WO2025102002A1 - Keto-amide-based fibroblast activation protein-targeted ligand linked to a pi3k inhibitor, compositions and methods of use - Google Patents

Keto-amide-based fibroblast activation protein-targeted ligand linked to a pi3k inhibitor, compositions and methods of use Download PDF

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WO2025102002A1
WO2025102002A1 PCT/US2024/055264 US2024055264W WO2025102002A1 WO 2025102002 A1 WO2025102002 A1 WO 2025102002A1 US 2024055264 W US2024055264 W US 2024055264W WO 2025102002 A1 WO2025102002 A1 WO 2025102002A1
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conjugate
alkyl
group
formula
moiety
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Philip Low
Madduri SRINIVASARAO
Spencer LINDEMAN
Ramesh Mukkamala
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Purdue Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present disclosure relates to conjugates comprising a fibroblast activation protein ⁇ (FAP- ⁇ )-targeted ligand, a bifunctional or trifunctional linker, and a phosphatidylinositol-3-kinase (PI3k) inhibitor; and methods of use of the conjugates as a pharmaceutical composition in the inhibiting the progression of a fibrosis in a subject.
  • FAP- ⁇ fibroblast activation protein ⁇
  • PI3k phosphatidylinositol-3-kinase
  • Idiopathic pulmonary fibrosis is a progressive fibrotic disease. It is believed to be caused by repetitive environmental injury to the lining of the lungs and resulting abnormal wound- healing responses. When lung tissues experience prolonged activation of wound healing responses, the result is typically permanent scarring, organ malfunction, and death.
  • IPF Idiopathic pulmonary fibrosis
  • the conjugate can have or comprise a conjugate of formula I, or be a stereoisomer or a pharmaceutically acceptable salt thereof.
  • Formula I can be or comprise: wherein A has the structure: wherein: represents a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R 1 and R 2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl; R 3 and R 4 are independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl; R 5 and R 6 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -
  • L can be attached to A at any carbon atom of the functionalized 5- to 10-membered N- containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl.
  • each R 2 is independently selected from the group consisting of -H, -D, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • R5 and R6 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • B can be or comprise a radical of a PI3k inhibitor or a dual PI3k/mTOR inhibitor.
  • the PI3k/mTOR inhibitor can be a radical of a compound selected from:
  • the PI3k inhibitor can be a radical o wherein X is or comprises a structure selected from: . [0014] In certain embodiments, the PI3k inhibitor is a radical of . [0015] The PI3k inhibitor is a radical of (GSK1059615), or (BEZ235, NVP-BEZ235 or dactolisib). [0016] L of the conjugate can be or can comprise a moiety of the formula: , wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula: , wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula: .
  • L can be or can comprise a moiety of the formula: wherein n is an integer from 0 to 20.
  • L can be or can comprise a moiety of the formula: .
  • L can be or can comprise a moiety of the formula: [0019]
  • L can be or can comprise a moiety of the formula: wherein n is an integer from 0 to 20.
  • L can be or can comprise a moiety of the formula: , wherein n is an integer from 0 to 20.
  • L can be a linker that can be cleaved (e.g., under physiological conditions).
  • L can be cleaved reductively, oxidatively, or enzymatically.
  • L can comprise an oxime ester.
  • L can comprise a hydrazone.
  • L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar.
  • L can be or can comprise
  • L can be or comprise: wherein: R 27 and R 28 are each independently selected from the group consisting of H and C 1 -C 6 alkyl; and Z is an integer from 1 to 8. [0021] L can comprise the structure: wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are each independently selected from the group consisting of H and C1-C6 alkyl. [0022] The conjugate can be selected from:
  • the conjugate can be selected from:
  • the conjugate can be selected from:
  • the conjugate of formula I can, in certain embodiments, further comprise a pharmacokinetic extender C (e.g., a radical of a pharmacokinetic extender C).
