WO2019032961A1 - Conjugués trioxacarcine-anticorps et utilisations associées - Google Patents

Conjugués trioxacarcine-anticorps et utilisations associées Download PDF

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WO2019032961A1
WO2019032961A1 PCT/US2018/046210 US2018046210W WO2019032961A1 WO 2019032961 A1 WO2019032961 A1 WO 2019032961A1 US 2018046210 W US2018046210 W US 2018046210W WO 2019032961 A1 WO2019032961 A1 WO 2019032961A1
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substituted
unsubstituted
cyclic
acyclic
branched
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Andrew G. Myers
Ethan L. MAGNO
Wei Yang
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President And Fellows Of Harvard College
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers

Definitions

  • ADCs Antibody-drug conjugates
  • a target-specific antibody e.g., a monoclonal antibody, mAb
  • antibody fragment e.g., a single-chain variable fragment (scFv)
  • scFv single-chain variable fragment
  • a payload often a cytotoxic drug
  • a linker connecting the drug to the antibody often a cytotoxic drug
  • the antibody binds to a target cell and the drug exerts its therapeutic effect, for example, by optional cleavage from the ADC and/or by internalization in the cell or proximity to the outside of the cell.
  • Targeted therapies are envisioned to provide many advantages including, but not limited to, decreased side effects and a wider therapeutic window as compared to untargeted therapies.
  • linker used is an important consideration in the design of the ADC.
  • ADCs with cleavable linkers are thought to have a less favorable therapeutic window, and are best designed for targets, such as tumor cell surface antigens that are internalized efficiently.
  • the linker should also be designed in a manner that ensures stability during circulation in blood but allows for the rapid release of the drug, preferably inside the target cell.
  • cleavable acid- and peptidase-labile linkers and non- cleavable linkers such as thioethers. See, e.g., Ducry et al., Bioconjugate Chemistry (2010) 21: 5-13.
  • trioxacarcins are a class of DNA- modifying natural products with antiproliferative effects.
  • the trioxacarcins were first described in 1981 by Tomita and coworkers. See, e.g., Tomita et al., J. Antibiotics,
  • Trioxacarcin A, B, and C were isolated by Tomita and coworkers from the culture broth of Streptomyces bottropensis DO-45 and shown to possess anti-tumor activity in murine models as well as gram-positive antibiotic activity. Subsequent work led to the discovery of other members of this family.
  • Trioxacarcin A is a powerful anticancer agent with subnanmolar IC 70 values against lung (LXFL 529L, H-460), mammary (MCF-7), and CNS (SF-268) cancer cell lines.
  • the trioxacarcins have also been shown to have antimicrobial activity, e.g., anti-bacterial and anti-malarial activity. See, e.g., Maskey et ah, J. Antibiotics (2004) 57:771-779.
  • trioxacarcin A bound to ⁇ - ⁇ of a guanidylate residue in a duplex DNA oligonucleotide substrate has provided compelling evidence for a proposed pathyway of DNA modification that proceeds by duplex intercalation and alkylation. See, e.g., Pfoh et ah, Nucleic Acids Research (2008) 36:3508-3514. All trioxacarcins appear to be derivatives of the aglycone, which is itself a bacterial isolate referred to in the patent literature as DC-45-A 2 .
  • U.S. Patent 4,459,291 issued July 10, 1984, describes the preparation of DC-45-A 2 by fermentation.
  • DC-45-A 2 is the algycone of trioxacarcins A, B, and C and is prepared by the acid hydrolysis of the fermentation products trioxacarcins A and C or the direct isolation from the fermentation broth of Streptomyces bottropensis.
  • the present disclosure provides access to novel trioxacarcin-antibody drug conjugates and trioxacarcin-antibody drug conjugate precursor compounds with
  • trioxacarcins are highly toxic to a variety of cell types. Linking a trioxacarcin to an antibody preserves the trioxacarcin' s potency against a particular cell type while increasing specificity to the target cell, and optionally increasing endocytosis of the trioxacarcin. These effects enable lowering the overall amount of trioxacarcin to be delivered, thereby reducing the associated toxicity.
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R D1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R E2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R F2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R 7 is -L-B
  • dialkylamino or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • NR uz C( 0)OR ul ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • G2 heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R 1 and R 10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 1 0 U and R 3 J are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 and R 4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 4 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 6 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 20 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • R 11 is substituted or unsubstituted alkylene
  • R 21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R 21 groups are joined to form an optionally substituted heterocyclyl ring;
  • R 22 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • A is a group of the formula
  • Q is -S-, or - -;
  • R wl is independently hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group
  • B is an antibody or an antibody fragment.
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R D1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R E2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R F2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R 7 is - ⁇ ⁇
  • NR 1 "C( 0)OR il ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl (e.g. , alkoxy; aryloxy; heteroaryloxy); substituted thiol (e.g. , alkylthio; arylthio; heteroarylthio); amino; or substituted amino (e.g., alkylamino,
  • dialkylamino or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • NR uz C( 0)OR ul ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • G2 heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R B2 is
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R 1 and R 10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 1 0 U and R 3 J are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 and R 4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 4 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 6 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • L 1 is of the formula:
  • R is substituted or unsubstituted alkylene; or substituted or unsubstituted
  • heteroalk lene ; heterocyclylene; or heteroarylene;
  • R 11 is substituted or unsubstituted alkylene
  • R 21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R 21 groups are joined to form an optionally substituted heterocyclyl ring; R is h drogen; substituted or unsubstituted alkyl; substituted or unsubstituted
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • Q is -S-, or -0-
  • R is a leaving group (e.g., halogen, tosylate, or mesylate);
  • R is hydrogen, substituted or unsubstituted alkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or an oxygen protecting group;
  • R wl is independently hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group.
  • the compound of Formula (I) or Formula (II) is of the formula:
  • the compound of Formula (I) or Formula (II) is of the formula:
  • the compound of Formula (I) or Formula (II) is of the formula:
  • novel trioxacarcin analogs (without linker groups or antibodies conjugated thereto).
  • compositions comprising any of the compounds of Formula (I), Formula (II), or novel trioxacarcin analogs as described herein, or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier.
  • cardiovascular disease e.g., cardiovascular disease
  • proliferative disease e.g., cancer
  • diabetic retinopathy e.g., inflammatory disease
  • autoimmune disease e.g., rhinitis
  • infectious disease e.g., rhinitis
  • kits comprising compounds of Formula (I), Formula (II), or novel trioxacarcin analogs as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such.
  • the kits further comprise instructions for administration (e.g., human administration).
  • compositions comprising any of the compounds of Formula (I), Formula (II), or novel trioxacarcin analogs as described herein, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier for use in treating cardiovascular disease, proliferative disease (e.g., cancer), diabetic retinopathy, inflammatory disease, autoimmune disease, or infectious disease, as well as uses of any of the compounds of Formula (I), Formula (II), or novel trioxacarcin analogs as described herein, or pharmaceutically acceptable salts thereof, for manufacturing a medicament for use in treating any of the target diseases.
