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WO2025117881A1 - Composés et procédés d'inhibition de l'autophagie - Google Patents

Composés et procédés d'inhibition de l'autophagie Download PDF

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Publication number
WO2025117881A1
WO2025117881A1 PCT/US2024/057953 US2024057953W WO2025117881A1 WO 2025117881 A1 WO2025117881 A1 WO 2025117881A1 US 2024057953 W US2024057953 W US 2024057953W WO 2025117881 A1 WO2025117881 A1 WO 2025117881A1
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Prior art keywords
optionally substituted
compound
aliphatic
heteroatoms selected
moiety
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English (en)
Inventor
Vinay Verghese EAPEN
Jian Lin
Erik Lee MEREDITH
John Kelly
Daniel W. BAIRD
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Casma Therapeutics Inc
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Casma Therapeutics Inc
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Publication of WO2025117881A1 publication Critical patent/WO2025117881A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds

Definitions

  • Autophagy is a cellular mechanism for the removal of aggregated proteins and cellular waste from the cell. See Turco, et cd., Molecular Cell, 74:330-346 (2019). The process is initiated by the formation of a double membraned structure termed the “phagophore” which forms around the cargo to be degraded and then upon closing matures into an “autophagosome”, completely encapsulating the cargo. The autophagosome along with its enclosed contents then fuse with the degradative lysosome wherein the autophagosome plus cargo are degraded. See Nakatogawa, H., Nat Rev Mol Cell Biol 21, 439-458 (2020).
  • the present disclosure provides, among other things, compounds and compositions useful for the inhibition of autophagy.
  • the present disclosure leverages the insights that particular heterobifunctional small molecule compounds can be used to disrupt the autophagy process by degrading precursors of autophagosome formation.
  • the present disclosure provides a compound represented by Formula I:
  • A is a moiety that binds to or associates with FIP200
  • B is a linker moiety
  • E3L is a ubiquitin E3 ligase binding moiety.
  • a compound described herein is a compound of formula I, wherein A is selected from formula II- 1 , II-2, II-3, or II-4 : or a pharmaceutically acceptable salt thereof, wherein:
  • G 1 is an optionally substituted Ce-Cn aryl or an optionally substituted 5- to 6- membered heteroaryl;
  • X 1 is -S-, -N(R 3 )-, -O-, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic;
  • X 2 is independently C(R 3 ) or N, provided that, when X 2 is N, then X 1 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X 3 and X 4 is a single bond, then X 3 is N(R 2a ), and X 4 is C(O) when a bond between X 3 and X 4 is a double bond, then X 3 is C(R 2b ) and X 4 is C(R 3 ), or N; each R 1 is independently selected from halogen, optionally substituted C 1 -C 6 aliphatic, and optionally substituted -O-C 1 -C 6 aliphatic; or two instances of R 1 come together with the atoms to which they are attached to form a n optionally substituted Ce-Cn aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membere
  • R 2a is optionally substituted C 1 -C 6 aliphatic
  • R 2b is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )- C 1 -C 6 aliphatic, or optionally substituted -O-C 1 -C 6 aliphatic; each R 3 is independently selected from hydrogen, halogen, and optionally substituted C 1 -C 6 aliphatic;
  • R 4 is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted C 1 -C 6 aliphatic;
  • R 5 is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C 1 -C 6 aliphatic;
  • L 1 is a bond, -C(O)-, -S(O)-, -S(O) 2 -, or -NR 3 -; n is independently 0, 1, 2, 3, 4, 5, or 6; each of X 5 , X 6 , and X 7 is independently selected from the group consisting of N and CH;
  • R 7 is hydrogen, an optionally substituted -O-C 1 -C 6 aliphatic, -S(O)2R 3 , optionally substituted C 1 -C 6 aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S
  • G 2 is optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;
  • G 3 is optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce-Ci 2 aryl;
  • L 2 is a bond, -NR 3 -C(O)-, -C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;
  • L 3 is -NR 3 -, -O-, -C(O)-, -NR 3 -C(O)-, -NR 3 -S(O) 2 -, -C(O)-NR 3 -, -S(O) 2 NR 3 -, -NR 3 - C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic ring;
  • R 6 is a bond, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Ci 2 aryl, or optionally substituted C3-C6 cycloaliphatic; and R 8 is halogen, -OR 3 , -C(O)N(R 3 ) 2 , - C(O)OR 3 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted Ce-Ci 2 aryl; and when A is of formula II-4, then R 6 is H, halogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroali
  • the present disclosure provides a method of treating a disease, disorder, or condition in a subject comprising administering to the subject a compound or composition described herein.
  • the present disclosure provides a method of inhibiting autophagy in a subject comprising administering to the subject a compound or composition described herein.
  • Figure 1 presents certain data illustrating remaining levels of FIP-200 (Rblccl) in different groups after treatment with 1-26.
  • Autophagy inhibition has emerged as a promising mode of treatment of particular diseases, disorders, and conditions, including, for example, cancer.
  • the present disclosure provides, among other things, certain compounds and compositions, and uses thereof, that inhibit autophagy, and can therefore be used for the treatment of said diseases, disorders, and conditions.
  • the present disclosure provides a compound represented by formula I:
  • A is a moiety that binds to or associates with FIP200
  • B is a linker moiety
  • E3L is a ubiquitin E3 ligase binding moiety. Classes and subclasses of A B, and E3L are described herein.
  • structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure.
  • the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure.
  • Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.
  • structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • About or approximately As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by "about” or “approximately” in that context.
  • the term "approximately” or “about” may encompass a range of values that are within (i.e., ⁇ ) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.
  • Administering typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated.
  • agents that are, or is included in, a composition to a target site or a site to be treated.
  • routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human.
  • administration may be ocular, oral, parenteral, topical, etc.
  • administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc. , enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc.
  • bronchial e.g., by bronchial instillation
  • buccal which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.
  • enteral intra-arterial, intradermal, intra
  • administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, administration may comprise a prime-and- boost protocol.
  • a prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine).
  • a prime-and-boost protocol can result in an increased immune response in a patient.
  • agent may refer to a compound, molecule, or entity of any chemical class including, for example, a small molecule, polypeptide, nucleic acid, saccharide, lipid, metal, or a combination or complex thereof.
  • agent may refer to a compound, molecule, or entity that comprises a polymer.
  • the term may refer to a compound or entity that comprises one or more polymeric moi eties.
  • agent may refer to a compound, molecule, or entity that is substantially free of a particular polymer or polymeric moiety.
  • the term may refer to a compound, molecule, or entity that lacks or is substantially free of any polymer or polymeric moiety.
  • Aliphatic refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point or more than one points of attachment to the rest of the molecule.
  • aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., Cue).
  • aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups and hybrids thereof. A preferred aliphatic group is Ci-6 alkyl.
  • Alkyl refers to a saturated, optionally substituted straight or branched chain hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2).
  • exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.
  • Alkylene refers to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent.
  • Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms.
  • the suffix “-ene” or “-enyl” when appended to certain groups herein are intended to refer to a bifunctional moiety of said group.
  • cyclopropyl when appended to “cyclopropyl” becomes “cyclopropylene” or “cyclopropylenyl” and is intended to refer to a bifunctional cyclopropyl group, e.g.,
  • Alkenyl refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3).
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hex enyl, and heptenyl.
  • cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Alkynyl refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e g-, C 2 -12, C2-10, C2-8, C2-6, C2-4, or C2-3).
  • exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.
  • Aryl refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., Ce-Cu), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., G,- C12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl groups are hydrocarbons.
  • an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include
  • biological sample typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein.
  • a source of interest comprises an organism, such as an animal or human.
  • a biological sample is or comprises biological tissue or fluid.
  • a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cellcontaining body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc.
  • a biological sample is or comprises cells obtained from an individual.
  • obtained cells are or include cells from an individual from whom the sample is obtained.
  • a sample is a “primary sample” obtained directly from a source of interest by any appropriate means.
  • a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane.
  • processing e.g., by removing one or more components of and/or by adding one or more agents to
  • a primary sample For example, filtering using a semi-permeable membrane.
  • Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
  • Bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered.
  • carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • carriers are or include one or more solid components.
  • Combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality(ies)).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
  • composition may be used to refer to a discrete physical entity that comprises one or more specified components.
  • a composition may be of any form - e.g., gas, gel, liquid, solid, etc.
  • Cycloaliphatic refers to a monocyclic C3-8 hydrocarbon or a bicyclic Ce-io hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.
  • Cycloalkyl refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Dosage form or unit dosage form may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject.
  • an active agent e.g., a therapeutic or diagnostic agent
  • each such unit contains a predetermined quantity of active agent.
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).
  • Dosing regimen or therapeutic regimen may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).
  • Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect.
  • suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Halogen means F, Cl, Br, or I.
  • heteroaliphatic or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • nitrogen also includes a substituted nitrogen.
  • heteroaliphatic groups contain 1-10 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, and the like.
  • Heteroaryl The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl); having 6, 10, or 14 7t-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroaryl and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl); having 6,
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2- a]pyrimidinyl, imidazo[l,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrol opyridyl, pyrrolopyrazinyl, thienopyrimidinyl, tri azol opyridyl
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms).
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotri azolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4// quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin- 3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazolyl.
  • Heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 6- to 10-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
  • a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
  • a bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.
  • Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodi oxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl.
  • a bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).
  • a bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.
  • oral administration and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.
  • Parenteral administration and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrastemal injection and infusion.
  • Partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moi eties, as herein defined.
  • Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions
  • composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
  • compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compositions that are appropriate for use in pharmaceutical contexts, i.e., 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, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • Substituted or optionally substituted As described herein, compounds of the invention may contain “optionally substituted” moieties.
  • the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more r hydrogens that are either explicit or implicit from the structure (e.g., refers to at ).
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein.
  • Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents.
  • Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0 2 R*, -(haloR*), -(CH 2 ) 0 2 OH, -(CH 2 ) 0 2 OR*, -(CH 2 ) 0
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR* 2 ) 2 -3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R* include halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -C(O)R f , -C(O)OR f , -C(O)C(O)R t , C(O)CH 2 C(O)R t , -S(O) 2 R ⁇ -SCO ⁇ NR ⁇ , -C(S)NR f 2 , -C(NH)NR ⁇ or -N(R t )S(O) 2 R t ; wherein each R 1 ' is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R 1 ', taken together with their intervening atom(s) form an unsubstituted 3- to
  • Suitable substituents on the aliphatic group of R 1 ' are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)o iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Small molecule means a low molecular weight organic and/or inorganic compound.
  • a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size.
  • a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD.
  • the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D.
  • a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer.
  • a small molecule does not include a polymeric moiety.
  • a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide).
  • a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide).
  • a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid.
  • a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent).
  • a small molecule is biologically active.
  • a small molecule is detectable (e.g., comprises at least one detectable moiety).
  • a small molecule is a therapeutic agent.
  • such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.
  • small molecule compounds have structures that can exist in one or more tautomeric forms.
  • such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.
  • small molecule compounds have structures that permit isotopic substitution (e.g., 2 H or 3 H for H; n C, 13 C or 14 C for 12 C; 13 N or 15 N for 14 N; 17 O or 18 O for 16 O; 36 C1 for 35 C1 or 37 C1; 18 F for 19 F; 131 I for 127 I; etc.).
  • such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.
  • reference to a particular small molecule compound may relate to a specific form of that compound.
  • a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or baseaddition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
  • a small molecule compound is one that exists or is found in nature
  • that compound may be provided and/or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature.
  • a reference preparation of interest e.g., in a primary sample from a source of interest such as a biological or environmental source
  • a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.
  • the symbol refers to a point of attachment between two atoms. Additionally or alternatively, the symbol refers to a point of attachment ring in a spirocyclic manner.
  • a cyclic structure such as: b J Ik A or , it is understood to encompass any of the following chemically feasible structures:
  • Treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • therapeutic agent in general refers to any agent that elicits a desired effect (e.g., a desired biological, clinical, or pharmacological effect) when administered to a subject.
  • a desired effect e.g., a desired biological, clinical, or pharmacological effect
  • an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population.
  • an appropriate population is a population of subjects suffering from and/or susceptible to a disease, disorder or condition.
  • an appropriate population is a population of model organisms.
  • an appropriate population may be defined by one or more criterion such as age group, gender, genetic background, preexisting clinical conditions, prior exposure to therapy.
  • a therapeutic agent is a substance that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms or features of a disease, disorder, and/or condition in a subject when administered to the subject in an effective amount.
  • a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans.
  • a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.
  • therapeutic agents may be KAT inhibitors, for example, KAT-5 inhibitors, as described herein.
