Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
  • C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
• • 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
• • 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
  • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
  • A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/18—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
  • C07K16/3076—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
  • C07K16/3092—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties against tumour-associated mucins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
  • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Definitions

• the present disclosure concerns maytansinoid compounds, derivatives thereof, conjugates thereof, and methods of treating or preventing proliferative diseases with the same.
• Proliferative diseases for example cancer, are characterized by the uncontrolled growth of abnormal cells.
• Current treatments of proliferative diseases include surgery, radiation, chemotherapy, hormone-based therapy and/or immunotherapy.
• a number of these treatments, particularly chemotherapy utilize anti-proliferative drugs that limit the spread of the abnormal cells.
• these drugs are typically indiscriminate in their ability to kill cells, affecting both normal and abnormal cells.
• various approaches to targeted drug delivery have been explored, including the use of conjugates of tumor-targeted probes (such as antibodies or growth factors) with toxins, to selectively target abnormal cells.
• ADCs are compounds composed of an antibody that is linked, via a chemical linker, to a cytotoxic agent. Such compounds leverage the antibody's binding specificity for its target to deliver a cytotoxic agent to an abnormal cell.
• ADCs Antibody drug conjugates
• A is a arylene or heteroarylene, optionally substituted as described herein;
• L is a linker, optionally substituted as described herein;
• BA is a binding agent
• k is an integer from 1 to 30. Also provided herein are stereoisomers of compounds of Formula (I).
• PP5 or a salt thereof, wherein A is arylene or heteroarylene, optionally substituted as described herein. Also provided herein are stereoisomers of compounds of Formula PP5.
• a compound of Formula PI comprising contacting a compound of Formula (II) with a reactive linker (RL) described herein.
• FIG. 1 depicts the plot of % Cell Viability OVCAR3 vs. Logio [M] of certain compounds tested in Example 28.
• FIG 2 depicts the plot of % Cell Viability SKBr3 vs. Logio [M] of certain compounds tested in Example 28.
• FIG. 3 depicts the plot of % Cell Viability SKBr3 vs. Logio [M] of certain compounds tested in Example 28.
• FIG 4 depicts the plot of % Cell Viability SKBr3 vs. Logio [M] of certain compounds tested in Example 28.
• FIG. 5 depicts the plot of % Cell Viability SKBr3 vs. Logio [M] of certain compounds tested in Example 28.
• FIG 6 depicts the plot of % Cell Viability C4-2 vs. Logio [M] of certain compounds tested in Example 28.
• FIG. 7 depicts the plot of % Cell Viability C4-2 vs. Logio [M] of certain compounds tested in Example 28.
• FIG 8 depicts the plot of % Cell Viability C4-2 vs. Logio [M] of certain compounds tested in Example 28.
• FIG. 9 depicts a reaction scheme referenced in Example 1.
• FIG. 10 depicts a reaction scheme referenced in Example 2.
• FIG. 11 depicts a reaction scheme referenced in Example 3.
• FIG. 12 depicts a reaction scheme referenced in Example 4.
• FIG. 13 depicts a reaction scheme referenced in Example 5.
• FIG. 14 depicts a reaction scheme referenced in Example 6.
• FIG. 15 depicts a reaction scheme referenced in Example 7.
• FIG. 16 depicts a reaction scheme referenced in Example 8.
• FIG. 17 depicts a reaction scheme referenced in Example 9.
• FIG. 18 shows the Deconvoluted Mass Spectrum of MCC-DMl Conjugated mAb from Example 26.
• alkyl refers to a monovalent and saturated hydrocarbon radical moiety. Alkyl is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkyl. Alkyl includes, but is not limited to, those having 1-20 carbon atoms, i.e., Ci- 2 o alkyl; 1-12 carbon atoms, i.e., C 1-12 alkyl; 1-8 carbon atoms, i.e., Ci -8 alkyl; 1-6 carbon atoms, i.e., Ci -6 alkyl; and 1-3 carbon atoms, i.e., C 1-3 alkyl.
• alkyl moieties include, but are not limited to methyl, ethyl, ⁇ -propyl, / ' -propyl, «-butyl, s-butyl, t-butyl, / ' -butyl, a pentyl moiety, a hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• haloalkyl refers to alkyl, as defined above, wherein the alkyl includes at least one substituent selected from a halogen, e.g., F, CI, Br, or I.
• alkenyl refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more non-aromatic carbon-carbon double bonds. Alkenyl is optionally substituted and can be linear, branched, or cyclic.
• Alkenyl includes, but is not limited to, those having 2-20 carbon atoms, i.e., C 2-2 o alkenyl; 2-12 carbon atoms, i.e., C 2 - 12 alkenyl; 2-8 carbon atoms, i.e., C 2-8 alkenyl; 2-6 carbon atoms, i.e., C 2- 6 alkenyl; and 2-4 carbon atoms, i.e., C 2 -4 alkenyl.
• alkenyl moieties include, but are not limited to vinyl, propenyl, butenyl, and cyclohexenyl.
• alkynyl refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl is optionally substituted and can be linear, branched, or cyclic. Alkynyl includes, but is not limited to, those having 2-20 carbon atoms, i.e., C 2 - 2 0 alkynyl; 2-12 carbon atoms, i.e., C 2 .
• alkynyl 12 alkynyl; 2-8 carbon atoms, i.e., C 2-8 alkynyl; 2-6 carbon atoms, i.e., C 2- 6 alkynyl; and 2-4 carbon atoms, i.e., C 2- 4 alkynyl.
• alkynyl moieties include, but are not limited to ethynyl, propynyl, and butynyl.
• alkoxy refers to a monovalent and saturated hydrocarbon radical moiety wherein the hydrocarbon includes a single bond to an oxygen atom and wherein the radical is localized on the oxygen atom 1 e. . 1 CH 3 CH 2 -0- for ethoxy.
• Alkoxy substituents bond to the compound which they substitute through this oxygen atom of the alkoxy substituent.
• Alkoxy is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkoxy.
• Alkoxy includes, but is not limited to, those having 1-20 carbon atoms, i.e., Ci -2 o alkoxy; 1-12 carbon atoms, i.e., C 1-12 alkoxy; 1-8 carbon atoms, i.e., Ci -8 alkoxy; 1-6 carbon atoms, i.e., Ci -6 alkoxy; and 1-3 carbon atoms, i.e., C 1-3 alkoxy.
• alkoxy moieties include, but are not limited to methoxy, ethoxy, «-propoxy, z-propoxy, «-butoxy, s-butoxy, t-butoxy, z-butoxy, a pentoxy moiety, a hexoxy moiety, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.
• haloalkoxy refers to alkoxy, as defined above, wherein the alkoxy includes at least one substituent selected from a halogen, e.g., F, CI, Br, or I.
• aryl refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms are carbon atoms.
• Aryl is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic.
• aryl moieties include, but are not limited to those having 6 to 20 ring carbon atoms, i.e., C 6- 2o aryl; 6 to 15 ring carbon atoms, i.e., C 6 -i5 aryl, and 6 to 10 ring carbon atoms, i.e., C 6- io aryl.
• Examples of aryl moieties include, but are limited to phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl.
• arylene refers to a divalent moiety of an aromatic compound wherein the ring atoms are only carbon atoms.
• Arylene is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic.
• aryl moieties include, but are not limited to those having 6 to 20 ring carbon atoms, i.e., C 6- 2o arylene; 6 to 15 ring carbon atoms, i.e., C 6 -i5 arylene, and 6 to 10 ring carbon atoms, i.e., C 6 -io arylene.