  • Compounds described herein may comprise one or more asymmetric centers, and thus may exist as stereoisomers, e.g., enantiomers and/or diastereomer s.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et ah,
  • Compounds may exist as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“Ci_io alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Ci_9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci_ 8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci_7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci_6 alkyl").
  • an alkyl group has 1 to 5 carbon atoms (“Ci_5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci_ 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci_ 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Q alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -6 alkyl”).
  • Ci_6 alkyl groups include methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C 6 ).
  • Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is
  • the alkyl group is an unsubstituted Ci_io alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is a substituted Ci_io alkyl.
  • heteroalkyl refers to an alkyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more
  • heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi_9 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi_ 8 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi_7 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi_6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi_5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi ⁇ alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain
  • heteroCi_3 alkyl a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi_ 2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2 -6 alkyl").
  • each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroCi_io alkyl.
  • the heteroalkyl group is a substituted heteroCi_io alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 2 to 9 carbon atoms ("C 2 -9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms ("C 2 - 8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2 -7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2 -6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C 2 -5 alkenyl”).
  • an alkenyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkenyl"). In some
  • an alkenyl group has 2 to 3 carbon atoms ("C 2 -3 alkenyl"). In some
  • an alkenyl group has 2 carbon atoms ("C 2 alkenyl").
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2 ⁇ alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • C 2 -6 alkenyl groups include the aforementioned C 2 ⁇ alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a
  • substituted alkenyl with one or more substituents.
  • the alkenyl group is an unsubstituted C 2 -io alkenyl.
  • the alkenyl group is a substituted C 2 -io alkenyl.
  • heteroalkenyl refers to an alkenyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -io alkenyl").
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -8 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -7 alkenyl").
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2
  • heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2
  • heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC 2 -3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2 -io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2 -io alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2 -io alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2 -9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2 -8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2 -7 alkynyl").
  • an alkynyl group has 2 to 6 carbon atoms ("C 2 -6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2 -5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2 -3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2 ⁇ alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2 -6 alkenyl groups include the aforementioned C 2 ⁇ alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents.
  • the alkynyl group is an unsubstituted C 2 10 alkynyl.
  • the alkynyl group is a substituted C 2 10 alkynyl.
  • heteroalkynyl refers to an alkynyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -io alkynyl").
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -s alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -7 alkynyl").
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 ⁇ alkynyl").
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC 2 - 3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heterod-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heterod-io alkynyl.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non- aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C 3 _io
  • carbocyclyl and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 carbocyclyl").
  • a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3 _ 7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io
  • C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _ 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 _io carbocyclyl groups include, without limitation, the
  • C 3 _ 8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 _io carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _io carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3 _io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("Cs_6 cycloalkyl").
  • a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs_io cycloalkyl").
  • Cs_ 6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C5).
  • C 3 _6 cycloalkyl groups include the aforementioned Cs_6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Examples of C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _ 6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an
  • the cycloalkyl group is an unsubstituted C 3 _io
  • the cycloalkyl group is a substituted C 3 _io cycloalkyl.
  • heterocyclyl or “heterocyclic” refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
  • decahydronaphthyridinyl decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e] [l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro- 5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH- pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6 -i 4 aryl”).
  • an aryl group has 6 ring carbon atoms ("C 6 aryi”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms ("Cio aryi”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms ("C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.
  • the aryl group is an unsubstituted C 6 - 14 aryl.
  • the aryl group is a substituted C 6 -i 4 aryl.
  • alkyl is a subset of “alkyl” and refers to an alkyl group, as described herein, substituted by an aryl group, as described herein, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • 6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group, as described herein, substituted by a heteroaryl group, as described herein, wherein the point of attachment is on the alkyl moiety.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.
  • saturated refers to a ring moiety that does not contain a double or triple bond, i.e. , the ring contains all single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as described herein, are, in certain embodiments, optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., "substituted” or "unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl,
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • R aa is, independently, selected from Ci_io alkyl, Ci_io perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, heteroCi_io alkyl, heteroC 2 _io alkenyl, heteroC 2 _ioalkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6 -i 4 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl,
  • each instance of R bb is, independently, selected from hydrogen, -OH, -OR aa , -
  • each instance of R cc is, independently, selected from hydrogen, Ci_io alkyl, Ci_io perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, heteroCi-ioalkyl, heteroC 2 _ioalkenyl, heteroC 2 _ l oalkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6 -i 4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R is, independently, selected from
  • each instance of R ee is, independently, selected from Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 6 alkenyl, C 2 _ 6 alkynyl, heteroCi_6alkyl, heteroC 2 _6alkenyl, heteroC 2 _6alkynyl, C 3 _io
  • each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R is, independently, selected from hydrogen, Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroCi_ 6 alkyl, heteroC 2 _ 6 alkenyl, heteroC 2 _ 6 alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, C 6 -io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • halo refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
  • R xl is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl,
  • heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R groups taken together form a 5- to 6-membered heterocyclic ring.
  • acyl groups include aldehydes (-CHO), carboxylic acids (-C0 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alky
  • a "counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g., F , Cl ⁇ , Br , ⁇ ), N0 3 , C10 4 , OH , H 2 P0 4 , HC0 ⁇ HS0 4 , sulfonate ions (e.g., methansulfonate,
  • exemplary counterions which may be multivalent include C0 3 , HP0 4 ,
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the
  • leaving group is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • suitable leaving groups include, but are not limited to, halogen (such as F, CI, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,
  • alkyl-carbonyloxy e.g., acetoxy
  • arylcarbonyloxy aryloxy
  • methoxy N,0-dimethylhydroxylamino, pixyl
  • haloformates e.g., acetoxy
  • the leaving group is a brosylate, such as /?-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy.
  • the leaving group may also be a phosphineoxide (e.g. , formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
  • phosphineoxide e.g. , formed during a Mitsunobu reaction
  • an internal leaving group such as an epoxide or cyclic sulfate.
  • Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • hydroxyl refers to the group -OH.
  • thiol refers to the group -SH.
  • amino refers to the group -NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino, as described herein. In certain embodiments, the "substituted amino” is a monosubstituted amino or a disubstituted amino group.
  • trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(R bb ) 3 and -N(R bb ) 3 + X ⁇ , wherein R bb and X are as described herein.
  • a "counterion” is a negatively charged group associated with a positively charged quarternary amine in order to maintain electronic neutrality.
  • exemplary counterions include halide ions (e.g., F , CI , Br , ⁇ ), N0 3 , C10 4 , OH , H 2 P0 4 , HS0 4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate,
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group").