  • therapeutically effective amount refers to an amount that produces a desired effect (e.g., a desired biological, clinical, or pharmacological effect) in a subject or population to which it is administered. In some embodiments, the term refers to an amount statistically likely to achieve the desired effect when administered to a subject in accordance with a particular dosing regimen (e.g., a therapeutic dosing regimen).
  • the term refers to an amount sufficient to produce the effect in at least a significant percentage (e.g., at least about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) of a population that is suffering from and/or susceptible to a disease, disorder, and/or condition.
  • a therapeutically effective amount is one that reduces the incidence and/or severity of, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition.
  • a therapeutically effective amount does not in fact require successful treatment be achieved in a particular individual.
  • a therapeutically effective amount may be an amount that provides a particular desired response in a significant number of subjects when administered to patients in need of such treatment, e.g., in at least about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more patients within a treated patient population.
  • reference to a therapeutically effective amount may be a reference to an amount sufficient to induce a desired effect as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine).
  • a therapeutically effective amount of a particular agent or therapy may be formulated and/or administered in a single dose.
  • a therapeutically effective agent may be formulated and/or administered in a plurality of doses, for example, as part of a dosing regimen.
  • the present disclosure provides, among other things, compounds useful for inhibiting autophagy, whereby inhibiting autophagy in a subject is useful for the treatment of particular diseases, disorders, and condition, as recited herein.
  • compounds of the present disclosure are degraders of FIP200.
  • compounds of the present disclosure are heterobifunctional compounds comprising on one end, a moiety that binds to or associates with FIP200, and on the other end an E3 ligase binder, wherein the moiety that binds to or associates with FIP200 and the moiety that is an E3 ligase binder are connected by a linker.
  • a compound of the present disclosure is represented by formula I: A-B-E3L
  • A is a moiety that binds to or associates with FIP200
  • B is a linker moiety
  • E3L is a ubiquitin E3 ligase binding moiety.
  • a moiety that binds or associates with FIP200 is one that covalently binds directly to FIP200 or one that undergoes one or more of hydrogen bonding, electrostatic interactions, pi stacking, van der Waals interactions, or dipole-dipole interactions with FIP200.
  • A is selected from a moiety of formula II- 1 , II-
  • G 1 is an optionally substituted C6-C12 aryl or an optionally substituted 5- to 6- membered heteroaryl;
  • X 1 is -S-, -N(R 3 )-, -O-, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic;
  • X 2 is C(R 3 ) or N, provided that, when X 2 is N, then X 1 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X 3 and X 4 is a single bond, then X 3 is N(R 2a ), and X 4 is C(O) when a bond between X 3 and X 4 is a double bond, then X 3 is C(R 2b ) and X 4 is C(R 3 ), or N; each R 1 is independently selected from halogen, optionally substituted C 1 -C 6 aliphatic, and optionally substituted -O-C 1 -C 6 aliphatic; or two instances of R 1 come
  • R 2a is optionally substituted C 1 -C 6 aliphatic
  • R 2b is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )- C 1 -C 6 aliphatic, or optionally substituted -O-C 1 -C 6 aliphatic; each R 3 is independently selected from hydrogen, halogen, and optionally substituted C 1 -C 6 aliphatic;
  • R 4 is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted C 1 -C 6 aliphatic;
  • R 5 is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C 1 -C 6 aliphatic;
  • L 1 is independently a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR 3 -; n is 0, 1, 2, 3, 4, 5, or 6; each of X 5 , X 6 , and X 7 are independently selected from the group consisting of N and
  • R 7 is hydrogen, an optionally substituted -O-C 1 -C 6 aliphatic, -S(O)2R 3 , optionally substituted C 1 -C 6 aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S
  • G 2 is an optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;
  • G 3 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6- membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce- C12 aryl;
  • L 2 is a bond, -NR 3 -C(O)-, -C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;
  • L 3 is-NR 3 -, -O-, -C(O)-, -NR 3 -C(O)-, -NR 3 -S(O) 2 -, -C(O)-NR 3 -, -S(O) 2 NR 3 -, -NR 3 - C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, or an optionally substituted C3- Ce cycloaliphatic ring;
  • R 6 is a bond, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic; and R 8 is independently halogen, -OR 3 , - C(O)N(R 3 )2, -C(O)OR 3 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 aryl; and when A is of formula II-4, then R 6 is H, halogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic
  • A is selected from a moiety of formula II- 1 or
  • G 1 is an optionally substituted C6-C12 aryl or an optionally substituted 5- to 6- membered heteroaryl;
  • X 1 is -S-, -N(R 3 )-, -O-, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic;
  • X 2 is C(R 3 ) or N, provided that, when X 2 is N, then X 1 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X 3 and X 4 is a single bond, then X 3 is N(R 2a ), and X 4 is C(O) when a bond between X 3 and X 4 is a double bond, then X 3 is C(R 2b ) and X 4 is C(R 3 ), or N; each R 1 is independently selected from halogen, optionally substituted C 1 -C 6 aliphatic, and optionally substituted -O-C 1 -C 6 aliphatic; or two instances of R 1 come together with the atoms to which they are attached to form a n optionally substituted Ce-Cn aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered
  • R 2a is optionally substituted C 1 -C 6 aliphatic,
  • R 2b is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )- C 1 -C 6 aliphatic, or optionally substituted -O-C 1 -C 6 aliphatic; each R 3 is independently selected from hydrogen, halogen, and optionally substituted C 1 -C 6 aliphatic;
  • R 4 is selected from optionally substituted C6-C12 aryl; optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S; and optionally substituted C 1 -C 6 aliphatic;
  • R 5 is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C 1 -C 6 aliphatic;
  • L 1 is a bond, -C(O)-, -S(O)-, -S(O) 2 -, or -NR 3 -; n is 0, 1, 2, 3, 4, 5, or 6; and
  • A is a moiety of formula II- 1 : or a pharmaceutically acceptable salt thereof, wherein:
  • G 1 is an optionally substituted Ce-Cn aryl or an optionally substituted 5- to 6- membered heteroaryl;
  • X 1 is -S-, -N(R 3 )-, -O-, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic;
  • X 2 is C(R 3 ) or N, provided that, when X 2 is N, then X 1 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X 3 and X 4 is a single bond, then X 3 is N(R 2a ), and X 4 is C(O) when a bond between X 3 and X 4 is a double bond, then X 3 is C(R 2b ) and X 4 is C(R 3 ), or N; each R 1 is independently selected from halogen, optionally substituted C 1 -C 6 aliphatic, and optionally substituted -O-C 1 -C 6 aliphatic; or two instances of R 1 come together with the atoms to which they are attached to form a n optionally substituted C6-C12 aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membere
  • R 2a is optionally substituted C 1 -C 6 aliphatic
  • R 2b is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )- C 1 -C 6 aliphatic, or optionally substituted -O-C 1 -C 6 aliphatic; each R 3 is independently selected from hydrogen, halogen, and optionally substituted C 1 -C 6 aliphatic; R 4 is selected from optionally substituted Ce-Cn aryl; optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S; and optionally substituted C 1 -C 6 aliphatic;
  • R 5 is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C 1 -C 6 aliphatic;
  • L 1 is a bond, -C(O)-, -S(O)-, -S(O) 2 -, or -NR 3 -; n is 0, 1, 2, 3, 4, 5, or 6; and
  • A is a moiety of formula II-2 :
  • G 1 is an optionally substituted C6-C12 aryl or an optionally substituted 5- to 6- membered heteroaryl;
  • X 1 is -S-, -N(R 3 )-, -O-, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic;
  • X 2 is C(R 3 ) or N, provided that, when X 2 is N, then X 1 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X 3 and X 4 is a single bond, then X 3 is N(R 2a ), and X 4 is C(O) when a bond between X 3 and X 4 is a double bond, then X 3 is C(R 2b ) and X 4 is C(R 3 ), or N; each R 1 is independently selected from halogen, optionally substituted C 1 -C 6 aliphatic, and optionally substituted -O-C 1 -C 6 aliphatic; or two instances of R 1 come together with the atoms to which they are attached to form a n optionally substituted Ce-Cn aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered
  • R 2a is optionally substituted C 1 -C 6 aliphatic,
  • R 2b is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )- C 1 -C 6 aliphatic, or optionally substituted -O-C 1 -C 6 aliphatic; each R 3 is independently selected from hydrogen, halogen, and optionally substituted C 1 -C 6 aliphatic;
  • R 4 is selected from optionally substituted C6-C12 aryl; optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S; and optionally substituted C 1 -C 6 aliphatic;
  • R 5 is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C 1 -C 6 aliphatic;
  • L 1 is a bond, -C(O)-, -S(O)-, -S(O) 2 -, or -NR 3 -; n is 0, 1, 2, 3, 4, 5, or 6; and
  • X 1 is S, N(R 3 ), O, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic.
  • X 1 is S, optionally substituted C 1 -C 6 aliphatic or optionally substituted C3-C6 cycloaliphatic.
  • X 1 is S or optionally substituted C 1 -C 6 aliphatic.
  • X 1 is S.
  • X 1 is N(R 3 ).
  • X 1 is N(H).
  • X 1 is O.
  • X 1 is optionally substituted Ci- Ce aliphatic. In some embodiments, X 1 is C 1 -C 6 alkylene. In some embodiments, X 1 is -CH2- In some embodiments, X 1 is optionally substituted C3-C6 cycloaliphatic. In some embodiments X 1 is cyclopropyl.
  • X 2 is, C(R 3 ) or N, provided that, when X 2 is N, then X 1 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic.
  • X 2 is C(R 3 ).
  • X 2 is C(H).
  • X 2 is N.
  • X 1 is S, N(R 3 ), or O and X 2 is C(R 3 ).
  • X 1 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic, and X 2 is N.
  • X 1 is S, and X 2 is C(R 3 ).
  • X 1 is S, and X 2 is C(H).
  • a moiety is:
  • a bond between X 3 and X 4 is a single bond
  • X 3 is N(R 2a )
  • X 4 is C(O).
  • a bond between X 3 and X 4 is a single bond.
  • X 3 is C(R 2b ) and X 4 is C(R 3 ) or N.
  • a bond between X 3 and X 4 is a double bond.
  • X 3 is C(R 2b ) and X 4 is N.
  • G 1 is an optionally substituted Ce-Cn aryl or an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, G 1 is optionally substituted monocyclic or bicyclic Ce-Cn aryl. In some embodiments, G 1 is optionally substituted phenyl. [0081] In some embodiments, G 1 is optionally substituted naphthyl. In some embodiments, G 1 is unsubstituted naphthyl.
  • G 1 is phenyl or naphthyl.
  • each R 1 is independently selected from halogen, optionally substituted C 1 -C 6 aliphatic, and optionally substituted -O-C 1 -C 6 aliphatic.
  • R 1 is halogen.
  • R 1 is chloride.
  • n is 2 and each R 1 is halogen.
  • n is 2 and each R 1 is chloride.
  • n is 2, and one instance of R 1 is halogen, and another instance of R 1 is C 1 -C 6 aliphatic or -O-C 1 -C 6 aliphatic.
  • R 1 is optionally substituted C 1 -C 6 aliphatic.
  • R 1 is C 1 -C 6 alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is optionally substituted O-C 1 -C 6 aliphatic. In some embodiments, R 1 is optionally substituted -O-C 1 -C 6 alkyl. In some embodiments, R 1 is -O-CH3.
  • two instances of R 1 come together with the atoms to which they are attached to form an optionally substituted C6-C12 aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S.
  • two instances of R 1 come together, with the atoms to which they are attached to form an optionally substituted C6-C12 aryl ring or a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S.
  • two instances of R 1 come together with the atoms to which they are attached to form an optionally substituted C6-C12 aryl ring.
  • two instances of R 1 come together with the atoms to which they are attached to form an optionally substituted C4-C6 cycloaliphatic ring. In some embodiments, two instances of R 1 come together to form a cyclopentyl or cyclohexyl ring.
  • two instances of R 1 come together with the atoms to which they are attached to form a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, two instances of R 1 come together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S.
  • a moiety [0089] In some embodiments, a moiety:
  • a moiety [0090] In some embodiments, a moiety:
  • R 2a is optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )-C 1 -C 6 aliphatic, or optionally substituted -O-C 1 -C 6 aliphatic. In some embodiments, R 2a is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 2a is Ci- Ce alkyl. In some embodiments is R 2a is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 2a is methyl or ethyl. In some embodiments, R 2a is ethyl. In some embodiments, R 2a is C 1 -C 6 optionally substituted with halogen. In some embodiments, R 2a is -CH2-CHF2.
  • R 2b is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )-C 1 -C 6 aliphatic, or optionally substituted -O-C 1 -C 6 aliphatic.
