WO2022150768A1 - Inhibiteurs d'yap-tead et leurs utilisations - Google Patents

Inhibiteurs d'yap-tead et leurs utilisations Download PDF

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WO2022150768A1
WO2022150768A1 PCT/US2022/011993 US2022011993W WO2022150768A1 WO 2022150768 A1 WO2022150768 A1 WO 2022150768A1 US 2022011993 W US2022011993 W US 2022011993W WO 2022150768 A1 WO2022150768 A1 WO 2022150768A1
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optionally substituted
compound
certain embodiments
instance
cancer
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PCT/US2022/011993
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Fernando CAMARGO
Sophia SHALHOUT
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Children's Medical Center Corporation
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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by 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
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • 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
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the Hippo/YAP signaling pathway is dysregulated in approximately 60% of all liver cancers, and patients with YAP-dependent liver cancer may benefit from target specific therapy.
  • YAP could serve as a potential diagnostic and/or prognostic marker for liver cancer.
  • YAP dysregulation occurs in several primary human cancers and YAP inhibitors may be used in the treatment of cancers from patients shown to have elevated YAP levels. In particular, it would be important to develop inhibitors of the YAP-TEAD interaction that can lead to drugs specifically targeting the Hippo pathway. This could be an important novel approach to treating malignancies of the liver and pancreatic cancer.
  • the compounds of Formulae (I), (II), and pharmaceutically acceptable salts, co- crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, prodrugs, and compositions thereof, may inhibit the activity of a transcription factor (e.g., TEAD) in a biological sample or subject.
  • a transcription factor e.g., TEAD
  • the transcription factor is a transcriptional enhanced associate domain (TEAD).
  • the compound of Formulae (I) or (II) is selective for a specific TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4) compared to other TEADs.
  • inventive compounds described herein may also be used as therapeutics for the prevention and/or treatment of diseases associated with dysregulation of the Hippo/YAP pathway, for example, dysregulation of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).
  • TEAD a transcription factor
  • the compounds described herein may be useful in treating and/or preventing a disease or condition, e.g., in treating and/or preventing a disease (e.g., proliferative disease (e.g., cancer), disease associated with dysregulation of YAP-TAZ transcriptional activity), in a subject in need thereof.
  • a disease e.g., proliferative disease (e.g., cancer)
  • YAP-TAZ transcriptional activity e.g., YAP-TAZ transcriptional activity
  • the present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 5A , R 5B , R 6 , R 7 , R 8 , X, a, x, y, and z are as defined herein.
  • Exemplary compounds of Formula (I) include, but are not limited to:
  • the present disclosure provides compounds of Formula (II): and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, and prodrugs thereof, wherein R 1A , R 2A , R 3A , R 3B , R 4A , R 5C , R 6A , p, q, and b are as defined herein.
  • Exemplary compounds of Formula (II), include, but are not limited to:
  • compositions including a compound described herein, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions described herein include a therapeutically or prophylactically effective amount of a compound described herein.
  • the pharmaceutical composition may be useful for treating and/or preventing a disease (e.g., proliferative disease (e.g., cancer), disease associated with dysregulation of YAP-TAZ transcriptional activity) in a subject in need thereof, inhibiting a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4), or inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a subject, and/or biological sample (e.g., tissue, cell).
  • a disease e.g., proliferative disease (e.g., cancer), disease associated with dysregulation of YAP-TAZ transcriptional activity
  • TEAD e.g., proliferative disease (e.g., cancer), disease associated with dysregulation of YAP-TAZ transcriptional activity
  • TEAD e.g., proliferative disease (e.
  • the proliferative disease is cancer (e.g., liver cancer, pancreatic cancer, lung cancer, cancer of the nervous system, brain cancer, thyroid cancer, sarcoma, carcinoma, breast cancer, colorectal cancer, skin cancer, uterine cancer, ovarian cancer, prostate cancer, eye cancer, bladder cancer, gastric cancer, esophageal cancer, kidney cancer).
  • a disease e.g., a proliferative disease, disease associated with dysregulation of YAP-TAZ transcriptional activity
  • an additional pharmaceutical agent for example, an anti- proliferative agent.
  • Exemplary proliferative diseases which may be treated include diseases associated with dysregulation of the Hippo/YAP pathway, for example, dysregulation of a TEAD, e.g., a proliferative disease, such as cancer, or a disease (e.g., cancer) associated with dysregulation of YAP-TAZ transcriptional activity.
  • the cancer is selected from the group consisting of liver cancer, pancreatic cancer, lung cancer, cancer of the nervous system, brain cancer, thyroid cancer, sarcoma, carcinoma, breast cancer, colorectal cancer, skin cancer, uterine cancer, ovarian cancer, prostate cancer, eye cancer, bladder cancer, gastric cancer, esophageal cancer, and kidney cancer.
  • the cancer is lung cancer (e.g., non-small cell lung cancer, mesothelioma).
  • the cancer is a sarcoma (e.g., Kaposi’s sarcoma).
  • the cancer is a carcinoma (e.g., squamous cell carcinoma, merkel cell carcinoma, bladder urothelial carcinoma, head squamous cell carcinoma or neck squamous cell carcinoma, Skin and mucosal squamous cell carcinoma).
  • the cancer is kidney cancer (e.g., kidney renal papillary cell carcinoma).
  • Another aspect relates to methods of inhibiting (e.g., inhibiting the activity of) a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) using a compound described herein in a biological sample (e.g., cell, tissue), which may be optionally administered in combination with an additional pharmaceutical agent, for example, anti-proliferative agents.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • a transcription factor e.g., such as TEAD1, TEAD2, TEAD3, TEAD4
  • the method involves the inhibition of TEAD (e.g., TEAD1) and/or inhibiting the interaction between YAP and TEAD.
  • TEAD e.g., TEAD1
  • Another aspect relates to methods of inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) using a compound described herein, which may be optionally administered in combination with an additional pharmaceutical agent, for example, anti-proliferative agents.
  • TEAD e.g., TEAD1
  • TEAD3 transcription factor
  • Described herein are methods for administering to a subject in need thereof an effective amount of a compound, or pharmaceutical composition thereof, as described herein, which may be optionally administered in combination with an additional pharmaceutical agent, for example, anti-proliferative agents.
  • a biological sample e.g., tissue, cell
  • an effective amount of a compound, or pharmaceutical composition thereof, as described herein which may be optionally administered in combination with an additional pharmaceutical agent, for example, anti- proliferative agents.
  • a method described herein further includes administering to the subject an additional pharmaceutical agent.
  • a method described herein further includes contacting the biological sample (e.g., tissue, cell) with an additional pharmaceutical agent (e.g., an anti-proliferative agent).
  • the additional pharmaceutical agent is an anti-proliferative agent.
  • the present disclosure provides compounds of Formulae (I), and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, which may be optionally administered in combination with an additional pharmaceutical agent, for example, anti-proliferative agents, for use in the treatment of a disease (e.g., a proliferative disease, inflammatory disease, autoimmune disease) in a subject.
  • a disease e.g., a proliferative disease, inflammatory disease, autoimmune disease
  • the present disclosure provides compounds of Formulae (I), and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, which may be optionally administered in combination with an additional pharmaceutical agent, for example, anti-proliferative agents, for use in inhibiting a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)), or inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4))) in a subject and/or biological sample (e.g., tissue, cell).
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • TEAD a gene controlled or regulated by a transcription factor (e.g., TEAD,
  • kits comprising a container with a compound, or pharmaceutical composition thereof, as described herein.
  • the kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition.
  • the kits may be useful in a method of the disclosure.
  • the kit further includes instructions for using the compound or pharmaceutical composition.
  • a kit described herein may also include information (e.g. prescribing information) as required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA).
  • FDA U.S. Food and Drug Administration
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) 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, Stereochemistry of Carbon Compounds (McGraw– Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
  • HPLC high pressure liquid chromatography
  • the invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • a range of values is listed, it is intended to encompass each value and sub– range within the range.
  • “C1–6” is intended to encompass C1, C2, C3, C4, C5, C6, C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 .
  • Hydrocarbon chain refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group.
  • a hydrocarbon chain includes at least one chain, each node (“carbon unit”) of which including at least one carbon atom, between the two radicals of the hydrocarbon chain.
  • carbon unit For example, hydrocarbon chain –C A H(C B H 2 C C H 3 )– includes only one carbon unit C A .
  • Cx hydrocarbon chain wherein x is a positive integer, refers to a hydrocarbon chain that includes x number of carbon unit(s) between the two radicals of the hydrocarbon chain. If there is more than one possible value of x, the smallest possible value of x is used for the definition of the hydrocarbon chain.
  • —CH(C2H5)— is a C1 hydrocarbon chain, and is a C 3 hydrocarbon chain.
  • a hydrocarbon chain may be saturated (e.g., –(CH2)4–).
  • the hydrocarbon chain is unsubstituted (e.g., –(CH 2 ) 4 –). In certain embodiments, the hydrocarbon chain is substituted (e.g., –CH(C2H5)– and –CF2–). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring. For instance, and are all examples of a hydrocarbon chain. In contrast, in certain embodiments are not within the scope of the hydrocarbon chains described herein.
  • Alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”).
  • an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“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”). In some embodiments, an alkyl group has 2 to 10 carbon atoms (“C 2–10 alkyl”).
  • C 1–6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents.
  • the alkyl group is unsubstituted C 1–10 alkyl (e.g., –CH 3 ).
  • the alkyl group is substituted C1–10 alkyl.
  • the alkyl group is substituted C2–10 alkyl.
  • Alkenyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds, and no triple bonds (“C2–20 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl).
  • Examples of C2–4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2–6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), 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 optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
  • the alkenyl group is unsubstituted C2–10 alkenyl.
  • the alkenyl group is substituted C 2–10 alkenyl.
  • Alkynyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds, and optionally one or more double bonds (“C 2–20 alkynyl”).
  • an alkynyl group has 2 to 10 carbon atoms (“C2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5 alkynyl”).
  • an alkynyl group has 2 to 4 carbon atoms (“C2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”).
  • the one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • C2–4 alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C 3 ), 1–butynyl (C 4 ), 2–butynyl (C 4 ), and the like.
  • Examples of C 2–6 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.
  • each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
  • the alkynyl group is unsubstituted C 2–10 alkynyl.
  • the alkynyl group is substituted C 2–10 alkynyl.
  • 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 (“C 3-12 carbocyclyl”).
  • a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 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 6 ring carbon atoms (“C 3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3–6 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 (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C6), and the like.
  • Exemplary C3–8 carbocyclyl groups include the aforementioned C3–6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like.
  • Exemplary C3–10 carbocyclyl groups include, without limitation, the aforementioned C3–8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged, or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic 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 optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C3–10 carbocyclyl.
  • the carbocyclyl group is a substituted C3–10 carbocyclyl.
  • the carbocyclyl group is an unsubstituted C3-14 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-14 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3–10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C3–8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C3–6 cycloalkyl”).
  • a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5–6 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 (C6). Examples of C3–6 cycloalkyl groups include the aforementioned C 5–6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3–8 cycloalkyl groups include the aforementioned C 3–6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C3–10 cycloalkyl.
  • the cycloalkyl group is substituted C3–10 cycloalkyl.