  • the conjugate of formula I has the formula (II):
  • A, B, and L of formula (II) can be or comprise any A, B, or L, respectively, described in connection with formula (I).
  • C can be an albumin binder, a plasma protein binder, or a hapten.
  • C can be an albumin binder, a plasma protein binder, or a hapten.
  • the albumin binder can be or can comprise albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti-albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06).
  • C can be or can comprise any of the following structures:
  • C can be or can comprise:
  • C can be or can comprise: H .
  • C can be or can comprise:
  • the hapten can be recognized (or recognizable) by an autologous antibody.
  • the hapten can be selected from the group consisting of rhamnose, an ⁇ -galactosyl moiety, a dinitrophenyl (DNP) moiety, and a trinitrophenyl (TNP) moiety.
  • the conjugate can have a structure selected from:
  • L is or comprises at least one carbon atom, and p is 0-3.
  • L can be or can comprise a moiety of the formula: , wherein n is an integer from 0 to 10.
  • L can be or can comprise a moiety of the formula: , wherein n is an integer from 0 to 10.
  • L can be or can comprise a moiety of the formula: [0031]
  • L can be or can comprise a moiety of the formula: wherein n is an integer from 0 to 10.
  • L can be or can comprise a moiety of the formula: .
  • L can be or can comprise a moiety of the formula: [0032]
  • L can be or can comprise a moiety of the formula: wherein n is an integer from 0 to 20.
  • L can be or can comprise a moiety of the formula: wherein n is an integer from 0 to 20.
  • L can be a linker that can be cleaved (e.g., under physiological conditions).
  • L can be cleaved reductively, oxidatively, or enzymatically.
  • L can comprise an oxime ester.
  • L can comprise a hydrazone.
  • L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar.
  • L can be or can comprise: .
  • L can be or comprise a structure selected from: wherein: R 27 and R 28 are each independently selected from the group consisting of H and C 1 -C 6 alkyl; and Z is an integer from 1 to 8. [0034] L can comprise the structure: wherein: R31 is H or C1-C6 alkyl; and R 29a , R 29b , R 30a, and R 30b are each independently selected from the group consisting of H and C1-C6 alkyl. [0035] Still further provided is a conjugate having a structure selected from:
  • conjugate hereof Uses of a conjugate hereof, or a stereoisomer or a pharmaceutically acceptable salt thereof, or optionally a pharmaceutical composition comprising an effective amount of such a conjugate, stereoisomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of the progression of fibrosis in a subject are also provided.
  • the conjugate can be any conjugate hereof.
  • the conjugate comprises an albumin binder, a plasma protein binder, or a hapten.
  • the C can be an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti-albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06).
  • Methods are also provided for inhibiting the progression of fibrosis in a subject. Such am ethod can comprise administering to the subject an effective amount of a conjugate hereof, or a stereoisomer or a pharmaceutically acceptable salt thereof, whereupon the progression of fibrosis in the subject is inhibited or otherwise alleviated.
  • FIG.1 is a synthesis scheme for conjugates hereof (further described in Example 1 below); and [0003] FIG.2 shows data from a liquid chromatography-mass spectrometry (LC-MS) analysis of conjugates hereof.
  • LC-MS liquid chromatography-mass spectrometry
  • Conjugates are provided that comprise a phosphatidylinositol-3-kinase (PI3K) inhibitor or a dual inhibitor of the PI3K/mTOR signaling pathway. Such conjugates can further comprise a linker and a FAP8 payload. In certain embodiments, the conjugates are useful for inhibiting progression of fibrosis in a subject. “Inhibiting” and its formatives means hindering, retarding, abrogating, or reversing the onset or progression of fibrosis or related symptoms.
  • PI3K phosphatidylinositol-3-kinase
  • the subject can be a human or a mammal of economic importance and/or social importance to humans, for instance, carnivores other than humans (e.g., cats and dogs), swine (e.g., pigs, hogs, and wild boars), ruminants (e.g., cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), horses, and birds including those kinds of birds that are endangered and kept in zoos, and fowl, more particularly domesticated fowl, e.g., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economic importance to humans.