  • R 2b is hydrogen.
  • R 2b is optionally substituted Ci- Ce aliphatic.
  • R 2b is In some embodiments, R 2b is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 2b is C 1 -C 6 alkyl.
  • R 2b is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R 2a is methyl or ethyl. In some embodiments, R 2a is ethyl.
  • R 2b is optionally substituted -N(R 3 )-C 1 -C 6 aliphatic. In some embodiments, R 2b is -N(H)-C 1 -C 6 aliphatic. In some embodiments, R 2b is -N(H)-CH2-CH3.
  • R 2b is optionally substituted -O-C 1 -C 6 aliphatic. In some embodiments, R 2b is -O-C 1 -C 6 alkyl. In some embodiments, R 2b is -O-CH2-CH3.
  • each R 3 is independently selected from hydrogen, halogen, and optionally substituted C 1 -C 6 aliphatic.
  • R 3 is hydrogen.
  • R 3 is halogen.
  • R 3 is optionally substituted C 1 -C 6 aliphatic.
  • R 3 is optionally substituted C 1 -C 6 alkyl.
  • R 3 is methyl.
  • R 4 is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S; and optionally substituted C 1 -C 6 aliphatic.
  • R 4 is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • R 4 is optionally substituted Ce-Cn aryl. In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is phenyl optionally substituted with halogen, -(CH2)o 4R 0 , -(CH2)o 4OR 0 , or -(CH2)o-4N(R°)2. In some embodiments, R 4 is phenyl optionally substituted with halogen. In some embodiments, R 4 is phenyl substituted with bromide or chloride. In some embodiments, R 4 is phenyl substituted with bromide. In some embodiments, R 4 is unsubstituted phenyl. In some embodiments, R 4 is optionally substituted napthyl.
  • R 4 is:
  • R 4 is: where * represents a point of attachment to moiety B of formula I.
  • R 4 is optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is optionally substituted monocyclic 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is pyrrolidine, pyrazole, imidazole, pyridine, pyrimidine, or pyrazine. In some embodiments of formula II-l, R 4 is:
  • R 4 is optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is optionally substituted monocyclic 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 4 is optionally substituted tetrahydropyran. In some embodiments of formula II- 1, R 4 is:
  • R 4 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 4 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 4 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 4 is methyl.
  • R 5 is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C 1 -C 6 aliphatic.
  • R 5 is optionally substituted 4- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 5 is optionally substituted 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 5 is optionally substituted 5-membered heterocyclyl. In some embodiments, R 5 is optionally substituted 6-membered heterocyclyl. In some embodiments, R 5 is azetidine, pyrrolidine, piperidine, or piperazine. In some embodiments of formula II- 1, R 5 is: where * represents a point of attachment to moiety B of formula I.
  • R 5 is:
  • L 1 is a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR 3 -. In some embodiments, L 1 is a bond. In some embodiments, L 1 is -C(O)-. In some embodiments, L 1 is -S(O)-. In some embodiments, L 1 is -S(O)2-. In some embodiments, L 1 is -NR 3 -. In some embodiments L 1 is -NH-.
  • n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.
  • A is selected from a moiety of formula II-3 or
  • each of X 5 , X 6 , and X 7 are independently selected from the group consisting of N and
  • R 7 is hydrogen, an optionally substituted -O-C 1 -C 6 aliphatic, -S(O)2R 3 , optionally substituted C 1 -C 6 aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S
  • G 2 is an optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;
  • G 3 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6- membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce- C12 aryl;
  • L 2 is a bond, -NR 3 -C(O)-, -C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;
  • L 3 is-NR 3 -, -O-, -C(O)-, -NR 3 -C(O)-, -NR 3 -S(O) 2 -, -C(O)-NR 3 -, -S(O) 2 NR 3 -, -NR 3 - C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, or an optionally substituted C3- Ce cycloaliphatic ring;
  • R 6 is a bond, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic; and R 8 is independently halogen, -OR 3 , - C(O)N(R 3 )2, -C(O)OR 3 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 aryl; and when A is of formula II-4, then R 6 is H, halogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroalipha
  • A is a moiety of formula II-3 :
  • each of X 5 , X 6 , and X 7 are independently selected from the group consisting of N and CH;
  • R 7 is hydrogen, an optionally substituted -O-C 1 -C 6 aliphatic, -S(O)2R 3 , optionally substituted C 1 -C 6 aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C6-C12 aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S
  • G 2 is an optionally substituted C6-C12 aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;
  • G 3 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6- membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce- C12 aryl;
  • L 2 is a bond, -NR 3 -C(O)-, -C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;
  • L 3 is-NR 3 -, -O-, -C(O)-, -NR 3 -C(O)-, -NR 3 -S(O) 2 -, -C(O)-NR 3 -, -S(O) 2 NR 3 -, -NR 3 - C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, or an optionally substituted C3- Ce cycloaliphatic ring;
  • R 6 is a bond, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Ci 2 aryl, or optionally substituted C3-C6 cycloaliphatic; and each R 8 is independently halogen, -OR 3 , -C(O)N(R 3 ) 2 , -C(O)OR 3 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted Ce-Ci 2 aryl.
  • A is a moiety of formula II-4 :
  • each of X 5 , X 6 , and X 7 are independently selected from the group consisting of N and
  • R 7 is hydrogen, an optionally substituted -O-C 1 -C 6 aliphatic, -S(O)2R 3 , optionally substituted C 1 -C 6 aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S
  • G 2 is an optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;
  • G 3 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6- membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce- C12 aryl;
  • L 2 is a bond, -NR 3 -C(O)-, -C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;
  • L 3 is-NR 3 -, -O-, -C(O)-, -NR 3 -C(O)-, -NR 3 -S(O) 2 -, -C(O)-NR 3 -, -S(O) 2 NR 3 -, -NR 3 - C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, or an optionally substituted C3- Ce cycloaliphatic ring;
  • R 6 is H, halogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic; and R 8 is a bond, -O-, -C(O)NR 3 -, -C(O)OR 3 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C6 cycloaliphatic, or optionally substituted C6-C12 aryl.
  • each of X 5 , X 6 , and X 7 are independently selected from the group consisting of N and CH.
  • each of X 5 , X 6 , and X 7 are N.
  • each of X 5 , X 6 , and X 7 are CH.
  • X 5 is N and X 6 and X 7 are CH.
  • X 6 is N and X 5 and X 7 are CH.
  • X 7 is N, and X 5 and X 6 are CH.
  • X 5 and X 6 are CH.
  • X 5 and X 6 are N and X 7 is CH.
  • X 5 and X 7 are N and X 6 is CH.
  • X 6 and X 7 are N and X 5 is CH.
  • R 7 is hydrogen, an optionally substituted -O-C 1 -C 6 aliphatic, - S(O)2R 3 , optionally substituted C 1 -C 6 aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C6-C12 aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • R 7 is hydrogen
  • each R 7 is independently an optionally substituted -O-C 1 -C 6 aliphatic, -S(O)2R 3 , optionally substituted C 1 -C 6 aliphatic, an optionally substituted 4- to 12- membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C6-C12 aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • R 7 is optionally substituted -O-C 1 -C 6 aliphatic. In some embodiments, R 7 is optionally substituted -O-C 1 -C 6 alkyl. In some embodiments, R 7 is -O- CH 3 .
  • R 7 is -S(O)2R 3 . In some embodiments, R 7 is optionally substituted -S(O)2-C 1 -C 6 aliphatic.
  • R 7 is optionally substituted C 1 -C 6 aliphatic.
  • R 7 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 7 is an optionally substituted monocyclic 4- to 6-membered heterocycle ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is optionally substituted tetrahydropyran or morpholine. In some embodiments, R 7 is a bicyclic or spirocyclic 6- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 7 is:
  • R 7 is optionally substituted Ce-Cn aryl. In some embodiments, R 7 is optionally substituted phenyl. In some embodiments, R 7 is phenyl optionally substituted with -(CH2)o-4R° or -(CH2)o-4N(R°)2. In some embodiments, R 7 is phenyl optionally substituted with -NH2. In some embodiments, R 7 is optionally substituted naphthyl. In some embodiments, R 7 is:
  • R 7 is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R 7 is optionally substituted monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with - (CH 2 )O 4R 0 or -(CH2)O 4N(R°)2.
  • R 7 is monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with -CH3 or -NH2.
  • R 7 is optionally substituted pyridine, pyrazine, pyrimidine, pyrazole, pyrrole, or imidazole.
  • R 7 is: ,
  • G 2 is an optionally substituted C6-C12 aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic.
  • G 2 is optionally substituted C6-C12 aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • G 2 is optionally substituted C6-C12 aryl. In some embodiments, G 2 is optionally substituted phenyl. In some embodiments, G 2 is unsubstituted phenyl. In some embodiments, G 2 is naphthyl.
  • G 2 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • G 2 is optionally substituted monocyclic 4- to 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • G 2 is optionally substituted bicyclic 7- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • G 2 is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • G 2 is optionally substituted C3-C6 cycloaliphatic. In some embodiments, G 2 is optionally substituted partially unsaturated Ce cycloaliphatic.
  • G 3 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6-membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring, or optionally substituted C6-C12 aryl.
  • G 3 is optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, G 3 is optionally substituted monocyclic 4- to 6-membered heterocycle ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, G 3 is optionally substituted pyrrolidine or piperidine. In some embodiments, G 3 is pyrrolidine or piperidine optionally substituted with -(CH2)o 4R 0 or -(CH2)o 4Ph, which may be substituted with R°. In some embodiments, G 3 is pyrrolidine or piperidine optionally substituted with -C(O)N(R 3 )2
  • G 3 is optionally substituted bicyclic or spirocyclic 6- to 12- membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • G 3 is bicyclic or spirocyclic 6- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with -(CH2)o 4R 0 or - C(O)N(R 3 )2.
  • G 3 is bicyclic or spirocyclic 6- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with -C(O)N(R 3 )2.
  • G 3 is bicyclic or spirocyclic 6- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with -C(O)N(R 3 )2. In some embodiments, G 3 is bicyclic or spirocyclic 6- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with -C(O)N(R 3 )2. . In some embodiments, G 3 is bicyclic or spirocyclic 6- to 10-membered heterocyclyl comprising 1 to 2 heteroatoms selected from N, O, and S, optionally substituted with -C(O)N(R 3 )2.
  • G 3 is an optionally substituted 5- to 6-membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S.
  • G 3 is an optionally substituted C3-C6 cycloaliphatic ring.
  • G 3 is optionally substituted C6-C12 aryl.
  • L 2 is a bond, -NR 3 -C(O)-, -C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3-C6 cycloaliphatic.
  • L 2 is a bond
  • L 2 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, L 2 is C 1 -C 6 alkylene. In some embodiments, L 2 is -C(H)(CH3)-, -C(CH3)2-, or - CH2-. In some embodiments, L 2 is a bond or selected from:
  • L 2 is:
  • L 2 is:
  • L 2 is:
  • L 2 is -NR 3 -C(O)-. In some embodiments, L 2 is -NH-C(O)-.
  • L 2 is -C(O)-NR 3 -. In some embodiments, L 2 is -C(O)-NH-.
  • L 2 is optionally substituted 4- to 6-membered heterocyclic.
  • L 2 is optionally substituted azetidine or oxetane. In some embodiments, L 2 is:
  • L 2 is optionally substituted C3-C6 cycloaliphatic. In some embodiments, L 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, L 2 is:
  • L 3 is-NR 3 -, -O-, -C(O)-, -NR 3 -C(O)-, -NR 3 -S(O) 2 -, -C(O)- NR 3 -, -S(O) 2 NR 3 -, -NR 3 -C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, or an optionally substituted C3-C6 cycloaliphatic ring.
  • L 3 is -NR 3 -.
  • L 3 is -NH-.
  • L 3 is -O-.
  • L 3 is - C(O)-.
  • L 3 is -NR 3 -C(O)-. In some embodiments, L 3 is -NH-C(O)-. In some embodiments, L 3 is -NR 3 -S(O) 2 -. In some embodiments, L 3 is -NH-S(O) 2 -. In some embodiments, L 3 is -C(O)-NR 3 -. In some embodiments, L 3 is -C(O)-NH-. In some embodiments, L 3 is -S(O)2 NR 3 -. In some embodiments, L 3 is-S(O)2-NH-. In some embodiments, L 3 is -NR 3 -C(O)-NR 3 -. In some embodiments, L 3 is -NH-C(O)-NH-.
  • L 3 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, L 3 is optionally substituted C 1 -C 6 alkylene. In some embodiments, L 3 is - (CH2)I-6-. In some embodiments, L 3 is -CH2-.