  • the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.
  • “Heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10–membered non– aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 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 a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl.
  • the heterocyclyl group is substituted 3–10 membered heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 3- to 7- membered, 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 the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of 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 the group consisting of nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione.
  • Exemplary 5– membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14 aryl”).
  • an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C6–14 aryl.
  • the aryl group is substituted C6–14 aryl.
  • “Aralkyl” is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In certain embodiments, the aralkyl is optionally substituted benzyl.
  • the aralkyl is benzyl. In certain embodiments, the aralkyl is optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl.
  • “Heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”).
  • heteroaryl groups that contain one or more nitrogen atoms
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).
  • a heteroaryl group is a 5–10 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 the group consisting of 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 the group consisting of 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 the group consisting of 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. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5–14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5–14 membered heteroaryl.
  • Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, 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, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Heteroaralkyl is a subset of alkyl and heteroaryl and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.
  • Partially unsaturated refers to a group that includes at least one double or triple bond.
  • a “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as defined herein.
  • “saturated” refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups are further referred to using the suffix –ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.
  • optionally substituted refers to substituted or unsubstituted.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (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 (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • 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 (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ), NO 3 – , ClO 4 – , OH – , H2PO4 – , HCO3 ⁇ , 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, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the
  • Exemplary counterions which may be multivalent include CO 3 2 ⁇ , HPO 4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO4 2 ⁇ , S2O3 2 ⁇ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, mal
  • Halo or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I).
  • acyl groups include aldehydes (–CHO), carboxylic acids (–CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
  • Alkoxy or “alkoxyl” refers to a radical of the formula: –O–alkyl. Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to 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.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9–fluorenylmethyl carbamate (Fmoc), 9–(2–sulfo)fluorenylmethyl carbamate, 9–(2,7–dibromo)fluoroenylmethyl carbamate, 2,7–di– t–butyl–[9–(10,10–dioxo–10,10,10,10–tetrahydrothioxanthyl)]methyl carbamate (DBD– Tmoc), 4–methoxyphenacyl carbamate (Phenoc), 2,2,2–trichloroethyl carbamate (Troc), 2– trimethylsilylethyl carbamate (Teoc), 2–phenylethyl carbamate (hZ), 1–(1–adamantyl)–
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, 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), methan
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl–(10)– acyl derivative, N′–p–toluenesulfonylaminoacyl derivative, N′–phenylaminothioacyl derivative, N–benzoylphenylalanyl derivative, N–acetylmethionine derivative, 4,5–diphenyl– 3–oxazolin–2–one, N–phthalimide, N–dithiasuccinimide (Dts), N–2,3–diphenylmaleimide, N–2,5–dimethylpyrrole, N–1,1,4,4–tetramethyldisilylazacyclopentane adduct (STABASE), 5–substituted 1,3–dimethyl–1,3,5–triazacyclohexan–2–one, 5–substituted 1,3–dibenzyl– 1,3,5–triazacyclohexan–2–one, 1–substit
  • 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.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (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–methoxycyclohexyl, 4– methoxytetrahydropyr
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
  • LG is an art-understood term referring to a molecular fragment that departs with a pair of electrons in a heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • Suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates.
  • halogen such as F, Cl, Br, or I (iodine
  • the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, – OTs), methanesulfonate (mesylate, –OMs), p-bromobenzenesulfonyloxy (brosylate, –OBs), or trifluoromethanesulfonate (triflate, –OTf).
  • the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy.
  • the leaving group is a sulfonate- containing group. In some embodiments, the leaving group is a tosylate group.
  • the leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
  • Other non-limiting examples of leaving groups are water, amines, ammonia, alcohols, ether moieties, sulfur-containing moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention 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, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 - salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction.
  • This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds of Formula (I) or (II) may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates.
  • solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H2O, wherein R is the compound and wherein x is a number greater than 0.
  • a given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H2O) and hexahydrates (R ⁇ 6 H2O)).
  • tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • isomers 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.” 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.”
  • the term “polymorphs” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement.
  • polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • the term “prodrugs” refer to compounds, including derivatives of the compounds of Formulae (I), and (II), which have cleavable groups and become by solvolysis or under physiological conditions the compounds of Formulae (I), and (II) which are pharmaceutically active in vivo.
  • Such examples include, but are not limited to, ester derivatives and the like.
  • Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult, or senior adult)) and/or other non–human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals, such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys).
  • mammals e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys)
  • commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs
  • the animal is a mammal.
  • the animal may be a male or female at any stage of development.
  • a non–human animal may be a transgenic animal.
  • the terms “administer,” “administering,” or “administration” refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound or a pharmaceutical composition thereof.
  • the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a “pathological condition” (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein. In some embodiments, treatment may be administered after one or more signs or symptoms have developed or have been observed.
  • pathological condition e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof
  • treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • the term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who does not have and did not have a disease but is at risk of developing the disease or 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.
  • condition refers to the ability of a compound to reduce, slow, halt, or prevent activity of a particular biological process (e.g., a transcription factor) in a cell relative to vehicle.
  • an “effective amount” of a compound of Formula (I), or (II) refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition, for example, inhibiting TEAD.
  • the effective amount of a compound of Formula (I), or (II) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • an effective amount of an inventive compound may reduce the tumor burden or stop the growth or spread of a tumor.
  • a “therapeutically effective amount” of a compound of Formula (I), or (II) 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 or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or 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.
  • 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 binding a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) and/or inhibiting the transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).
  • a prophylactically effective amount is an amount sufficient for binding a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) and/or inhibiting the transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).
  • a prophylactically effective amount is an amount sufficient for preventing a disease and/or condition (e.g., proliferative disease, inflammatory disease, autoimmune disease).
  • a prophylactically effective amount is an amount sufficient for binding a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4), and treating and/or preventing a disease and/or condition (e.g., proliferative disease, inflammatory disease, autoimmune disease).
  • a prophylactically effective amount is an amount sufficient for binding a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) and/or inhibiting the transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).
  • 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, 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, 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, mucus, 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.
  • Biological samples also include those biological samples that are transgenic, such as a transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus, or cells or cell lines derived from biological samples.
  • tissue refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a compound, particle, and/or composition of the invention is delivered.
  • a tissue may be an abnormal or unhealthy tissue, which may need to be treated.
  • a tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented.
  • the tissue is the central nervous system.
  • the tissue is the brain.
  • 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.
  • proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases)
  • the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, lymphoma, non- Hodgkin’s lymphoma, Waldenstrom macroglobulinemia, MYD88-mutated Waldenstrom macroglobulinemia, activated B-cell diffuse large B-cell lymphoma, leukemia, sarcoma, lung cancer, thyroid cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, colorectal cancer, skin cancer, esophageal cancer, and carcinoma.
  • cancers i.e., “malignant neoplasms”
  • benign neoplasms lymphoma
  • non- Hodgkin’s lymphoma Waldenstrom macroglobulinemia
  • MYD88-mutated Waldenstrom macroglobulinemia activated B-cell diffuse large B-cell lymphoma
  • leukemia sarcoma
  • lung cancer thyroid cancer
  • Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms,” sarcoma, lung cancer, thyroid cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, colorectal cancer, skin cancer, esophageal cancer; carcinoma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
  • cancers i.e., “malignant neoplasms,” sarcoma, lung cancer, thyroid cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, colorectal cancer, skin cancer, esophageal cancer; carcinoma
  • benign neoplasms angiogenesis
  • inflammatory diseases e.g., autoinflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
  • autoimmune diseases include cancers (i.e., “malignant neoplasms,” sarcoma, lung cancer, thyroid cancer, breast cancer, liver
  • 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 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 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 malignant neoplasm (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 neuroendocrinetumor (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
  • therapeutic agent refers to any substance having therapeutic properties that produce a desired, usually beneficial, effect.
  • therapeutic agents may treat, ameliorate, and/or prevent disease.
  • Therapeutic agents, as disclosed herein, may be biologics or small molecule therapeutics.
  • a “transcription factor” is a type of protein that is involved in the process of transcribing DNA into RNA, and/or modulating the transcription of one or more genes. Transcription factors can work independently or with other proteins in a complex to either stimulate or repress transcription. Transcription factors contain at least one DNA-binding domain that give them the ability to bind to specific sequences of DNA.
  • proteins such as coactivators, chromatin remodelers, histone acetyltransferases, histone deacetylases, kinases, and methylases are also essential to gene regulation, but lack DNA-binding domains, and therefore are not transcription factors.
  • exemplary human transcription factors include, but are not limited to, YAP, EGFR, MEK, TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4), AC008770.3, AC023509.3, AC092835.1, AC138696.1, ADNP, ADNP2, AEBP1, AEBP2, AHCTF1, AHDC1, AHR, AHRR, AIRE, AKAP8, AKAP8L, AKNA, ALX1, ALX3, ALX4, ANHX, ANKZF1, AR, ARGFX, ARHGAP35, ARID2, ARID3A, ARID3B, ARID3C, ARID5A, ARID5B, ARNT, ARNT2, ARNTL, ARNTL2, ARX, ASCL1, ASCL2, ASCL3, ASCL4, ASCL5, ASH1L, ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, ATF6B, ATF7, ATMIN, ATOH1, ATOH7, ATOH8, BACH1, BACH2, BAR
  • TEAD refers to transcriptional enhanced associate domain (TEAD) transcription factors.
  • TEADs are primary transcription factors for the Yes-associated protein (YAP)/PDZ-binding domain (TAZ) transcription coactivators of the Hippo signaling pathway.
  • Examples of TEADs include, but are not limited to, TEAD1, TEAD2, TEAD3, and TEAD4.
  • exemplary NCBI sequences from GenBank are: NM_001256660.2 (Homo sapiens) and NM_001256659.2 (Homo sapiens).
  • TEADs include, but are not limited to, TGF, CYR61, WNT5A/B, DKK1, TGFB2, BMP4, AREG, EGFR, PD-L1, MYC, LATS2, amino acid transporters SLC38A1/SLC7A5, and glucose transporter GLUT3.
  • TEADs bind to DNA sequences including, but not limited to, MCAT DNA sequences, and the 5′-GGAATG-3′ consensus sequence.
  • FIG.1 shows a schematic diagram of the Hippo signaling kinase cascade and the main downstream effector, the transcriptional coactivator YAP.
  • YAP orchestrates a pro- proliferative transcriptional program upon nuclear translocation and binding to the transcription factor TEAD. Dysregulation of this pathway leads to the development of several human cancers and has therapeutic potential.
  • FIG.2 shows a diagram of the drug discovery campaign utilizing a DNA encoded library with 65 million compounds to screen for direct binding against purified human YAP- Binding domain of TEAD1 protein.
  • FIG.3 shows a Heat Map of the results of the TEAD1 binding screen displaying the relational Tanimoto Scores (Tc) of the hits and main cluster/chemotypes of structures.
  • the heat map is color coded by Tc cut offs and columns on the left reveal the compounds that were hits from screen1, screen2, associated molecular weights, cLogP, and the compounds that were re-synthesized off DNA for testing in biophysical and cell based YAP-TEAD assays.
  • Screen1 and Screen2 were independent TEAD1 protein binding screens with different protein buffer/binding conditions. The hits revealed four main cluster/chemotypes.