• alkaryl refers to an aryl that is substituted with at least one alkyl. Alkaryl is optionally substituted.
• heteroalkyl refers to an alkyl in which one or more carbon atoms are replaced by heteroatoms.
• heteroalkenyl refers to an alkenyl in which one or more carbon atoms are replaced by heteroatoms.
• heteroalkynyl refers to an alkenyl in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heteroalkyl is optionally substituted.
• heteroaryl refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms contain carbon atoms and at least one oxygen, sulfur, nitrogen, or phosphorus atom.
• heteroaryl moieties include, but are not limited to those having 5 to 20 ring atoms; 5 to 15 ring atoms; and 5 to 10 ring atoms. Heteroaryl is optionally substituted.
• heteroarylene refers to an arylene in which one or more carbon ring atoms of the aromatic ring are replaced with an oxygen, sulfur, nitrogen, or phosphorus atom. Heteroarylene is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic.
• optionally substituted when used to describe a radical moiety, e.g., optionally substituted alkyl, means that such moiety is optionally bonded to one or more substituents.
• substituents include, but are not limited to halo, cyano, nitro, haloalkyl, azido, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl - OR A NR A R B
• R A , R B , and R c are, independently at each occurrence, a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, alkaryl, arylalkyl, heteroaryl, or heterocycloalkyl, or R and R , together with the atoms to which they are bonded, form a saturated or unsaturated carbocyclic ring, wherein the ring is optionally substituted and wherein one or more ring atoms is optionally
• R , R , and R are not hydrogen atoms.
• binding agent refers to any molecule capable of binding with specificity to a given binding partner.
• linker refers to a divalent moiety that covalently links the binding agent to the maytansinoid compounds and derivatives described herein.
• amide synthesis conditions refers to reaction conditions suitable to effect the formation of an amide, e.g., by the reaction of a carboxylic acid, activated carboxylic acid, or acyl halide with an amine.
• amide synthesis conditions refer to reaction conditions suitable to effect the formation of an amide bond between a carboxylic acid and an amine.
• the carboxylic acid is first converted to an activated carboxylic acid before the activated carboxylic acid reacts with an amine to form an amide.
• Suitable conditions to effect the formation of an amide include, but are not limited to, those utilizing reagents to effect the reaction between a carboxylic acid an amine, including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol- 1 - yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-l- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP),
• a carboxylic acid is first converted to an activated carboxylic ester before reacting with an amine to form an amide bond.
• the carboxylic acid is reacted with a reagent.
• the reagent activates the carboxylic acid by deprotonating the carboxylic acid and then forming a product complex with the deprotonated carboxylic acid as a result of nucleophilic attack by the deprotonated carboxylic acid onto the protonated reagent.
• this activated ester is more susceptible subsequently to nucleophilic attack by an amine than the carboxylic acid is before it is converted into an activated ester. This results in amide bond formation.
• the carboxylic acid is described as activated.
• Exemplary reagents include DCC and DIC.
• terapéuticaally effective amount refers to an amount (of a compound) that is sufficient to provide a therapeutic benefit to a patient in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
• Lewis acid refers to a molecule or ion that accepts an electron lone pair.
• the Lewis acids used in the methods described herein are those other than
• Lewis acids include, but are not limited to, non-metal acids, metal acids, hard Lewis acids, and soft Lewis acids.
• Lewis acids include, but are not limited to, Lewis acids of aluminum, boron, iron, tin, titanium, magnesium, copper, antimony, phosphorus, silver, ytterbium, scandium, nickel, and zinc.
• Illustrative Lewis acids include, but are not limited to, AlBr 3 , A1C1 3 , BC1 3 , boron trichloride methyl sulfide, BF 3 , boron trifluoride methyl etherate, boron trifluoride methyl sulfide, boron trifluoride tetrahydrofuran, dicyclohexylboron trifluoromethanesulfonate, iron (III) bromide, iron (III) chloride, tin (IV) chloride, titanium (IV) chloride, titanium (IV) isopropoxide, Cu(OTf) 2 , CuCl 2 , CuBr 2 , zinc chloride, alkylaluminum halides (R n AlX 3-11 , wherein R is hydrocarbyl), Zn(OTf) 2 , ZnCl 2 , Yb(OTf) 3 , Sc(OTf) 3 , MgBr 2 , NiC
• -K CH 3 has the following structure: .
• substituents bonded to a cyclic group e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or
• heterocycloalkyl through a bond between ring atoms are meant to indicate, unless specified otherwise, that the cyclic group may be substituted with that substituent at any ring position in the cyclic group or on any ring in the fused ring group, according to techniques set forth herein or which are known in the field to which the instant disclosure pertains.
• R 1 are described s ecifically: ? R ? R
• the group, in which the positions of substituents other than R 1 which are bonded to the cyclic group through a bond between ring atoms are described generically, includes the following groups in which the positions of these substituents other than R 1 are described specifically:
• the group, in which the positions of substituents other than R 1 which are bonded to the cyclic group through a bond between ring atoms are described generically, includes the following groups in which the positions of these substituents other than R 1 are described specifically:
• the substituent R 1 may be bonded to any ring position in the cyclic group or on any ring in the fused ring group which is not occupied by one of these substituents other than R 1 .
• the following non-limiting representative illustrations indicate that the cyclic group can be substituted with the indicated substituent at any ring position or on either ring in the fused ring
• reactive linker refers to a monovalent group that includes a reactive group and spacer group, depicted for example as ⁇ , wherein RG is the reactive group and SP is the spacer group.
• a reactive linker may include more than one reactive group and more than one spacer group.
• the spacer group is any divalent moiety that bridges the reactive group to another group, such as a payload.
• the reactive linkers (RL), together with the payloads to which they are bonded, provide intermediates ("linker-payloads”) useful as synthetic precursors for the preparation of the antibody conjugates described herein.
• the reactive linker contains a reactive group ("RG”), which is a functional group or moiety that is capable of reacting with a reactive portion of another group, for instance, an antibody, modified antibody, or antigen binding fragment thereof, or an enhancement group.
• RG reactive group
• the "reactive group” is a functional group or moiety (e.g., maleimide or N- hydroxysuccinimide (NHS) ester) that reacts with a cysteine or lysine residue of an antibody or antigen-binding fragment thereof.
• the "reactive group” is a functional group or moiety that is capable of undergoing a click chemistry reaction (see, e.g., click chemistry, Hui sgen Proc. Chem. Soc. 1961, Wang et al. J. Am. Chem. Soc. 2003, and Agard et al. J. Am. Chem. Soc. 2004).
• the reactive group is an alkyne that is capable of undergoing a 1,3-cycloaddition reaction with an azide.
• Such suitable reactive groups include, but are not limited to, strained alkynes, e.g., those suitable for strain-promoted alkyne-azide cycloadditions (SPAAC), cycloalkynes, e.g., cyclooctynes, benzannulated alkynes, and alkynes capable of undergoing 1,3-cycloaddition reactions with alkynes in the absence of copper catalysts.
• Suitable alkynes also include, but are not limited to,
• DIBAC dibenzoazacyclooctyne
• DIBO dibenzocyclooctyne
• BARAC biarylazac clooctynone
• DIFO substituted, e.g., fluorinated alkynes, aza-cycloalkynes,
• bicycle[6.1.0]nonyne or R is alkyl, alkoxy, or acyl), and derivatives thereof.
