US20160375147A1 - Maytansinoid derivatives, conjugates thereof, and methods of use - Google Patents

Maytansinoid derivatives, conjugates thereof, and methods of use Download PDF

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US20160375147A1
US20160375147A1 US15/081,759 US201615081759A US2016375147A1 US 20160375147 A1 US20160375147 A1 US 20160375147A1 US 201615081759 A US201615081759 A US 201615081759A US 2016375147 A1 US2016375147 A1 US 2016375147A1
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compound
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methyl
antibody
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Thomas Nittoli
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Regeneron Pharmaceuticals Inc
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    • A61K47/48384—
    • 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
    • A61K31/5365—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K47/48561—
    • 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
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • 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
    • A61K47/6849—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 receptor, a cell surface antigen or a cell surface determinant
    • 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
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/08—Bridged 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

Definitions

  • the present disclosure concerns maytansinoid derivatives, conjugates thereof, and methods of treating or preventing proliferative diseases with the same.
  • Proliferative diseases for example cancer
  • 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.
  • ADCs Antibody drug conjugates
  • 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.
  • A is arylene or heteroarylene
  • L is a linker
  • BA is a binding agent
  • k is an integer from 1 to 30. Also provided herein are stereoisomers of compounds of Formula (I).
  • A is arylene or heteroarylene.
  • A is arylene or heteroarylene and L is a linker.
  • stereoisomers of compounds of Formula PT1 are also provided herein.
  • FIG. 1 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-4-aminobenzamido-citrulline-valine-caprolyl-6-maleimidyl.
  • FIG. 2 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 41.
  • FIG. 3 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 41.
  • FIG. 4 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 41.
  • FIG. 5 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 41.
  • FIG. 6 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(4-amino-2-fluoro)benzamido-Cit-Val-Cap-Mal.
  • FIG. 7 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(4-amino-2-trifluoromethyl)benzamido-Cit-Val-Cap-Mal.
  • FIG. 8 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(4-amino-2-methoxy)benzamido-Cit-Val-Cap-Mal.
  • FIG. 9 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-4-aminobenzamide.
  • FIG. 10 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-fluoro-4-amino)benzamide
  • FIG. 11 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-trifluoromethyl-4-amino)benzamide.
  • FIG. 12 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-methoxy-4-amino)benzamide.
  • FIG. 13 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-trifluoromethyl-4-amino)benzamide.
  • FIG. 14 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2-chloro-4-amino-5-fluoro)benzamide.
  • FIG. 15 depicts a general synthetic sequence for preparing compounds of Formula (II) wherein substituent R is defined herein and below.
  • FIG. 16 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2,5-difluoro-4-amino)benzamide.
  • FIG. 17 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-fluoro-4-amino)benzamide
  • FIG. 18 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-chloro-4-amino)benzamide.
  • FIG. 19 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(5-amino-8-carboxyquinoline)carboxamide.
  • FIG. 20 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-bromo-4-amino)benzamide.
  • FIG. 21 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-methoxy-4-amino)benzamide.
  • FIG. 22 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-methyl-4-amino)benzamide.
  • FIG. 23 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-methyl-4-amino)benzamide.
  • FIG. 24 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(8-amino-5-carboxyquinoline)carboxamide.
  • FIG. 25 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(3-methoxy-4-amino)benzamido-Cit-Val-Cap-Mal.
  • FIG. 26 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-(2-fluoro-4-amino)benzamido-Cit-Val-Cap-6-amine.
  • FIG. 27 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2-methoxy-5-amino)benzamide.
  • FIG. 28 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-amino-4-methoxy)benzamide.
  • FIG. 29 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-amino-5-fluoro)benzamide.
  • FIG. 30 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2-fluoro-5-amino)benzamide.
  • FIG. 31 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-amino)benzamide.
  • FIG. 32 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-amino-4-fluoro)benzamide.