  • FIG.4A is a diagram depicting the YAP-TEAD transcriptional reporter assay, 14xTBS-Luc, that utilizes 293T cell line with a stably integrated cassette containing 14 copies of the TEAD binding element upstream of luciferase.
  • FIG.4B shows single dose assessment of each of the indicated compounds in the YAP-TEAD transcriptional reporter assay, 14xTBS-LUC. Compounds that were hits from the original screen (compounds 1, 59, 67, 13, 63, 61, and 69) and the building block ‘D2’ which was present in many of the original screen hits, were re-synthesized ‘off-DNA’ and assessed in the 14x TBS-Luc assay at 10 ⁇ M twice daily.
  • FIG.5A is a diagram showing a cell based protein-protein YAP-TEAD interaction luminescence assay which monitors the interaction between YAP and TEAD, as the physical proximity between both proteins results in luciferase reconstitution.
  • FIG.5B shows single dose assessment of each of the indicated compounds in the YAP-TEAD Gaussia Luciferase protein-protein interaction assay. Compounds that were hits from the original screen (compounds 1, 59, 67, 13, 63, 61, and 69) and the building block ‘D2’ which was present in many of the original screen hits, were re-synthesized ‘off-DNA’ and assessed in the YAP- TEAD Gaussia Luciferase assay at 10 ⁇ M twice daily.
  • FIG.6 shows the structure of compound 1 (70).
  • FIG.7 shows the structure of compound 59.
  • FIG.8 shows the structure of compound 67.
  • FIG.9 shows the structure of compound 13.
  • FIG.10 shows the structure of compound 63.
  • FIG.11 shows the structure of compound 61.
  • FIG.12 shows the structure of compound 69.
  • FIG.13 shows the structure of compound D2.
  • FIGs.14A-14B show dose response curves in cell based YAP-TEAD reporter assays.
  • FIG.14A shows a DRC-TBS-Luc assay based on administration of each of the indicated exemplary compounds at the indicated concentrations.
  • FIG.14B shows a DRC-split-GLuc assay based on administration of each of the indicated exemplary compounds at the indicated concentrations.
  • FIGs.15A-15B show dose response curves in YAP-insensitive versus YAP-sensitive mesothelioma cell lines. YAP sensitivity was determined via siRNA KD of YAP and its effects on proliferation.
  • FIG.15A shows a Cell Titer Glo (CTG) proliferation assay in Met5A YAP insensitive cells based on administration of each of the indicated exemplary compounds at the indicated concentrations.
  • FIG.15B shows a CTG proliferation assay in NCI-H2052 YAP sensitive cells based on administration of each of the indicated exemplary compounds at the indicated concentrations.
  • CTG Cell Titer Glo
  • FIGs.16A-16D show dose response curves in Cell Titer Glo (CTG) proliferation assays within the indicated YAP-insensitive (YAPC, BxPC3) versus YAP-sensitive (PANC1, L3.3), pancreatic cancer cell lines based on administration of each of the indicated exemplary compounds at the indicated concentrations.
  • YAP sensitivity was determined via siRNA KD of YAP and its effects on proliferation.
  • FIGs.17A-17C show dose response curves in a Cell Titer Glo Proliferation assay within the indicated YAP-insensitive (TE9) versus YAP-sensitive esophageal cancer cell lines (Det562, PJ41), based on administration of each of the indicated exemplary compounds at the indicated concentrations.
  • FIG.18 shows the structure of exemplary compound 9.
  • FIG.19 shows the Biolayer interferometry (BLI) assessment with the YBD (Yap- binding domain) of TEAD and compound 9, in the presence or absence of purified Tead binding domain (TBD) of YAP protein.
  • This competitive BLI Octet 384 Red
  • FIG.20 shows the Biolayer interferometry (BLI) assessment with the YBD (Yap- binding domain) of TEAD and compound 61, in the presence or absence of purified Tead binding domain (TBD) of YAP protein.
  • FIG.21 is a graph showing the isothermal calorimetry (ITC) thermogram of Compound 9 with hTEAD1-YBD. The Kd is shown and the thermogram reveals baseline noise with endothermic artifacts.
  • FIG.22 is a graph showing the isothermal calorimetry (ITC) thermogram assay of Compound 61 with hTEAD1-YBD.
  • FIG.23 shows the Cell Titer Glo Proliferation Assays of YAP- insensitive cancer cell lines, as determined by YAP siRNA knock down, upon administration of Compound 9.
  • FIG.24 shows the Cell Titer Glo Proliferation Assays of YAP- sensitive cancer cell lines, as determined by YAP siRNA knock down, upon administration of Compound 9.
  • FIG.25 depicts the experimental in vivo study. Six TetO-YAP mice were injected with AAV-Cre, followed by doxycycline on day 4. Three mice received Compound 9 at 40mg/kg via intraperitoneal injections (IP) twice daily (bid) and three mice received vehicle control via IP twice daily. Livers were harvested and assessed for size, liver/body mass ratio, and YAP target genes via qPCR.
  • IP intraperitoneal injections
  • FIG.26 shows representative harvested livers and their sizes from a mouse that received vehicle control (right) versus a liver from a mouse that received compound 9 (left) in the in vivo study depicted in FIG.25.
  • FIG.27 depicts the mRNA levels of YAP-target genes CTGF, Cyr61, and Amotl2 from the harvested livers of mice treated with vehicle control or compound 9 from the in vivo study depicted in FIG.25. Levels were determined via quantitative PCR.
  • FIG.28 depicts the liver to body mass ratio from the mice treated with vehicle control or compound 9 from the in vivo study depicted in FIG.25.
  • TEAD a transcription factor
  • inventive compounds inhibit (e.g., the activity of) TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4).
  • the present disclosure further provides methods of using the compounds described herein, e.g., for inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)), and as therapeutics, e.g., in the treatment and/or prevention of diseases associated with dysregulation of the Hippo/YAP pathway, for example, dysregulation of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).
  • the diseases treated and/or prevented include, but are not limited to, proliferative diseases and diseases associated with dysregulation of the Hippo/YAP pathway.
  • the proliferative diseases include, but are not limited to, cancer (e.g., liver cancer, pancreatic cancer, lung cancer, cancer of the nervous system, brain cancer, thyroid cancer, sarcoma, carcinoma, breast cancer, colorectal cancer, skin cancer, uterine cancer, ovarian cancer, prostate cancer, eye cancer, bladder cancer, gastric cancer, esophageal cancer, and kidney cancer).
  • the cancer is lung cancer (e.g., non-small cell lung cancer, mesothelioma).
  • the cancer is a sarcoma (e.g., Kaposi’s sarcoma).
  • the cancer is a carcinoma (e.g., squamous cell carcinoma, merkel cell carcinoma, bladder urothelial carcinoma, head squamous cell carcinoma or neck squamous cell carcinoma, Skin and mucosal squamous cell carcinoma).
  • the cancer is kidney cancer (e.g., kidney renal papillary cell carcinoma).
  • the cancer is associated with the dysregulation of a transcription factor in the Hippo/YAP pathway (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).
  • TEAD transcription factor in the Hippo/YAP pathway
  • the compounds described herein are TEAD inhibitors (e.g., inhibitors of the interaction between YAP and TEAD).
  • the compounds described herein may be useful in treating and/or preventing diseases (e.g., proliferative diseases, diseases associated with dysregulation of the Hippo/YAP pathway, for example, dysregulation of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject, inhibiting the activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4), or inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject or biological sample.
  • diseases e.g., proliferative diseases, diseases associated with dysregulation of the Hippo/YAP pathway, for example, dysregulation of a transcription factor (e.g., TEAD, such as
  • a compound described herein is a compound of Formula (I), (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
  • a compound described herein is a compound of Formula (I), or (II), or a pharmaceutically acceptable salt thereof.
  • a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a compound described herein is a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) described herein is of Formula (I-A): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • a compound of Formula (I) described herein is of Formula (I-B): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • a compound of Formula (I) described herein is of Formula (I-A), (I-B), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • each instance of R 1A is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -NO 2 , -OR D1 , -N(R D1a ) 2 , or -SR D1 ; wherein R D1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally
  • b is 1.
  • a compound of Formula (II) described herein is of Formula (II-A): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • b is 0.
  • a compound of Formula (II) described herein is of Formula (II-B): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • a compound of Formula (II) described herein is of Formula (II-A), (II-B), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • Formula (I) includes substituent X in the moiety .
  • X C-, as valency permits.
  • X N-, as valency permits.
  • Formula (I) includes zero or more instances of substituent R 1 attached to the moiety .
  • x is 0.
  • x is 1.
  • x is 2.
  • At least one instance of R 1 is optionally substituted n-butyl. In certain embodiments, at least one instance of R 1 is optionally substituted t-butyl. In certain embodiments, at least one instance of R 1 is alkyl optionally substituted with halogen. In certain embodiments, at least one instance of R 1 is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R 1 is C1-6 alkyl optionally substituted with halogen. In certain embodiments, at least one instance of R 1 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R 1 is substituted or unsubstituted ethyl.
  • At least one instance of R 1 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R 1 is optionally substituted alkenyl (e.g., substituted or unsubstituted C 2-6 alkenyl). In certain embodiments, at least one instance of R 1 is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of R 1 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • At least one instance of R 1 is optionally substituted carbocyclyl (e.g., optionally substituted C 3–14 carbocyclyl, optionally substituted C 3–10 carbocyclyl).
  • at least one instance of R 1 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R 1 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • At least one instance of R 1 is benzyl. In certain embodiments, at least one instance of R 1 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R 1 is of formula: , wherein: each instance of R A is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -NO2, -OR D2 , -N(R D2a )2, or -SR D2 ; and w is 0, 1, 2, 3, 4, or 5.
  • R 1 is of the formula: wherein each instance of R A is independently halogen, optionally substituted acyl, optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl), optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl), or optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl).
  • R A is independently halogen, optionally substituted acyl, optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl), optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl), or optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl).
  • At least one instance of R 1 is of the formula: certain embodiments, at least one instance of R 1 is of the formula: . In certain embodiments, at least one instance of R 1 is of the formula: , wherein each instance of R A is independently halogen, optionally substituted acyl, optionally substituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl), optionally substituted alkenyl (e.g., substituted or unsubstituted C 2-6 alkenyl), or optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl).
  • each instance of R A is independently halogen, optionally substituted acyl, optionally substituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl), optionally substituted alkenyl (e.g., substituted or unsubstituted C 2-6 alkenyl), or optionally substituted alkyny
  • At least one instance of R 1 is of formula: In certain embodiments, at least one instance of R 1 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R 1 is –CN. In certain embodiments, at least one instance of R 1 is –NO 2 .
  • At least one instance of R 1 is –OR D1 (e.g., – OH or –OMe). In certain embodiments, at least one instance of R 1 is –N(R D1a )2 (e.g., -NMe2). In certain embodiments, at least one instance of R 1 is -N(R D1a )2, and each instance of R D1a is independently hydrogen or optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R 1 is –NHMe. In certain embodiments, at least one instance of R 1 is -NH2, – NHMe, or –NMe2.
  • R 1 is –SR D1 (e.g., -SMe).