  • carnivores other than humans e.g., cats and dogs
  • swine e.g., pigs, hogs, and wild boars
  • ruminants e.g., cattle, oxen, sheep
  • subject does not denote a particular age. Thus, adult, juvenile and newborn subjects are covered.
  • subject, “ “individual” and “patient” may be used interchangeably herein.
  • the subject is a mammal.
  • the subject is a human.
  • a method of treating fibrosis in a subject is also provided.
  • the terms “treat,” “treatment,” and “treating” refer to any and all uses which remedy a condition or symptom, or otherwise prevent, hinder, retard, abrogate or reverse the onset or progression of fibrosis or other undesirable symptoms in any way whatsoever.
  • the term “treating,” and the like is to be considered in its broadest possible context.
  • treatment does not necessarily imply that a subject is treated until total recovery or cure.
  • the treatment need not necessarily remedy, prevent, hinder, retard, abrogate or reverse all signs or symptoms, but can remedy, prevent, hinder, retard, abrogate or reverse one or more signs or symptoms.
  • the method can comprise administering to the subject an effective amount of a conjugate hereof or a stereoisomer or pharmaceutically acceptable salt thereof, whereupon the subject is treated for fibrosis.
  • the conjugate can be or comprise formula I or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the conjugate of formula I Formula I can be or comprise: wherein A has the structure: wherein: a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R 1 and R 2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl; R 3 and R 4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • the conjugate can optionally be formulated as a pharmaceutical composition, for example, further comprising a pharmaceutically acceptable carrier.
  • administering of the conjugate or composition to a subject means that the conjugate or composition is presented such that the conjugate can be transferred to the subject.
  • the mode of administration can be by way of oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intracerebrally, intranasally, intrathecal, and intraspinal), inhalation (including nebulisation), topical, rectal or vaginal modes.
  • the conjugate or composition can also be administered directly into a tumor and/or into tissue adjacent to one or more segments of a tumor or administered directly into blood vessels.
  • the conjugate can be administered in, as appropriate, a treatment or diagnostic effective amount.
  • a treatment or diagnostic effective amount is intended to include an amount which, when administered according to the desired dosing regimen, achieves a desired therapeutic or diagnostic effect, including one or more of: alleviating the symptoms of, preventing or delaying the onset of, inhibiting or slowing the progression of, diagnosing, or halting or reversing altogether the onset or progression of a particular condition being treated and/or assessed.
  • the expressions “effective amount” and “therapeutically effective amount” mean the amount of conjugate when administered to a mammal, in particular a human, in need of such treatment, is sufficient to treat cancer.
  • the precise amount of conjugate to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the subject.
  • Suitable dosage amounts and dosing regimens to achieve this can be determined by the attending physician and can depend on the particular condition being treated or diagnosed, the severity of the condition as well the general age, health and weight of the subject.
  • Dosing can occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods.
  • Suitable dosages of the particulate material per se can lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage.
  • the dosage can be in the range of 1 ⁇ g to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage.
  • the dosage can be in the range of 1 mg to 500 mg per kg of body weight per dosage.
  • the dosage can be in the range of 1 mg to 400 mg per kg of body weight per dosage.
  • the dosage can be in the range of 1 mg to 350 mg per kg of body weight per dosage.
  • the dosage can be in the range of 1 mg to 300 mg per kg of body weight per dosage.
  • the dosage can be in the range of 1 mg to 275 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 250 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 200 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 150 mg per kg of body weight per dosage. In yet another embodiment, the dosage can be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage. All ranges set forth in this paragraph are inclusive of their stated end points and all 1 mg increments encompassed thereby.
  • Conjugates or compositions can be administered in a single dose or a series of doses.
  • L can be attached to A at any carbon atom of the functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl.