  • FIG. 33 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-4-aminobenzamide-adipic-NHS.
  • FIG. 34 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-4-aminobenzamide-Cap-Mal.
  • FIG. 35 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-methylsulfonyl-4-amino)benzamide.
  • FIG. 36 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-hydroxy-4-amino)benzamide.
  • FIG. 37 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(2-amino)benzamide.
  • FIG. 38 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(4-methoxy-2-amino)benzamide.
  • FIG. 39 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-morpholino-4-amino)benzamide.
  • FIG. 40 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-(3-acetamido-4-amino)benzamide.
  • FIG. 41 depicts a synthetic sequence for preparing maytansin-N-methyl-L-alanine-N-4-aminobenzamide-Cit-Val-cap-diBromomethylacryl.
  • FIG. 42 depicts the deconvoluted mass spectroscopy (MS) spectrum of the antibody drug conjugate, PRLR-Q-63 conjugate from EXAMPLE 43.
  • FIG. 43 depicts the deconvoluted MS spectrum of the Isotype Control-Q-63 conjugate from EXAMPLE 43.
  • FIG. 44 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 45.
  • FIG. 45 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 45.
  • FIG. 46 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 45.
  • FIG. 47 depicts the plot of % Cell Viability vs. Log 10 [M] of certain compounds tested in EXAMPLE 45.
  • 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., C 1-20 alkyl; 1-12 carbon atoms, i.e., C 1-12 alkyl; 1-8 carbon atoms, i.e., C 1-8 alkyl; 1-6 carbon atoms, i.e., C 1-6 alkyl; and 1-3 carbon atoms, i.e., C 1-3 alkyl.
  • alkyl moieties include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-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, Cl, 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 2-20 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. Examples of 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 2-20 alkynyl; 2-12 carbon atoms, i.e., C 2-12 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, e.g., CH 3 CH 2 —O 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., C 1-20 alkoxy; 1-12 carbon atoms, i.e., C 1-12 alkoxy; 1-8 carbon atoms, i.e., C 1-8 alkoxy; 1-6 carbon atoms, i.e., C 1-6 alkoxy; and 1-3 carbon atoms, i.e., C 1-3 alkoxy.
  • alkoxy moieties include, but are not limited to methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-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, Cl, 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 6-20 aryl; 6 to 15 ring carbon atoms, i.e., C 6-15 aryl, and 6 to 10 ring carbon atoms, i.e., C 6-10 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.
  • Examples of aryl moieties include, but are not limited to those having 6 to 20 ring carbon atoms, i.e., C 6-20 arylene; 6 to 15 ring carbon atoms, i.e., C 6-15 arylene, and 6 to 10 ring carbon atoms, i.e., C 6-10 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.
  • heteroalkyl moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, sulfinylalkyl.
  • heteroalkyl moieties also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl.
  • 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 ring atoms of the aromatic ring are replaced with an oxygen, sulfur, nitrogen, or phosphorus atom. Heteroarylene is optionally substituted.
  • heterocycloalkyl refers to a cycloalkyl in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heterocycloalkyl is optionally substituted. Examples of heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl, or thianyl.
  • 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,
  • R A , R B , and R C are, independently at each occurrence, a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B , 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 replaced with a heteroatom.
  • R A , R B , and R C are not hydrogen atoms.
  • R A is methyl.
  • R A is methylamino, methylsulfonyl, and methylsulfinyl. In some examples, R A is methylamino.
  • R A is methylamino, methylsulfonyl, and methylsulfinyl. In some examples, R A is methylamino.
  • the substituents on the optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring, if they are substituted, are not substituted with substituents which are further optionally substituted with additional substituents.
  • the substituent bonded to the group is unsubstituted unless otherwise specified.
  • 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 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 refers 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-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexaflu
  • 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. 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.
  • Certain groups, moieties, substituents, and atoms are depicted with a wiggly line that intersects a bond or bonds to indicate the atom through which the groups, moieties, substituents, atoms are bonded.