  • L 3 is an optionally substituted C3-C6 cycloaliphatic ring. In some embodiments, L 3 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, L 3 is cyclopropyl.
  • R 6 is a bond, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic.
  • R 6 is a bond or optionally substituted C 1 -C 6 aliphatic.
  • R 6 is a bond.
  • R 6 is optionally substituted C 1 -C 6 aliphatic.
  • R 6 is C 1 -C 6 alkylene. In some embodiments, R 6 is -CH2-. In some embodiments, R 6 is C2-C6 alkynlene.
  • R 6 is optionally substituted 2- to 6-membered heteroaliphatic.
  • R 6 is optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S.
  • R 6 is optionally substituted C6-C12 aryl.
  • R 6 is optionally substituted C3-C6 cycloaliphatic.
  • each R 8 is independently halogen, -OR 3 , -C(O)N(R 3 )2, -C(O)OR 3 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 aryl.
  • R 8 is halogen.
  • R 8 is -OR 3 .
  • In some embodiments of formula II-3, R 8 is a halogen.
  • R 8 is -OH. In some embodiments of formula II-3, R 8 is -O-CH3.
  • R 8 is -C(O)N(R 3 )2. In some embodiments of formula II-3, R 8 is -C(O)NH2. In some embodiments of formula II-3, R 8 is -C(O)N(H)(Ci- Ce aliphatic). In some embodiments of formula II-3, R 8 is -C(O)N(H)(CH3). In some embodiments of formula II-3, R 8 is -C(O)N(H)-CH2-CH2-O-CH3.
  • R 8 is -C(O)OR 3 . In some embodiments, R 8 is -C(O)OH. In some embodiments, R 8 is -C(O)OCH3.
  • R 8 is optionally substituted C 1 -C 6 aliphatic.
  • R 8 is methyl, ethyl, or propyl.
  • R 8 is -CH3 or - C(H)(CH 3 ) 2 .
  • R 8 is optionally substituted C3-C6 cycloaliphatic. In some embodiments, R 8 is optionally substituted cyclopropyl.
  • R 8 is optionally substituted C6-C12 aryl. In some embodiments, R 8 is optionally substituted phenyl.
  • R 6 is H, halogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic.
  • R 6 is H.
  • R 6 is halogen
  • R 6 is optionally substituted C 1 -C 6 aliphatic.
  • R 6 is optionally substituted 2- to 6-membered heteroaliphatic.
  • R 6 is optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S.
  • R 6 is optionally substituted Ce-Cn aryl.
  • R 6 is optionally substituted C3-C6 cycloaliphatic.
  • R 8 is a bond, -O-, -C(O)NR 3 -, - C(O)OR 3 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C6 cycloaliphatic, or optionally substituted C6-C12 aryl.
  • R 8 is a bond.
  • R 8 is -O-.
  • R 8 is -C(O)NR 3 -. In some embodiments, R 8 is -C(O)NH-. In some embodiments, R 8 is -C(O)N(C 1 -C 6 aliphatic)-.
  • R 8 is -C(O)OR 3 -. In some embodiments, R 8 is -C(O)OCH 2 -.
  • R 8 is optionally substituted C 1 -C 6 aliphatic.
  • R 8 is methyl, ethyl, or propyl.
  • R 8 is -CH3 or - C(H)(CH 3 ) 2 .
  • R 8 is optionally substituted C3-C6 cycloaliphatic. In some embodiments, R 8 is optionally substituted cyclopropyl.
  • R 8 is optionally substituted C6-C12 aryl.
  • A is selected from:
  • R 1 , R 2a , R 2b , R 4 , R 5 , L 1 , G 1 , n, G 2 , G 3 , L 3 , R 6 , R 7 , and R 8 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is selected from:
  • the present disclosure provides a compound of formula I:
  • each G 1 is independently an optionally substituted Ce-Cn aryl
  • X 1 is -S-;
  • X 2 is -C(R 3 )-; a bond between X 3 and X 4 is a single bond each X 3 is independently -C(H)(R 2b )- or -N(R 2a )-;
  • X 4 is -C(O)-; each R 1 is independently selected from halogen, optionally substituted C 1 -C 6 aliphatic, and optionally substituted -O-C 1 -C 6 aliphatic; or two instances of R 1 come together with the atoms to which they are attached to form a n optionally substituted C6-C1 2ryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S; each R 2a is independently optionally substituted C 1 -C 6 aliphatic; each R 2b is independently hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )-C 1 -C 6 aliphatic, or optionally substituted -
  • B is a linker moiety that is an optionally substituted C2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NR Z -, - N(R Z )C(O)-, -C(O)N(R Z )-, -N(R Z )C(O)O-, -OC(O)N(R Z )-, -N(R Z )C(O)N(R Z ) -, - OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered heterocyclyl ring having 1- 3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted
  • the present disclosure provides a compound of formula I: A-B-E3L or a pharmaceutically acceptable salt thereof, wherein:
  • A is a moiety of formula II-2 : II-2 wherein:
  • G 1 is an optionally substituted Ce-Cn aryl
  • X 1 is -S-;
  • X 2 is -C(R 3 )-; a bond between X 3 and X 4 is a single bond each X 3 is independently -C(H)(R 2b )- or -N(R 2a )-;
  • X 4 is -C(O)-; each R 1 is independently selected from halogen, optionally substituted C 1 -C 6 aliphatic, and optionally substituted -O-C 1 -C 6 aliphatic; or two instances of R 1 come together with the atoms to which they are attached to form a n optionally substituted Ce-Cn aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S;
  • R 2a is optionally substituted C 1 -C 6 aliphatic
  • R 2b is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )- C 1 -C 6 aliphatic, or optionally substituted -O-C 1 -C 6 aliphatic; each R 3 is independently selected from hydrogen, halogen, and optionally substituted C 1 -C 6 aliphatic;
  • R 4 is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S;
  • R 5 is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, or an optionally C3-C6 cycloaliphatic ring;
  • L 1 is a bond, -C(O)-; n is 0, 1, 2, 3, 4, 5, or 6;
  • B is a linker moiety that is an optionally substituted C2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NR Z -, - N(R Z )C(O)-, -C(O)N(R Z )-, -N(R Z )C(O)O-, -OC(O)N(R Z )-, -N(R Z )C(O)N(R Z ) -, - OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered heterocyclyl ring having 1- 3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted
  • A is a moiety of formula II-l or II-2
  • X 4 is C(O)
  • a bond between X 4 and X 3 is a single bond
  • G 1 is napthyl
  • X 1 is S
  • X 2 is C(R 3 )
  • R 4 is optionally substituted phenyl
  • R 5 is optionally substituted 5- to 6-membered heterocycle.
  • A is a moiety of formula II-l
  • X 4 is C(O)
  • a bond between X 4 and X 3 is a single bond
  • G 1 is napthyl
  • X 1 is S
  • X 2 is C(R 3 )
  • R 4 is optionally substituted phenyl
  • R 5 is optionally substituted 5- to 6-membered heterocycle.
  • A is a moiety of formula II-2
  • X 4 is C(O)
  • a bond between X 4 and X 3 is a single bond
  • G 1 is napthyl
  • X 1 is S
  • X 2 is C(R 3 )
  • R 4 is optionally substituted phenyl
  • R 5 is optionally substituted 5- to 6-membered heterocycle.
  • the present disclosure provides a compound of formula I: A-B-E3L
  • A is a moiety of formula II-3 :
  • Each of X 5 , X 6 , and X 7 are independently selected from the group consisting of N and CH;
  • R 7 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S
  • G 2 is an optionally substituted Ce-Cn aryl, or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • G 3 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S;
  • L 2 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic;
  • L 3 is-NR 3 -, -O-, -C(O)-, -NR 3 -C(O)-, -NR 3 -S(O) 2 -, -C(O)-NR 3 -, -S(O) 2 NR 3 -, or - NR 3 -C(O)-NR 3 -;
  • R 6 is a bond; and each R 8 is independently halogen, -OR 3 , -C(O)N(R 3 ) 2 , -C(O)OR 3 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted Ce-Ci 2 aryl.
  • the present disclosure provides a compound of formula I:
  • A is a moiety of formula II-4 : each of X 5 , X 6 , and X 7 are independently selected from the group consisting of N and CH;
  • R 7 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S
  • G 2 is an optionally substituted Ce-Cn aryl, or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;
  • G 3 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S;
  • L 2 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic;
  • L 3 is-NR 3 -, -O-, -C(O)-, -NR 3 -C(O)-, -NR 3 -S(O) 2 -, -C(O)-NR 3 -, -S(O) 2 NR 3 -, or - NR 3 -C(O)-NR 3 -;
  • R 6 is H, halogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Ci 2 aryl, or optionally substituted C3-C6 cycloaliphatic; and
  • R 8 is a bond.
  • A is a moiety of formula II-3 or II-4
  • X 5 and X 7 are each N
  • X 6 is CH
  • G 3 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S
  • L 2 is optionally substituted C 1 -C 6 aliphatic
  • L 3 is - NR 3 -C(O)- or -C(O)-NR 3 -
  • G 2 is optionally substituted phenyl
  • R 7 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • X 5 and X 7 are each N
  • X 6 is CH
  • G 3 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S
  • L 2 is optionally substituted C 1 -C 6 aliphatic
  • L 3 is -NR 3 - C(O)- or -C(O)-NR 3 -
  • G 2 is optionally substituted phenyl
  • R 7 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • A is a moiety of formula II-4
  • X 5 and X 7 are each N
  • X 6 is CH
  • G 3 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S
  • L 2 is optionally substituted C 1 -C 6 aliphatic
  • L 3 is -NR 3 - C(O)- or -C(O)-NR 3 -
  • G 2 is optionally substituted phenyl
  • R 7 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • A is represented by: wherein R 1 , n, G 1 , R 2a , R 4 , R 5 , and L 1 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is represented by: wherein R 1 , n, G 1 , R 2a , R 4 , R 5 , and L 1 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is represented by: wherein R 1 , n, G 1 , R 2b , R 4 , R 5 , and L 1 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is represented by: wherein R 1 , n, G 1 , R 2b , R 4 , R 5 , and L 1 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is represented by: wherein R 6 , G 2 , G 3 , L 2 , R 7 , and L 3 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is represented by: wherein R 6 , G 2 , G 3 , L 2 , R 7 , and L 3 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is represented by: wherein R 6 , G 3 , L 2 , R 7 , and L 3 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is represented by: wherein R 6 , G 3 , L 2 , R 7 , and L 3 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is represented by: wherein R 6 , G 2 , L 2 , R 7 , and L 3 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • A is represented by: wherein R 6 , G 2 , G 3 , L 2 , R 7 , and L 3 are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.
  • E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon. In some embodiments, E3L is a moiety that binds a Von-Hippel Lindau tumor suppressor. In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is selected from:
  • a moiety that binds a Von-Hippel Lindau tumor suppressor is:
  • a moiety that binds a Von-Hippel Lindau tumor suppressor is:
  • a moiety that binds a Von-Hippel Lindau tumor suppressor is:
  • a moiety that binds a Von-Hippel Lindau tumor suppressor is:
  • a moiety that binds a Von-Hippel Lindau tumor suppressor is:
  • a moiety that binds a Von-Hippel Lindau tumor suppressor is:
  • a moiety that binds a Von-Hippel Lindau tumor suppressor is:
  • a moiety that binds a Von-Hippel Lindau tumor suppressor is:
  • a moiety that binds a Von-Hippel Lindau tumor suppressor is:
  • E3L is a moiety that is an inhibitor of apoptosis protein.
  • a moiety that is an inhibitor of apoptosis protein is selected from:
  • a moiety that is an inhibitor of apoptosis protein is:
  • a moiety that is an inhibitor of apoptosis protein is:
  • a moiety that is an inhibitor of apoptosis protein is:
  • E3L is a moiety that binds cereblon.
  • a moiety that binds cereblon is selected from:
  • a moiety that binds cereblon is:
  • a moiety that binds cereblon is:
  • a moiety that binds cereblon is:
  • a moiety that binds cereblon is:
  • a moiety that binds cereblon is:
  • a moiety that binds cereblon is: [0229] In some embodiments, a moiety that binds cereblon is:
  • a moiety that binds cereblon is:
  • a moiety that binds cereblon is:
  • A is a moiety of formula II- 1 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon.
  • A is a moiety of formula II- 1 and E3L is a moiety that binds a Von Hippel- Lindau tumor suppressor.
  • A is a moiety of formula 11-1 and E3L is a moiety that binds an inhibitor of apoptosis protein.
  • A is a moiety of formula 11-1 and E3L is a moiety that binds cereblon.
  • A is a moiety of formula 11-2 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon.
  • A is a moiety of formula II-2 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor.
  • A is a moiety of formula 11-2 and E3L is a moiety that binds an inhibitor of apoptosis protein.