  • each R 2 is selected from the group consisting of -H, -D, -OH, -F, -Cl, -Br, I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • R5 and R6 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • PI3k kinases are members of a unique and conserved family of intracellular lipid kinases that can phosphorylate the 3'-OH group on phosphatidylinositols or phosphoinositides.
  • PI3k kinases are key signaling enzymes that rcan relay signals from cell surface receptors to downstream effectors.
  • the PI3k signaling pathway can be highly mutated in human cancers, and PI3k signaling can be a key factor in disease states including inflammatory disease states and fibrosis.
  • Downstream mediators of the PI3k signal transduction pathway include Akt and mammalian target of rapamycin (mTOR).
  • mTOR is a serine-threonine kinase related to the lipid kinases of the PI3k family and has been implicated in a wide range of biological processes including cell growth, cell proliferation, cell motility and survival. Disregulation of the mTOR pathway can occur in various disease states, including cancer.
  • B of formula I can be or comprise a PI3k inhibitor or a dual PI3k/mTOR inhibitor, or a radical of a PI3k inhibitor or a radical of a dual PI3k/mTOR inhibitor.
  • the PI3k/mTOR inhibitor can be or comprise a compound selected from: [0052]
  • the PI3k inhibitor can be a radical o wherein X is or comprises a structure selected from: .
  • the PI3k inhibitor is a radical of .
  • the PI3k inhibitor is a radical o
  • L of the conjugates can be a bifunctional or trifunctional linker.
  • L of the conjugates can be a linker that can be cleaved or a “releasable” linker.
  • L of the compounds hereof can be a non- releasable linker.
  • the term “releasable linker” is a linker that includes at least one bond that can be broken or cleaved under physiological conditions, such as reductive, acidic, basic, oxidative, metabolic, biochemical, enzymatic (e.g., cathepsin B-cleavable), or other conditions (e.g., p-aminobenzylic- based multivalent releasable bond (see, e.g., International Patent Application Publication Number WO 2017/0205661)).
  • a “releasable linker” is a linker that can be cleaved to varying degrees under certain conditions and, in particular, can be fragmented or cleaved in less than about 1 week when under, or otherwise exposed to, certain metabolic, physiological, or cellular conditions that can initiate a cascade of fragmentation or bond cleavage (which may, for example, result in the release of one or more moieties connected through one or more portions of the linker (e.g., A and B)).
  • Bond cleavage can occur by standard chemical hydrolysis reactions that occur, for example, at physiological pH, or as a result of compartmentalization into a cellular organelle such as an endosome having a lower pH than cytosolic pH.
  • Bond cleavage can also occur by acid catalyzed elimination. Alternatively, fragmentation can be initiated by a nucleophilic attack on a disulfide group of the quick-release linker, causing cleavage to form a thiolate, for example. In any of these cases, the quick-release nature of such linkers can be realized by whatever mechanism may be relevant to the chemical, metabolic, physiological, or biological conditions present.
  • a releasable linker comprises one or more sulfide bridges.
  • a non-releasable linker means a linker that includes at least one bond that is not easily or quickly broken (i.e.
  • the bond does not cleave) and, while potentially cleavable or fragmentable to varying degrees under certain conditions, does not cleave, fragment, or otherwise release one or more of the moieties connected through one or more portions of the linker (e.g., A and B) when subjected to certain metabolic, physiological, or cellular conditions that may initiate a cascade of fragmentation (e.g., after administration to a subject) for more than about 1 week (e.g., 1 week), more than about 1 month (e.g., 1 month), more than about 4 months (e.g., 4 months), more than about 6 months (e.g., 6 months), or more than about 1 year (e.g., 1 year).
  • the linker e.g., A and B
  • a non-releasable linker comprises one or more amides, esters, ethers, amines, or thioethers (e.g., thio-maleimide), for example.