  • cyclic group e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl
  • substituents bonded to a cyclic group 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.
  • subscript q is an integer from 0 to 4 and in which the positions of substituent R 1 are described generically, includes the following groups in which the positions of substituent 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 group:
  • 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. In some embodiments, 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 is:
  • A is:
  • R 1 is C 1-6 alkyl or C 1-6 alkoxy. In some of these embodiments, R 1 is methyl, ethyl, methoxy, or ethoxy. In some of these embodiments, R 1 is methoxy.
  • R 1 is, independently, alkyl or halo. In some embodiments, R 1 is, independently, C 1-6 alkyl, C 1-6 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 N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R A is methyl.
  • R 1 is hydroxyl.
  • R 1 is N-methylformamide.
  • R 1 is morpholinyl.
  • R 1 is, independently, alkyl, alkoxy, or halo. In some embodiments, R 1 is, independently, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 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.
  • A is:
  • A is:
  • A is:
  • A is:
  • n 0, 1 or 2.
  • A is:
  • n 0, 1 or 2.
  • A is:
  • n is 0 or 1; and R 1 is alkoxy, halo, or haloalkyl.
  • A is:
  • n is 0 or 1; and R 1 is alkoxy, halo, or haloalkyl. In some examples, R 1 is alkoxy.
  • A is:
  • n is 0 or 1; and R 1 is C 1-6 alkoxy, halo, or C 1-6 haloalkyl.
  • A is:
  • n is 0 or 1; and R 1 is C 1-6 alkoxy, halo, or C 1-6 haloalkyl. In some examples, R 1 is C 1-6 alkoxy.
  • A is:
  • n 0 or 1
  • R 1 is C 1-6 alkoxy, halo, or C 1-6 haloalkyl
  • L is
  • b is an integer from 2 to 8.
  • A is:
  • n 0 or 1
  • R 1 is C 1-6 alkoxy, halo, or C 1-6 haloalkyl
  • L is
  • b is an integer from 2 to 8.
  • A is:
  • n 0, 1, 2, 3, or 4.
  • A is:
  • n 0, 1, 2, 3, or 4.
  • A is:
  • R 1 is C 1-6 alkyl, halo, or C 1-6 haloalkyl
  • n 0, 1 or 2.
  • A is:
  • A is:
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy, halo, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • n 0, 1, 2, 3, or 4.
  • A is:
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy, halo, C 1-6 haloalkyl, or C 1-6 haloalkoxy;
  • n 0, 1, 2, 3, or 4.
  • A is:
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy, halo, or C 1-6 haloalkyl. In certain of these embodiments, R 1 is methoxy or methyl. In some specific embodiments, R 1 is methoxy.
  • A is:
  • A is:
  • R 1 is halo or trifluoromethyl
  • n 0, 1 or 2.
  • A is:
  • A is:
  • X is a hydrogen atom, halo, or trifluoromethyl.
  • A is:
  • X is a hydrogen atom, halo, or trifluoromethyl
  • A is:
  • R 1 is the bond to the carbonyl.
  • R 1 is 1-methylethyl-thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • R 1 is hydrogen.
  • A is:
  • R 1 is the bond to the carbonyl.
  • R 1 is 1-methylethyl-thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • R 1 is hydrogen.
  • R 1 is sulfonyl. In some embodiments, R 1 is N-methylformamide. In some embodiments, R 1 is hydroxyl. In some embodiments, R 1 is morpholinyl.
  • A is:
  • R 1 is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, aryl, heteroalkyl, halo, haloalkyl, or haloalkoxy;
  • R 1 is the bond to the carbonyl.
  • R 1 is alkyl or alkoxy.
  • R 1 is propylamino, difluoro-methoxy, phenyl, 2-fluorophenyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • R 1 is hydrogen.