  • x is 1; and R 1 is optionally substituted alkyl (e.g., optionally substituted C 1-6 alkyl), -N(R D1a ) 2 , and each instance of R D1a is independently hydrogen or optionally substituted C1-6 alkyl; or optionally substituted phenyl (e.g., of formula: wherein: each i A nstance of R is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -NO 2 , -OR D2 , -N(R D2a ) 2 , or -SR D2 ; and w is 0, 1, 2, 3, 4,
  • At least one instance of R A is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R A is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl). In certain embodiments, at least one instance of R A is optionally substituted alkenyl (e.g., substituted or unsubstituted C 2- 6 alkenyl). In certain embodiments, at least one instance of R A is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl).
  • halogen e.g., F, Cl, Br, or I
  • at least one instance of R A is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl).
  • at least one instance of R A is optionally substituted alkenyl (e.g., substituted or unsubstituted C 2- 6 alkenyl
  • At least one instance of R A is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R A is optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C 3–10 carbocyclyl).
  • At least one instance of R A is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R A is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • at least one instance of R A is benzyl.
  • at least one instance of R A is substituted or unsubstituted phenyl.
  • At least one instance of R A is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R A is –CN.
  • at least one instance of R A3 is –NO 2 .
  • At least one instance of R A is –OR D2 (e.g., – OH or –OMe). In certain embodiments, at least one instance of R A is –N(R D2a )2 (e.g., - NMe2). In certain embodiments, at least one instance of R A is -N(R D2a )2, and each instance of R D2a is independently hydrogen or optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R A is –NHMe. In certain embodiments, at least one instance of R A is -NH2, –NHMe, or –NMe2.
  • At least one instance of R A is –SR D2 (e.g., -SMe).
  • Formulas (I) and (II) include R D1 and R D1a , which are as defined herein.
  • at least one instance of R 1 is -OR D1 , -N(R D1a )2, or -SR D1 , and R D1 and R D1a are as defined herein.
  • at least one instance of R 1A is -OR D1 , -N(R D1a ) 2 , or -SR D1 , and R D1 and R D1a are as defined herein.
  • At least one instance of R 3 is -OR D1 , -N(R D1a )2, or -SR D1 , and R D1 and R D1a are as defined herein.
  • at least one instance of R 3B is -OR D1 , -N(R D1a )2, or -SR D1 , and R D1 and R D1a are as defined herein.
  • at least one instance of R 5A is -OR D1 , -N(R D1a ) 2 , or -SR D1 , and R D1 and R D1a are as defined herein.
  • At least one instance of R 5B is -OR D1 , -N(R D1a )2, or -SR D1 , and R D1 and R D1a are as defined herein.
  • at least one instance of R 8 is -OR D1 , -N(R D1a ) 2 , or -SR D1 , and R D1 and R D1a are as defined herein.
  • R D1 is hydrogen.
  • R D1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl). In certain embodiments, R D1 is substituted or unsubstituted methyl. In certain embodiments, R D1 is substituted or unsubstituted ethyl. In certain embodiments, R D1 is substituted or unsubstituted propyl. In certain embodiments, R D1 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C 2-6 alkenyl).
  • R D1 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl).
  • R D1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • R D1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R D1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • R D1 is benzyl.
  • R D1 is substituted or unsubstituted phenyl.
  • R D1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently
  • R D1 is an oxygen protecting group when attached to an oxygen atom (e.g., methyl, carbonate protecting group, silyl ether protecting group, ether protecting group, ester protecting group, benzoate, acetate, acetal protecting group, methanesulfonate (mesylate), benzylsulfonate, tosylate (Ts)).
  • an oxygen atom e.g., methyl, carbonate protecting group, silyl ether protecting group, ether protecting group, ester protecting group, benzoate, acetate, acetal protecting group, methanesulfonate (mesylate), benzylsulfonate, tosylate (Ts)).
  • at least one R D1a is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl). In certain embodiments,
  • At least one instance of R D1a is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, at least one instance of R D1a is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of R D1a is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7- membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • At least one instance of R D1a is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R D1a is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10- membered aryl).
  • at least one instance of R D1a is benzyl.
  • at least one instance of R D1a is substituted or unsubstituted phenyl.
  • At least one instance of R D1a is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen
  • At least one instance of R D1a is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9- fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p- toluenesulfonamide (Ts)).
  • a nitrogen protecting group e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9- fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p- toluenesulfonamide (Ts)
  • two instances of R D1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur) or substituted or unsubstituted heteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • a substituted or unsubstituted heterocyclic ring e.g., substituted or unsub
  • Formula (I) includes substituent R 2 .
  • R 2 is hydrogen.
  • R 2 is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl).
  • R 2 is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl).
  • R 2 is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl).
  • R 2 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R 2 is optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C 3–10 carbocyclyl).
  • R 2 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R 2 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • R 2 is benzyl.
  • R 2 is substituted or unsubstituted phenyl.
  • R 2 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • R 2 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • Formula (I) includes zero or more instances of substituent R 3 attached to the benzyl moiety.
  • y is 0.
  • y is 1.
  • y is 2.
  • y is 3.
  • y is 4.
  • y is 5.
  • At least one instance of R 3 is optionally substituted butyl (e.g., optionally substituted t-butyl). In certain embodiments, at least one instance of R 3 is optionally substituted n-butyl. In certain embodiments, at least one instance of R 3 is optionally substituted t-butyl. In certain embodiments, at least one instance of R 3 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R 3 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R 3 is substituted or unsubstituted propyl.
  • At least one instance of R 3 is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, at least one instance of R 3 is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of R 3 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • At least one instance of R 3 is optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl).
  • at least one instance of R 3 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R 3 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • At least one instance of R 3 is benzyl. In certain embodiments, at least one instance of R 3 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R 3 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9-
  • At least one instance of R 3 is –CN. In certain embodiments, at least one instance of R 3 is –NO2. In certain embodiments, at least one instance of R 3 is –OR D1 (e.g., –OH or –OMe). In certain embodiments, at least one instance of R 3 is –N(R D1a ) 2 (e.g., -NMe 2 ). In certain embodiments, at least one instance of R 3 is -N(R D1a )2, and each instance of R D1a is independently hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R 3 is – NHMe.
  • At least one instance of R 3 is -NH2, –NHMe, or –NMe2. In certain embodiments, at least one instance of R 3 is –SR D1 (e.g., -SMe). In certain embodiments, y is 1; and R 3 is halogen (e.g., -F, -Cl, -Br).
  • the moiety is of the formula: wherein: each instance of R 3 is independently halogen, optionally substituted acyl, optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl), optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl), or optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl).
  • the moiety is of the formula: .
  • the moiety is of the formula:
  • Formula (I) includes substituent R 4 .
  • R 4 is hydrogen.
  • R 4 is optionally substituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl).
  • R 4 is substituted or unsubstituted, branched or unbranched C1-6 alkyl.
  • R 4 is optionally substituted butyl (e.g., optionally substituted n-butyl, optionally substituted t-butyl, optionally substituted iso-butyl, optionally substituted sec- butyl).
  • R 4 is optionally substituted n-butyl.
  • R 4 is optionally substituted t-butyl. In certain embodiments, R 4 is substituted or unsubstituted methyl. In certain embodiments, R 4 is substituted or unsubstituted ethyl. In certain embodiments, R 4 is substituted or unsubstituted propyl (e.g., optionally substituted n-propyl, optionally substituted isopropyl).
  • R 4 is or In certai 4 n embodiments, R is In certain embodiments, R 4 is –(CH2)paR Z , wherein pa is 1, 2, 3, 4, 5, or 6; and R Z is optionally substituted C3–10 carbocyclyl (e.g., R Z is unsubstituted C3–10 carbocyclyl). In certain embodiments, R Z is unsubstituted C 3–10 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In certain embodiments, R 4 is In certain embodiments, R 4 is or .
  • R is or In certain emb 4 odiments, R is optionally substituted alkenyl (e.g., substituted or unsubstituted C 2-6 alkenyl). In certain embodiments, R 4 is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, R 4 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • R 4 is optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl). In certain embodiments, R 4 is optionally substituted C 3–10 carbocyclyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl).
  • R 4 is unsubstituted C3-6 carbocyclyl (e.g., unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl). In certain embodiments, R 4 is unsubstituted cyclopentyl. In certain embodiments, R 4 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • heterocyclyl e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur.
  • R 4 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R 4 is benzyl. In certain embodiments, R 4 is substituted or unsubstituted phenyl.
  • R 4 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • R 4 is -CN.
  • R 4 is hydrogen, optionally substituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl), optionally substituted alkenyl (e.g., substituted or unsubstituted C 2-6 alkenyl), optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl), or optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl).
  • Formula (I) includes substituent R 5 .
  • R 5 is hydrogen.
  • R 5 is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl).
  • R 5 is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl).
  • R 5 is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl).
  • R 5 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R 5 is optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl).
  • R 5 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R 5 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • R 5 is benzyl.
  • R 5 is substituted or unsubstituted phenyl.
  • R 5 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • R 5 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • Formula (I) includes substituents R 5A and R 5B attached to the alkylene backbone.
  • each of R 5A and R 5B is independently hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, -CN, -NO2, -OR D1 , -N(R D1a )2, or -SR D1 ; wherein each substituent is as described herein.
  • at least one instance of R 5A or R 5B is hydrogen.
  • R 5A and R 5B are each hydrogen.
  • at least one instance of R 5A or R 5B is halogen (e.g., F, Cl, Br, or I).
  • at least one instance of R 5A or R 5B is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl). In certain embodiments, at least one instance of R 5A or R
  • At least one instance of R 5A or R 5B is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl).
  • at least one instance of R 5A or R 5B is –CN.
  • at least one instance of R 5A or R 5B is –NO2.
  • at least one instance of R 5A or R 5B is –OR D1 (e.g., –OH or –OMe).
  • at least one instance of R 5A or R 5B is – N(R D1a ) 2 (e.g., -NMe 2 ).
  • At least one instance of R 5A or R 5B is -N(R D1a ) 2 , and each instance of R D1a is independently hydrogen or optionally substituted C1-6 alkyl.
  • at least one instance of R 5A or R 5B is —NHMe.
  • at least one instance of R 5A or R 5B is -NH2, –NHMe, or –NMe2.
  • at least one instance of R 5A or R 5B is –SR D1 (e.g., -SMe).
  • Formula (I) includes substituent R 6 .
  • R 6 is hydrogen.
  • R 6 is optionally substituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl).
  • R 6 is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl).
  • R 6 is optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl).
  • R 6 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R 6 is optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C 3–10 carbocyclyl).
  • R 6 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R 6 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • R 6 is benzyl.
  • R 6 is substituted or unsubstituted phenyl.
  • R 6 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • R 6 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • Formula (I) includes substituent R 7 .
  • R 7 is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl).
  • R 7 is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, R 7 is optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl). In certain embodiments, R 7 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • R 7 is optionally substituted carbocyclyl (e.g., optionally substituted C 3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl).
  • R 7 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R 7 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • R 7 is benzyl.
  • R 7 is substituted or unsubstituted phenyl.