  • the linker comprises an ester, phosphate, oxime, acetal, pyrophosphate, polyphosphate, disulfide, sulfate, hydrazide, imine, carbonate, carbamate or enzyme-cleavable amino acid sequence.
  • L can comprise an oxime ester.
  • L can comprise a hydrazone.
  • L can comprise polyethylene glycol (PEG).
  • L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar.
  • the linker(s) can comprise a self-immolative disulfide group.
  • An example of a self- immolative disulfide also includes a sterically protected disulfide bond.
  • the steroid can be attached to the linker via any other suitable self-immolative bond, including via a self-immolative cathepsin cleavable amino acid sequence; via a self-immolative furin cleavable amino acid sequence; via a self-immolative ⁇ -glucuronidase cleavable moiety; via a self-immolative phosphatase cleavable moiety; or via a self-immolative sulfatase cleavable moiety. Multiple self- immolative linkages are also contemplated. [0058] In some embodiments, the linker comprises a self-immolative moiety.
  • the linker comprises a self-immolative disulfide and or sterically protected disulfide bond. In some embodiments, the linker comprises a self-immolative cathepsin-cleavable amino acid sequence. In some embodiments, the linker comprises a self-immolative furin-cleavable amino acid sequence. In some embodiments, the linker comprises a self-immolative ⁇ - glucuronidase-cleavable moiety. In some embodiments, the linker comprises a self-immolative phosphatase-cleavable moiety. In some embodiments, the linker comprises a self-immolative sulfatase-cleavable moiety.
  • the linker comprises a phosphate or pyrophosphate group. In some embodiments, the linker comprises a cathepsin B cleavable group. In some embodiments, the cathepsin B cleavable group is Valine-Citrulline. In some embodiments, the linker comprises a carbamate moiety. In some embodiments, the linker comprises a ⁇ -glucuronide.
  • L comprises one or more spacer linkers (e.g., S 1 ). Spacer linkers can be hydrophilic spacer linkers comprising a plurality of hydroxyl functional groups. A spacer can comprise any stable arrangement of atoms.
  • Each spacer can be independently selected from the group consisting an amide, ester, urea, carbonate, carbamate, disulfide, amino acid, amine, ether, alkyl, alkene, alkyne, heteroalkyl (e.g., PEG), cycloakyl, aryl, heterocycloalkyl, heteroaryl, carbohydrate, glycan, peptidoglycan, polypeptide, or any combination thereof.
  • a spacer comprises any one or more of the following units: an amide, ester, urea, carbonate, carbamate, disulfide, amino acid, amine, ether, alkyl, alkene, alkyne, heteroalkyl (e.g., PEG), cycloakyl, aryl, heterocycloalkyl, heteroaryl, carbohydrate, glycan, peptidoglycan, polypeptide, or any combination thereof.
  • a spacer comprises one or more monosaccharide, disaccharide, polysaccharide, glycan, or peptidoglycan.
  • a spacer comprises a releasable moiety (e.g., a disulfide bond, an ester, or other moieties that can be cleaved in vivo).
  • a spacer comprises one or more units such as ethylene (e.g., polyethylene), ethylene glycol (e.g., PEG), ethanolamine, ethylenediamine, and the like (e.g., propylene glycol, propanolamine, propylenediamine).
  • a spacer comprises an oligoethylene, PEG, alkyl chain, oligopeptide, polypeptide, rigid functionality, peptidoglycan, oligoproline, oligopiperidine, or any combination thereof.
  • a spacer comprises an oligoethylene glycol or a PEG.
  • a spacer can comprise an oligoethylene glycol.
  • a spacer comprises a PEG.
  • a spacer comprises an oligopeptide or polypeptide.
  • a spacer comprises an oligopeptide.
  • a spacer comprises a polypeptide.
  • a spacer comprises a peptidoglycan.