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • X is F, Cl, Br, CN, methoxy, dimethylamino or cyclopropyl
  • A is:
  • X is F, Cl, Br, CN, methoxy, dimethylamino, 1-methyl-ethyl-thio or cyclopropyl;
  • A is:
  • each R 1 is independently, at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy;
  • R 1 is the bond to the carbonyl.
  • R 1 is hydrogen, fluoro, trifluoromethyl, or methoxy.
  • 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,
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • n 0, 1 2, or 3.
  • A is:
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy, halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 heteroalkyl;
  • n 0, 1 2, 3 or 4.
  • A is:
  • A is:
  • A is:
  • X is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkoxy, haloalkyl, heteroalkyl.
  • X is fluoro, chloro, bromo, iodo, dimethylamino, methylamino, methoxy, ethoxy, or trifluoromethyl.
  • A is:
  • X is, independently at each occurrence, a hydrogen atom, alkyl, alkoxy, halo, haloalkoxy, haloalkyl, heteroalkyl.
  • X is fluoro, chloro, bromo, iodo, dimethylamino, methylamino, methoxy, ethoxy, trifluoromethyl or methoxy;
  • linker portion of the conjugates described herein is a divalent moiety that covalently links the binding agent to the maytansinoid derivatives described herein.
  • Suitable linkers include those that release 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 linker comprises a non-cleavable moiety. In some embodiments, the non-cleavable linker is
  • the non-cleavable linker is
  • 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 - ⁇ -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
  • AA 1 is an amino acid
  • AA 2 is an amino acid.
  • the spacer is a divalent moiety that connects the AA 1 -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.
  • suitable spacers include, but are not limited to, a primary amine-terminated alkylene or a primary amine-terminated polyethylene glycol.
  • the primary amine-terminating end of the spacer can be directly bonded to a deglycosylated antibody or aglycosylated antibody in the presence of transglutaminase.
  • the spacer comprises an alkylene. In some embodiments, the spacer comprises a C 5-7 alkylene. In some embodiments, the spacer is:
  • b is an integer from 2 to 8.
  • the spacer comprises a primary amine-terminated alkylene. In some embodiments, the spacer comprises a NH 2 —C 5-7 alkylene. In some embodiments, the spacer is:
  • b is an integer from 2 to 8.
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • R N is a hydrogen atom or alkyl
  • R M is alkyl
  • bonds to cysteines of a binding agent are bonds to cysteines of a binding agent
  • 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
  • n is an integer from 4 to 10. In some embodiments, n is 4, 5, 6, 7, 8, 9, or 10.
  • the spacer is:
  • the spacer is
  • n is an integer from 4 to 10. In some embodiments, n is 4, 5, 6, 7, 8, 9, or 10.
  • 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 N and R M are each, independently, hydrogen or alkyl
  • b is an integer from 1 to 8.
  • AA 1 -AA 2 is: valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, 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, or asparagine-alanine.
  • AA 1 -AA 2 is: valine-citrulline or citrulline-valine. In some embodiments, AA 1 -AA 2 is: valine-citrulline.
  • the linker is:
  • SP is a spacer
  • 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 ⁇ -carbon of an ⁇ -amino acid, including natural and non-natural amino acids.
  • exemplary amino acid side chains include, but are not limited to, the ⁇ -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
  • the linker is:
  • b is an integer from 2 to 8.
  • the linker is:
  • b is an integer from 2 to 8.
  • BA is an antibody and the linker is:
  • b is an integer from 2 to 8.
  • BA is an antibody and the linker is:
  • b is an integer from 2 to 8.
  • BA is an antibody and the linker is:
  • R N is a hydrogen atom or alkyl
  • R M is alkyl
  • b is an integer from 2 to 8.
  • the linker is:
  • 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 is:
  • the linker is:
  • 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 U.S. Pat. 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; alpha1-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
  • antigens also include, but are not limited to, BCMA, SLAMF7, B7H4, GPNMB, UPK3A, and LGR5.