  • R 7 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl wherein one, two, three, or four atoms in the heteroaryl
  • R 7 is -OR D2 or -N(R D2a )2, and R D2 and R D2a are as defined herein.
  • R 7 is -OR D2 or -N(R D2a ) 2
  • R D2 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group when attached to an oxygen atom
  • each instance of R D2a is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R D2a
  • R 7 is -N(R D2a ) 2 ; and each instance of R D2a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In certain embodiments, R 7 is -N(R D2a )2; and each instance of R D2a is hydrogen or optionally substituted alkyl (e.g., C1-6 optionally substituted alkyl). In certain embodiments, R 7 is –NH2.
  • R D2 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group when attached to an oxygen atom.
  • R D2 is hydrogen.
  • R D2 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl).
  • R D2 is substituted or unsubstituted methyl. In certain embodiments, R D2 is substituted or unsubstituted ethyl. In certain embodiments, R D2 is substituted or unsubstituted propyl. In certain embodiments, R D2 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C 2-6 alkenyl). In certain embodiments, R D2 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl).
  • R D2 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • R D2 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R D2 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R D2 is benzyl. In certain embodiments, R D2 is substituted or unsubstituted phenyl.
  • R D2 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • R D2 is an oxygen protecting group when attached to an oxygen atom (e.g., methyl, carbonate protecting group, silyl ether protecting group, ether protecting group, ester protecting group, benzoate, acetate, acetal protecting group, methanesulfonate (mesylate), benzylsulfonate, tosylate (Ts)).
  • at least one instance of R D2a is hydrogen.
  • At least one R D2a is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl). In certain embodiments, at least one instance of R D2a is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R D2a is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R D2a is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R D2a is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl).
  • At least one instance of R D2a is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl). In certain embodiments, at least one instance of R D2a is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7- membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • At least one instance of R D2a is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • at least one instance of v is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • at least one instance of R D2a is benzyl.
  • at least one instance of R D2a is substituted or unsubstituted phenyl.
  • At least one instance of R D2a is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen
  • At least one instance of R D2a is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9- fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p- toluenesulfonamide (Ts)).
  • a nitrogen protecting group e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9- fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p- toluenesulfonamide (Ts)
  • two instances of R D2a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur) or substituted or unsubstituted heteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • a substituted or unsubstituted heterocyclic ring e.g., substituted or unsub
  • Formula (I) includes zero or more instances of substituent R 8 attached to the sulfonylphenyl moiety. In certain embodiments, z is 0. In certain embodiments, Formula (I) includes one or more instances of substituent R 8 attached to the sulfonylphenyl moiety. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is 4.
  • At least one instance of R 8 is halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, - NO2, -OR D1 , -N(R D1a )2, or -SR D1 ; wherein R D1 and R D1a are defined herein.
  • at least one instance of R 8 is halogen (e.g., F, Cl, Br, or I).
  • at least one instance of v is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl).
  • at least one instance of R 8 is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl).
  • at least one instance of R 8 is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl).
  • At least one instance of R 8 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R 8 is optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl).
  • At least one instance of R 8 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R 8 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • at least one instance of R 8 is benzyl.
  • at least one instance of R 8 is substituted or unsubstituted phenyl.
  • At least one instance of R 8 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R 8 is –CN.
  • at least one instance of R 8 is –NO2.
  • At least one instance of R 8 is –OR D1 (e.g., –OH or –OMe). In certain embodiments, at least one instance of R 8 is –N(R D1a ) 2 (e.g., -NMe 2 ). In certain embodiments, at least one instance of R 8 is -N(R D1a ) 2 , and each instance of R D1a is independently hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R 8 is – NHMe. In certain embodiments, at least one instance of R 8 is -NH2, –NHMe, or –NMe2.
  • R 8 is –SR D1 (e.g., -SMe).
  • the compound of Formula (I) is of formula: , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • the compound of Formula (I) is of formula: , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • the compound of Formula (I) is of formula: , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • the compound of Formula (I) is of formula: , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • the compound of Formula (I) is of formula: , , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • the compound of Formula (I) is of the formula: , , , , , , ,
  • the compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, co- crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • Formula (II) includes zero or more instances of substituent R 1A attached to the phenyl moiety.
  • p is 0.
  • Formula (II) includes one or more instances of substituent R 1A .
  • p is 1.
  • p is 2.
  • At least one instance of R 1A is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl). In certain embodiments, at least one instance of R 1A is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R 1A is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R 1A is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R 1A is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl).
  • alkyl e.g., substituted or unsubstituted C1-6 alkyl
  • at least one instance of R 1A is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R 1A is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R 1A
  • At least one instance of R 1A is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl).
  • at least one instance of R 1A is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • at least one instance of R 1A is optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C 3–10 carbocyclyl).
  • At least one instance of R 1A is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R 1A is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • at least one instance of R 1A is benzyl.
  • at least one instance of R 1A is substituted or unsubstituted phenyl.
  • At least one instance of R 1A is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R 1A is –CN.
  • at least one instance of R 1A is –NO 2 .
  • At least one instance of R 1A is – OR D1 (e.g., –OH or –OMe). In certain embodiments, at least one instance of R 1A is -OR D1 and R D1 is hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R 1A is –OH or -O(C 1-6 alkyl optionally substituted with halogen, -CN, -NO 3 , or – NH2). In certain embodiments, at least one instance of R 1A is –OCF3. In certain embodiments, at least one instance of R 1A is –N(R D1a )2 (e.g., -NMe2).
  • At least one instance of R 1A is -N(R D1a ) 2 , and each instance of R D1a is independently hydrogen or optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R 1A is – NHMe. In certain embodiments, at least one instance of R 1A is -NH2, –NHMe, or –NMe2. In certain embodiments, at least one instance of R 1A is –SR D1 (e.g., -SMe). In certain embodiments, p is 2, and one instance of R 1A is –OH and one instance of R 1A is – O(optionally substituted C1-6 alkyl) (e.g., -OCF3).
  • R 1A is 3, and one instance of R 1A is –OH and two instances of R 1A are halogen (e.g., -Cl, -Br).
  • the moiety is of formula: In certain embodiments, the moiety is of formula: , 1A wherein each instance of R is independently halogen, optionally substituted C 1-6 alkyl, -OH, or –O(optionally substituted C1-6 alkyl).
  • Formula (II) includes substituent R 2A .
  • R 2A is hydrogen.
  • R 2A is optionally substituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl). In certain embodiments, R 2A is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, R 2A is optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl). In certain embodiments, R 2A is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • alkyl e.g., substituted or unsubstituted C 1-6 alkyl
  • R 2A is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl).
  • R 2A is
  • R 2A is optionally substituted carbocyclyl (e.g., optionally substituted C 3–14 carbocyclyl, optionally substituted C 3–10 carbocyclyl).
  • R 2A is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R 2A is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • R 2A is benzyl.
  • R 2A is substituted or unsubstituted phenyl.
  • R 2A is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • R 2A is –CN.
  • Formula (II) includes substituent R 3A .
  • R 3A is hydrogen.
  • R 3A is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl).
  • R 3A is optionally substituted alkenyl (e.g., substituted or unsubstituted C 2-6 alkenyl).
  • R 3A is optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl).
  • R 3A is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R 3A is optionally substituted carbocyclyl (e.g., optionally substituted C3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl).
  • R 3A is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R 3A is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • R 3A is benzyl.
  • R 3A is substituted or unsubstituted phenyl.
  • R 3A is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or
  • R 3A is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • Formula (II) includes zero or more instances of substituent R 3B attached to the 2,3- dihydro-1H-indene moiety.
  • q is 0.
  • Formula (II) includes one or more instances of substituent R 3B .
  • q is 1.
  • halogen e.g., F, Cl, Br, or I
  • at least one instance of R 3B is optionally substituted alkyl (
  • At least one instance of R 3B is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, at least one instance of R 3B is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of R 3B is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • At least one instance of R 3B is optionally substituted carbocyclyl (e.g., optionally substituted C 3–14 carbocyclyl, optionally substituted C 3–10 carbocyclyl).
  • at least one instance of R 3B is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R 3B is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • At least one instance of R 3B is benzyl. In certain embodiments, at least one instance of R 3B is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R 3B is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted
  • At least one instance of R 3B is –CN. In certain embodiments, at least one instance of R 3B is –NO 2 . In certain embodiments, at least one instance of R 3B is –OR D1 (e.g., –OH or –OMe). In certain embodiments, at least one instance of R 3B is –N(R D1a )2 (e.g., -NMe2). In certain embodiments, at least one instance of R 3B is -N(R D1a )2, and each instance of R D1a is independently hydrogen or optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R 3B is –NHMe.
  • R 4A is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, R 4A is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, R 4A is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system).
  • R 4A is optionally substituted carbocyclyl (e.g., optionally substituted C 3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl).
  • R 4A is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R 4A is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • R 4A is benzyl.
  • R 4A is substituted or unsubstituted phenyl.
  • R 4A is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl wherein one, two, three, or four atoms in the heteroary
  • R 4A is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • R 2A is hydrogen
  • R 3A is hydrogen
  • R 4A is hydrogen.
  • R 2A is hydrogen
  • R 3A is hydrogen
  • q 0, and R 4A is hydrogen.
  • b is 1, and Formula (II) includes substituent R 5C .
  • R 5C is optionally substituted C 3-10 alkyl (e.g., substituted or unsubstituted C3-6 alkyl). In certain embodiments, R 5C is optionally substituted C3-6 alkyl. In certain embodiments, R 5C is substituted or unsubstituted, branched or unbranched C3-6 alkyl. In certain embodiments, R 5C is optionally substituted butyl (e.g., optionally substituted n- butyl, optionally substituted t-butyl, optionally substituted iso-butyl, optionally substituted sec-butyl). In certain embodiments, R 5C is optionally substituted n-butyl.
  • R 5C is optionally substituted t-butyl. In certain embodiments, R 5C is substituted or unsubstituted propyl (e.g., optionally substituted n-propyl, optionally substituted isopropyl). In certain embodiments, R 5C is In certain embodiments, R 5C is optionally substituted C 3-10 alkenyl (e.g., substituted or unsubstituted C3-6 alkenyl). In certain embodiments, R 5C is In certain embodiments, R 5C is optionally substituted C 3-6 alkenyl. In certain embodiments, R 5C is unsubstituted C 3-6 alkenyl.
  • R 5C is In certain embodiments, R 5C is optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl). In certain embodiments, R 5C is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R 5C is optionally substituted carbocyclyl (e.g., optionally substituted C 3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl).
  • R 5C is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • R 5C is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • R 5C is benzyl.
  • R 5C is optionally substituted phenyl.
  • R 5C is , wherein each instance of R A2 is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -CN, -NO2, -OR D2 , -N(R D2a )2, or -SR D2 ; and w is 0, 1, 2, 3, 4, or 5.
  • at least one instance of R A2 is halogen (e.g., F, Cl, Br, or I).
  • at least one instance of R A2 is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl).
  • At least one instance of R A2 is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, at least one instance of R A2 is optionally substituted alkynyl (e.g., substituted or unsubstituted C2-6 alkynyl). In certain embodiments, at least one instance of R A2 is –CN. In certain embodiments, at least one instance of R A2 is –NO2. In certain embodiments, at least one instance of R A2 is –OR D2 (e.g., –OH or –OMe).