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-i-butyl-[9-( 10, 10-dioxo-lO, 10, 10, 10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (l-adamantyl)-l-methylethyl
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, /?-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5, 6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanes
  • Ts /?-toluenesulfonamide
  • Mtr
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl- (10)-acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl- 3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl- l,3,5-triazacyclohexan-2-one, 1-
  • benzenesulfenamide o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl,
  • triphenylmethyl triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group").
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), i-butylthiomethyl,
  • DPMS diphenylmethylsilyl
  • TMPS i-butylmethoxyphenylsilyl
  • benzoylformate acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, /?-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9- fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(
  • an oxygen protecting group is silyl.
  • an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate,
  • methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group").
  • a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
  • salts and “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et ah, describes pharmaceutically acceptable salts in detail in . Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,
  • glycerophosphate gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci ⁇ alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • a "peptidyl group” refers to a divalent amino acid moiety.
  • a “polypeptidyl” group refers to a divalent moiety comprising three or more consecutively linked amino acid residues (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 19, 20, or more linked amino acid residues).
  • Peptidyl, dipeptidyl, and polypeptidyl moieties may contain only natural amino acids, although non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and/or amino acid analogs as are known in the art may alternatively be employed.
  • one or more of the amino acids in a peptidyl, dipeptidyl, or polypeptidyl moiety may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation,
  • cysteine (-CH 2 SH) side chain may be modified to a formyl (-CHO) side chain.
  • Exemplary amino acids contemplated useful in providing the peptidyl, dipeptidyl, and polypeptidyl moieties of interest include, without limitation, natural alpha-amino acids such as D- and L-isomers of the 20 common naturally occurring alpha-amino acids found in peptides (e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V), natural beta-amino acids (e.g., beta-alanine), and unnnatural amino acids.
  • natural alpha-amino acids such as D- and L-isomers of the 20 common naturally occurring alpha-amino acids found in peptides (e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V)
  • natural beta-amino acids e.g., beta-alanine
  • amino acids contemplated useful in providing the peptidyl, dipeptidyl, and polypeptidyl moieties of interest include without limitation, ornithine, citrulline (Cit), -methyl- Alanine (Aib), 4-hydroxyproline, desmosine, gamma-aminobutyric acid, beta-cyanoalanine, norvaline, 4-(E)-butenyl-4(R)-methyl-N-methyl-L-threonine, N-methyl-L-leucine, 1- amino-cyclopropanecarboxylic acid, l-amino-2-phenyl-cyclopropanecarboxylic acid, 1- amino-cyclobutanecarboxylic acid, 4-amino-cyclopentenecarboxylic acid, 3-amino- cyclohexanecarboxy
  • a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other non-human animals, for example mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as rodents (e.g., mice, rats), guinea pigs, cattle, pigs, horses, sheep, goats, cats, and/or dogs.
  • the non-human animal may be male or female and at any stage of development.
  • a non-human animal may be a transgenic animal.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or retards or slows the progression of the disease, disorder, or condition
  • therapeutic treatment or “therapeutically treating”
  • therapeutically treating an action that occurs before a subject begins to suffer from the specified disease, disorder, or condition, and which inhibits or reduces the severity of the disease, disorder, or condition.
  • the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.
  • the effective amount of a compound with anti-proliferative activity is the amount that results in a sufficient concentration to inhibit the proliferation of cells.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder, or condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the disease, disorder, or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactic ally effective amount of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder, or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
  • Figure 1 is a graph showing the stability of exemplary trioxacarcin-linker species R02-B5, R02-B4, R02-B8, R02-A3, and R02-A8 at 37 °C in pH 5.0 buffer.
  • Figure 2 is a graph showing the stability of exemplary trioxacarcin-linker species R02-B5, R02-B4, R02-B8, R02-A3, and R02-A8 under physiological conditions at 37 °C in pH 7.4 buffer.
  • Figure 3 is a graph showing the stability of exemplary free drug trioxacarcin species R02-B1, R02-A9, R02-B7, R02-A1, and R02-A7 under physiological conditions at 37 °C in pH 7.4 buffer.
  • Figure 4 is a graph showing the release kinetics of exemplary trioxacarcin-linker species R02-A3 upon exposure to Cathepsin B (ti /2 of R02-A3: 0.45 hours).
  • Figure 5 is a graph showing the release kinetics of exemplary trioxacarcin-linker species R02-A8 upon exposure to Cathepsin B (ti /2 of R02-A8: 0.21 hours).
  • Figure 6 is a graph showing the release kinetics of exemplary trioxacarcin-linker species R02-B4 upon exposure to Cathepsin B (ti /2 of R02-B4: 0.44 hours).
  • Figure 7 is a graph showing the release kinetics of exemplary trioxacarcin-linker species R02-B5 upon exposure to Cathepsin B (ti /2 of R02-B5: 0.25 hours).
  • Trioxacarcins are highly toxic to a variety of cell types. Linking a trioxacarcin to an antibody preserves the trioxacarcin' s potency against the cell type while increasing specificity to the target cell, and optionally increasing endocytosis of the trioxacarcin. These effects enable lowering the overall amount of trioxacarcin to be delivered, thereby reducing the associated toxicity. By taking advantage of established synthetic methods, complex and therapeutically relevant trioxacarcins are accessible. In turn, conjugating these trioxacarcins to antibodies through linking groups provide trioxacarcin-antibody drug conjugates.
  • trioxacarcin-antibody drug conjugates e.g., compounds of Formula (I)
  • trioxacarcin-antibody drug conjugate precursors comprising a trioxacarcin and a linking group
  • novel trioxacarcin analogs e.g., free drug species.
  • the compounds may be provided for use in any composition, kit, or method described herein as a pharmaceutically acceptable salt.
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino, or two R A2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R E2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R F2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R 7 is -L-B;
  • NR 1 "C( 0)OR il ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl (e.g. , alkoxy; aryloxy; heteroaryloxy); substituted thiol (e.g. , alkylthio; arylthio; heteroarylthio); amino; or substituted amino (e.g., alkylamino,
  • dialkylamino or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • NR uz C( 0)OR ul ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • G2 heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R 1 and R 10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 1 0 U and R 3 J are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 and R 4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 4 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 6 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R is substituted or unsubstituted alkylene; or substituted or unsubstituted
  • heteroalk lene ; heterocyclylene; or heteroarylene;
  • R 11 is substituted or unsubstituted alkylene
  • R 21 is independently substituted or unsubstituted alkyl; substituted or unsubstituted carbocyclyl; or two R 21 groups are joined to form an optionally substituted heterocyclyl ring;
  • R 22 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted
  • N R 1 carbocyclyl; or V ⁇ ⁇ N(R W112 ;
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted
  • A is a group of the formula
  • Q is - -, or -0-
  • R wl is independently hydrogen; substituted or unsubstituted alkyl; or a nitrogen protecting group
  • B is an antibody or an antibody fragment.