• Particularly useful alkynes include and ker-payloads including such reactive groups are useful for conjugating antibodies that have been functionalized with azido groups.
• Such functionalized antibodies include antibodies functionalized with azido-polyethylene glycol groups.
• such functionalized antibody is derived by treating an antibody having at least one glutamine residue, e.g., heavy chain Glnl95, with a compound bearing an azide group, in the presence of the enzyme transglutaminase.
• the reactive group is an alkyne, e.g., , which can react via click chemistry with an azide, e.g., to form a click
• the group reacts with an azide on a modified antibody or antigen binding fragment thereof.
• the group reacts with an azide on a modified antibody or antigen binding fragment thereof.
• reactive group is an alkyne, e.g. with an
• the reactive group is a functional group, e.g., ,which reacts with a cysteine residue on an antibody or antigen-binding fragment thereof, to form a bond thereto, e.g.,
• Ab refers to an antibody or antigen-binding fragment thereof and S refers to the S atom on a cysteine residue through which the functional group bonds to the Ab.
• the reactive group is a functional group, e.g., ,which reacts with a lysine residue on an antibody or antigen-binding fragment thereof, to form a bond thereto, e.g., wherein Ab refers to an antibody or antigen-binding fragment thereof and NH refers to the NH atom on a lysine side chain residue through which the functional group bonds to the Ab.
• A is arylene or heteroarylene
• L is a linker
• BA is a binding agent
• k is an integer from 1 to 30.
• A is arylene. In some embodiments, A is heteroarylene.
• the arylene or heteroarylene is substituted with one or more electron withdrawing groups and/or one or more electron donating groups.
• A is a divalent radical of benzene, of pyridine, of naphthalene, or of quinolone, which are optionally substituted.
• A is a divalent radical of benzene which is optionally substituted with a member selected from the group consisting of amino, amido, alkyl, halo, haloalkyl, alkoxy, and haloalkoxy.
• A is a divalent radical of benzene which is optionally substituted with a member selected from the group consisting of alkyl, alkoxy, haloalkyl, and halo. In some embodiments, A is a divalent radical of benzene which is optionally substituted with a member selected from the group consisting of methyl, methoxy, trifluoromethyl, fluoro, chloro, and bromo.
• A is a divalent radical of benzene which is optionally substituted with a member selected from the group consisting of halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl,
• A is:
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, cyano, nitro, amino, ⁇ ⁇ ⁇ OR ? ⁇ S0 2 R ⁇ R , or azido,
• R A is alkyl
• n is an integer from 0 to 4.
• n is an integer from 0 to 3;
• p is an integer from 0 to 6;
• q is an integer from 0 to 5.
• A is ,
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, cyano, nitro, am o,
• R A is alkyl
• n is an integer from 0 to 4. In some embodiments, n is 0, 1, 2, or 3. In some
• n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1.
• A is ,
• R 1 independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl;
• n is an integer from 0 to 4. In some embodiments, n is 0, 1, 2, or 3. In some
• n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1.
• A is: wherein:
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl, cyano, nitro, amino, ⁇ ⁇ ⁇ OR ? ⁇ S0 2 R ⁇ R , or azido,
• R A is alkyl
• n is an integer from 0 to 4.
• n is an integer from 0 to 3;
• p is an integer from 0 to 6;
• q is an integer from 0 to 5.
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl, cyano, nitro, amino, o,
• R A is alkyl
• R 1 independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl.
• R 1 is Ci -6 alkyl or Ci -6 alkoxy. In some embodiments, R 1 is
• R 1 Ci alkyl. In some embodiments, R 1 is Ci alkoxy. In some embodiments, R 1 is halo. In some embodiments, R 1 is haloalkyl. In some embodiments, R 1 is heterocycloalkyl. In some of these embodiments, R 1 is methyl, ethyl, methoxy, or ethoxy. In some of these embodiments, R 1 is methyl. In some of these embodiments, R 1 is methoxy. In some of these embodiments, R 1 is trifluoromethyl. In some embodiments, R 1 is fluoro, chloro, or bromo. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is bromo. In some of these embodiments, R 1 is pyrrolidinyl. In some of these embodiments, R 1 is morpholinyl.
• R 1 is, independently, alkyl or halo. In some embodiments,
• R 1 is, independently, Ci -6 alkyl, Ci -6 haloalkyl, or halo. In some embodiments, R 1 is,
• R 1 is, independently, fluoro, chloro, bromo, iodo, or trifluoromethyl.
• n, m, p, or q is 0, 1 or 2.
• n, m, p, or q is 0 or 1.
• n, m, p, or q is 0. [0065]
• R is, independently, alkyl, alkoxy, or halo.
• R 1 is, independently, Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, Ci -6 haloalkoxy, or halo.
• R is, independently, halo. In some embodiments, R is, independently, fluoro, chloro, bromo, iodo, or trifluoromethyl. In some embodiments, R 1 is Ci alkoxy. In some embodiments, R 1 is halo. In some of these embodiments, R 1 is methyl. In some of these embodiments, R 1 is methoxy. In some of these embodiments, R 1 is trifluorom ethyl. In some embodiments, R 1 is fluoro, chloro, or bromo. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is bromo. In some embodiments, n, m, p, or q is 0, 1 or 2. In some embodiments, n, m, p, or q is 0 or 1. In some embodiments, n, m, p, or q is 0.
• A is:
• A is:
• A is:
• n 0, 1, 2, 3, or 4.
• A is:
• n 0, 1, or 2.
• n is 0 or 1 ; and R 1 is alkyl, alkoxy, halo, haloalkyl, or haloalkoxy.
• R 1 is alkyl, alkoxy, halo, haloalkyl, or heterocycloalkyl.
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl, cyano,
• A is:
• n 0, 1, or 2.
• n is 0 or 1 ; and R 1 is Ci -6 alkyl, Ci -6 alkoxy, halo, Ci -6 haloalkyl, Ci -6 haloalkoxy.
• R 1 is heterocycloalkyl.
• R 1 is methyl, methoxy, tnfluoromethyl, fluoro, chloro, or bromo.
• R 1 is methyl.
• R 1 is methoxy.
• R 1 is tnfluoromethyl.
• R 1 is fluoro.
• R 1 is bromo.
• R 1 is chloro.
• R 1 is pyrrolidinyl.
• R 1 is morpholinyl.
• A is:
• n 0, 1, or 2.
• R 1 is Ci -6 alkyl, Ci -6 alkoxy, halo, Ci -6 haloalkyl, Ci -6 haloalkoxy, or heterocycloalkyl
• L is
• b is an integer from 2 to 8 and a bond to the binding agent.
• A is:
• n 0, 1, 2, 3, or 4.
• A is:
• R 1 is Ci -6 alkyl, Ci -6 alkoxy, halo, Ci -6 haloalkyl, Ci -6 haloalkoxy, or heterocycloalkyl.
• R 1 is methoxy or methyl. In some specific embodiments, R 1 is methoxy. In some embodiments, R 1 is methyl. In some embodiments, R 1 is methyl, methoxy, trifluoromethyl, fluoro, chloro, or bromo. In some embodiments, R 1 is methyl. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is trifluoromethyl. In some
• R 1 is fluoro. In some embodiments, R 1 is bromo. In some embodiments, R 1 is chloro. In some examples, R 1 is pyrrolidinyl. In some examples, R 1 is morpholinyl. In some examples, R 1 is alkyl, alkoxy, halo, haloalkyl, or heterocycloalkyl.
