to TEAD. Similarly, HC278-Neg2, which cannot bind to CRBN, also failed to form a stable ternary complex (FIG. 5B). Consistent with the isoform selectivity observed in the Western blotting assay, TEAD1 and TEAD3 could form stable ternary complexes with HC278 and CRBN/DDB1, whereas TEAD2 and TEAD4 weakly formed ternary complex (FIG. 5C). Taken together, these results suggest that HC278- induced paralog-selective TEAD degradation is derived from its ability to differentially promote ternary complex formation among the TEAD proteins.
[0363] HC278 selectively depletes TEAD1/3 in the whole proteome. To further investigate the degradation selectivity of HC278 beyond the TEAD family of proteins, an unbiased global proteomic analysis was performed. NCI-H226 cells were treated with either DMSO or 500 nM of HC278 for 24 h, total protein extracted, and the proteins up or downregulated by HC278 treatment identified. There was significant downregulation of TEAD1 and TEAD3 (FIGs. 6A-6B), while TEAD2 was not detectable, presumably because it is not expressed in these cells. Consistent with these findings, Western blotting analysis of the cell lysates from NCI-H226 cells treated with either DMSO or 100 and 500 nM of HC278 for 24 h revealed that TEAD1 and TEAD3 are significantly degraded by 100 nM of HC278 (FIGs. 6E-6F). In contrast, TEAD4 was only mildly degraded even at 500 nM dose of HC278. Consistent with the proteomics result, TEAD2 was not detected in these cells. HC242 and HC286 also exhibited a similar degradative effect on different TEAD isoforms. In addition, several other proteins including INHBA, ADAMTS1, F3, and ZNF367 were downregulated. This could be due to the fact that they are transcriptional targets of TEAD/YAP. To address this possibility, NCI-H226 cells were treated with either DMSO or 500 nM HC278 for 24 h, following which the RNA was isolated for RNA Sequencing (RNA-Seq) analysis to examine the effect of this PROTAC on the global transcriptome. Proteins such as INHBA, ADAMTS1, F3, and ZNF367 that were downregulated in the proteomics experiment were also downregulated in the RNA-seq experiment, indicating that the downregulation of these proteins in response to HC278 treatment is due to inhibition of TEAD transcriptional effect (FIGs. 6C-6D). Recently, a PROTAC developed from a TEAD palmitoylation inhibitor was reported to induce the degradation of PDCD2. However, these proteomics data showed that HC278 does not cause PDCD2 degradation. This was further confirmed by Western blotting. These results also indicate that HC278 specifically depletes TEAD1/3 and to a lesser extent TEAD4 and downregulates their transcriptional targets.
[0364] HC278 downregulates TEAD/Y AP-regulated transcriptome. Given that HC278 depletes TEAD1 and TEAD3 and degrades TEAD4 to some extent, it was predicted that it would inhibit TEAD/YAP transcriptional activity. To address this possibility, the RNA-Seq data was compared with published YAP signature data sets. Overall, a small set of genes was found to be downregulated or upregulated by > 2 fold (p < 0.05) in cells treated with HC278 compared to those treated with DMSO (FIG. 7A). Gene Set Enrichment Analysis (GSEA) of the differentially expressed genes revealed that several gene sets in the MSigDB oncogene dataset were highly enriched (FIG. 7B). Specifically, the Cordonensi YAP signature gene set is highly downregulated in the differentially expressed genes in cells treated with HC278 (FIGs. 7B-7C). Consistently, a significant number of YAP-target genes such as CTGF, CYR61, and ANKRD1 were significantly downregulated (FIG. 7A). To further verify the RNA-Seq results, transcript levels were examined for well-known YAP target genes such as CTGF, CYR61, and ANKRD1 by quantitative RT-PCR. Consistent with the RNA-seq analysis, the mRNA levels of CTGF, CYR61, and ANKRD1 were significantly downregulated in NCI-H226 cells treated with HC278 compared to cells treated with DMSO (FIG. 7D). Taken together, these results demonstrate that HC278 inhibits TEAD/YAP transcriptional activity.
[0365] The TEAD-degrading PROTACs inhibit growth of NCI-H226 cells. Inhibition of YAP transcriptional activity by HC278 suggested that it can potentially inhibit the proliferation of YAP- driven cancer cells. HCNCI-HC226 mesothelioma cells harbor deletions in NF2, causing activation of YAP. Genetic studies have established that they exhibit vulnerability to loss of YAP/TEAD activity. Furthermore, several TEAD palmitoylation inhibitors are known to inhibit the proliferation of these cells. To determine how HC278 affects growth of NCI-HC226 cells, a small number of cells were plated and treated with DMSO or 100 and 200 nM of HC242, HC278, and HC286 for a week, and the colony size was quantified. These experiments revealed that HC278 and HC286 significantly inhibited colony forming ability of NCI-H226 cells at 200 nM (FIGs. 8A-8C) while had little effect at 100 nM dose. In contrast, the PROTACs had no apparent effect on the colony-forming ability of the NCI-H28 control mesothelioma cells that do not have mutations in Hippo pathway components (FIGs. 8D-8F), even at 200 nM dose. Together, these results indicate that these PROTACs specifically inhibit colony forming ability of YAP-dependent mesothelioma cells.