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino, or two R A2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R D1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R D2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R E2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R 7 is -L-B;
  • NR 1 "C( 0)OR il ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl (e.g. , alkoxy; aryloxy; heteroaryloxy); substituted thiol (e.g. , alkylthio; arylthio; heteroarylthio); amino; or substituted amino (e.g., alkylamino,
  • dialkylamino or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • NR uz C( 0)OR ul ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • G2 heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R 1 and R 10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 1 0 U and R 3 J are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 and R 4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 4 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 6 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R is substituted or unsubstituted alkylene; or substituted or unsubstituted
  • R is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R 21 groups are joined to form an optionally substituted heterocyclyl ring;
  • R 22 is hydrogen; substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl;
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted
  • A is a grou of the formula
  • Q is -S-, or -0-
  • R wl is hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group
  • B is an antibody or an antibody fragment.
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R D1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R E2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R F2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R 7 is -L-B;
  • NR 1 "C( 0)OR il ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl (e.g. , alkoxy; aryloxy; heteroaryloxy); substituted thiol (e.g. , alkylthio; arylthio; heteroarylthio); amino; or substituted amino (e.g., alkylamino,
  • dialkylamino or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • NR uz C( 0)OR ul ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • G2 heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R 1 and R 10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 1 0 U and R 3 J are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 and R 4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 4 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 6 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R is substituted or unsubstituted alkylene; or substituted or unsubstituted
  • R is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; R is hydrogen; substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl;
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • A is a grou of the formula
  • Q is -S-, or -0-
  • R wl is hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group; and B is an antibody or an antibody fragment.
  • the compound of Formula (I) is of Formula (I-a):
  • the compound of Formula (I) is of Formula (I-b):
  • the com ound of Formula (I) is of Formula (I-c):
  • the compound of Formula (I) is of Formula (I-d):
  • the antibody or antibody fragment B is a large molecule with many sites of attachment, and thus may have many instances of a compound of Formula (I) attached thereto.
  • the antibody or antibody fragment comprises 1 to 200 independent instances of a compound of Formula (I) attached thereto, inclusive, e.g. , 1 to 150, 1 to 100, 1 to 75, 1 to 50, 1 to 25, 1 to 15, 1 to 10, inclusive, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 independent instances.
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R E2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R Fl is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • F2 heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R 7 is - ⁇ ⁇
  • NR 1 "C( 0)OR il ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl (e.g. , alkoxy; aryloxy; heteroaryloxy); substituted thiol (e.g. , alkylthio; arylthio; heteroarylthio); amino; or substituted amino (e.g., alkylamino,
  • dialkylamino or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; and wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R G2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R 1 and R 10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 1 0 U and R 3 J are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 and R 4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 4 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 6 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • L 1 is of the formula:
  • R is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • R 11 is substituted or unsubstituted alkylene
  • R 21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R 21 groups are joined to form an optionally substituted heterocyclyl ring;
  • R 22 is h drogen; substituted or unsubstituted alkyl; substituted or unsubstituted
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • R is halogen, tosylate, mesylate, or triflate
  • R X2 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or an oxygen protecting group; and
  • R wl is independently hydrogen; substituted or unsubstituted alkyl; or a nitrogen protecting group.
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R D1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R E2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • F2 heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R 7 is - ⁇ ⁇
  • NR 1 "C( 0)OR il ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl (e.g. , alkoxy; aryloxy; heteroaryloxy); substituted thiol (e.g. , alkylthio; arylthio; heteroarylthio); amino; or substituted amino (e.g., alkylamino,
  • dialkylamino or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R G2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R B2 is
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R 1 and R 10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 1 0 U and R 3 J are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 and R 4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 4 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety; or R 6 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety;
  • R is substituted or unsubstituted alkylene; or substituted or unsubstituted
  • R is independently substituted or unsubstituted alkyl; or substituted or unsubstituted
  • R is hydrogen; substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl;
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted
  • R is halogen, tosylate, mesylate, or triflate
  • R is hydrogen, substituted or unsubstituted alkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or an oxygen protecting group;
  • R wl is hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group.
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R D1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R E2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R Fl is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • F2 heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R 7 is - ⁇ ⁇
  • NR 1 "C( 0)OR il ; or -C(R ⁇ ) 3 ; wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl (e.g. , alkoxy; aryloxy; heteroaryloxy); substituted thiol (e.g. , alkylthio; arylthio; heteroarylthio); amino; or substituted amino (e.g., alkylamino,
  • dialkylamino or two R groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; and wherein each occurrence of R G2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R G2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
  • R B2 is
  • cyclic or acyclic independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R 1 and R 10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 1 0 U and R 3 J are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 1 and R 4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 4 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • R 6 and R 9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety
  • L 1 is of the formula: j— R 20 -X-CH 2 -Ar-NH-Z m -Y m -E-C(O)-R 40 — j .
  • R 20 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • R is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl;
  • R 22 is hydrogen; substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl;
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • R is halogen, tosylate, mesylate, or triflate
  • R X2 is hydrogen, substituted or unsubstituted alkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or an oxygen protecting group; and
  • R wl is hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group.
  • the compound of Formula (II) is of Formula (Il-a):
  • the compound of Formula (II) is of Formula (Il-b):
  • the com ound of Formula (II) is of Formula (II-c):
  • the compound of Formula (II) is of Formula (Il-d):
  • Compounds of Formula (I) are prepared by coupling a compound of Formula (II) with an antibody or antibody fragment.
  • an antibody may couple with 1 to 200 compounds of Formula (II) and form corresponding compounds of Formula (I).
  • R 1 is hydrogen; and R 2 is hydrogen. 1 2
  • R is halogen (e.g., -F, -CI, Br, or -I); and R is hydrogen.
  • R 1 is substituted or unsubstituted alkyl, e.g. , substituted or unsubstituted Ci 6 alkyl, substituted or unsubstituted Ci_ 2 alkyl, substituted or unsubstituted C 2 - 3 alkyl, substituted or unsubstituted C 3 ⁇ alkyl, substituted or unsubstituted C ⁇ salkyl, or
  • R Ci_ 6 alkyl groups include, but are not limited to, substituted or unsubstituted methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), n-hexyl (C 6 ).
  • R 1 is substituted or unsubstituted alkenyl, e.g. , substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2 - 3 alkenyl, substituted or unsubstituted C 3 ⁇ alkenyl, substituted or unsubstituted C 4 _salkenyl, or substituted or unsubstituted C5_ 6 alkenyl, and R is hydrogen.