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, cyano, nitro, amino, ' -OR A or azido, wherein R is alkyl.
• A is:
• R 1 is halo, methyl, methoxy, or trifluoromethyl
• n 0, 1 or 2.
• A is:
• A is:
• X is a hydrogen atom, halo, methyl, methoxy, or trifluoromethyl.
• A is:
• X is a hydrogen atom, halo, methyl, methoxy, or trifluorom ethyl
• ⁇ is the bond to the nitrogen atom of the amino-ester which is directly bonded to the drug molecule; and ⁇ is the bond to the nitrogen atom which is bonded to the linker.
• A is:
• R 1 is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, aryl, heteroalkyl, heterocycloalkyl, halo, haloalkyl, or haloalkoxy;
• R 1 is 1-methylethyl- thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl. In some embodiments, R 1 is trifluoromethyl. In some embodiments, R 1 is methyl. In some embodiments,
• R 1 is methoxy. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is bromo. In some embodiments, R 1 is hydrogen.
• A is:
• R 1 is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, aryl, heteroalkyl, heterocycloalkyl, halo, haloalkyl, haloalkoxy;
• R 1 is 1-methylethyl- thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
• R 1 is trifluoromethyl.
• R 1 is methyl.
• R 1 is methoxy.
• R 1 is fluoro.
• R 1 is chloro.
• R 1 is bromo.
• R 1 is hydrogen.
• A is:
• R 1 is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, aryl, heteroalkyl, heterocycloalkyl, halo, haloalkyl, or haloalkoxy; ⁇ and ⁇ are as defined above.
• R 1 is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, aryl, heteroalkyl, heterocycloalkyl, halo, haloalkyl, or haloalkoxy.
• R 1 is alkyl or alkoxy.
• R 1 is propylamino, difluoro-methoxy, phenyl, 2- fluorophenyl.
• R 1 is trifluoromethyl. In some embodiments, R 1 is methoxy. In some embodiments, R 1 is methyl. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is bromo. In some embodiments, R 1 is hydrogen. In some examples, R 1 is pyrrolidinyl. In some examples, R 1 is morpholinyl.
• A is:
• ⁇ and ⁇ are as defined above.
• A is:
• A is: and * are as defined above.
• A is:
• ⁇ and ⁇ are as defined above.
• A is:
• ⁇ and ⁇ are as defined above.
• A is:
• ⁇ and ⁇ are as defined above.
• A is:
• A is:
• A is:
• A is:
• A is:
• A is:
• A is:
• ⁇ and ⁇ are as defined above.
• A is:
• A is:
• A is:
• A is:
• A is:
• A is:
• ⁇ and ⁇ are as defined above.
• A is:
• A is:
• A is:
• A is:
• A is:
• A is:
• A is:
• ⁇ and ⁇ are as defined above.
• A is: * and * are as defined above.
• A is: , wherein X is F, CI, Br, CN, methoxy, methyl, trifluoromethyl, dimethylamino or cyclopropyl; re as defined above. In some embodiments, A is: , wherein X is F, CI, Br, CN, methoxy, methyl, trifluoromethyl, dimethylamino, 1- methyl-ethyl-thio or cyclopropyl;
• ⁇ and ⁇ are as defined above .
• A is:
• each R 1 is independently, at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy;
• R 1 is hydrogen, fluoro, methyl, trifluoromethyl, or methoxy. In some embodiments, R 1 is fluoro, chloro, bromo, or iodo.
• A is:
• A is:
• each R 1 is independently, at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy; wherein * and * are as defined above
• A is: wherein * and * are as defined above .
• A is:
• A is:
• A is:
• A is:
• A is:
• A is: wherein: wherein * and * are as defined above .
• A is:
• A is:
• A is:
• n 0, 1 2, or 3.
• A is:
• n 0, 1 2, or 3.
• A is:
• R 1 is Ci-6 alkyl, Ci -6 alkoxy, halo, Ci -6 haloalkyl, Ci -6 haloalkoxy, Ci -6 heteroalkyl, or heterocycloalkyl; and n is 0, 1 2, 3 or 4. In some embodiments, R 1 is Ci -6 alkyl, Ci-6 alkoxy, halo, Ci -6 haloalkyl, Ci -6 haloalkoxy, Ci -6 heteroalkyl, or heterocycloalkyl.
• A is:
• A is:
• A is:
• X is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkoxy, haloalkyl, heteroalkyl, or heterocycloalkyl. In some embodiments, X is
• X is fluoro, chloro, bromo, iodo, dimethylamino, methylamino, methyl, methoxy, ethoxy, or trifluoromethyl.
• X is methyl. In some embodiments, X is methoxy. In some embodiments, X is trifluoromethyl. In some embodiments, X is fluoro. In some embodiments, X is chloro. In some embodiments, X is bromo. In some embodiments, X is morpholinyl. In some embodiments, X is pyrrolidinyl.
• A is:
• X is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkoxy, haloalkyl, heteroalkyl, or heterocycloalkyl. In some embodiments, X is
• X independently at each occurrence, fluoro, chloro, bromo, iodo, dimethylamino, methyl, methylamino, methoxy, ethoxy,
• X is methyl. In some embodiments, X is methoxy. In some embodiments, X is trifluoromethyl. In some
• X is fluoro. In some embodiments, X is chloro. In some embodiments, X is bromo. In some embodiments, X is morpholinyl. In some embodiments, X is pyrrolidinyl.
• A is:
• X is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkoxy, haloalkyl, heteroalkyl, or heterocycloalkyl. In some embodiments, X is
• X is fluoro, chloro, bromo, iodo, dimethylamino, methylamino, methyl, methoxy, ethoxy, or trifluoromethyl.
• X is methyl. In some embodiments, X is methoxy. In some embodiments, X is trifluoromethyl. In some embodiments, X is fluoro. In some embodiments, X is chloro. In some embodiments, X is bromo. In some embodiments, X is morpholinyl. In some embodiments, X is pyrrolidinyl.
• A is:
• X is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkoxy, haloalkyl, heteroalkyl, or heterocycloalkyl.
• X independently at each occurrence, fluoro, chloro, bromo, iodo, dimethylamino, methyl, methylamino, methoxy, ethoxy, trifluoromethyl methoxy, pyrrolidinyl, or morpholinyl; wherein ⁇ and ⁇ are as defined above.
• X is methyl.
• X is methoxy.
• X is trifluoromethyl.
• X is fluoro. In some embodiments, X is chloro. In some embodiments, X is bromo. In some embodiments, X is morpholinyl. In some embodiments, X is pyrrolidinyl.
• linker portion of the conjugates described herein is a divalent moiety that covalently links the binding agent to the maytansinoid compounds and derivatives described herein.
• Suitable linkers include those that release at least the maytansinoid portion in the presence of an enzyme or at a particular pH range or value.
• the linker comprises an enzyme-cleavable moiety.
• Illustrative enzyme-cleavable moieties include, but are not limited to, peptide bonds, ester linkages, hydrazones, and disulfide linkages.
• the linker comprises a cathepsin-cleavable linker.
• the reactive linker comprises a non-cleavable moiety.
• the non-cleavable reactive linker is a residue
• the non-cleavable reactive or a residue thereof is not limited to the non-cleavable reactive or a residue thereof.
• Suitable linkers also include, but are not limited to, those that are chemically bonded to two cysteine residues of a single binding agent, e.g., antibody. Such linkers can serve to mimic the antibody's disulfide bonds that are disrupted as a result of the conjugation process.