[0366] Discussion. The oncogenic transcriptional activators YAP/TAZ function as the terminal effectors of the Hippo signaling pathway and are frequently hyperactivated in many human cancers. Thus, they provide a critical point for therapeutic intervention in cancers. YAP/TAZ exert their oncogenic activity by regulating gene expression by associating primarily with the TEAD transcription factors. Thus, YAP activity can be impaired by inhibiting TEAD. The TEAD transcription factors exist as four different paralogs TEAD 1-4, which are highly similar in sequence and structure. A unique feature of TEAD proteins is that they get autopalmitoylated, and inhibiting this posttranslational modification interferes with their function. Therefore, several TEAD palmitoylation inhibitors have been developed over the last few years. A few of these have even entered clinical trials. However, it has been reported that cancer cells can rapidly develop resistance, which could limit their effectiveness. In some cases, the resistance is mediated by TEAD binding partner and transcriptional corepressors VGLL3. Consequently, degrading TEAD through proximity induced ubiquitination would be an attractive alternative approach. In this disclosure, PROTACs that can potently degrade TEAD1 and TEAD3 at low nanomolar concentrations while degrading TEAD2 and 4 only at higher doses were developed and characterized. These molecules degrade TEAD in a proteasome and CRBN-dependent manner and inhibit YAP transcriptional response. Consistently they exhibit antiproliferative effects on the YAP-dependent mesothelioma cells. This has important biological and clinical implications for treatment of disease conditions that are primarily dependent on TEAD1 and TEAD3. Investigations will be required to determine if the TEAD degraders have an advantage over the autopalmitoylation inhibitors with respect to the development of resistance.
[0367] To study the paralog-specific effect of PROTACs a stable cell line was created that expresses the different TEAD paralogs with unique epitope tags. Currently, most studies on TEAD use the commercially available pan-TEAD antibody, which does not provide any information about specific effects on any TEAD paralogs. Similarly, the commercially available antibodies against the different paralogs are not very specific. Transient transfection with individual epitope-tagged TEAD paralog also introduces error due to variable transfection efficiency. Thus, the stable cell line provides a valuable tool for high throughput screening to detect the paralog-specific degrading activity of small molecule degraders.
[0368] Mechanistic studies revealed that lead PROTAC, HC278, is capable of forming a stable ternary complex with CRBN/DDB1 and either TEAD1 or TEAD3 but not with TEAD2 or TEAD4. Forming a stable ternary complex is believed necessary for PROTACs to trigger ubiquitination of their targets, though may not be the only requirement. Thus, the isoform-selective degradation observed with PROTACs of the present disclosure towards TEAD1/3 could be attributed to their differential efficiency in inducing the formation of TEAD: PROTAC: CRBN/DDB1 ternary complex across the TEAD paralogs. PROTACs developed from non-selective ligands can degrade specific paralogs depending on the linker length, type, and geometry of orientation, which together can affect stable ternary complex formation. Further studies are needed to elucidate the structural basis that governs the ternary complex formation.
[0369] Proteome-wide analysis revealed that HC278 specifically degrades TEAD1 and TEAD3, and several other proteins were downregulated with HC278 treatment. However, transcriptome analysis revealed that these proteins were transcriptionally regulated by TEAD. Further, GSEA revealed that the YAP signature gene set was specifically downregulated upon HC278 treatment, indicating that HC278 specifically inhibits YAP transcriptional activities. Collectively, the present disclosure identified potent and specific PROTAC degraders for TEAD1 and TEAD3, which will be valuable tools to study the biological functions of these TEAD paralogs and their potential in treating disease conditions specifically driven by them.
INCORPORATION BY REFERENCE
[0370] The present application refers to various issued patent, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Figures, the Examples, and the Claims.
EQUIVALENTS AND SCOPE
[0371] In the articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Embodiments or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
[0372] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claims that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[0373] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the embodiments. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any embodiment, for any reason, whether or not related to the existence of prior art. [0374] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended embodiments. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

What is claimed is:
A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
L1 is of formula:
R1 is hydrogen or optionally substituted alkyl; each instance of X is independently CH or N;
L2 is optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R2 is independently hydrogen or optionally substituted alkyl; and
Y is a moiety capable of binding to an E3 ubiquitin ligase.
2. A compound of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen or optionally substituted alkyl; each instance of X is independently CH or N;
L2 is optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R2 is independently hydrogen or optionally substituted alkyl; and
Y is of Formulae (II- a), (Il-b), or (II-c): wherein:
R3 is hydrogen or optionally substituted alkyl;
R4 is optionally substituted alkyl or optionally substituted cycloalkyl; and
R5 is optionally substituted alkyl or optionally substituted cycloalkyl.