  • At least one instance of R A2 is –N(R D2a ) 2 (e.g., -NMe 2 ). In certain embodiments, at least one instance of R A2 is -N(R D2a )2, and each instance of R D2a is independently hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R A2 is –NHMe. In certain embodiments, at least one instance of R A2 is -NH 2 , –NHMe, or –NMe 2 . In certain embodiments, at least one instance of R A2 is –SR D2 (e.g., -SMe).
  • R 5C wherein w is 0, 1, or 2; and at least one instance of R A2 is halogen, -NH2, or –OR D2 ; and R D2 is hydrogen or optionally substituted C 1-6 alkyl. In certain embodiments, R 5C is .
  • R 5C is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or
  • R 5C is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • R 5C is or A3 wherein each instance of R is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, -CN, -NO 2 , -OR D2 , -N(R D2a ) 2 , or -SR D2 ; and w1 is 0, 1, 2, or 3;
  • R D2 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group when attached to
  • At least one instance of R A3 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R A3 is optionally substituted alkyl (e.g., substituted or unsubstituted C1-6 alkyl). In certain embodiments, at least one instance of R A3 is optionally substituted alkenyl (e.g., substituted or unsubstituted C 2-6 alkenyl). In certain embodiments, at least one instance of R A3 is optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl). In certain embodiments, at least one instance of R A3 is –CN.
  • At least one instance of R A3 is –NO 2 . In certain embodiments, at least one instance of R A3 is –OR D2 (e.g., –OH or –OMe). In certain embodiments, at least one instance of R A3 is –N(R D2a ) 2 (e.g., -NMe2). In certain embodiments, at least one instance of R A3 is -N(R D2a )2, and each instance of R D2a is independently hydrogen or optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R A3 is –NHMe. In certain embodiments, at least one instance of R A3 is -NH2, –NHMe, or –NMe2.
  • R A3 is –SR D2 (e.g., -SMe).
  • R 5C is wherein w1 is 0 or 1.
  • R 5C is In certain embodiments, R 5C is In ce 5C rtain embodiments, R is In certain embodiments, R 5C is 5C
  • R is Formula (II) includes two instances of substituent R 6A .
  • at least one instance of R 6A is hydrogen.
  • both instances of R 6A are hydrogen.
  • At least one instance of R 6A is optionally substituted alkyl (e.g., substituted or unsubstituted C 1-6 alkyl). In certain embodiments, at least one instance of R 6A is optionally substituted alkenyl (e.g., substituted or unsubstituted C2-6 alkenyl). In certain embodiments, at least one instance of R 6A is optionally substituted alkynyl (e.g., substituted or unsubstituted C 2-6 alkynyl).
  • At least one instance of R 6A is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 14-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R 6A is optionally substituted carbocyclyl (e.g., optionally substituted C 3–14 carbocyclyl, optionally substituted C3–10 carbocyclyl).
  • At least one instance of R 6A is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur).
  • at least one instance of R 6A is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
  • at least one instance of R 6A is benzyl.
  • at least one instance of R 6A is substituted or unsubstituted phenyl.
  • At least one instance of R 6A is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).
  • heteroaryl e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur
  • At least one instance of R 6A is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • the compound of Formula (II) is of formula: or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • the compound of Formula (II) is of formula: or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
  • the compound of Formula (II) is of formula:
  • the compound of Formula (II) is of formula:
  • compositions, Kits, and Administration The present disclosure also provides pharmaceutical compositions comprising a compound described herein and optionally a pharmaceutically acceptable excipient.
  • a compound described herein is of Formula (I) or (II).
  • 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.
  • a therapeutically effective amount is an amount effective for inhibiting, for example, inhibiting the aberrant activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).
  • a therapeutically effective amount is an amount effective for treating a disease (e.g., a disease associated with dysregulation of a transcription factor (e.g., TEAD (e.g., proliferative diseases), diseases associated with dysregulation of the Hippo/YAP pathway).
  • a therapeutically effective amount is an amount effective for inhibiting, for example, inhibiting the aberrant activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) and treating a disease (e.g., a disease associated with dysregulation of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) (e.g., proliferative disease))).
  • a therapeutically effective amount is an amount effective for inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject and/or biological sample.
  • a prophylactically effective amount is an amount effective for inhibiting the aberrant activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4). In certain embodiments, a prophylactically effective amount is an amount effective for preventing or keeping a subject in need thereof in remission of a disease (e.g., a disease associated with dysregulation or aberrant activity of a transcription factor (e.g., TEAD) (e.g., proliferative disease)).
  • a disease e.g., a disease associated with dysregulation or aberrant activity of a transcription factor (e.g., TEAD) (e.g., proliferative disease)
  • a prophylactically effective amount is an amount effective for inhibiting the aberrant activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4), and preventing or keeping a subject in need thereof in remission of a disease (e.g., a disease associated with dysregulation or aberrant activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) (e.g., proliferative disease)).
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • a prophylactically effective amount is an amount effective for inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject and/or biological sample.
  • the effective amount is an amount effective for inhibiting the activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%.
  • the effective amount is an amount effective for inhibiting the activity of a transcription factor (e.g., TEAD, such as 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%.
  • a transcription factor e.g., TEAD1, TEAD2, TEAD3, TEAD4
  • the effective amount is an amount effective for increasing the activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • the effective amount is an amount effective for increasing the activity of a transcription factor (e.g., TEAD, such as 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%.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • the effective amount is an amount effective for inhibiting the interaction between YAP and a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%.
  • TEAD a transcription factor
  • the effective amount is an amount effective for inhibiting the interaction between YAP and a transcription factor (e.g., TEAD, such as 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%.
  • TEAD a transcription factor
  • 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 being contacted with a compound or pharmaceutical composition thereof described herein is in vitro.
  • the cell being contacted with a compound or pharmaceutical composition thereof described herein is in vivo.
  • Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • 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.
  • Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
  • Relative amounts of the 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.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients 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 include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (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 carboxyvinyl polymer), carrageenan, cellulos
  • Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or
  • 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.
  • Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ® Plus, Phenonip ® , methylparaben, Germall ® 115, Germaben ® II, Neolone ® , Kathon ® , and Euxyl ® .
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer
  • Exemplary lubricating agents include 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 buckt
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral 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.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • 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.
  • 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.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (a) fillers or
  • the dosage form may include a buffering agent.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • 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.
  • 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. Examples of 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.
  • 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.
  • 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.
  • 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. 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).
  • additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, 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.
  • a flavoring agent such as saccharin sodium
  • a volatile oil such as a liquid oil
  • a buffering agent such as a liquid oil
  • a surface active agent such as methylhydroxybenzoate
  • 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
  • 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 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 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.
  • the compound or composition is administered intradermally, intramuscularly, intravaginally, intravenously, intranasally, orally, subcutaneously, topically,and/or sublingually.
  • 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 biological sample is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample is one dose per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample 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 biological sample (e.g., tissue, 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 ⁇ g and 1 ⁇ g, 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.
  • 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. 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 pharmaceutical composition thereof, 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 inhibiting, for example, inhibiting the activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject and/or biological sample (e.g., tissue, cell)), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject and/or biological sample (e.g., tissue, cell).
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • biological sample
  • 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 compounds described herein and the additional pharmaceutical agent, but not both.
  • the compound or pharmaceutical composition thereof 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 prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, inflammatory disease, autoimmune disease).
  • a disease e.g., proliferative disease, inflammatory disease, autoimmune disease.
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or pharmaceutical composition thereof described herein in a single dose or administered separately in different doses.
  • the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, 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, and a combination thereof.
  • the additional pharmaceutical agent is an anti-proliferative agent (e.g., anti-cancer agent).
  • the additional pharmaceutical agent is an inhibitor of a gene and/or protein in the Hippo signaling pathway.
  • the additional pharmaceutical agent is a binder or inhibitor of TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4)).
  • the additional pharmaceutical agent is a binder or inhibitor of TEAD. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of TEAD1. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of TEAD2. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of TEAD3. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of TEAD4.
  • the additional pharmaceutical agent is selected from the group consisting of epigenetic and transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC 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 and transcriptional modulators e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors
  • antimitotic drugs e.g., taxanes and vinca
  • 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.
  • 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, disease associated with dysregulation of the Hippo/YAP pathway) in a subject in need thereof.
  • the kits are useful for preventing a disease (e.g., proliferative disease, disease associated with dysregulation of the Hippo/YAP pathway) in a subject in need thereof.
  • kits are useful for inhibiting, for example, inhibiting the activity (e.g., aberrant activity or dysregulated activity, such as increased activity) of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a subject and/or biological sample (e.g., tissue, cell).
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • the kits are useful for inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject and/or biological sample.
  • a kit described herein further includes instructions for using the compound or pharmaceutical composition included in the kit.
  • kits 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.
  • the kits and instructions provide for treating a disease (e.g., proliferative disease, disease associated with dysregulation of the Hippo/YAP pathway) in a subject in need thereof.
  • the kits and instructions provide for preventing a disease (e.g., proliferative disease, disease associated with dysregulation of the Hippo/YAP pathway) in a subject in need thereof.
  • kits and instructions provide for inhibiting, for example, inhibiting the activity (e.g., aberrant activity, such as increased activity) of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4), and/or inducing apoptosis in a subject and/or biological sample (e.g., tissue, cell).
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • the kits and instructions provide for inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)), and/or inducing apoptosis in a subject and/or biological sample.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • Methods of Treatment and Uses The present disclosure provides methods of inhibiting, for example, inhibiting the activity (e.g., aberrant activity, such as increased or decreased activity) of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) using compounds described herein, which may be optionally administered in combination with an additional pharmaceutical agent, for example, an anti-proliferative agent.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • the present disclosure provides methods of inhibiting, for example, inhibiting the activity (e.g., aberrant activity, such as increased or decreased activity) of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a subject and/or biological sample (e.g., tissue, cell), using compounds described herein, which may be optionally administered in combination with an additional pharmaceutical agent, for example, an anti-proliferative agent.
  • a transcription factor e.g., TEAD1, TEAD2, TEAD3, TEAD4
  • the present disclosure also provides methods for the treatment of a range of diseases, such as diseases associated with the aberrant activity (e.g., increased activity) or dysregulation of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4), and/or diseases associated with the dysregulation of the Hippo/YAP pathway (e.g., dysregulation of YAP- TAZ transcriptional activity) using compounds described herein, which may be optionally administered in combination with an additional pharmaceutical agent, for example, for treating proliferative diseases in a subject in need thereof.
  • diseases associated with the aberrant activity e.g., increased activity
  • a transcription factor e.g., TEAD1, TEAD2, TEAD3, TEAD4
  • diseases associated with the dysregulation of the Hippo/YAP pathway e.g., dysregulation of YAP- TAZ transcriptional activity
  • the present disclosure provides methods for the treatment and/or prevention of a proliferative disease (e.g., cancers (e.g., carcinoma, sarcoma); liver cancer, pancreatic cancer, lung cancer, cancer of the nervous system, brain cancer, thyroid cancer, sarcoma, carcinoma, breast cancer, colorectal cancer, skin cancer, uterine cancer, ovarian cancer, prostate cancer, eye cancer, bladder cancer, gastric cancer, esophageal cancer, kidney cancer, using compounds described herein, which may be optionally administered in combination with an additional pharmaceutical agent.