  • A is a moiety of formula 11-2 and E3L is a moiety that binds cereblon.
  • A is a moiety of formula II- 3 and E3L is a moiety that binds a Von Hippel- Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon.
  • A is a moiety of formula 11-3 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor.
  • A is a moiety of formula 11-3 and E3L is a moiety that binds an inhibitor of apoptosis protein.
  • A is a moiety of formula II-3 and E3L is a moiety that binds cereblon.
  • A is a moiety of formula II-4 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon.
  • A is a moiety of formula II-4 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor.
  • A is a moiety of formula II-4 and E3L is a moiety that binds an inhibitor of apoptosis protein.
  • A is a moiety of formula II-4 and E3L is a moiety that binds cereblon.
  • a compound of formula l is a compound of formula III- 1 :
  • R 1 , R 2a , R 4 , R 5 , L 1 , G 1 , n and B are as described in classes and subclasses herein.
  • a compound of formula I is a compound of formula III-2 :
  • R 1 , R 2a , R 4 , R 5 , L 1 , G 1 , n and B are as described in classes and subclasses herein.
  • a compound of formula l is a compound of formula III-3 :
  • a compound of formula I is a compound of formula III-4 :
  • R 7 , R 8 , L 3 , G 2 , G 3 , and B are as described in classes and subclasses herein.
  • a compound of formula I is a compound of formula III-5 :
  • R 1 , R 2a , R 4 , R 5 , L 1 , G 1 , n and B are as described in classes and subclasses herein.
  • a compound of formula I is a compound of formula III-6 :
  • R 1 , R 2a , R 4 , R 5 , L 1 , G 1 , n and B are as described in classes and subclasses herein.
  • a compound of formula I is a compound of formula III-7:
  • a compound of formula I is a compound of formula III-8 :
  • R 7 , R 8 , L 3 , G 2 , G 3 , and B are as described in classes and subclasses herein.
  • a compound of formula I is a compound of formula III-9 :
  • R 7 , R 8 , L 3 , G 2 , G 3 , and B are as described in classes and subclasses herein.
  • a compound of formula I is a compound of formula III- 10: III- 10 or a pharmaceutically acceptable salt thereof, wherein R 7 , R 8 , L 3 , G 2 , G 3 , and B are as described in classes and subclasses herein.
  • a compound of formula l is a compound of formula III- 11 :
  • a compound of formula I is a compound of formula III- 12: or a pharmaceutically acceptable salt thereof, wherein R 7 , R 8 , L 3 , G 2 , G 3 , and B are as described in classes and subclasses herein.
  • a compound of formula I is a compound of formula III-l 3 :
  • R 7 , R 8 , L 3 , G 2 , G 3 , and B are as described in classes and subclasses herein.
  • a compound of formula I is a compound of formula III- 14:
  • B is a linker moiety.
  • B is a linker moiety that is an optionally substituted C2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by - Cy-, -NR Z -, -N(R Z )C(O)-, -C(O)N(R Z )-, -N(R Z )C(O)O-, -OC(O)N(R Z )-, -N(R Z )C(O)N(R Z ) -, -0C(0)0-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted C3-
  • B is a linker moiety represented by formula IV:
  • G 4 is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -C(O)N(R Z )- or -O-, and each R z is independently H or an optionally substituted C1-C4 aliphatic group;
  • G 5 is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NR Z -, or -O-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S or optionally substituted C3-C6 cycloalkyl, and each R z is independently H or an optionally substituted C1-C4 aliphatic group; and
  • G 6 is a bond or an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NR Z -, -O-, or -C(O)-, wherein each - Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, and each R z is independently H or an optionally substituted C1-C4 aliphatic group.
  • G 4 is an optionally substituted C1-4 aliphatic group wherein one or more carbons are optionally and independently replaced by -C(O)N(R Z )- or -O-, and each R z is independently H or an optionally substituted C1-C4 aliphatic group.
  • G 4 is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O-. In some embodiments, G 4 is a C1-4 aliphatic group wherein one carbon atom is replaced by -O-. In some embodiments, G 4 is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O- and further wherein the C1-4 aliphatic group contains one or more units of unsaturation. In some embodiments, G 4 is a C1-4 aliphatic group wherein one carbon atom is replaced by -O- and further wherein the C1-4 aliphatic group contains one or more units of unsaturation.
  • G 4 is an optionally substituted C1-4 aliphatic group. In some embodiments, G 4 is an optionally substituted C1-3 aliphatic group. In some embodiments, G 4 is an optionally substituted C1-2 aliphatic group. In some embodiments, G 4 is an unsaturated C1-2 aliphatic group. In some embodiments, G 4 is C2 alkynyl. In some embodiments, G 4 is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O- or -C(O)N(R Z )-.
  • G 4 is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O- or -C(O)NH-. In some embodiments, G 4 is a C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O- or - C(O)NH-.
  • G 5 is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NR Z -, or -O-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S or optionally substituted C3-C6 cycloalkyl, and each R z is independently H or an optionally substituted C1-C4 aliphatic group.
  • G 5 is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O-. In some embodiments, G 5 is a C1-5 aliphatic group wherein one carbon is replaced by -O-. In some embodiments, G 5 is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S or optionally substituted C3-C6 cycloalkyl.
  • G 5 is an optionally substituted C1-5 aliphatic group wherein one carbon atom is replaced by -Cy-, wherein -Cy- is an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S. In some embodiments, G 5 is an optionally substituted C1-5 aliphatic group wherein one carbon atom is replaced by piperidinyl.
  • G 5 is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy- or -NR Z -, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S.
  • G 5 is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl or -NH-.
  • G 5 is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy- or -NR Z -, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S or optionally substituted C3-C6 cycloalkyl.
  • G 5 is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl, cyclobutyl, or -NH-.
  • G 6 is a bond or an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NR Z -, -O-, or -C(O)-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, and each R z is independently H or an optionally substituted C1-C4 aliphatic group.
  • G 6 is a bond
  • G 6 is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O-. In some embodiments, G 6 is a C1-4 aliphatic group wherein one carbon atom is replaced by -O-. In some embodiments, G 6 is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy- or -NR Z -, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S.
  • G 6 is an optionally substituted Ci-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl or -NH-. In some embodiments, G 6 is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S.
  • G 6 is an optionally substituted C1-4 aliphatic group wherein one carbon atom is replaced by -Cy-, wherein -Cy- is an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S.
  • G 6 is an optionally substituted Ci-4 aliphatic group wherein one carbon atom is replaced by piperizinyl.
  • G 6 is an optionally substituted Ci-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy- or -O-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S.
  • G 6 is an optionally substituted Ci-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl or -O-.
  • G 6 is an optionally substituted Ci-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NR Z -, or -C(O)-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1- 3 heteroatoms selected from N, O, and S.
  • G 6 is an optionally substituted Ci-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl, -NH-, or -C(O)-.
  • B is selected from Table B 1 :
  • B is selected from Table B2:
  • B is selected from Table B3:
  • Table B3 Attorney Docket No. 2013075-0110 wherein * represents a point of attachment to A and # represents a point of attachment to E3L.
  • a compound of formula I is selected from Table 1 : Table 1
  • a compound of formula I is selected from Table 2:
  • provided compounds are provided and/or utilized in a salt form (e.g., a pharmaceutically acceptable salt form).
  • a salt form e.g., a pharmaceutically acceptable salt form.
  • Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the present disclosure encompasses an insight that particular proteins associated with the autophagy process are critical for normal autophagy function, and that by degrading said proteins, autophagy can therefore be inhibited or otherwise reduced relative to a normal cell system.
  • the present disclosure encompasses an insight that degradation of FIP200 disrupts autophagy, which can be leveraged into the treatment of particular diseases, disorders, or conditions.
  • Autophagy is the cellular process of degradation of cellular materials, including protein aggregates, whole organelles, and pathogens. In cells, autophagy is initiated by the formation of a double membraned structure termed the “phagophore ” which forms around the cargo to be degraded.
  • the phagophore then matures into an “autophagosome”, which has completely encapsulated the cargo.
  • the formation of the phagophore is initiated by the dual action of two distinct molecular cascades (the ATG5-ATG12 lipidation pathway) and the ULK1-FIP200-ATG13- ATG101 complex (referred to herein as the “ULK1 complex”). Both pathways act synergistically to promote the formation of phagophores and completion into the final autophagosome.
  • FIP200 is a central component of the ULK1 complex and was originally identified as an interacting partner of ULK1.
  • the ULK1 complex comprises of the Unc51-like kinase (ULK1), the scaffold protein FAK family kinase-interacting protein of 200 kDa (FIP200, also known as RB1CC1), ATG13 and ATG101.
  • FIP200 is an essential component of the autophagy pathway.
  • PROTACs PRoteOlysis TArgeting Chimaeras
  • FIP200 FIP200
  • PROTACs are heterobifunctional molecules which link a cargo binder to an E3 ubiquitin ligase via a binder, thereby promoting ubiquitination and destruction of the target via the proteasome.
  • binders of E3 ubiquitin ligase are known and described in various publications, including WO 2023/283606, and Bricelj, et al., Frontiers in Chemistry, 9:70317 (July 2021), each of which is incorporated by reference in its entirety.
  • the present disclosure leverages the insight that compounds comprising a E3 ubiquitin ligase binder and a moiety that binds to or associates with FIP200 causes degradation of FIP200, and thereby inhibits the autophagy pathway in a cell.
  • the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a composition described herein comprises a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a composition described herein is formulated for administration to a patient in need of such composition.
  • a composition described herein is formulated for oral administration to a patient.
  • a compound or composition as described herein can be used for the treatment of a disease, disorder, or condition. In some embodiments, a compound as described herein can be used for the treatment of a disease, disorder, or condition. In some embodiments, a composition as described herein can be used for the treatment of a disease, disorder or condition.
  • a compound or composition as described herein can be used to inhibit autophagy in a subject.
  • a compound as described herein can be used to inhibit autophagy in a subject.
  • a composition as described herein can be used to inhibit autophagy in a subject.
  • Compounds and compositions, according to method of the present disclosure are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.
  • compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intraci stemally or via an implanted reservoir.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • 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.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food. Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adj
  • compositions described herein may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds 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 compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions described herein may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • Dosage forms for topical or transdermal administration of a compound disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the present disclosure provides a method of treating a disease, disorder, or condition in a subject comprising administering to the subject a compound described herein (e.g., a compound of formula I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, as described in classes and subclasses herein.
  • said disease, disorder, or condition is a form of cancer, Ischemia-Reperfusion injury following a stroke or myocardial infarction, a neurodegenerative disease, a bacterial infection, a viral infection or an inflammatory disease.
  • a form of cancer includes pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, multiple myeloma, lung adenocarcinoma, skin cutaneous melanoma, uterine corpus endometrioid carcinoma, uterine carcinosarcoma, thyroid carcinoma, acute myeloid leukemia, bladder urothelial carcinoma, gastric adenocarcinoma, cervical adenocarcinoma, head and neck squamous cell carcinoma, or other Ras family- associated cancer.
  • the method further comprises administering a compound described herein and a RTK, RAS, RAF, MEK, ERK, or MAPK inhibitor for treatment of a RAS family-associated cancer. In some embodiments, the method further comprises administering a compound described herein and a RTK, RAS, RAF, MEK, or ERK inhibitor for treatment of a RAS family-associated cancer. In some embodiments, the method further comprises administering a compound described herein and an immune checkpoint inhibitor. In some embodiments, an immune checkpoint inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, a LAG-3 inhibitor, and a TIGIT inhibitor.
  • the method further comprises administering a compound described herein and a T-cell engager or immunotherapy that binds to both a cancer cell and an immune cell.
  • a T-cell engager or immunotherapy is a bispecific antibody.
  • a bispecific antibody binds to CD3 on a T-cell and a target on a cancer cell.
  • a bacterial infection is Porphyromonas gingivalis and Brucella abortus.
  • a viral infection is a coronavirus.
  • a viral infection is a coronavirus, e.g., SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-NL63, HCoV-229E, HCoV-OC43, or HKUl.
  • an inflammatory disease is Crohn’s disease or inflammatory bowel disease.
  • the present disclosure provides a method of inhibiting autophagy in a subject comprising administering to the subject a compound of formula I or a pharmaceutical composition as described in classes and subclasses herein.
  • Embodiment 1 A compound of formula I:
  • A is a moiety that binds to or associates with FIP200
  • B is a linker moiety
  • E3L is a ubiquitin E3 ligase binding moiety.