3. A compound of Formula (V): or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen or optionally substituted alkyl; each instance of X is independently CH or N;
L2 is optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, optionally substituted heterocyclylene, or a combination thereof, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, or optionally substituted heterocyclylene are independently replaced with -O-, -NR2-, =N-, -N=, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each instance of R2 is independently hydrogen or optionally substituted alkyl;
L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; and
L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein
5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof,
6. The compound of any one of claims 1-3 or 5, or a pharmaceutically acceptable salt thereof, wherein L1 is of formula:
7. The compound of any one of claims 1-3 or 5, or a pharmaceutically acceptable salt thereof, wherein L1 is of formula:
8. The compound of any one of claims 1-3 or 5-7, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.
9. The compound of any one of claims 1-3 or 5-7, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted C1-6 alkyl.
10. The compound of any one of claims 1-3, 5, 6, or 8, or a pharmaceutically acceptable salt thereof, wherein
11. The compound of any one of claims 1-3, 5, 7, or 9, or a pharmaceutically acceptable salt thereof, wherein
12. The compound of any one of claims 1-3, 5, 7, 9, or 11, or a pharmaceutically acceptable salt thereof, wherein
13. The compound of any one of claims 1-4, wherein the compound is of Formula (I-a): or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1-3 or 5-12, wherein the compound is of Formula (I-b) or (I-c): or a pharmaceutically acceptable salt thereof.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein L2 comprises optionally substituted C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-, -NR2-, -S-, -S(=O)-, -S(=O)2- — C(— O)— , optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein L2 comprises optionally substituted C1-20 alkylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C1-20 alkylene are independently replaced with -O-, -NR2-, — C(— O)— , or optionally substituted heterocyclylene.
17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein L2 comprises optionally substituted C2-20 alkenylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkenylene are independently replaced with -O-, -NR2-, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein L2 comprises optionally substituted C2-20 alkenylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkenylene are independently replaced with -O-, -NR2-, — C(— O)— , or optionally substituted heterocyclylene.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein L2 comprises optionally substituted C2-20 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkynylene are independently replaced with -O-, -NR2-, — S— , -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein L2 comprises optionally substituted C2-20 alkynylene, optionally wherein one or more backbone carbon atoms in the optionally substituted C2-20 alkynylene are independently replaced with -O-, -NR2-, — C(— O)— , or optionally substituted heterocyclylene.
21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein L2 comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR2-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein L2 comprises optionally substituted heterocyclylene containing 1 or 2 ring N atoms, optionally wherein one or more backbone carbon atoms in the optionally substituted heterocyclylene containing 1 or 2 ring N atoms are independently replaced with -O-, -NR2-, -C(=O)-, or optionally substituted heterocyclylene.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein: each instance of X is independently CH or N; each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, or 5; and each p is independently 1, 2, 3, or 4.
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof,
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein Y is of Formulae (Il-a), (Il-b), or (II-c): wherein:
R3 is hydrogen or optionally substituted alkyl;
R4 is optionally substituted alkyl or optionally substituted cycloalkyl; and
R5 is optionally substituted alkyl or optionally substituted cycloalkyl.
27. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein Y is of Formula (III): wherein:
X is CH or N;
L3 is optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene;
L4 is a bond, -C(R2)2-, -NR2-, -C(=O)-, or a combination thereof; and each instance of R2 is independently hydrogen or optionally substituted alkyl.
28. The compound of any one of claims 1-24 or 27, or a pharmaceutically acceptable salt thereof,
29. The compound of any one of claims 1-28, wherein the compound is of formula:
30. A pharmaceutical composition comprising the compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
31. The pharmaceutical composition of claim 30 further comprising an additional pharmaceutical agent.
32. The pharmaceutical composition of claim 31 , wherein the additional pharmaceutical agent is an anti-cancer agent.
33. The pharmaceutical composition of claim 32, wherein the anti-cancer agent is an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof.
34. A method of degrading a TEAD protein in a subject or in a cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of the compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 30-33.
35. The method of claim 34, wherein the TEAD protein is TEAD1, TEAD2, TEAD3, and/or TEAD4.
36. The method of any one of claims 34 or 35, wherein the cell, tissue, or biological sample is in vitro.
37. The method of any one of claims 34 or 35, wherein the cell, tissue, or biological sample is in vivo.
38. The method of any one of claims 34-37, wherein the cell is a cancer cell.
39. A method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 30-33.
40. The method of claim 39, wherein the disease is a cancer.
41. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 30-33.
42. The method of any one of claims 40 or 41, wherein the cancer is associated with a TEAD protein.
43. The method of any one of claims 40-42, wherein the cancer is associated with TEAD1, TEAD2, TEAD3, and/or TEAD4.
44. The method of any one of claims 40-43, wherein the cancer is esophageal cancer, liver cancer, glioma, breast cancer, lung cancer, colorectal cancer, mesothelioma, ovarian cancer, gastric cancer, thyroid cancer, skin cancer, pancreatic cancer, uveal melanoma, Ewing sarcoma, head and neck cancer, prostate cancer, or bone cancer.
45. The method of any one of claims 34-44, wherein the subject is a mammal.
46. The method of any one of claims 34-45, wherein the subject is a human.
PCT/US2025/013644 2024-01-29 2025-01-29 Bifunctional tead degraders Pending WO2025165908A1 (en)

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Citations (3)

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