  • R 1 is substituted or unsubstituted alkynyl, e.g. , substituted or unsubstituted C 2 - 6 alkynyl, substituted or unsubstituted C 2 - 3 alkynyl, substituted or unsubstituted C 3 ⁇ alkynyl, substituted or unsubstituted C 4 _salkynyl, or substituted or unsubstituted C5_ 6 alkynyl, and R is hydrogen.
  • R 1 is substituted or unsubstituted carbocyclyl, e.g. , substituted or unsubstituted C 3 _ 6 carbocyclyl, substituted or unsubstituted C 3 ⁇ carbocyclyl, substituted or unsubstituted C 4 _ 5 carbocyclyl, or substituted or unsubstituted Cs_ 6 carbocyclyl, and R is hydrogen.
  • R 1 is substituted or unsubstituted heterocyclyl, e.g. , substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 3-4 membered heterocyclyl, substituted or unsubstituted 4-5 membered heterocyclyl, or substituted or unsubstituted 5-6 membered heterocyclyl, and R is hydrogen.
  • R 1 is substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl, and R is hydrogen.
  • R 1 is substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted 5-6 membered heteroaryl, and R is hydrogen.
  • R A1 or R A2 represent a group of Formula (i):
  • M 1 is -0-, -NR A8 -, or -CHR A - wherein R A8 is hydrogen; substituted or
  • R is independently hydrogen; substituted or unsubstituted alkyl; acyl; or an oxygen protecting group.
  • R A1 or R A2 is hydrogen.
  • R ⁇ is hydrogen.
  • R ⁇ is substituted or unsubstituted alkyl, e.g., methyl.
  • R ⁇ is -OR A9 , e.g., -OH or -O-alkyl.
  • R A4 is hydrogen.
  • R A4 is substituted or unsubstituted alkyl, e.g., methyl.
  • R A4 is -OR A9 , e.g., -OH or -O-alkyl.
  • R ⁇ is hydrogen.
  • R ⁇ is substituted or unsubstituted alkyl, e.g., methyl.
  • R ⁇ is -OR A9 , e.g., -OH or -O-alkyl.
  • R A6 is hydrogen.
  • R A6 is substituted or unsubstituted alkyl, e.g., methyl.
  • R A6 is -OR A9 , e.g., -OH or -O-alkyl.
  • R A7 is hydrogen.
  • R A7 is substituted or unsubstituted alkyl, e.g., methyl.
  • R A7 is -OR A9 , e.g., -OH or -O-alkyl.
  • M 1 is -0-, -NR A8 -, or -CHR A8 - wherein R A8 is hydrogen; substituted or unsubstituted alkyl; a nitrogen protecting group if attached to nitrogen; or -OR A9 ; wherein R A9 is independently hydrogen; substituted or unsubstituted alkyl; acyl; or an oxygen protecting group.
  • R A3 is a non-hydrogen equatorial group.
  • R C 1 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • R C2 is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino; or substituted amino; or two R C2 groups are optionally joined to form a heterocyclyl or heteroaryl ring.
  • R 3 is hydrogen or -OR CI , wherein R CI is hydrogen; an oxygen protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl;
  • R is hydrogen.
  • R 3 is -OR cl , e.g., -OH or -OCH 3 .
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; substituted hydroxyl; substituted thiol; amino;
  • R 4 is hydrogen or -OR D1 , wherein R D1 is hydrogen; an oxygen protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl;
  • R 4 is hydrogen. In certain embodiments, R 4 is -OR D1 , e.g., -OH or -OCH 3 .
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted
  • R is hydrogen or -OR , wherein R is hydrogen; an oxygen protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl;
  • R 5 is hydrogen. In certain embodiments, R 5 is -OR E1 , e.g. , -OH or -OCH 3 .
  • R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; acyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; and wherein each occurrence of R is independently hydrogen; carbohydrate; a protecting group; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or
  • R 6 is hydrogen; halogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or
  • R 6 is hydrogen
  • R 6 is halogen; e.g., -F, -CI, Br, or -I.
  • R 6 is substituted or unsubstituted alkyl, e.g. , substituted or unsubstituted Q 6 alkyl, substituted or unsubstituted Q 2 alkyl, substituted or unsubstituted
  • R 6 Ci_ 6 alkyl groups include, but are not limited to, substituted or unsubstituted methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), n-hexyl (C 6 ).
  • R 6 is substituted or unsubstituted alkenyl, e.g. , substituted or unsubstituted C 2 _ 6 alkenyl, substituted or unsubstituted C 2 _ 3 alkenyl, substituted or unsubstituted C 3 ⁇ alkenyl, substituted or unsubstituted C 4 _salkenyl, or substituted or unsubstituted Cs ⁇ alkenyl.
  • R 6 is substituted or unsubstituted alkynyl, e.g. , substituted or unsubstituted C 2 _ 6 alkynyl, substituted or unsubstituted C 2 _ 3 alkynyl, substituted or unsubstituted C 3 ⁇ alkynyl, substituted or unsubstituted C 4 _salkynyl, or substituted or unsubstituted Cs ⁇ alkynyl.
  • R 6 is substituted or unsubstituted carbocyclyl, e.g. , substituted or unsubstituted C 3 _ 6 carbocyclyl, substituted or unsubstituted C 3 ⁇ carbocyclyl, substituted or unsubstituted C 4 _ 5 carbocyclyl, or substituted or unsubstituted Cs_ 6 carbocyclyl.
  • R 6 is substituted or unsubstituted cyclopropyl.
  • R 6 is substituted or unsubstituted heterocyclyl, e.g. , substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 3-4 membered heterocyclyl, substituted or unsubstituted 4-5 membered heterocyclyl, or substituted or unsubstituted 5-6 membered heterocyclyl.
  • R 6 is substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl.
  • R 6 is substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted5-6 membered heteroaryl.
  • each occurrence of R is independently hydrogen; an oxygen protecting group if attached to oxygen; a sulfur protecting group if attached to sulfur; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or acyl; and each occurrence of R F2 is independently hydrogen; a nitrogen protecting group if attached to nitrogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted
  • R Fl or R F2 is hydrogen
  • R 3 is hydrogen or -OH
  • R 4 is -OCH 3
  • R 5 is -OH
  • R 3 is hydrogen or -OH
  • R 4 is -OCH 3
  • R 5 is -OH
  • R 6 substituted or unsubstituted alkyl or -OR Fl .
  • R is -L-B; wherein L is a group of the formula:
  • R 20 is substituted or unsubstituted alkylene; or substituted or unsubstituted
  • R 11 is substituted or unsubstituted alkylene
  • R 21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R 21 groups are joined to form an optionally substituted heterocyclyl ring;
  • R 22 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted
  • Ar is substituted or unsubstituted arylene; each occurrence of Z is independently an amino acid;
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • A is a group of the formula
  • Q is -S-, or -0-
  • R wl is independently hydrogen; substituted or unsubstituted alkyl; or a nitrogen protecting group
  • B is an antibody or an antibody fragment.