  • a spacer does not comprise a glycan. In some embodiments, a spacer does not comprise a sugar. In some embodiments, a rigid functionality is an oligoproline or oligopiperidine. In some embodiments, a rigid functionality is an oligoproline. In some embodiments, a rigid functionality is an oligopiperidine. In some embodiments, a rigid functionality is an oligophenyl. In some embodiments, a rigid functionality is an oligoalkyne.
  • an oligoproline or oligopiperidine has about two up to and including about fifty, about two to about forty, about two to about thirty, about two to about twenty, about two to about fifteen, about two to about ten, or about two to about six repeating units (e.g., prolines or piperidines).
  • L can be or can comprise a moiety of the formula: , wherein n is an integer from 0 to 10.
  • L can be or can comprise a moiety of the formula: , .
  • L can be or can comprise a moiety of the formula: wherein n is an integer from 0 to 20.
  • L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar.
  • L can be or can comprise .
  • L can comprise a structure selected from: wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8.
  • L can comprise the structure: wherein: R 31 is H or C 1 -C 6 alkyl; and R29a, R29b, R30a, and R30b are each independently selected from the group consisting of H and C 1 -C 6 alkyl.
  • the conjugate can be selected from: [0068]
  • the conjugate can be selected from:
  • the conjugate can be selected from: .
  • the conjugate of formula I further comprises a pharmacokinetic extender C and has the formula (II): .
  • C can be an albumin binder, a plasma protein binder, or a hapten.
  • the albumin binder can be or can comprise albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide- stabilized Fv fragment (dsFv), an anti-albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06).
  • C can be or can comprise: .
  • C can be or can comprise:
  • C can be or can comprise: .
  • H C can be or can comprise: .
  • C can be or can comprise: .
  • the hapten is recognized by an autologous antibody. The hapten can be selected from the group consisting of rhamnose, an ⁇ -galactosyl moiety, a dinitrophenyl (DNP) moiety, and a trinitrophenyl (TNP) moiety.
  • the conjugate can have a structure selected from:
  • L comprises at least one carbon atom; and p is 0-3.
  • L can be or can comprise a moiety of the formula: , wherein n is an integer from 0 to 10.
  • L can be or can comprise a moiety of the formula: , wherein n is an integer from 0 to 10.
  • L can be or can comprise a moiety of the formula: [0076]
  • L can be or can comprise a moiety of the formula: wherein n is an integer from 0 to 10.
  • L can be or can comprise a moiety of the formula: .
  • L can be or can comprise a moiety of the formula: [0077]
  • L can be or can comprise a moiety of the formula: wherein n is an integer from 0 to 20.
  • L can be or can comprise a moiety of the formula: wherein n is an integer from 0 to 20.
  • L can be a linker that can be cleaved (e.g., under physiological conditions).
  • L can be cleaved reductively, oxidatively, or enzymatically.
  • L can comprise an oxime ester.
  • L can comprise a hydrazone.
  • L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar.
  • L can be or can comprise: .
  • L can comprise a structure selected from: wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8.
  • L can comprise the structure: wherein: R31 is H or C1-C6 alkyl; and R 29a , R 29b , R 30a, and R 30b are independently selected from the group consisting of H and C1-C6 alkyl.
  • the conjugate can have a structure selected from:
  • the conjugates can be synthesized as described herein or otherwise by one of ordinary skill in the art having the benefit of this disclosure via standard synthesis methods generally known in the art using commercially available starting materials and reagents.
  • the conjugate (or stereoisomer or pharmaceutical salt therof) can be formulated into a pharmaceutical composition.
  • the pharmaceutical composition can comprise any conjugate hereof and a pharmaceutically acceptable carrier, such as a composition comprising a conjugate dispersed in a pharmaceutically acceptable liquid carrier.
  • the pharmaceutical composition can comprise a plurality of conjugates and a pharmaceutically acceptable carrier.
  • the composition is suitable for administration to a subject for diagnostic, mapping, and/or therapeutic applications.
  • Liquids within which the conjugate may be dispersed include a carrier liquid or an in vivo liquid.