  • a proliferative disease e.g., cancers (e.g., carcinoma, sarcoma); liver cancer, pancreatic cancer, lung cancer, cancer of the nervous system, brain cancer, thyroid cancer, sarcoma, carcinoma, breast cancer, colorectal cancer, skin cancer, uterine cancer, ovarian cancer, prostate cancer, eye cancer, bladder cancer, gastric cancer, esophageal cancer, kidney cancer, using compounds described herein, which
  • the present disclosure provides methods for inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject and/or biological sample (e.g., tissue, cell), using compounds described herein, which may be optionally administered in combination with an additional pharmaceutical agent.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • the present disclosure also provides a compound of Formula (I), or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition thereof, which may be optionally administered in combination with an additional pharmaceutical agent, for example, an anti-proliferative agent, for use in the treatment of diseases, such as proliferative diseases, in a subject in need thereof.
  • an additional pharmaceutical agent for example, an anti-proliferative agent, for use in the treatment of diseases, such as proliferative diseases, in a subject in need thereof.
  • the present disclosure also provides uses of a compound of Formula (I), or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, prodrug, or pharmaceutical composition thereof, which may be optionally administered in combination with an additional pharmaceutical agent, in the manufacture of a medicament for the treatment of various diseases, such as proliferative diseases, in a subject in need thereof.
  • the present disclosure provides methods of inhibiting, for example, inhibiting the activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a subject and/or biological sample (e.g., cell, tissue) using compounds described herein, which may be optionally administered in combination with an additional pharmaceutical agent.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • the compounds described herein may exhibit transcription factor inhibitory activity; the ability to inhibit TEAD; the ability to inhibit TEAD1, without inhibiting another transcription factor (e.g., a different TEAD); the ability to inhibit TEAD2, without inhibiting another transcription factor (e.g., a different TEAD); the ability to inhibit TEAD3, without inhibiting another transcription factor (e.g., a different TEAD); the ability to inhibit TEAD4, without inhibiting another transcription factor (e.g., a different TEAD); a therapeutic effect and/or preventative effect in the treatment of cancers; a therapeutic effect and/or preventative effect in the treatment of proliferative diseases; and/or a therapeutic profile (e.g., optimum safety and curative effect) that is superior to existing chemotherapeutic agents, or agents for treating inflammatory diseases and/or autoimmune diseases.
  • a therapeutic profile e.g., optimum safety and curative effect
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • a subject or biological sample e.g., cell, tissue
  • the activity of a transcription factor in a subject or biological sample (e.g., cell, tissue) is decreased by a method described herein by at least about 1%, at least about 3%, 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%, or at least about 90%.
  • the activity of a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4 in a subject or biological sample (e.g., cell, tissue) is selectively inhibited by the compound.
  • the activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a subject or biological sample (e.g., cell, tissue) is selectively decreased by the compound.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • the compounds described herein are able to bind the transcription factor being inhibited.
  • a compound described herein is able to bind the transcription factor.
  • the compound is capable of binding TEAD1.
  • the compound is capable of binding TEAD2.
  • the compound is capable of binding TEAD3.
  • the compound is capable of binding TEAD4.
  • the compound is capable of binding the YAP/TAZ domain of a TEAD family transcription factor. In certain embodiments, the compound is capable of inhibiting the interaction between YAP and TEAD. In certain embodiments, the compound is In another aspect, the present disclosure provides methods of inhibiting a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a subject, the methods comprising administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound, or pharmaceutical composition thereof, as described herein.
  • TEAD transcription factor
  • TEAD such as TEAD1, TEAD2, TEAD3, TEAD4
  • the present disclosure provides methods of inhibiting, for example, inhibiting the activity of a transcription factor (e.g., TEAD, such asTEAD1, TEAD2, TEAD3, TEAD4) in a subject, the methods comprising administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound, or pharmaceutical composition thereof, as described herein.
  • a transcription factor e.g., TEAD, such asTEAD1, TEAD2, TEAD3, TEAD4
  • the present disclosure provides methods of inhibiting, for example, inhibiting the activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a biological sample, the methods comprising contacting the biological sample with an effective amount of a compound, or pharmaceutical composition thereof, as described herein.
  • the present disclosure provides methods of inhibiting, for example, inhibiting the activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) in a biological sample (e.g., tissue, cell), the methods comprising contacting the biological sample (e.g., tissue, cell) with an effective amount of a compound, or pharmaceutical composition thereof, as described herein.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • TEAD transcription factor
  • the present disclosure provides methods of inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a subject, the methods comprising administering to the subject an effective amount (e.g., therapeutically effective amount) of a compound, or pharmaceutical composition thereof, as described herein.
  • a gene e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)
  • TEAD transcription factor
  • the present disclosure provides methods of inhibiting the transcription of a gene (e.g., a gene controlled or regulated by a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4)) in a biological sample (e.g., tissue, cell), the methods comprising contacting the biological sample (e.g., tissue, cell) with an effective amount of a compound, or pharmaceutical composition thereof, as described herein.
  • a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • TEAD transcription factor
  • the present disclosure provides methods of inducing apoptosis in a cell in a biological sample or subject, the method comprising contacting the biological sample or administering to the subject a therapeutically effective amount of a compound, or pharmaceutical composition thereof, as described herein.
  • the subject being treated is a mammal.
  • the subject is a human.
  • 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, dog, or non-human primate.
  • the subject is a non-human transgenic animal, such as a transgenic mouse or transgenic pig.
  • the biological sample being contacted with the compound or pharmaceutical composition thereof is breast tissue, bone marrow, lymph node, lymph tissue, spleen, or blood. In certain embodiments, the biological sample being contacted with the compound or pharmaceutical composition thereof is a tumor or cancerous tissue. In certain embodiments, the biological sample being contacted with the compound or pharmaceutical composition thereof is serum, 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 thebiological sample.
  • the cell or tissue being contacted with the compound or pharmaceutical composition thereof is present in vitro. In certain embodiments, the cell or tissue being contacted with the compound or pharmaceutical composition thereof is present in vivo. In certain embodiments, the cell or tissue being contacted with the compound or pharmaceutical composition thereof is present ex vivo. In certain embodiments, the cell or tissue being contacted with the compound or pharmaceutical composition thereof is a malignant cell (e.g., malignant blood cell). In certain embodiments, the cell being contacted with the compound or pharmaceutical composition thereof is a carcinoma cell. In certain embodiments, the cell being contacted with the compound or pharmaceutical composition thereof is a breast carcinoma cell. In certain embodiments, the cell being contacted with the compound or pharmaceutical composition thereof is a sarcoma cell.
  • a malignant cell e.g., malignant blood cell
  • the cell being contacted with the compound or pharmaceutical composition thereof is a carcinoma cell. In certain embodiments, the cell being contacted with the compound or pharmaceutical composition thereof is a breast carcinoma cell. In certain embodiments, the cell being contacted with
  • the cell being contacted with the compound or pharmaceutical composition thereof is a sarcoma cell from breast tissue.
  • the biological sample is from tissue or cells with cancer (e.g., liver cancer, pancreatic cancer, lung cancer, cancer of the nervous system, brain cancer, thyroid cancer, sarcoma, carcinoma, breast cancer, colorectal cancer, skin cancer, uterine cancer, ovarian cancer, prostate cancer, eye cancer, bladder cancer, gastric cancer, esophageal cancer, and kidney cancer) or a proliferative disease.
  • the biological sample is from tissue or cells with cancer that is a human malignancy driven by YAP/TAZ transcriptional activity.
  • the disease (e.g., proliferative disease) to be treated or prevented using the compounds described herein may be associated with increased activity and/or dysregulation of a transcription factor, such as TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4).
  • TEAD e.g., TEAD1, TEAD2, TEAD3, TEAD4
  • the disease (e.g., proliferative disease,) to be treated or prevented using the compounds described herein may be associated with the dysregulation of YAP-TAZ transcriptional activity, for example, dysregulation of a transcription factor, such as TEAD (e.g., TEAD1, TEAD2, TEAD3, TEAD4).
  • the disease (e.g., proliferative disease) to be treated or prevented using the compounds described herein may be associated with the dysregulation of YAP-TAZ transcriptional activity, for example, dysregulation of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).
  • a disease (e.g., proliferative disease) may be associated with aberrant activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4).
  • Aberrant activity of a transcription factor e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4
  • TEAD such as TEAD1, TEAD2, TEAD3, TEAD4
  • the compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof may inhibit, for example, inhibit the activity of a transcription factor (e.g., TEAD, such as TEAD1, TEAD2, TEAD3, TEAD4) and be useful in treating and/or preventing diseases (e.g., proliferative diseases, diseases associated with the dysregulation of YAP-TAZ transcriptional activity).
  • a transcription factor e.g., TEAD1, TEAD2, TEAD3, TEAD4
  • diseases e.g., proliferative diseases, diseases associated with the dysregulation of YAP-TAZ transcriptional activity
  • the compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, may inhibit the activity of a transcription factor (e.g., TEAD) and be useful in treating and/or preventing diseases (e.g., proliferative disease).
  • a transcription factor e.g., TEAD
  • diseases e.g., proliferative disease
  • the compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, may inhibit the activity of a transcription factor (e.g., TEAD) and be useful in treating and/or preventing a disease (e.g., proliferative disease, disease associated with the dysregulation of YAP-TAZ transcriptional activity). All types of biological samples described herein or known in the art are contemplated as being within the scope of the invention.
  • the disease e.g., proliferative disease
  • the disease to be treated or prevented using the compounds described herein is cancer.
  • the proliferative disease is a disease associated with dysregulation of the Hippo/YAP pathway (e.g., dysregulation of YAP-TAZ transcriptional activity, for example, dysregulation of a TEAD).
  • the disease is a cancer that is a human malignancy associated with (e.g., driven by) YAP/TAZ transcriptional activity.
  • the cancer is selected from the group consisting of liver cancer, pancreatic cancer, lung cancer, cancer of the nervous system, brain cancer, thyroid cancer, sarcoma, carcinoma, breast cancer, colorectal cancer, skin cancer, uterine cancer, ovarian cancer, prostate cancer, eye cancer, bladder cancer, gastric cancer, esophageal cancer, and kidney cancer.
  • the cancer is liver cancer.
  • the cancer is pancreatic cancer.
  • the cancer is lung cancer (e.g., small cell lung cancer (SCLC), non-small cell lung cancer, mesothelioma).
  • the lung cancer is mesothelioma.
  • the cancer is esophageal cancer.
  • the proliferative disease is a disease of the nervous system (e.g., a disease of the brain). In certain embodiments, the disease of the nervous system is neurofibromatosis. In certain embodiments, the cancer is brain cancer. In certain embodiments, the brain cancer is glioblastoma. In certain embodiments, the cancer is a sarcoma (e.g., Kaposi’s Sarcoma) or carcinoma. In certain embodiments, the cancer is a sarcoma (e.g., Kaposi’s sarcoma). In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is skin cancer. In certain embodiments, the cancer is uterine cancer.