  • R is -L-B; wherein L is a group of the formula:
  • R 20 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • X is ⁇ / or O ;
  • R is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R 21 groups are joined to form an optionally substituted heterocyclyl ring;
  • R 22 is hydrogen; substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl;
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • Q is -S- or -0-
  • R wl is hydrogen; substituted or unsubstituted alkyl; or a nitrogen protecting group
  • B is an antibody or an antibody fragment.
  • R is -L-B; wherein L is a group of the formula
  • R is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalk lene;
  • R is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl;
  • R 22 is hydrogen; substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl;
  • Ar is substituted or unsubstituted arylene
  • each occurrence of Z is independently an amino acid
  • each occurrence of Y is independently an amino acid
  • E is a bond or an amino acid
  • n is independently 1, 2, or 3;
  • R 40 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • A is a group of the formula:
  • Q is -S-, or -0-
  • R wl is hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group
  • B is an antibody or an antibody fragment.
  • R is -L-B; wherein L is a group of the formula:
  • R is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;
  • R 11 is substituted or unsubstituted alkylene
  • R 21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R 21 groups are joined to form an optionally substituted heterocyclyl ring;
  • R 22 is hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted
  • B is an antibody or an antibody fragment.
  • R is -L-B; wherein L is a group of the formula:
  • R 20 is substituted or unsubstituted alkylene
  • R 11 is substituted or unsubstituted alkylene
  • R 22 is hydrogen; or substituted or unsubstituted alkyl
  • B is an antibody or an antibody fragment.
  • R 20 is substituted or unsubstituted alkylene. In certain embodiments, R 20 is unsubstituted alkylene. In certain embodiments, R 20 is unsubstituted Ci_ 6 alkylene. In certain embodiments, R 20 is unsubstituted C 1-5 alkylene. In certain embodiments,
  • R 20 is unsubstituted C 1-4 alkylene. In certain embodiments, R 20 is unsubstituted C 2 _ 6 alkylene.
  • R 20 is unsubstituted C 20
  • R is unsubstituted C 2 _ 4 alkylene.
  • R 20 is unsubstituted C 2 _ 3 alkylene.
  • R 20 is unsubstituted ethylene.
  • R 20 is unsubstituted propylene.
  • R 20 is unsubstituted butylene.
  • R 20 is unsubstituted pentylene.
  • R 20 is unsubstituted hexylene.
  • X is ; and R is independently substituted or unsubstituted alkyl; or substituted or unsubstituted carbocyclyl; or two R 21 groups are oined
  • X is and R 21 is independently substituted or unsubstituted alkyl; or substituted or unsubstituted
  • X is independently substituted or
  • X is and R is independently
  • X is ; and R is independently R 21 R 2
  • X is ⁇ ® f ; and R 21 is independently
  • R 21 R 2 unsubstituted C 1-3 alkyl.
  • X is ⁇ ® f ; and R 21 is independently
  • Ci_ 2 alkyl unsubstituted Ci_ 2 alkyl.
  • X ; and two R 21 groups are joined to form an optionally substituted heterocyclyl ring.
  • X is ; and two R 21 groups are optionally joined to form an optionally substituted 5-6
  • R 2 R 21 membered heterocyclyl ring.
  • X is V ⁇ ® ' ; and two R 21 groups are joined to form an optionally substituted 6 membered heterocyclyl ring.
  • X is V * ® ' ; and two R 21 groups are joined to form an unsubstituted 6
  • R 21 membered heterocyclyl ring.
  • X is v ⁇ ® N y ' ; and two R 21 groups are joined to form an optionally substituted pyrrolidine, piperidine, piperazine, thiomorpholine
  • X is v ⁇ ® N y ' ; and two R 21 groups are
  • R 2 R 21 joined to form an optionally substituted morpholine.
  • X is Y ⁇ ft ⁇ y ' and two R 21 groups are joined to form an unsubstituted morpholine.
  • X is ; and R 22 is hydrogen; substituted or
  • X is y O y ; and R 22 is hydrogen; substituted or unsubstituted
  • R is hydrogen; or substituted or unsubstituted alkyl.
  • X is R 22
  • R 22 is hydrogen; or substituted or unsubstituted Ci_6 alkyl.
  • X is O ; and R 22 is hydrogen; or substituted or unsubstituted Ci_ 2
  • X is v A Y
  • alkyl O°y alkyl O°y ; and R 22 is hydrogen; or substituted or
  • R 22 unsubstituted Q_ 2 alkyl.
  • X is y O ; and R 22 is hydrogen; or
  • R 22 substituted Ci_ 2 alkyl.
  • X is vV O v ; and R 22 is hydrogen; or
  • R 22 unsubstituted Q_ 2 alkyl.
  • X is y O ; and R 22 is hydrogen.
  • R 22 certain embodiments, X is y O ; and R 22 is substituted or unsubstituted Q_ 2 alkyl.
  • X is y O ; and R 22 is substituted Ci_ 2 alkyl (e.g., haloalkyl).
  • X is O ; and R 22 is unsubstituted Ci_ 2 alkyl.
  • X is yl (e.g., C3 cycloalkyl).
  • X is ; and R is .
  • X is .
  • X is heterocyclylene or heteroarylene. In certain embodiments, X is heterocyclylene. In certain embodiments, X is a 6-membered
  • X is a piperazinylene. In certain embodiments, X is heteroarylene. In certain embodiments, X is a 5-membered heteroarylene. In certain embodiments, X is an imidazolylene.
  • Ar is substituted or unsubstituted arylene. In certain embodiments, Ar is substituted or unsubstituted phenylene. In certain embodiments, Ar is unsubstituted phenylene.
  • each occurrence of Z is independently an amino acid.
  • Z is independently a naturally occurring amino acid.
  • Z is independently lysine, arginine, histidine, ornithine, or citrulline.
  • Z is lysine or citrulline.
  • Z is citrulline.
  • each occurrence of Y is independently an amino acid. In certain embodiments, Y is independently a naturally occurring amino acid. In certain embodiments, Y is alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan. In certain embodiments, Y is valine or phenylalanine. In certain embodiments, Y is valine.
  • each occurrence of m is 1, 2, or 3. In certain embodiments, each occurrence of m is 1 or 2. In certain embodiments, each occurrence of m is 1.
  • -Z m -Y m - is -citrulline- valine-.
  • E is a bond or an amino acid. In certain embodiments, E is a bond or a naturally occurring amino acid. In certain embodiments, E is a bond or a substituted naturally occurring amino acid. In certain embodiments, E is a bond. In certain embodiments, E is a naturally occurring amino acid. In certain embodiments, E is a substituted naturally occurring amino acid. In certain embodiments, E is a substituted lysine. [00162] In certain embodiments, E is of the formula:
  • R 70 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • E is of the formula:
  • n 2-30.