  • the antigens include prolactin receptor (PRLR) or prostate-specific membrane antigen (PSMA).
  • PRLR prolactin receptor
  • PSMA prostate-specific membrane antigen
  • 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, 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., U.S. Pat. No. 5,208,020; US 2010/0129314; Hollander et al., Bioconjugate Chem., 2008, 19:358-361; WO 2005/089808; U.S. Pat. No.
  • cysteine see, e.g., US 2007/0258987; WO 2013/055993; WO 2013/055990; WO 2013/053873; WO 2013/053872; WO 2011/130598; US 2013/0101546; and U.S. Pat. No. 7,750,116
  • selenocysteine see, e.g., WO 2008/122039; and Hofer et al., Proc. Natl. Acad. Sci., USA, 2008, 105:12451-12456
  • formyl glycine see, e.g., Carrico et al., Nat. Chem.
  • 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, 13:127-130) 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:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • A is:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • 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:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • 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
  • R AA1 is an amino acid side chain
  • R AA2 is an amino acid side chain.
  • A is:
  • SP is a spacer
  • 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 C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • 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:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • 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:
  • A is:
  • R 1 independently at each occurrence, is C 1-6 alkyl, C 1-6 haloalkyl, or halo;
  • n, m, p, and q are 0, 1, or 2;
  • b is an integer from 2 to 8.
  • A is:
  • b is an integer from 2 to 8.
  • A is:
  • A is:
  • A is:
  • b is an integer from 2 to 8.
  • A is:
  • A is:
  • A is:
  • A is:
  • A is:
  • R 1 is the bond to the carbonyl.
  • R 1 is 1-methylethyl-thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • R 1 is hydrogen.
  • A is:
  • R 1 is the bond to the carbonyl.
  • R 1 is 1-methylethyl-thiol, phenyl, 2-fluorophenyl, pyridinyl, 4-pyridinyl, pyrrolidinyl, or 1-pyrrolidinyl.
  • R 1 is trifluoromethyl.
  • R 1 is methoxy.
  • R 1 is fluoro.
  • 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:
  • A is:
  • R AA2 is an amino acid side chain.
  • A is:
  • b is an integer from 2 to 8.
  • A is:
  • A is:
  • R 1 independently at each occurrence, is alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, aralkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroalkyl, heterocycloalkyl, cyano, nitro,
  • 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+t 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.
  • 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:
  • the linker is:
  • SP is a spacer
  • AA 1 is an amino acid
  • AA 2 is an amino acid.
  • the spacer is a divalent moiety that connects the AA 1 -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 C 5-7 alkylene. In some embodiments, the spacer is:
  • b is an integer from 2 to 8.
  • the spacer is:
  • the spacer is:
  • R N is a hydrogen atom or alkyl
  • R M is alkyl
  • bonds to cysteines of a binding agent are bonds to cysteines of a binding agent
  • 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:
  • the spacer is:
  • the spacer is:
  • the spacer is:
  • X is N or O
  • R N and R M are each, independently, hydrogen or alkyl
  • b is an integer from 1 to 8.
  • AA 1 -AA 2 is: valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, 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, or asparagine-alanine.
  • AA 1 -AA 2 is: valine-citrulline or citrulline-valine. In some embodiments, AA 1 -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:
  • the compound of Formula I is:
  • 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 embodiments, the drug-antibody ratio (DAR) of the conjugate is from 1.0 to 3.0.
  • DAR drug-antibody ratio
  • A is arylene or heteroarylene.
  • 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 therapeutically effective amount of 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:
  • the compound of Formula (II) is a compound of the Formula (IIA):
  • R 1 and n are as defined herein.
  • the compound of Formula (II) is a compound of the Formula (IIB):
  • R 1 and q are as defined herein.
  • the compound of Formula (II) is a compound of the Formula (IIB2):

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CL2017002422A1 (es) 2018-03-16
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