  • the cancer is ovarian cancer. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is eye cancer (e.g., uveal melanoma). In certain embodiments, the cancer is a carcinoma (e.g., squamous cell carcinoma, merkel cell carcinoma, bladder urothelial carcinoma, head squamous cell carcinoma or neck squamous cell carcinoma, skin and mucosal squamous cell carcinoma). In certain embodiments, the cancer is squamous cell carcinoma. In certain embodiments, the cancer is merkel cell carcinoma. In certain embodiments, the cancer is bladder cancer, for example, a bladder carcinoma (e.g., bladder urothelial carcinoma).
  • the cancer is bladder urothelial carcinoma. In certain embodiments, the cancer is head squamous cell carcinoma or neck squamous cell carcinoma. In certain embodiments, the cancer is skin and mucosal squamous cell carcinoma. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is kidney cancer (e.g., kidney renal papillary cell carcinoma). In certain embodiments, the cancer is kidney renal papillary cell carcinoma.
  • the present disclosure provides methods of preventing a a disease to be treated with a compound or pharmaceutical composition described herein in a subject in need thereof, the methods comprising administering to the subject a prophylactically effective amount of a compound or pharmaceutical composition described herein.
  • the present disclosure provides the compounds described herein for use in a method described herein (e.g., a method of treating a disease (e.g., proliferative disease, disease associated with dysregulation of the Hippo/YAP pathway, for example, dysregulation of a TEAD; or a disease (e.g., cancer) associated with dysregulation of YAP- TAZ transcriptional activity)).
  • a disease e.g., proliferative disease, disease associated with dysregulation of the Hippo/YAP pathway, for example, dysregulation of a TEAD; or a disease (e.g., cancer) associated with dysregulation of YAP- TAZ transcriptional activity
  • the present disclosure provides the compounds described herein for use in treating and/or preventing a proliferative disease in a subject.
  • the present disclosure provides the compounds described herein for use as a medicament.
  • the present disclosure provides the pharmaceutical compositions described herein for use in a method described herein (e.g., proliferative disease, disease associated with dysregulation of the Hippo/YAP pathway, for example, dysregulation of a TEAD; or a disease (e.g., cancer) associated with dysregulation of YAP- TAZ transcriptional activity)).
  • a method described herein e.g., proliferative disease, disease associated with dysregulation of the Hippo/YAP pathway, for example, dysregulation of a TEAD; or a disease (e.g., cancer) associated with dysregulation of YAP- TAZ transcriptional activity
  • Example 1 Preparation of the compounds described herein
  • the compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.
  • Example 1-A Example 1-A.
  • Resin was washed with N,N-dimethylformamide (2 x 10 mL), 2-propanol (2 x 10 mL), and dichloromethane (2 x 10 mL). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 10 mL). Resin was washed with N,N-dimethylformamide (2 x 10 mL), 2-propanol (2 x 10 mL), and dichloromethane (2 x 10 mL).
  • Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 10 mL). Resin was washed with N,N-dimethylformamide (2 x 10 mL), 2-propanol (2 x 10 mL), and dichloromethane (2 x 10 mL).
  • Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 10 mL). Resin was washed with N,N-dimethylformamide (2 x 10 mL), 2-propanol (2 x 10 mL), and dichloromethane (2 x 10 mL).
  • Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 10 mL). Resin was washed with N,N-dimethylformamide (2 x 10 mL), 2-propanol (2 x 10 mL), and dichloromethane (2 x 10 mL).
  • Resin was washed with N,N-dimethylformamide (2 x 10 mL), 2-propanol (2 x 10 mL), and dichloromethane (2 x 10 mL). Fmoc group was removed by treatment with 20% piperidine in N,N-dimethylformamide (1 x 5 min, 1 x 30 min, 2 x 10 mL). Resin was washed with N,N-dimethylformamide (2 x 10 mL), 2-propanol (2 x 10 mL), and dichloromethane (2 x 10 mL).
  • the crystal structure of TEADs shows a deep hydrophobic pocket that is palmitoylated and shown to stabilize its structure and function.
  • a screen was run to identify compounds from the DNA-encoded library with capacity to bind to the protein of interest (TEAD).
  • Screening of YBD of TEAD1 The overall objective was the identification of compounds from the DNA-encoded library with capacity to bind to the protein of interest, and modulate the function of the protein.
  • the following passed quality control parameters DNAse activity, DNA binding activity, Mass Spec, Binding to YAP, and CD secondary structure.
  • the following biological assays involving exemplary compounds described herein were also conducted. Biolayer Interferometry Biolayer Interferometry using exemplary compounds described herein was conducted. Biolayer interferometry(BLI) assessment was conducted with the YBD (Yap-binding domain) of TEAD and compound 61, in the presence or absence of purified Tead binding domain (TBD) of YAP protein. This competitive BLI (Octet 384 Red) was used to assess the ability of small molecule compound 61 to bind purified hTEAD 1-YBD protein and inhibit or reduce the binding of YAP protein with IC50 shown.
  • ITC and Pull-down Assays ITC (isothermal calorimetry) and pull-down assays using exemplary compounds described herein were conducted. The results are shown in Figs.21 and 22. Results of an isothermal calorimetry (ITC) thermogram assay of Compound 61 with hTEAD1-YBD are shown in FIG.22. Proliferation assay - qPCR of YAP target genes Cell Titer Glo 2.0 proliferation assays were conducted using the indicated compounds in particular pancreatic cancer cell lines: BxPC3 – a YAP insensitive cell line (Figs.16A, 16C) and L3.3 – a YAP sensitive cell line (Figs.16B, 16D).
  • Cell Titer Glo 2.0 proliferation assays were conducted using the indicated compounds in particular carcinoma cancer cell lines: TE9 – a YAP insensitive esophageal squamous cell carcinoma cell line (Fig.17A), DET562 – a YAP sensitive esophageal squamous cell carcinoma cell line (FIG.17B), and PJ41 (a YAP sensitive squamous cell carcinoma cell line; FIG.17C).
  • Cell Titer Glo proliferation assays were conducted using the indicated compounds in of YAP- insensitive cancer cell lines, as determined by YAP siRNA knock down, upon administration of Compound 9: for TE9 – a YAP insensitive esophageal squamous cell carcinoma cell line; SNU398 (a YAP-low activity hepatocellular carcinoma cell line); Met5a – a YAP insensitive mesothelioma cell line; and YAPC – a pancreatic carcinoma cell line. (FIG.23).
  • Cell Titer Glo proliferation assays were conducted using the indicated compounds in of YAP- sensitive cancer cell lines, as determined by YAP siRNA knock down, upon administration of Compound 9: for DET562 – a squamous cell carcinoma cell line; HUCCT1 (an intrahepatic cholangiocarcinoma cell line); NCI-H2052 – a mesothelioma cell line; and PANC1 – a pancreatic carcinoma cell line. (FIG.24). Thermal Shift Assay Thermal shift assays were conducted using the indicated compounds to test which compounds stabilize TEAD.
  • TBS-Luc assay TBS-Luc assays using exemplary compounds described herein were conducted. The results of a DRC-TBS-Luc assay and DRC-split-GLuc assay are shown in Figs.14A based on administration of each of the indicated exemplary compounds at the indicated concentrations.
  • YAP-TEAD SPLIT-GLUC Assay A YAP-TEAD SPLIT-GLUC assay was conducted, which is a cell based protein- protein interaction assay of YAP-TEAD binding. YAP was fused to the N-terminus of luciferase and TEAD was fused to the C-terminus of luciferase, as shown in FIG.14B. 14X TBS-Luc Assay A 14X TBS-Luc Assay was conducted, which is a cell-based assay that is a transcriptional reporter of the YAP-TEAD interaction, as shown in FIG.4A, 4B, and 14A. The assay includes 14 TEAD binding sites upstream of a luciferase reporter.
  • YAP-TEAD Gaussia Luciferase protein-protein interaction assay A YAP-TEAD Gaussia Luciferase protein-protein interaction assay was conducted. Compounds that were hits from the original screen (compounds 1, 59, 67, 13, 63, 61, and 69) and the building block ‘D2’ which was present in many of the original screen hits, were re- synthesized ‘off-DNA’ and assessed in the YAP-TEAD Gaussia Luciferase assay at 10 ⁇ M twice daily. See FIG.5B. In Vivo Mouse Study Six TetO-YAP mice were injected with AAV-Cre, followed by doxycycline on day 4.
  • FIG.25 shows representative harvested livers and their sizes from a mouse that received vehicle control (left) versus a liver from a mouse that received compound 9 (right) in the in vivo study depicted in FIG.25.
  • FIG.27 shows the mRNA levels of YAP-target genes CTGF, Cyr61, and Amotl2 from the harvested livers of mice treated with vehicle control or compound 9 from the in vivo study depicted in FIG.25. Levels were determined via quantitative PCR.
  • FIG.28 depicts the liver to body mass ratio from the mice treated with vehicle control or compound 9 from the in vivo study depicted in FIG.25.
  • Example 2. Structures of Exemplary Compounds of Formulas (I) and (II) The structures for exemplary compounds of Formulas (I) and (II) are shown below in Table 1. Table 1. Exemplary compounds of Formulas (I) and (II)
  • the invention 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 claim 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 invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

La présente invention concerne des composés de formule (I) ou (II), et leurs sels, solvates, hydrates, polymorphes, co-cristaux, tautomères, stéréo-isomères, dérivés marqués isotopiquement, et promédicaments pharmaceutiquement acceptables. L'invention concerne également des méthodes, des utilisations et des kits comprenant les composés de l'invention et des compositions pharmaceutiques de ceux-ci pour le traitement et/ou la prévention de maladies (par exemple, des maladies prolifératives (par exemple <i />, les cancers), les maladies associées à une dysrégulation de l'activité transcriptionnelle YAP-TAZ) chez un sujet. L'invention concerne des méthodes permettant d'inhiber un facteur de transcription (par exemple <i />, TEAD) et/ou d'inhiber la transcription d'un gène (par exemple <i />, un gène contrôlé ou régulé par un facteur de transcription (par exemple <i />, TEAD) chez un sujet, et/ou d'induire l'apoptose.
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US12103915B2 (en) 2022-09-29 2024-10-01 Insilico Medicine Ip Limited TEAD inhibitors and methods of uses thereof

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US20180215721A1 (en) * 2015-09-23 2018-08-02 The General Hospital Corporation Tead transcription factor autopalmitoylation inhibitors
WO2020110008A1 (fr) * 2018-11-27 2020-06-04 Novartis Ag Composés pentamères cycliques servant d'inhibiteurs de proprotéine convertase subtilisine/kexine de type 9 (pcsk9) pour le traitement d'un trouble métabolique

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US20180215721A1 (en) * 2015-09-23 2018-08-02 The General Hospital Corporation Tead transcription factor autopalmitoylation inhibitors
WO2020110008A1 (fr) * 2018-11-27 2020-06-04 Novartis Ag Composés pentamères cycliques servant d'inhibiteurs de proprotéine convertase subtilisine/kexine de type 9 (pcsk9) pour le traitement d'un trouble métabolique

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US12103915B2 (en) 2022-09-29 2024-10-01 Insilico Medicine Ip Limited TEAD inhibitors and methods of uses thereof

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