• the linker comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteinogenic, non- proteinogenic, and L-, or D- a- amino acids.
• the linker comprises alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, or derivative thereof.
• the linker comprises valine and citrulline.
• the linker is:
• SP is a spacer
• ⁇ is one or more bonds to the binding agent
• AA 1 is an amino acid
• AA 2 is an amino acid.
• the linker is:
• SP is a spacer
• the spacer is a divalent moiety that connects the AA X -AA 2 moiety to the binding agent (BA).
• Suitable spacers include, but are not limited to, those comprising alkylene or polyethylene glycol.
• the ends of the spacers, i.e., the portion of the spacer directly bonded to the binding agent or AA 1 can be moieties derived from reactive moieties that are used for purposes of coupling the naked antibody or AA 1 to the spacer during the chemical synthesis of the conjugate.
• the ends of the spacers i.e., the portion of the spacer directly bonded to the binding agent or AA 1
• the spacer can be residues of reactive moieties that are used for purposes of coupling the naked antibody or AA 1 to the spacer during the chemical synthesis of the conjugate.
• the spacer comprises an alkylene. In some embodiments, the spacer comprises a C5-7 alkylene. In some embodiments, the spacer is:
• b is an integer from 2 to 8. In some examples, b is selected from 2, 3, 4, 5, 6, 7, or 8. In some examples, b is 2. In some examples, b is 3. In some examples, b is 4. In some examples, b is 5. In some examples, b is 6. In some examples, b is 7. In some examples, b is 8.
• the spacer is:
• the spacer is:
• -I 5 is a bond to the binding agent.
• the spacer is: wherein:
• R is a hydrogen atom or alkyl
• R M is alkyl; the two bonds represented by ⁇ are bonds to cysteines of a binding agent; and b is an integer from 2 to 8.
• the spacer is:
• b is an integer from 2 to 8.
• the spacer is:
• g is an integer from 2 to 20. In some embodiments, g is 2-8. In some embodiments, g is 2, 4, 6, or 8.
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is: o o
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is:
• X is N or O; R and R are each, independently, hydrogen or alkyl; and b is an integer from 1 to
• AA -AA 2 is: valine-citrulline, citrulline-valine, lysine- phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, asparagine-threonine, threonine-asparagine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid- asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, asparagine-alan
• AA -AA 2 is: valine-citrulline or citrulline-valine. In some embodiments, AA -AA 2 is: valine-citrulline.
• the linker is: wherein:
• SP is a spacer
• ⁇ is one or more bonds to the binding agent
• R AA1 is an amino acid side chain
• R AA2 is an amino acid side chain.
• amino acid side chain refers the monovalent non-hydrogen substituent bonded to the a- carbon of an a-amino acid, including natural and non-natural amino acids.
• exemplary amino acid side chains include, but are not limited to, the a-carbon substituent of alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and citrulline.
• the linker is:
• SP is a spacer
• * is one or more bonds to the binding agent.
• the linker is:
• the linker is:
• BA is an antibody and the linker is:
• the two bonds represented by ⁇ are bonds to cysteines of the antibody; and b is an integer from 2 to 8.
• BA is an antibody and the linker is:
• BA is an antibody and the linker is:
• R is a hydrogen atom or alkyl
• R M is alkyl; the two bonds represented by ' are bonds to cysteines of the antibody; and b is an integer from 2 to 8.
• b is an integer from 2 to 8.
• the linker is:
• g is an integer from 2 to 20. In some embodiments, g is 2 to 8. In some embodiments, g is 2, 4, 6, or 8.
• the linker is:
• the linker is:
• the linker is:
• the linker is:
• the linker is:
• the linker is:
• the linker [0177] In some embodiments, the linker
• Suitable binding agents include, but are not limited to, antibodies, lymphokines, hormones, growth factors, viral receptors, interleukins, or any other cell binding or peptide binding molecules or substances.
• the binding agent is an antibody.
• the antibody is a monoclonal antibody, polyclonal antibody, antibody fragment (Fab, Fab', and F(ab)2, minibody, diabody, tribody, and the like), or bispecific antibody.
• Antibodies herein can be humanized using methods described in US Patent No. 6,596,541 and US Publication No. 2012/0096572, each incorporated by reference in their entirety.
• the binding agent binds to an antigen binding partner that is a polypeptide and may be a transmembrane molecule (e.g., receptor) or a growth factor that might be glycosylated or phosphorylated.
• an antigen binding partner that is a polypeptide and may be a transmembrane molecule (e.g., receptor) or a growth factor that might be glycosylated or phosphorylated.
• antigens include, but are not limited to, molecules such as renin; a growth hormone, including human growth hormone and bovine growth hormone; growth hormone releasing factor; parathyroid hormone; thyroid stimulating hormone; lipoproteins; alphal -antitrypsin; insulin A-chain; insulin B-chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; glucagon; clotting factors such as factor vmc, factor IX, tissue factor (TF), and von Willebrands factor; anti-clotting factors such as Protein C; atrial natriuretic factor; lung surfactant; a plasminogen activator, such as urokinase or human urine or tissue-type plasminogen activator (t-PA); bombesin; thrombin; hemopoietic growth factor; tumor necrosis factor-alpha and -beta; enkephalinase; RANTES (regulated on activation normally T-cell expressed and secreted); human macrophag
• erythropoietin erythropoietin
• osteoinductive factors immunotoxins
• a bone morphogenetic protein BMP
• an interferon such as interferon- alpha, -beta, and -gamma
• colony stimulating factors CSFs
• ILs interleukins
• superoxide dismutase T-cell receptors
• surface membrane proteins e.g., IL-1 to IL-10
• superoxide dismutase e.g., IL-1 to IL-10
• superoxide dismutase T-cell receptors
• surface membrane proteins accelerating factor
• viral antigen such as, for example, a portion of the HIV envelope; transport proteins; homing receptors; addressins; regulatory proteins; integrins, such as CD1 la, CD1 lb, CD1 lc, CD 18, an ICAM, VLA-4 and VCAM; a tumor associated antigen such as AFP, ALK, B7H4, BAGE proteins
• the GAGE proteins are selected from GAGE-1 and GAGE-2.
• the MAGE proteins are selected from MAGE-1, -2, -3, -4, -6, and - 12
• Exemplary antigens also include, but are not limited to, BCMA, SLAMF7, B7H4,
• Exemplary antigens also include, but are not limited to, MUC16, PSMA, STEAP2, and HER2.
• the antigens include prolactin receptor (PRLR) or prostate-specific membrane antigen (PSMA).
• PRLR prolactin receptor
• PSMA prostate-specific membrane antigen
• the antigens include MUC16.
• the antigens include STEAP2.
• the antigens include PSMA.
• the antigens include HER2.
• the antigen is prolactin receptor (PRLR) or
• binding agents also include, but are not limited to, ankyrin repeat proteins, interferons, lymphokines such as IL-2 or IL-3, hormones like insulin and glucocorticoids, growth factors such as EGF, transferrin and fibronectin type III.
• the binding agents interact with or bind to tumor antigens, including antigens specific for a type of tumor or antigens that are shared, overexpressed or modified on a particular type of tumor.
• tumor antigens include, but are not limited to: alpha-actinin-4 with lung cancer, ARTC1 with melanoma, BCR-ABL fusion protein with chronic myeloid leukemia, B-RAF, CLPP or Cdc27 with melanoma, CASP-8 with squamous cell carcinoma, and hsp70-2 with renal cell carcinoma as well as the following shared tumor-specific antigens, for example: BAGE-1, GAGE, GnTV, KK-LC-1, MAGE-A2, NA88-A, TRP2-INT2.