  • Embodiment 2 The compound of Embodiment 1, wherein A is selected from formula G 1 is an optionally substituted Ce-Cn aryl or an optionally substituted 5- to 6- membered heteroaryl;
  • X 1 is -S-, -N(R 3 )-, -O-, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic;
  • X 2 is independently C(R 3 ) or N, provided that, when X 2 is N, then X 1 is optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X 3 and X 4 is a single bond, then X 3 is N(R 2a ), and X 4 is C(O) when a bond between X 3 and X 4 is a double bond, then X 3 is C(R 2b ) and X 4 is C(R 3 ), or N; each R 1 is independently selected from halogen, optionally substituted C 1 -C 6 aliphatic, and optionally substituted -O-C 1 -C 6 aliphatic; or two instances of R 1 come together with the atoms to which they are attached to form a n optionally substituted C6-C12 aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- member
  • R 2a is optionally substituted C 1 -C 6 aliphatic
  • R 2b is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted -N(R 3 )- C 1 -C 6 aliphatic, or optionally substituted -O-C 1 -C 6 aliphatic; each R 3 is independently selected from hydrogen, halogen, and optionally substituted C 1 -C 6 aliphatic;
  • R 4 is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted C 1 -C 6 aliphatic;
  • R 5 is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted Ce-Cn aryl, or an optionally substituted C 1 -C 6 aliphatic;
  • L 1 is a bond, -C(O)-, -S(O)-, -S(O) 2 -, or -NR 3 -; n is independently 0, 1, 2, 3, 4, 5, or 6; each of X 5 , X 6 , and X 7 is independently selected from the group consisting of N and CH;
  • R 7 is hydrogen, an optionally substituted -O-C 1 -C 6 aliphatic, -S(O)2R 3 , optionally substituted C 1 -C 6 aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S
  • G 2 is optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;
  • G 3 is optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted C6-C12 aryl;
  • L 2 is a bond, -NR 3 -C(O)-, -C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;
  • L 3 is -NR 3 -, -O-, -C(O)-, -NR 3 -C(O)-, -NR 3 -S(O) 2 -, -C(O)-NR 3 -, -S(O) 2 NR 3 -, -NR 3 - C(O)-NR 3 -, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C3-C6 cycloaliphatic ring;
  • R 6 is a bond, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cn aryl, or optionally substituted C3-C6 cycloaliphatic; and R 8 is halogen, -OR 3 , -C(O)N(R 3 )2, - C(O)OR 3 , optionally substituted C 1 -C 6 aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 aryl; and when A is of formula II-4, then R 6 is H, halogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic,
  • Embodiment 3 The compound of Embodiment 2, wherein two R 1 come together, with the atoms to which they are attached, to form an optionally substituted C6-C12 aryl ring or a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Embodiment 4 The compound of Embodiment 2, wherein n is 2 and each R 1 is halogen.
  • Embodiment 5 The compound of Embodiment 4, wherein each R 1 is chloride.
  • Embodiment 6 The compound of any one of Embodiments 2-5, wherein a bond between X 4 and X 3 is a single bond.
  • Embodiment 7. The compound of any one of Embodiments 2-5, wherein a bond between X 4 and X 3 is a double bond, X 3 is C(R 2b ), and X 4 is N.
  • Embodiment 8 The compound of any one of Embodiments 2-7, wherein X 1 is S.
  • Embodiment 9 The compound of any one of Embodiments 2-8, wherein R 4 is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Embodiment 10 The compound of any one of Embodiments 2-9, wherein a moiety:
  • Embodiment 11 The compound of any one of Embodiments 2-10, wherein G 1 is phenyl or naphthyl.
  • Embodiment 12 The compound of any one of Embodiments 2-11, wherein R 5 is optionally substituted 5- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Embodiment 13 The compound of any one of Embodiments 2-12, wherein L 1 is C(O).
  • Embodiment 14 The compound of Embodiment 2, wherein A is of formula II- 1 or II-2,
  • X 4 is C(O), a bond between X 4 and X 3 is a single bond, G 1 is napthyl, X 1 is S, X 2 is
  • R 4 is optionally substituted phenyl
  • R 5 is optionally substituted 5- to 6- membered heterocycle.
  • Embodiment 16 The compound of Embodiment 2, wherein X 5 and X 7 are each N and X 6 is CH.
  • Embodiment 17 The compound of Embodiment 2, wherein G 3 is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Embodiment 18 The compound of Embodiment 17, wherein G 3 is optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.
  • Embodiment 19 The compound of Embodiment 17, wherein G 3 is optionally substituted 6- to 12-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Embodiment 20 The compound of any one of Embodiments 2 or 16-19, wherein L 2 is optionally substituted C 1 -C 6 aliphatic.
  • Embodiment 21 The compound of any one of Embodiments 2 or 16-19, wherein L 2 is a bond or selected from: Embodiment 22.
  • Embodiment 23 The compound of any one of Embodiments 2 or 16-22, wherein G 2 is optionally substituted Ce-Cn aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Embodiment 24 The compound of any one of Embodiments 2 or 16-23, wherein R 7 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Embodiment 25 The compound of Embodiment 2, wherein A is of formula II-3 or II-4,
  • X 5 and X 7 are each N, X 6 is CH, G 3 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, L 2 is optionally substituted C 1 -C 6 aliphatic, L 3 is -NR 3 -C(O)- or -C(O)-NR 3 -, G 2 is optionally substituted phenyl, and R 7 is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.
  • Embodiment 26 The compound of Embodiment 2, wherein a moiety:
  • Embodiment 27 The compound of Embodiment 2, wherein a moiety:
  • Embodiment 28 The compound of Embodiment 2, wherein A is selected from: Embodiment 30.
  • Embodiment 30 The compound of any one of Embodiments 2-29, wherein E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon.
  • Embodiment 31 The compound of Embodiment 30, wherein E3L is a moiety that binds a Von-Hippel Lindau tumor suppressor.
  • Embodiment 32 The compound of Embodiment 31, wherein E3L is a moiety that binds a Von-Hippel Lindau tumor suppressor and is represented by any one of the following structures:
  • Embodiment 33 The compound of Embodiment 30, wherein E3L is a moiety that binds an inhibitor of apoptosis protein.
  • Embodiment 34 The compound of Embodiment 33, wherein E3L is a moiety that binds an inhibitor of apoptosis protein and is represented by any one of the following structures:
  • Embodiment 35 The compound of Embodiment 30, wherein E3L is a moiety that binds cereblon.
  • Embodiment 36 The compound of Embodiment 35, wherein E3L is a moiety that binds cereblon and is represented by any one of the following structures:
  • Embodiment 37 The compound of Embodiment 2, wherein the compound is represented by formula III-l :
  • Embodiment 38 The compound of Embodiment 2, wherein the compound is represented by formula III-2:
  • Embodiment 39 The compound of Embodiment 2, wherein the compound is represented by formula III-3
  • Embodiment 40 The compound of Embodiment 2, wherein the compound is represented by formula III-4:
  • Embodiment 4E The compound of Embodiment 2, wherein the compound is represented by formula III-5 :
  • Embodiment 42 The compound of Embodiment 2, wherein the compound is represented by formula III-6:
  • Embodiment 43 The compound of Embodiment 2, wherein the compound is represented by formula III-7
  • Embodiment 44 The compound of Embodiment 2, wherein the compound is represented by formula III-8 :
  • Embodiment 45 The compound of Embodiment 2, wherein the compound is represented by formula HI-9:
  • Embodiment 46 The compound of Embodiment 2, wherein the compound is represented by formula III- 10:
  • Embodiment 47 The compound of Embodiment 2, wherein the compound is represented by formula III- 11 :
  • Embodiment 48 The compound of Embodiment 2, wherein the compound is represented by formula III- 12:
  • Embodiment 49 The compound of Embodiment 2, wherein the compound is represented by formula III- 13 :
  • Embodiment 50 The compound of Embodiment 2, wherein the compound is represented by formula III- 14:
  • Embodiment 51 The compound of any one of Embodiments 1-50, wherein B is a linker moiety that is an optionally substituted C2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NR Z -, -N(R Z )C(O)-, - C(O)N(R Z )-, -N(R Z )C(O)O-, -OC(O)N(R Z )-, -N(R Z )C(O)N(R Z ) -, -OC(O)O-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered heteroaryl ring having 1-4
  • Embodiment 52 The compound of any one of Embodiments 1-50, wherein B is selected from Table Bl.
  • Embodiment 53 The compound of Embodiments 1 or 2, wherein the compound is selected from Table 1.
  • Embodiment 54 A pharmaceutical composition comprising a compound of any one of Embodiments 1-53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Embodiment 55 A method of treating a disease, disorder, or condition in a subject comprising administering to the subject a compound of any one of Embodiments 1-53 or a pharmaceutical composition of Embodiment 54.
  • Embodiment 56 The method of Embodiment 55, wherein the disease, disorder, or condition is selected from forms of cancer, Ischemia-Reperfusion injury following a stroke or myocardial infarction, a neurodegenerative disease, a bacterial infection, a viral infection and an inflammatory disease.
  • the disease, disorder, or condition is selected from forms of cancer, Ischemia-Reperfusion injury following a stroke or myocardial infarction, a neurodegenerative disease, a bacterial infection, a viral infection and an inflammatory disease.
  • Embodiment 57 The method of Embodiment 56, wherein the form of cancer is selected from pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, multiple myeloma, lung adenocarcinoma, skin cutaneous melanoma, uterine corpus endometrioidcarcinoma, uterine carcinosarcoma, thyroid carcinoma, acute myeloid leukemia, bladder urothelial carcinoma, gastric adenocarcinoma, cervical adenocarcinoma, head and neck squamous cell carcinoma, or other Ras family- associated cancer.
  • Embodiment 58 The method of Embodiment 57, wherein the method further comprises administering a RTK, RAS, RAF, MEK, ERK, or MAPK inhibitor.
  • Embodiment 59 The method of Embodiment 57, wherein the method further comprises administering an immune checkpoint inhibitor.
  • Embodiment 60 The method of Embodiment 59, wherein the immune checkpoint inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, a LAG-3 inhibitor, and a TIGIT inhibitor.
  • the immune checkpoint inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, a LAG-3 inhibitor, and a TIGIT inhibitor.
  • Embodiment 61 The method of Embodiment 57, wherein the method further comprises administering a T-cell engager or immunotherapy that binds to both a cancer cell and an immune cell.
  • Embodiment 62 The method of Embodiment 61, wherein a T-cell engager or immunotherapy is a bispecific antibody.
  • Embodiment 63 The method of Embodiment 62, wherein the bispecific antibody binds to CD3 on a T-cell and a target on a cancer cell.
  • Embodiment 64 The method of Embodiment 56, wherein the neurodegenerative disease is selected from Alzheimer disease (AD), Parkinson disease (PD), and Huntington disease (HD).
  • Embodiment 65 The method of Embodiment 56, wherein the bacterial infection is selected from Porphyromonas gingivalis and Brucella abortus.
  • Embodiment 66 The method of Embodiment 56, wherein the viral infection is a coronavirus.
  • Embodiment 67 The method of Embodiment 56, wherein the inflammatory disease is selected from Crohn’s disease and inflammatory bowel disease.
  • Embodiment 68 A method of inhibiting autophagy in a subject comprising administering to the subject a compound of any one of Embodiments 1-53, or a pharmaceutical composition of Embodiment 54.
  • Embodiment 69 Use of a compound of any one of Embodiments 1-53 or a pharmaceutical composition of Embodiment 54 for the treatment of a disease, disorder, or condition.
  • Embodiment 70 Use of a compound of any one of Embodiments 1-53 or a pharmaceutical composition of Embodiment 54 for inhibiting autophagy in a subject.
  • CDI l,l'-carbonyldiimidazole
  • DIAD diisopropyl azodi carb oxy late
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide eq. or equiv.: equivalent or equivalents h or hr: hour or hours
  • HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
  • LiHDMS lithium bis(trimethylsilyl)amide
  • m-CPBA meta-chloroperbenzoic acid
  • PE petroleum ether RT or rt: room temperature
  • Step-1 Synthesis of tert-butyl (2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)-2- phenylacetyl)-D-prolinate
  • reaction was stirred at 50 °C for 16 h under N2 atmosphere.
  • Step-2 Synthesis of (2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)-2- phenylacetyl)-D-proline [0304]
  • Step-3 Synthesis of ((R)-2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)-2- phenylacetyl)-D-proline, INT-2 & ((S)-2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2- yl) thio) -2-phenylace tyl ) -D -proline, INT-3
  • Step-1 Synthesis of ethyl (4S)-4- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -3-oxopentanoate [0306] To a stirred solution of (2S)-2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ propanoic acid (30.0 g, 158 mmol) in tetrahydrofuran (300 mL) were added l-(lH-imidazole-l-carbonyl)-lH- imidazole (38.2 g, 236 mmol) at room temperature. The reaction was stirred for 16.0 hours at room temperature.