  • E is of the formula:
  • R is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene.
  • R 40 is substituted or unsubstituted Ci_6 alkylene; or substituted or unsubstituted Ci_ 4 o heteroalkylene.
  • R 40 is substituted or unsubstituted alkylene.
  • R 40 is substituted or unsubstituted C 1-6 alkylene.
  • R 40 is substituted C 1-6 alkylene.
  • R 40 is unsubstituted C 1-6 alkylene.
  • R 40 is substituted or unsubstituted heteroalkylene.
  • R 40 is substituted or unsubstituted Ci_ 4 o heteroalkylene. In certain embodiments, R 40 is substituted Ci_ 4 o heteroalkylene. In certain embodiments, R 40 is unsubstituted C 1-4 o heteroalkylene. In certain embodiments, R 40 is , Ci_6 unsubstituted alkylene, or ; wherein p is
  • R 40 is . In certain embodiments, R 40 is Ci_ 6 unsubstituted alkylene. In certain embodiments, R is P ; wherein p is 1-8. In certain R 40 is P ; wherein p is 2-8. In certain embodiments, R 40 is ; wherein p is 2, 4, or 8. In certain embodiments, R 40 is 2 . In certain embodiments, R 40 is 4 . In certain embodiments, R 40 is
  • A is a group of the formula:
  • Q is -S-, or -0-; and R wl is hydrogen, substituted or unsubstituted alkyl; or a nitrogen protecting group.
  • A is a group of the formula:
  • A is a group of the formula:
  • L is a group of Formula (L-1):
  • R is substituted or unsubstituted C 1-6 alkylene
  • R 22 is hydrogen, or substituted or unsubstituted Ci_ 6 alkyl
  • R 40 is substituted or unsubstituted Ci_ 6 alkylene, or substituted or unsubstituted Ci ⁇ o heteroalkylene
  • R 50 is the sidechain of lysine, arginine, histidine, ornithine, or citruUine
  • R 60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan.
  • L is a group of Formula (L-2):
  • R 20 is substituted or unsubstituted Ci_ 6 alkylene
  • R 22 is hydrogen, or substituted or unsubstituted Ci_ 6 alkyl
  • R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted Ci ⁇ o heteroalkylene
  • R 50 is the sidechain of lysine, arginine, histidine, ornithine, or citruUine
  • R 60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan.
  • L is a group of Formula (L-3):
  • R 20 is substituted or unsubstituted Ci_ 6 alkylene
  • R 22 is hydrogen, or substituted or unsubstituted Ci_ 6 alkyl
  • R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted Ci ⁇ o heteroalkylene.
  • L is a group of Formula (L-4):
  • R is substituted or unsubstituted C 1-6 alkylene; and R 22 is hydrogen or substituted or unsubstituted Ci_ 6 alkyl.
  • R is unsubstituted C 2 -5 alkylene; and R is hydrogen or methyl.
  • L is a group of Formula (L-5):
  • R 20 is substituted or unsubstituted C 1-6 alkylene;
  • R 22 is hydrogen, or substituted or unsubstituted Ci_ 6 alkyl; and
  • p is 1- 10.
  • R ⁇ is unsubstituted C 2 -5 alkylene; R is hydrogen or methyl; and p is 2-8.
  • L is a group of Formula (L-6):
  • R u is substituted or unsubstituted Ci- alkylene; and R 22 is hydrogen or substituted or unsubstituted Ci_ 6 alkyl.
  • R 20 is unsubstituted C 2 -5 alkylene; and R 22 is hydrogen or methyl.
  • L is a group of Formula (L-7):
  • R u is substituted or unsubstituted Ci_ 6 alkylene; and R 22 is hydrogen or substituted or unsubstituted C 1-6 alkyl.
  • R 20 is unsubstituted C 2 -5 alkylene; and R 22 is hydrogen or methyl.
  • L is a group of Formula (L-8):
  • R is substituted or unsubstituted C 1-6 alkylene;
  • R 22 is hydrogen or substituted or unsubstituted C 1-6 alkyl;
  • R 40 is substituted or
  • R 20 is unsubstituted C 2 -5 alkylene; R 22 is hydrogen or methyl; R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted C 1-4 o heteroalkylene; and R 70 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 20 is unsubstituted C 2 -5 alkylene; R 22 is hydrogen or methyl; R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted C 1-4 o heteroalkylene; and R 70 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 20 is unsubstituted C 2 -5 alkylene
  • R 22 is hydrogen or methyl; R 40 is substituted or unsubstituted Ci_ 6 alkylene, or substituted or unsubstituted C 1-4 o heteroalkylene; and R 70 is unsubstituted C 1-4 o heteroalkylene.
  • R 20 is unsubstituted C 2 22
  • R is hydrogen or methyl; R is substituted or unsub alkylene, or substituted or unsubstituted Ci_ 4 o heteroalkylene; and R is ; wherein p is 1-30.
  • R is unsubstituted C 2 -5 alkylene;
  • R is hydrogen or methyl;
  • R is substituted or unsubstituted Ci_ 6 alkylene, or substituted or unsubstituted Ci_ 4 o heteroalkylene;
  • L is a group of Formula (L-9):
  • n 2-30.
  • R 20 is substituted or unsubstituted Ci_ 6 alkylene; R 22 is hydrogen or substituted or unsubstituted 40
  • R is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted Ci ⁇ o heteroalkylene; and n is 1-9.
  • R 20 is unsubstituted 22
  • R 20 is hydrogen or methyl;
  • R 40 is substituted or unsubstituted Ci_ 6 alkylene, or substituted or unsubstituted Ci_ heteroalkylene; and
  • n is 1-9.
  • R 20 is hydrogen or methyl;
  • R 20 is unsubstituted 22
  • R is hydrogen or methyl
  • R 40 is unsubstituted Ci_ 4 o heteroalkylene
  • n is 1-9.
  • L is a group of Formula (L-10):
  • R is substituted or unsubstituted C 1-6 alkylene;
  • R 21 is independently substituted or unsubstituted Ci_ 6 alkyl;
  • R 40 is substituted or unsubstituted Ci_ 6 alkylene, or substituted or unsubstituted Ci ⁇ o heteroalkylene;
  • R 50 is the sidechain of lysine, arginine, histidine, ornithine, or citrulline; and
  • R 60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan.
  • L is a group of Formula (L-11):
  • R is substituted or unsubstituted Ci_ 6 alkylene
  • R 21 is independently substituted or unsubstituted C 1-6 alkyl
  • R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted Ci ⁇ o heteroalkylene
  • R 50 is the sidechain of lysine, arginine, histidine, ornithine, or citrulline
  • R 60 is the sidechain of alanine, valine, leucine, isoleucine, methionine, phenylalanine, or tryptophan.