• the binding agent is an antibody. In some embodiments, the binding agent is a monoclonal antibody. In some embodiments, the binding agent is a polyclonal antibody. In some embodiments, the antibody is an anti-PSMA, anti-MUC16, anti- HER2, or anti-EGFRvIII, or anti-STEAP-2 antibody.
• the linkers can be bonded to the binding agent, e.g., antibody or antigen-binding molecule, through an attachment at a particular amino acid within the antibody or antigen- binding molecule.
• exemplary amino acid attachments that can be used in the context of this aspect of the disclosure include, e.g., lysine (see, e.g., US 5,208,020; US 2010/0129314;
• Linkers can be conjugated via glutamine via transglutaminase-based chemo-enzymatic conjugation (see, e.g., Dennler et al, Bioconjugate Chem. 2014, 25, 569-578). Linkers can also be conjugated to an antigen-binding protein via attachment to carbohydrates (see, e.g., US 2008/0305497, WO 2014/065661, and Ryan et al, Food & Agriculture Immunol, 2001, 73: 127- 130) and disulfide linkers (see, e.g., WO 2013/085925, WO 2010/010324, WO 2011/018611, WO 2014/197854, and Shaunak et al, Nat. Chem. Biol, 2006, 2:312-313).
• the binding agent is an antibody, and the antibody is bonded to the linker through a lysine residue. In some embodiments, the antibody is bonded to the linker through a cysteine residue.
• A is:
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, cyano,
• R A is alkyl
• n is an integer from 0 to 4.
• n is an integer from 0 to 3;
• p is an integer from 0 to 6;
• q is an integer from 0 to 5;
• SP is a spacer
• AA 1 is an amino acid
• AA 2 is an amino acid.
• A is:
• R 1 independently at each occurrence, is Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl,
• n is an integer from 0 to 4.
• n is an integer from 0 to 3;
• p is an integer from 0 to 6;
• q is an integer from 0 to 5;
• SP is a spacer; s one or more bonds to the binding agent;
• AA 1 is an amino acid
• AA 2 is an amino acid.
• A is:
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaiyl, aiylalkyl, heteroalkyl, heteroaiyl, heterocycloalkyl, cyano, nitro, -OR A S °2R A or azido,
• R is alkyl; m is an integer from 0 to 3;
• p is an integer from 0 to 6;
• q is an integer from 0 to 5;
• SP is: -(CH 2 ) b -N-LLj- wherein:
• b is an integer from 2 to 8.
• AA 1 is an amino acid
• AA 2 is an amino acid.
• A is:
• R 1 independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl;
• n is an integer from 0 to 4.
• SP is a spacer; is one or more bonds to the binding agent
• AA 1 is an amino acid
• AA 2 is an amino acid.
• A is:
• R 1 independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl;
• n is an integer from 0 to 4.
• SP is a spacer
• -f 5 - is one or more bonds to the binding agent.
• A is:
• R 1 is, independently at each occurrence, is Ci -6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, Ci-6 haloalkoxy, halo, or heterocycloalkyl;
• n 0, 1, or 2;
• SP is a spacer; one or more bonds to the binding agent
• R is an amino acid side chain
• R AA2 is an amino acid side chain.
• A is:
• R 1 independently at each occurrence, is halo, haloalkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, aiylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, cyano,
• R A is alkyl
• n is an integer from 0 to 4.
• SP is a spacer: one or more bonds to the binding agent
• R is an amino acid side chain
• R AA2 is an amino acid side chain.
• A is:
• R 1 is, independently at each occurrence, is halo
• n 0, 1, or 2;
• b is an integer from 2 to 8.
• A is:
• R 1 independently at each occurrence, is halo, haloalkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl, cyano, nitro, ⁇ ⁇ ⁇ OR ? ⁇ S0 2 R ⁇ R , or azido,
• R A is alkyl
• n is an integer from 0 to 4; and b is an integer from 2 to 8.
• A is:
• R 1 is, independently at each occurrence, is halo; and n is 0, 1, or 2;
• A is:
• R 1 independently at each occurrence, is halo, haloalkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl, cyano,
• R A is alkyl
• n is an integer from 0 to 4.
• A is:
• A is:
• R 1 is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, aryl, heteroalkyl, halo, haloalkoxy, or haloalkyl; ⁇ is the bond to the nitrogen atom of the amino-ester which is directly bonded to the drug molecule; and ⁇ is the bond to the nitrogen atom which is bonded to the linker.
• R 1 is 1-methylethyl-thiol, phenyl, 2- fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
• R 1 is trifluoromethyl.
• R 1 is methyl.
• R 1 is methoxy.
• R 1 is fluoro.
• R 1 is chloro.
• R 1 is bromo.
• R 1 is hydrogen.
• A is:
• R 1 is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, aryl, heteroalkyl, halo, haloalkyl, haloalkoxy;
• R 1 is 1-methylethyl-thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
• R 1 is trifluoromethyl.
• R 1 is methyl.
• R 1 is methoxy.
• R 1 is fluoro.
• R 1 is chloro.
• R 1 is bromo.
• R 1 is hydrogen.
• A is:
• BA is an antibody
• A is:
• R 1 is, independently at each occurrence, is halo
• n 0, 1 , or 2;
• A is:
• R 1 independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl;
• n is an integer from 0 to 4.
• A is:
• A is: * and ⁇ are as defined above.
• A is:
• A is:
• A is:
• A is:
• A is:
• A is a
• A is:
• ⁇ and ⁇ are as defined above.
• A is:
• A is:
• ⁇ and ⁇ are as defined above.
• A is:
• A is:
• A is:
• n 0, 1 2, or 3.
• A is:
• R 1 independently at each occurrence, is halo, haloalkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, cyano, nitro, ⁇ ⁇ ⁇ OR ? ⁇ S0 2 R ⁇ R , or azido; and
• q is an integer from 0 to 5;
• SP is a spacer; one or more bonds to the binding agent
• R AA1 is an amino acid side chain
• R AA2 is an amino acid side chain.
• A is:
• R 1 independently at each occurrence, is halo, haloalkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, cyano,
• q is an integer from 0 to 5;
• SP is a spacer; one or more bonds to the binding agent;
• R is an amino acid side chain
• R is an amino acid side chain.
• A is:
• R 1 independently at each occurrence, is halo, haloalkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl, cyano,
• q is an integer from 0 to 5;
• b is an integer from 2 to 8.
• A is:
• R 1 independently at each occurrence, is halo, haloalkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, aiyl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl, cyano,
• q is an integer from 0 to 5;
• A is:
• R 1 independently at each occurrence, is halo, haloalkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, aiyl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl, cyano, nitro, i-OR A
• q is an integer from 0 to 5;
• A is:
• the compound of Formula I is:
• A is arylene or heteroarylene
• L 1 and L 2 are linkers
• BA is a binding agent
• k is an integer from 0 to 30
• t is an integer from 0 to 8.
• L 1 is a linker which binds to the BA through a lysine residue.
• the subscript, k represents the number of linkers, L 1 , bonded to the BA through lysine residues on the BA.
• L 2 is a linker which binds to the BA through a cysteine residue.
• the subscript, t represents the number of linkers, L 2 , bonded to the BA through cysteine residues on the BA.