  • Step-2 Synthesis of tert-butyl (S)-(l-(6-hydroxy-2-methylpyrimidin-4-yl)ethyl)carbamate
  • Step-4 Synthesis of tert-butyl N-(4'- ⁇ [(lS)-l-(6-hydroxy-2-methylpyrimidin-4- yl)ethyl carbamoyl ⁇ - [ 1, 1 '-biphenyl / -4 -y I) carbamate
  • Step-5 Synthesis of tert-butyl N-(4'- ⁇ [(lS)-l-[2-methyl-6-(trifluoromethanesulfo nyloxy)pyrimidin-4-yl] ethyl] carbamoyl ⁇ -[l, 1 '-biphenyl] -4-yl)carbamate, INT-4
  • the resulting mixture was extracted with ethyl acetate (20 mL x 2) and the combined organic phase was washed with brine (2 mL).
  • Step-6 Synthesis of (2S,3aS, 7aS)-l- ⁇ 6-[(lS)-l-[(4'- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -[l,l'- biphenyl ]-4-yl) formamido ] ethyl ]-2-methylpyrimidin-4-yl ⁇ -octahydro-lH-indole-2-carboxylic acid, INT-5
  • reaction mixture was stirred for 0.5 hour at 80 °C.
  • the resulting mixture was extracted with ethyl acetate (2 mL x 2) and the combined organic phase was washed with brine (2 mL).
  • Step-1 Synthesis of tert-butyl (2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro-lH-indole-l- carboxylate
  • Step-3 Synthesis of benzyl N-[(lS)-l- ⁇ 6-[(2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro-lH- indol-l-yl ]-2-chloropyrimidin-4-yl ⁇ ethyl ] carbamate
  • Step-4 Synthesis of tert-butyl N-[(lS)-l- ⁇ 6-[(2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro- IH-indol-l-yl ]-2-bromopyrimidin-4-yl ⁇ ethyl ] carbamate
  • Step-1 Synthesis of (2S,3aS, 7aS)-l- ⁇ 6-[(lS)-l-aminoethyl]-2-bromopyrimidin-4-yl ⁇ -N- methyl-octahydro-lH-indole-2-carboxamide
  • Step-2 Synthesis of (2S,3aS, 7aS)-l- ⁇ 2-bromo-6-[(lS*)-l- ⁇ [4-(morpholin-4- yl)phenyl]formamido ⁇ ethyl]pyrimidin-4-yl ⁇ -N-methyl-octahydro-lH-indole-2-carboxamide
  • Step-1 Synthesis of l-(2,6-dichloropyrimidin-4-yl)ethan-l-one
  • Step-3 Synthesis of f(R)-N-[(lS)-l-(2,6-dichloropyrimidin-4-yl)ethyl]-2-methylpropane-2- sulfinamide and f(R)-N-[(lR)-l-(2,6-dichloropyrimidin-4-yl)ethyl]-2-methylpropane-2- sulfinamide
  • Step-4 Synthesis of (2S,3aS, 7aS)-l- ⁇ 2-chloro-6-[(lS)-l- ⁇ [(R)-2-methylpropane-2- sulfmyl]amino ⁇ ethyl]pyrimidin-4-yl ⁇ -octahydro-lH-indole-2-carboxylic acid
  • Step-6 Synthesis of (2S,3aS, 7aS)-l- ⁇ 6-[(lS)-l-aminoethyl]-2- bromopyrimidin-4-yl ⁇ -N- methyl-octahydro-lH-indole-2-carboxamide
  • Step-1 Synthesis of (2S,3aS, 7aS)-l-(6-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-2- chloropyrimidin-4-yl)octahydro-lH-indole-2-carboxylic acid
  • Step-2 Synthesis of (2S,3aS, 7aS)-l- ⁇ 2-chloro-6-[(lR)-l- ⁇ [(R)-2-methylpropane-2- sulfmyl]amino ⁇ ethyl]pyrimidin-4-yl ⁇ -N-methyl-octahydro-lH-indole-2-carboxamide
  • Step-3 Synthesis of (2S,3aS, 7aS)-l- ⁇ 6-[(lR)-l-aminoethyl]-2-bromopyrimidin-4-yl ⁇ -N- methyl-octahydro-lH-indole-2-carboxamide
  • Step-4 Synthesis of (2S,3aS, 7aS)-l- ⁇ 2-bromo-6-[(lR)-l- ⁇ [4-(morpholin-4- yl)phenyl]formamido ⁇ ethyl]pyrimidin-4-yl ⁇ -N-methyl-octahydro-lH-indole-2-carboxamide, INT-8
  • Step-1 Synthesis of (2S,3aS, 7aS)-l-(2-iodo-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide,
  • Step-1 Synthesis of [2-(prop-2-yn-l-yloxy) ethoxy] methyl me thane sulfonate.
  • Step-3 Synthesis of l- ⁇ [2-(prop-2-yn-l-yloxy) ethoxy] methyl ⁇ piper idin-4-amine.
  • Step-2 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-[(piperidin-4-yl)amino]-2,3-dihydr o-lH- isoindole-1 , 3-dione, INT-11
  • Step-1 Synthesis of (2S,3 aS, 7aS)-l- ⁇ 2-[3-(2-hydroxyethoxy)prop-l-yn-l-yl]-6-[(lS)-l- ⁇ [4- (morpholin-4-yl)phenyl]formamido ⁇ ethyl]pyrimidin-4-yl ⁇ -N-methyl-octahydro -lH-indole-2- carboxamide.
  • Step-2 Synthesis of 2-[(3- ⁇ 4-[(2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l-yl] ⁇ 6-[ ( 1S)-1 ⁇ [ 4-(morpholin-4-yl)phenyl ]formamido ⁇ ethyl ]pyrimidin-2-yl ⁇ prop-2-yn-l- yl)oxy ] ethylmethane sulf onate, INT-12
  • Step-1 Synthesis of benzyl 4-(4- ⁇ [(tert-butoxy)carbonyl]amino ⁇ piperidine-l-carbon yl)piperidine-l -carboxylate.
  • Step-3 Synthesis of benzyl 4-[(4-aminopiperidin-l-yl)methyl]piperidine-l-carboxylate.
  • Step-4 Synthesis of benzyl 4-[(4- ⁇ [2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl]amino ⁇ piperidin-l-yl)methyl]piperidine-l-carboxylate.
  • Step-5 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-( ⁇ l-[(piperidin-4-yl)methyl]piperid in-4- yl ⁇ amino)-2, 3-dihydro-lH-isoindole-l , 3-dione, INT-13
  • Step-2 Synthesis of 2-(2, 6-dioxopiperidin-3-yl)-5- ⁇ 4-[(piperidin-4-yl)methyl]piperaz in-l-yl ⁇ - 2, 3-dihydro-lH-isoindole-l , 3-dione
  • Step-1 Synthesis of (2S,3aS, 7aS)-N-methyl-l- ⁇ 6-[(lS)-l- ⁇ [4-(morpholin-4- yl)phenyl]forma mido ⁇ ethyl]-2- ⁇ 3-[(trimethylsilyl)oxy]prop-l-yn-l-yl ⁇ pyrimidin-4-yl ⁇ -octahydro-lH-indole-2 -carboxamide
  • reaction mixture was replaced with N2, then sealed and stirred for 6 hours at 50°C. After cooling to ambient temperature, the reaction mixture was diluted with water (50 mL), and then extracted with ethyl acetate (25 mLx3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum.
  • Step-3 Synthesis of 3- ⁇ 4-[(2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l-yl]-6-[(l S)-l- ⁇ [4-(morpholin-4-yl)phenyl]formamido ⁇ ethyl]pyrimidin-2-yl ⁇ prop-2-yn-l-ylmethanesul fonate, INT-15
  • Step-2 Synthesis of 2-(2, 6-dioxopiperidin-3-yl)-5- ⁇ 4-[(piperidin-4-yl)methyl]piperaz in-l-yl ⁇ - 2, 3-dihydro-lH-isoindole-l , 3-dione, INT-16
  • Step-1 Synthesis of (2S,3aS, 7aS)-l-(2- ⁇ 3-[2-(2- hydroxyethoxy)ethoxy]prop-l-yn-l-yl ⁇ -6-[(l
  • Step-2 Synthesis of 2- ⁇ 2-[(3- ⁇ 4-[(2S,3aS, 7 aS) -2 -(methylcarbamoyl)- octahydro- IH-indol-l-y I ]-6-[ ( lS)-l- ⁇ [ 4-(morpholin-4-yl)phenyl ]formamido ⁇ ethyl ]pyrimidin-2-yl ⁇ prop-2-yn-l-yl)oxy ]ethoxy ⁇ ethyl me thane sulfonate- INT-17
  • Step-2 Synthesis of (2R)-N-(2- ⁇ 2-[2-(4- ⁇ [2-(2, 6-dioxopiperidin-3-yl) ⁇ 1 , 3-dioxo-2, 3-dihydro- lH-isoindol-4-yl]amino]piperidin-l-yl)ethoxy]ethoxy ⁇ ethyl)-l-[(2R)-2-( ⁇ 3-ethyl-4-oxo- 3H,4H-benzo[g]quinazolin-2-yl ⁇ sulfanyl)-2-phenylacetyl]pyrrolidine-2-carboxamide
  • the mixture solution was stirred at RT for 2 h.
  • the reaction mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step-1 Synthesis of (2R)-N-(2- ⁇ 2-[2-(4- ⁇ [2-(2, 6-dioxopiperidin-3-yl)-l , 3-dioxo-2, 3-dihydro- lH-isoindol-4-yl]amino ⁇ piperidin-l-yl)ethoxy]ethoxy ⁇ ethyl)-l-[(2S)-2-( ⁇ 3-ethyl-4-oxo-
  • Step-1 Synthesis of (2S,4R)-l-[(2S)-2-(3- ⁇ 2-[2-(2- ⁇ [(2R)-l-[(2R)-2-( ⁇ 3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl ⁇ sulfanyl)-2-phenylacetyl]pyrrolidin-2-yl]formamido ⁇ ethoxy)ethoxy]ethoxy ⁇ propanamido)-3, 3-dimethylbutanoyl]-4-hydroxy-N- ⁇ [4-(4-me thyl-1, 3- thiazol-5-yl)phenyl methyl ⁇ pyrrolidine-2-carboxamide
  • the mixture solution was stirred at rt for 2 h.
  • the reaction mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step-1 Synthesis of tert-butyl (3aS, 7aS)-2-[(2- ⁇ 2-[2-(4- ⁇ [2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-4-yl]amino ⁇ piperidin-l-yl)ethoxy]ethoxy ⁇ ethyl) carbamoyl] - octahydro-lH-indole-l-carboxylate [0357] To a solution of 4-[(l- ⁇ 2-[2-(2-aminoethoxy)ethoxy]ethyl ⁇ piperidin-4-yl)amino]-2- (2, 6-dioxopiperidin-3-yl)-2,3-dihydro-lH-isoindole-l, 3-dione (95 mg, 0.195 mmol) in DMF (2 mL) and DIPEA(0.1
  • the mixture solution was stirred at RT for 4 h.