  • L is a group of Formula (L-12):
  • R 20 is substituted or unsubstituted C 1-6 alkylene;
  • R 21 is independently substituted or unsubstituted Ci_ 6 alkyl; and
  • R 40 is substituted or unsubstituted Ci_ 6 alkylene, or substituted or unsubstituted Ci ⁇ o heteroalkylene.
  • L is a group of Formula (L-13):
  • R 20 is substituted or unsubstituted Ci_ 6 alkylene; and R 21 is independently substituted or unsubstituted C 1-6 alkyl.
  • R 20 is unsubstituted C 2 -5 alkylene; and R 21 is methyl.
  • L is a group of Formula (L-14):
  • R is substituted or unsubstituted Ci_ 6 alkylene; R 21 is independently substituted or unsubstituted Ci_ 6 alkyl; and p is 1-10.
  • R 20 is unsubstituted C 2 _5 alkylene; R 21 is methyl; and p is 2-
  • L is a group of Formula (L-15):
  • R is substituted or unsubstituted Ci_ 6 alkylene; and R 21 is independently substituted or unsubstituted Ci_ 6 alkyl.
  • R 20 is unsubstituted C 2 _5 alkylene; and R 21 is methyl.
  • L is a group of Formula (L-16):
  • R is substituted or unsubstituted Ci_ 6 alkylene; and R 21 is independently substituted or unsubstituted Ci_ 6 alkyl.
  • R is unsubstituted C 2 _5 alkylene; and R 1 is methyl.
  • L is a group of Formula (L-17):
  • R is substituted or unsubstituted Ci_ 6 alkylene; R 21 is independently substituted or unsubstituted Ci_ 6 alkyl; R 40 is substituted or
  • R 20 is unsubstituted C 2 -5 alkylene; R 21 is methyl; R 40 is substituted or unsubstituted Ci_ 6 alkylene, or substituted or unsubstituted Ci_ 4 o heteroalkylene; and R 70 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 20 is unsubstituted C 2 -5 alkylene; R 21 is methyl; R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted C 1-4 o
  • R 20 is unsubstituted C 2 -5 alkylene; R 21 is methyl; R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted C 1-4 o heteroalkylene; and R 70 is unsubstituted alkylene.
  • R 20 is unsubstituted C 2 -5 alkylene; R 21 is methyl; R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted C 1-4 o heteroalkylene; and R 70 is unsubstituted alkylene.
  • R 20 is unsubstituted C 2 -5 alkylene; R 21 is methyl; R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted C 1-4 o heteroalkylene; and R 70 is unsubstituted alkylene.
  • R 21 is methyl
  • R 40 is substituted d Ci_ 6 alkylene
  • Ci_ 4 o heteroalkylene or substituted or unsubstituted Ci_ 4 o heteroalkylene; and R is P ; wherein p is
  • R is unsubstituted C 2 -5 alkylene; R is bstituted or unsubstituted Ci_ 4 o
  • L is a group of Formula (L-18):
  • n 2-30.
  • R is substituted or unsubstituted Ci_ 6 alkylene
  • R 21 is independently substituted or unsubstituted Ci_ 6 alkyl
  • R 40 is substituted or unsubstituted Ci_ 6 alkylene, or substituted or unsubstituted Ci ⁇ o heteroalkylene
  • n is 1-9.
  • R 20 is unsubstituted ;
  • C 2 -5 alkylene is independently unsubstituted C 1-6 alkyl; R 40 is substituted or unsubstituted C 1-6 alkylene, or substituted or unsubstituted Ci_ 4 o heteroalkylene; and n is 1-9.
  • R 20 is unsubstituted C 2 -5 alkylene; R 21 is methyl; R 40 is substituted or unsubstituted C 1-6 alkylene; and n is 1-9.
  • R 20 is unsubstituted C 2 -5 alkylene; R 21 is methyl; R 40 is unsubstituted C 1-4 o heteroalkylene; and n is 1-9.
  • R 7 is -L 1 -T; wherein is a group of the formula:
  • R 20 is substituted or unsubstituted alkylene; or substituted or unsubstituted heteroalkylene;

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Abstract

L'invention concerne des conjugués de médicament trioxacarcine-anticorps de formule (I) : et des sels pharmaceutiquement acceptables de ceux-ci, dans laquelle R7 représente -L-B, dans lequel L représente un groupe de liaison, et B représente un anticorps ou un fragment d'anticorps. L'invention concerne également des procédés de préparation des conjugués anticorps-médicament, des compositions pharmaceutiquement acceptables associées, et des méthodes de traitement et d'utilisation de ceux-ci. L'invention concerne en outre des précurseurs des conjugués de médicament trioxacarcine-anticorps (par exemple des composés de formule (II), de nouvelles trioxacarcines sans anticorps conjugué à celles-ci), des compositions pharmaceutiques associées, et des méthodes de traitement et d'utilisation de ceux-ci.<i />
PCT/US2018/046210 2017-08-11 2018-08-10 Conjugués trioxacarcine-anticorps et utilisations associées WO2019032961A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021252708A1 (fr) 2020-06-11 2021-12-16 President And Fellows Of Harvard College Conjugués médicament trioxacarcine-anticorps stabilisés et utilisations de ceux-ci
WO2023096904A2 (fr) 2021-11-24 2023-06-01 President And Fellows Of Harvard College Trioxacarcines modifiées en c-16, conjugués anticorps-médicament, et leurs utilisations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120177568A1 (en) * 2010-10-08 2012-07-12 Williams John C Novel meditopes and related meditope-monoclonal antibody delivery systems, synthesis and therapeutic uses thereof
US20140227180A1 (en) * 2012-12-13 2014-08-14 Immunomedics, Inc. Antibody-sn-38 immunoconjugates with a cl2a linker
US20150297747A1 (en) * 2012-11-26 2015-10-22 President And Fellows Of Harvard College Trioxacarcins, trioxacarcin-antibody conjugates, and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120177568A1 (en) * 2010-10-08 2012-07-12 Williams John C Novel meditopes and related meditope-monoclonal antibody delivery systems, synthesis and therapeutic uses thereof
US20150297747A1 (en) * 2012-11-26 2015-10-22 President And Fellows Of Harvard College Trioxacarcins, trioxacarcin-antibody conjugates, and uses thereof
US20140227180A1 (en) * 2012-12-13 2014-08-14 Immunomedics, Inc. Antibody-sn-38 immunoconjugates with a cl2a linker

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021252708A1 (fr) 2020-06-11 2021-12-16 President And Fellows Of Harvard College Conjugués médicament trioxacarcine-anticorps stabilisés et utilisations de ceux-ci
WO2023096904A2 (fr) 2021-11-24 2023-06-01 President And Fellows Of Harvard College Trioxacarcines modifiées en c-16, conjugués anticorps-médicament, et leurs utilisations

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