• t when the linker, L 2 , is a monodentate linker, t is an integer from 0 to 8. In some embodiments, when the linker, L 2 , is a bidentate linker, t is an integer from 0 to 4. In some of these examples, the sum of k + 1 is equal to 1-8.
• the compound of Formula I is:
• L 1 and L 2 are linkers
• BA is a binding agent.
• L 1 is a linker which binds to the BA through a lysine residue.
• L 2 is a linker which binds to the BA through a cysteine residue.
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, arylalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, cyano, nitro, -OR
• R A is alkyl
• m is an integer from 0 to 3
• p is an integer from 0 to 6
• q is an integer from 0 to 5;
• A is arylene or heteroarylene
• L 1 and L 2 are linkers
• BA is a binding agent
• k is an integer from 0 to 30
• t is an integer from 0 to 8.
• L 1 is a linker which binds to the BA through a lysine residue.
• the subscript, k represents the number of linkers, L 1 , bonded to the BA through lysine residues on the BA.
• L 2 is a linker which binds to the BA through a cysteine residue.
• the subscript, t represents the number of linkers, L 2 , bonded to the BA through cysteine residues on the BA.
• t when the linker, L 2 , is a monodentate linker, t is an integer from 0 to 8. In some embodiments, when the linker, L 2 , is a bidentate linker, t is an integer from 0 to 4. In some of these examples, the sum of k + 1 is equal to 1-8. [0228] In some embodiments, the compound of Formula I is:
• L 1 and L 2 are linkers
• BA is a binding agent.
• L 1 is a linker which binds to the BA through a lysine residue.
• L 2 is a linker which binds to the BA through a cysteine residue.
• the compound of Formula I is:
• L 1 and L 2 are linkers
• BA is a binding agent.
• L 1 is a linker which binds to the BA through a lysine residue.
• L 2 is a linker which binds to the BA through a cysteine residue.
• A is:
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, aiylalkyl, heteroalkyl, heteroaiyl, heterocycloalkyl, cyano, nitro, :-OR
• R A is alkyl
• n is an integer from 0 to 4.
• n is an integer from 0 to 3;
• p is an integer from 0 to 6;
• q is an integer from 0 to 5;
• A is arylene or heteroarylene
• L X ; L 2 , and L 3 are linkers
• BA is a binding agent
• k is an integer from 0 to 30
• t is an integer from 0 to 8
• g is an integer from 0 to 4.
• L 1 is a linker which binds to the BA through a lysine residue.
• the subscript, k represents the number of linkers, L 1 , bonded to the BA through lysine residues on the BA.
• L 2 is a linker which binds to the BA through a cysteine residue.
• the subscript, t represents the number of linkers, L 2 , bonded to the BA through cysteine residues on the BA.
• the linker, L 2 when the linker, L 2 , is a monodentate linker, t is an integer from 0 to 8.
• the linker, L 2 when the linker, L 2 , is a bidentate linker, t is an integer from 0 to 4.
• the sum of k + 1 is equal to 1-8.
• L 3 is a linker which binds to the B A through a glutamine residue.
• the subscript, g represents the number of linkers, L 3 , bonded to the BA through glutamine residues on the BA.
• the compound of Formula I is:
• A is arylene or heteroarylene
• L 2 , and L 3 are linkers
• B A is a binding agent.
• L 1 is a linker which binds to the BA through a lysine residue.
• L 2 is a linker which binds to the BA through a cysteine residue.
• L 3 is a linker which binds to the BA through a glutamine residue.
• A is: wherein:
• R 1 is, independently at each occurrence, halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, aryl, alkaryl, arylalkyl, heteroaryl, heteroalkyl,
• R A is alkyl
• n is an integer from 0 to 4.
• n is an integer from 0 to 3;
• p is an integer from 0 to 6;
• q is an integer from 0 to 5.
• the linker is:
• AA 1 is an amino acid
• AA 2 is an amino acid.
• the spacer is a divalent moiety that connects the AA*-AA 2 moiety to the binding agent (BA).
• Suitable spacers include, but are not limited to, those comprising alkylene or polyethylene glycol.
• the ends of the spacers, i.e., the portion of the spacer directly bonded to the binding agent or AA 1 can be moieties derived from reactive moieties that are used for purposes of coupling the antibody or AA 1 to the spacer during the chemical synthesis of the conjugate.
• the spacer comprises an alkylene. In some embodiments, the spacer comprises a C5-7 alkylene. In some embodiments, the spacer is:
• b is an integer from 2 to 8.
• the spacer is:
• the spacer is:
• R is a hydrogen atom or alkyl
• R M is alkyl; the two bonds represented by * are bonds to cysteines of a binding agent; and b is an integer from 2 to 8.
• the spacer is:
• b is an integer from 2 to 8.
• the spacer is:
• ⁇ is a bond to the binding agent.
• the spacer is
• ⁇ is a bond to the binding agent
• g is an integer from 2 to 20. In some embodiments, g is 2-8. In some embodiments, g is 2, 4, 6, or 8.
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is:
• the spacer is:
• X is N or O; R and R are each, independently, hydrogen or alkyl; and b is an integer from 1 to 8.
• AA -AA 2 is: valine-citrulline, citrulline-valine, lysine- phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, asparagine-threonine, threonine-asparagine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid- asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, asparagine-alan
• AA -AA 2 is: valine-citrulline or citrulline-valine. In some embodiments, AA -AA 2 is: valine-citrulline.
• the compound of Formula I is:
• R N and R M are each, independently, hydrogen or aryl
• b is an integer from 1 to 8
• A is aryl or heteroaryl
• t is an integer from 1-8.
• the compound of Formula I is:
• Ab is an antibody
• — ⁇ — is a bond to a cysteine of the antibody
• — -— is a bond to a lysine of the antibody
• k is an integer from 1 to 30;
• t is an integer from 1 to 8.
• k is an integer from 1 to 8.
• t is an integer from 1 to 4.
• k is an integer from 1 to 30. In some embodiment, k is an integer from 1 to 8. In some embodiment, k is an integer from 1 to 6. In some embodiments, k is an integer from 1 to 4. In some embodiments, k is an integer from 1 to 3. In some
• the drug-antibody ratio (DAR) of the conjugate is from 1 to 30.
• A is arylene or heteroaiyl ene.
• these compounds represent the payload portion of the conjugates described herein and are released, e.g., by enzyme proteolysis, following
• the methods provided herein include methods of treating a proliferative disease, e.g., cancer, comprising administering to a patient a proliferative disease, e.g., cancer, comprising administering to a patient a proliferative disease, e.g., cancer, comprising administering to a patient a proliferative disease, e.g., cancer, comprising administering to a patient a proliferative disease, e.g., cancer, comprising administering to a patient a proliferative disease, e.g., cancer
• a conjugate e.g. , antibody-drug conjugate that releases a compound of Formula (II) following internalization of said conjugate into a cell in said patient.
• these compounds represent the metabolic product of the conjugates described herein, e.g. , enzyme proteolysis product. In some embodiments, these compounds represent the catabolic product of the conjugates described herein. In some embodiments, these compounds represent the cellular product of the conjugates described herein.
• A is a divalent radical of benzene, of pyridine, of naphthalene, or of quinolone, which are optionally substituted.
• A is arylene
• A is:
• R 1 independently at each occurrence, is halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaiyl, aiylalkyl, heteroaiyl, heteroalkyl, heterocycloalkyl, cyano, nitro, amino, ⁇ ⁇ "0R ? ⁇ S0 2 R ⁇ ⁇ R ⁇ or azido,
• R A is alkyl
• n is an integer from 0 to 4.