  • the reaction mixture was poured into water (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step-2 Synthesis of (3aS, 7aS)-N-(2- ⁇ 2-[2-(4- ⁇ [2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino ⁇ piperidin-l-yl) ethoxy] ethoxy ⁇ ethyl) -octa hydro-lH-indole- 2-carboxamide
  • Step-4 Synthesis of l- ⁇ 6-[(lS)-l-( ⁇ 4'-amino-[lf '-biphenyl]-4-yl ⁇ formamido) ethyl]-2- methylpyrimidin-4-yl ⁇ -N-(2- ⁇ 2-[2-(4- ⁇ [2-(2, 6-dioxopiperidin-3-yl)-l , 3-di oxo-2, 3-dihydro- lH-isoindol-4-yl]amino ⁇ piperidin-l-yl)ethoxy]ethoxy ⁇ ethyl)-octa hydro-lH-indole-2- carboxamide
  • Step-1 Synthesis of tert-butyl 2-[2-(prop-2-yn-l-yloxy)ethoxy]acetate
  • Step-3 Synthesis of tert-butyl N-(l- ⁇ 2-[2-(prop-2-yn-l-yloxy)ethoxy]acetyl ⁇ piperidin-4- yl)carbamate
  • Step-4 Synthesis of tert-butyl N-(4'- ⁇ [(lS)-l- ⁇ 6-[(2S,3aS, 7aS)-2-(methylcarbamoyl)- octahydro-lH-indol-l-yl -2-( 3- ⁇ 2-[2-( 4- ⁇ [ ( tert-butoxy)carbonyl ]amino ⁇ piperidin-l-yl)-2- oxoethoxy ] ethoxy ⁇ pr op- l-yn-l-yl)pyrimidin-4-yl ⁇ ethyl ] carbamoyl ⁇ - [ 1, 1 '-biphenyl ]-4- yl)carbamate
  • Step-5 Synthesis of tert-butyl N-(4'- ⁇ [(lS)-l- ⁇ 6-[(2S,3aS, 7aS)-2-(methylcarbamoyl)- octahydro-lH-indol-l-yl ]-2-( 3- ⁇ 2-[2-( 4- ⁇ [ ( tert-butoxy)carbonyl ]amino ⁇ piperidin-l-yl)-2- oxoethoxy ] ethoxy ⁇ pr op- l-yn-l-yl)pyrimidin-4-yl ⁇ ethyl ] carbamoyl ⁇ - [ 1, 1 '-biphenyl ]-4- yl)carbamate
  • Step-7 Synthesis of (2S,3aS, 7aS)-l- ⁇ 6-[(lS)-l-( ⁇ 4'-amino-[lf'-biphenyl]-4-yl ⁇ formamido) ethyl] -2-(3- ⁇ 2-[2-(4- ⁇ [2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2, 3-dihydro-lH-isoindol-4- yl]amino ⁇ piperidin-l-yl)-2-oxoethoxy]ethoxy ⁇ propyl) pyrimidin-4-yl ⁇ -N-methyl-octahydro- lH-indole-2-carboxamide
  • Step-2 Synthesis of tert-butyl N-(l- ⁇ 2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl ⁇ piperidin-4-yl) carbamate
  • Step-3 Synthesis of tert-butyl N-[l-(2- ⁇ 2-[(3- ⁇ 4-[(2S,3aS, 7aS)-2-(methylcarbamoyl)- octahydro-lH-indol-l-yl ]-6-[ (1S)-1 ⁇ [ ⁇ 4'- ⁇ [(tert-butoxy)carbonyl ] amino ⁇ - [ 1, 1 '-biphenyl ]-4- yl)formamido] ethyl]pyrimidin-2-yl ⁇ prop-2-yn-l-yl)oxy]ethoxy ⁇ ethyl) piperidineyl] carbamate
  • Step-4 Synthesis of tert-butyl N-(l- ⁇ 2-[2-(3- ⁇ 4-[(2S,3aS, 7aS)-2-(methylcarbamoyl) ⁇ octahydro-lH-indol-l-yl ]-6-[ (1S)-1 ⁇ [ e'- ⁇ [(tert-butoxy)carbonyl ] amino ⁇ - [ 1, 1 '-biphenyl ]-4- yl)formamido]ethyl]pyrimidin-2-yl ⁇ propoxy)ethoxy]ethyl ⁇ piperidin-4-yl)carbamate [0371] To a solution of tert-butyl A-[l-(2- ⁇ 2-[(3- ⁇ 4-[(2S',3aS,7aS)-2-(methylcarbamoyl)- octahydro-lJ/-indol-l-yl]-6-[(15)-l-[
  • Step-5 Synthesis of (2S,3aS, 7aS)-l- ⁇ 6-[(lS)-l-( ⁇ 4'-amino-[l,r-biphenyl]-4- yl ⁇ formamido)ethyl]-2-(3- ⁇ 2-[2-(4-aminopiperidin-l-yl)ethoxy]ethoxy ⁇ propyl) pyrimidin-4- yl ⁇ -N-methyl-octa hydro- lH-indole-2-carboxamide
  • Step-6 Synthesis of (2S,3aS, 7aS)-l- ⁇ 6-[(lS)-l-( ⁇ 4’-amino-[l,r-biphenyl]-4-yl ⁇ formamido)ethyl]-2-(3- ⁇ 2-[2-(4- ⁇ [2-(2,6-dioxopiperidin-3-yl)-l, 3-dioxo-2,3-dihydro-lH- isoindol-4-yl]amino ⁇ piperidin-l-yl)ethoxy]ethoxy ⁇ propyl)pyrimidin-4-yl ⁇ -N-methyl- octahydro-lH-indole-2-carboxamide
  • Step-7 Synthesis of tert-butyl N-(2- ⁇ 2-[2-(2- ⁇ [(2S)-l-[(2S,4R)-4-hydroxy-2-( ⁇ [4-(4-methyl-
  • Step-2 Synthesis of (2S,4R)-l-[(2S)-2-(3- ⁇ 2-[2-(2-aminoethoxy)ethoxy]ethoxy ⁇ pro panamido)-3, 3 -dimethylbutanoyl ]-4-hydroxy-N- ⁇ [ 4-( 4-methyl-l, 3-thiazol-5- yl)phenyl methyl ⁇ pyrrolidine-2-carboxamide
  • the mixture solution was stirred at RT for 2 h.
  • the reaction mixture was poured into water (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step-4 Synthesis of (2S,4R)-l-[(2S)-3,3-dimethyl-2- ⁇ 3-[2-(2- ⁇ 2-[(octahydro-lH-indol-2- yl)formamido ]ethoxy ⁇ ethoxy)ethoxy]propanamido ⁇ butanoyl ]-4-hydroxy-N- ⁇ [ 4-( 4-methyl-l, 3- thiazol-5-yl)phenyl methyl ⁇ pyrrolidine-2-carboxamide
  • Step-5 Synthesis of tert-butyl N-(4'- ⁇ [(lS)-l-(6- ⁇ 2-[(2- ⁇ 2-[2-(2- ⁇ [(2S)-l-[(2S,4R)-4-hydroxy- 2-( ⁇ [ 4-( 4-methyl-l, 3-thiazol-5-yl)phenyl ]methyl ⁇ carbamoyl)pyrrolidin-l-y I -3, 3-dimethyl-l- oxobutan-2-yl ]carbamoyl ⁇ ethoxy)ethoxy ]ethoxy ⁇ ethyl) carbamoyl / -octahydro- IH-indol-l-yl ⁇ - 2-methylpyrimidin-4-yl)ethyl carbamoyl ⁇ - [ 1, 1 '-biphenyl / -4-yl) carbamate
  • Step-6 Synthesis of (2S,4R)-l-[(2S)-2- ⁇ 3-[2-(2- ⁇ 2-[(l- ⁇ 6-[(lS)-l-( ⁇ 4'-amino-[l, -biphenyl]- 4-yl ⁇ formamido)ethyl]-2-methylpyrimidin-4-yl ⁇ -octahydro-lH-indol-2-yl) formamido]ethoxy ⁇ ethoxy)ethoxy]propanamido ⁇ -3, 3 -dimethylbutanoyl] -4-hydroxy-N- ⁇ [4-(4- methyl-1, 3-thiazol-5-yl)phenyl methyl ⁇ pyrrolidine-2-carboxamide
  • Step-1 Synthesis of tert-butyl 3- ⁇ 2-[2-(prop-2-yn- 1 -yloxy)ethoxy] ethoxyfpropanoate
  • Step-2 Synthesis of tert-butyl 3-(2-(2-((3-(4-((S)-l-(4'-((tert-butoxycarbonyl)amino)-[l,r- biphenyl]-4-carboxamido)ethyl)-6-((2S,3aS, 7aS)-2-(methylcarbamoyl)octahydro -IH-indol-l-yl) pyrimidin-2-yl)prop-2-yn-l-yl)oxy)ethoxy)ethoxy)propanoate
  • Step-3 Synthesis of tert-butyl 3-(2-(2-(3-(4-((S)-l-(4'-((tert-butoxycarbonyl)amino)-fl,r- biphenyl]-4-carboxamido)ethyl)-6-((2S,3aS, 7 aS) -2 -(methylcarbamoyl) octahydro- IH-indol-l-yl) pyrimidin-2-yl)propoxy)ethoxy)ethoxy)propanoate
  • Step-4 Synthesis of 3-(2-(2-(3-(4-((S)-l-(4'-amino-[l,r-biphenyl]-4-carboxamido) ethyl)-6- ((2S,3aS, 7aS)-2-(methylcarbamoyl)oclahydro-lH-indol-l-yl)pyrimidin-2-yl)propoxy)elhoxy)elh oxy)propanoic acid
  • Step-1 Synthesis of tert-butyl 4- ⁇ [2-(2, 6-di oxopiper idin- 3 -yl)-l , 3-dioxo-2, 3-dihydro-lH-isoindol- 4-yl]oxy ⁇ piperidine-l -carboxylate
  • Step-2 Synthesis of 2-(2, 6-dioxopiperidin-3-yl)-4-(piperidin-4-yloxy)-2, 3-dihydro-lH-isoindole- 1, 3-dione
  • Step-3 Synthesis of (2S,3aS, 7aS)-l-(2-(3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)piperidin-l-yl)ethoxy)ethoxy)prop-l-yn-l-yl)-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide
  • Step-4 Synthesis of 2S,3aS, 7aS)-l-(2-(3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindo lin-4-yl)oxy)piperidin-l-yl)ethoxy)ethoxy)propyl)-6-((S)-l-(4-morpholinobenzamido)ethyl)pyrimi din-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide, 1-10
  • Step-1 Synthesis of (2S,3aS, 7aS)-l- ⁇ 2-[3-(2- ⁇ 4-[(4- ⁇ [2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino ⁇ piperidin-l-yl)methyl]piperidin-l-yl ⁇ etho xy)prop-l-yn-l-yl]-6- [(1 S)-l- ⁇ [4-(morpholin-4-yl)phenyl ]formamido ⁇ ethyl Jpyrimidi n-4-yl ⁇ -N-methyl-octahydro-lH- indole-2-carboxamide.
  • Step-2 Synthesis of (2S,3aS, 7aS)-l- ⁇ 2-[3-(2- ⁇ 4-[(4- ⁇ [2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino ⁇ piperidin-l-yl)methyl]piperidin-l-yl ⁇ etho xy)propyl]-6-[ ( 1 S)-l- Attorney Docket No. 2013075-00110
  • Step-1 Synthesis of (2S,3aS, 7aS)-l-(2-(3-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindol in-5-yl)piperazin-l-yl)ethoxy)ethoxy)propyl)-6-((S)-l-(4-morpholinobenzamido)ethyl)pyrimidin- 4-yl)-N-methyloctahydro-lH-indole-2-carboxamide, 1-12:
  • Step-1 Synthesis of (2S,3aS, 7aS)-l-[2-(3- ⁇ 4-[(4- ⁇ [2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl ]amino ⁇ piperidin-l-yl)methyl ]piperidin-l-yl ⁇ propyl)-6-[ ( 1 S)-l- ⁇ [ 4- (morpholin-4-yl)phenyl]formamido ⁇ ethyl]pyrimidin-4-yl]-N-methyl-octahydro-lH-indole-2- carboxamide , 1-13

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Abstract

La présente divulgation concerne des composés de formule I : A-B-E3L I ou un sel pharmaceutiquement acceptable de celui-ci, et leurs utilisations, par exemple dans l'inhibition de l'autophagie, et le traitement de maladies, de troubles et d'affections par l'inhibition de l'autophagie.
PCT/US2024/057953 2023-12-01 2024-11-29 Composés et procédés d'inhibition de l'autophagie Pending WO2025117881A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110224225A1 (en) * 2010-03-10 2011-09-15 Lutz Zeitlmann Inhibitors of protein kinases
WO2017015562A1 (fr) * 2015-07-22 2017-01-26 Araxes Pharma Llc Composés de quinazoline substitués et leur utilisation en tant qu'inhibiteurs de protéines kras, hras et/ou nras mutantes g12c
WO2022081976A1 (fr) * 2020-10-16 2022-04-21 Dana-Farber Cancer Institute, Inc. Agents de dégradation de protéine helios à base de petites molécules de pipéridinyl et procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110224225A1 (en) * 2010-03-10 2011-09-15 Lutz Zeitlmann Inhibitors of protein kinases
WO2017015562A1 (fr) * 2015-07-22 2017-01-26 Araxes Pharma Llc Composés de quinazoline substitués et leur utilisation en tant qu'inhibiteurs de protéines kras, hras et/ou nras mutantes g12c
WO2022081976A1 (fr) * 2020-10-16 2022-04-21 Dana-Farber Cancer Institute, Inc. Agents de dégradation de protéine helios à base de petites molécules de pipéridinyl et procédés d'utilisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE 18 October 2012 (2012-10-18), XP093332782, Database accession no. 144695533 *
TAKAHASHI DAIKI, ARIMOTO HIROKAZU: "Selective autophagy as the basis of autophagy-based degraders", CELL CHEMICAL BIOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 28, no. 7, 1 July 2021 (2021-07-01), AMSTERDAM, NL , pages 1061 - 1071, XP093333723, ISSN: 2451-9456, DOI: 10.1016/j.chembiol.2021.05.006 *

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