• n is and integer from 0 to 3;
• p is an integer from 0 to 6;
• q is an integer from 0 to 5.
• the compound of Formula (II) is a compound having the following chemical bonds:
• R 1 and n are as defined herein.
• the compound of Formula (II) is a compound of the
• R 1 and n are as defined herein.
• R 1 is alkyl, alkoxy, haloalkyl, or halo.
• R 1 is methyl, trifluoromethyl, methoxy, fluoro, chloro, or bromo.
• R 1 is methyl.
• R 1 is methoxy.
• R 1 is trifluoromethyl. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is bromo.
• the compound of Formula (II) is a compound of the
• R 1 and q are as defined herein.
• the compound of Formula (II) is a compound of the
• R 1 and q are as defined herein.
• the compound of Formula (II) is a compound of the
• the compound of Formula (II) is a compound of the
• R 1 and q are as defined herein.
• the compound of Formula (II) is a compound of the
• R 1 and q are as defined herein.
• the compound of Formula (II) is a compound of the
• the compound of Formula (II) is a compound of the
• R 1 and q are as defined herein.
• the compound of Formula (II) is a compound of the
• R 1 and q are as defined herein.
• R 1 is, independently, alkyl or halo. In some embodiments,
• R 1 is, independently, Ci -6 alkyl, Ci -6 haloalkyl, or halo. In some embodiments, R 1 is,
• R 1 is, independently, halo. In some embodiments, R 1 is, independently, fluoro, chloro, bromo, iodo, or trifluoromethyl. In some embodiments, n, m, p, or q is 0, 1 or 2. In some embodiments, n, m, p, or q is 0 or 1. In some embodiments, n, m, p, or q is 0.
• R 1 is, independently, alkyl, alkoxy, heteroalkyl, halo, haloalkyl, or haloalkoxy. In some embodiments, R 1 is, independently, Ci -6 alkyl, Ci -6 alkoxy, Ci. 6 haloalkyl, Ci -6 haloalkoxy, or halo. In some embodiments, R 1 is, independently, Ci -6 alkyl or Ci-6 alkoxy. In some embodiments, R 1 is, independently, alkoxy. In some embodiments, R 1 is, independently, methoxy, ethoxy, propoxy. In some embodiments, n, m, p, or q is 0, 1 or 2. In some embodiments, n, m, p, or q is 0 or 1. In some embodiments, n, m, p, or q is 0.
• the compound of Formula (II) is a compound of Formula
• R 1 is, independently at each occurrence, halo, methyl, methoxy, or tnfluoromethyl; and n is 0, 1, or 2.
• R 1 is alkyl, alkoxy, haloalkyl, or halo.
• R 1 is methyl, trifluoromethyl, methoxy, fluoro, chloro, or bromo.
• R 1 is methyl.
• R 1 is methoxy.
• R 1 is trifluoromethyl.
• R 1 is fluoro.
• R 1 is chloro.
• R 1 is bromo.
• R 1 is heterocycloalkyl.
• R 1 is pynolidinyl. In some examples, R 1 is morpholinyl.
• a compound of Formula IIA 1-3 is a compound of Formula IIA 1-3 :
• A is:
• R 1 independently at each occurrence, is selected from alkyl, alkoxy, halo, haloalkyl, and heterocycloalkyl; ann is an integer from 0 to 4.
• the compound is selected from a compound of the Formula IIAl), a compound of the Formula ( ⁇ 2), and a compound of the Formula (IIA3):
• R 1 is, independently at each occurrence, selected from methyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, pyrrolidinyl, and morpholinyl.
• R 1 is methyl
• R 1 independently at each occurrence, is selected from fluoro, chloro, and bromo.
• R 1 is chloro
• R 1 is trifluoromethyl.
• R 1 is methoxy
• R 1 is, independently at each occurrence, selected from methyl, morpholinyl, and pyrrolidinyl.
• the compound of Formula (II) is a compound of Formula
• R 1 is, independently at each occurrence, halo or trifluoromethyl; and q is 0, 1, or 2.
• the compound of Formula (II) is:
• the compound of Formula (II) is:
• these compounds represent the payload portion of the conjugates described herein and are released, e.g., by enzyme proteolysis, following internalization of the conjugate into a cell.
• the methods provided herein include methods of treating a proliferative disease, e.g., cancer, comprising administering to a patient a proliferative disease, e.g., cancer, comprising administering to a patient a proliferative disease, e.g., cancer, comprising administering to a patient a proliferative disease, e.g., cancer, comprising administering to a patient a proliferative disease, e.g., cancer
• a conjugate e.g., antibody-drug conjugate that releases a compound of Formula (II) following internalization of said conjugate into a cell in said patient.
• these compounds represent the metabolic product of the conjugates described herein, e.g., enzyme proteolysis product.
• A is a divalent radical of benzene, of pyridine, of naphthalene, or of quinolone, which are optionally substituted.
• A is arylene
• A is:
• R 1 is, independently at each occurrence, alkyl, alkenyl, alkynyl, aryl, alkaryl, arylalkyl,
• R A is alkyl
• n is an integer from 0 to 4.
• n is and integer from 0 to 3;
• p is an integer from 0 to 6;
• q is an integer from 0 to 5.
• the compound of Formula (II) is a compound of the
• R 1 is, independently at each occurrence, methyl, methoxy, halo or trifluorom ethyl; and n is 0, 1, or 2.
• R 1 is methyl, trifluoromethyl, methoxy, fluoro, chloro, or bromo.
• R 1 is methyl.
• R 1 is methoxy.
• R 1 is trifluoromethyl.
• R 1 is fluoro.
• R 1 is chloro.
• R 1 is bromo.
• the compound of Formula (II) is a compound of the
• R 1 is, independently at each occurrence, methoxy, methyl, halo or trifluoromethyl; and q is 0, 1, or 2.
• the compound of Formula (II) is a compound of the
• R 1 is, independently at each occurrence, methoxy, halo or trifluoromethyl; and q is 0, 1, or 2.
• the compound of Formula (II) is a compound of the
• R 1 is, independently at each occurrence, methoxy, halo or
• R 1 is, independently, alkyl or halo. In some embodiments, R 1 is, independently, Ci -6 alkyl, Ci -6 haloalkyl, or halo. In some
• R 1 is, independently, Ci -6 haloalkyl or halo. In some embodiments, R 1 is, independently, halo. In some embodiments, R 1 is, independently, fluoro, chloro, bromo, iodo, or trifluoromethyl. In some embodiments, n, m, p, or q is 0, 1 or 2. In some embodiments, n, m, p, or q is 0 or 1. In some embodiments, n, m, p, or q is 0.
• R 1 is, independently, alkyl, alkoxy, heteroalkyl, halo, haloalkyl, or haloalkoxy. In some embodiments, R 1 is, independently, Ci -6 alkyl, Ci -6 alkoxy, Ci. 6 haloalkyl, Ci -6 haloalkoxy, or halo. In some embodiments, R 1 is, independently, Ci -6 alkyl or Ci-6 alkoxy. In some embodiments, R 1 is, independently, alkoxy. In some embodiments, R 1 is, independently, methoxy, ethoxy, propoxy. In some embodiments, n, m, p, or q is 0, 1 or 2. In some embodiments, n, m, p, or q is 0 or 1. In some embodiments, n, m, p, or q is 0.

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