  • the conjugate being “dispersed” throughout or in a liquid is meant that the conjugate presents as a dispersed phase within the liquid which itself, relative to the conjugate, presents as a continuous liquid medium or phase.
  • liquid in the context of a liquid carrier is intended to mean a vehicle in which the conjugate is dispersed and which is in a liquid state at least at the temperature of intended use.
  • a liquid carrier used in accordance with the invention can be made up of one or more different liquids.
  • Suitable pharmacologically acceptable liquid carriers are described in Martin, Remington's Pharmaceutical Sciences, 18 th Ed., Mack Publishing Co., Easton, PA, (1990), and include, but are not limited to, liquids that may be sterilized, such as water and oils, including those of petroleum, animal, vegetable, mineral or synthetic origin, such as peanut oil, soya bean oil, mineral oil, sesame oil, and the like.
  • Other liquid carriers include methylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, ethanol, isopropyl alcohol, and benzyl alcohol.
  • the conjugate can be taken up by a subject in vivo, for example, when the conjugate is administered orally or parenterally.
  • a liquid carrier originally carrying the conjugate can become so dilute in vivo that the surrounding liquid environment throughout which the conjugate is dispersed becomes more representative of an in vivo liquid (i.e., a biological liquid/fluid within the subject) than the original liquid carrier.
  • the conjugate might more aptly be described as being dispersed throughout blood rather than an original liquid carrier.
  • compositions can comprise one or more pharmacologically acceptable additives known to those in the art.
  • the liquid carrier may comprise one or more additives such as wetting agents, de-foaming agents, surfactants, buffers, electrolytes, preservatives, colourings, flavourings, and sweeteners.
  • additives such as wetting agents, de-foaming agents, surfactants, buffers, electrolytes, preservatives, colourings, flavourings, and sweeteners.
  • suitable liquid carrier and additive can be selected for the intended application of the composition.
  • conjugate or compositions are suitable for parenteral administration, they will generally be in the form of an aqueous or non-aqueous isotonic sterile injection solution that may contain one or more of an anti-oxidant, buffer, bactericide or solute which renders the composition isotonic with the blood of the intended subject.
  • Such compositions can be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials.
  • the term "about” or “approximately” means within an acceptable range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system.
  • “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value.
  • the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
  • the term “about” means within an acceptable error range for the particular value, such as ⁇ 1-20%, preferably ⁇ 1-10% and more preferably ⁇ 1-5%.
  • Alkyl generally refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C 1 - C15 alkyl). "Alkyl” is intended to include independent recitations of a saturated “alkyl, " unless otherwise stated. An alkyl can comprise one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl). An alkyl can comprise one to eight carbon atoms (e.g., C1-C8 alkyl). An alkyl can comprise one to five carbon atoms (e.g., C 1 -C 5 alkyl).
  • An alkyl can comprise one to four carbon atoms (e.g., C 1 - C4 alkyl).
  • An alkyl can comprise one to three carbon atoms (e.g., C1-C3 alkyl).
  • An alkyl can comprise one to two carbon atoms (e.g., C 1 -C 2 alkyl).
  • An alkyl can comprise one carbon atom (e.g., C1 alkyl).
  • An alkyl can comprise five to fifteen carbon atoms (e.g., C5-C15 alkyl).
  • An alkyl can comprise five to eight carbon atoms (e.g., C 5 -C 8 alkyl).
  • An alkyl can comprise two to five carbon atoms (e.g., C2-C5 alkyl).
  • An alkyl can comprise three to five carbon atoms (e.g., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n- propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2- methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Alkylene or “alkylene chain” generally refers to a straight or branched divalent alkyl group linking the rest of the molecule to a radical group, such as having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, i-propylene, n-butylene, and the like.
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring systems from which aryl groups are derived include, but are not limited to, benzene, fluorene, indane, indene, tetralin and naphthalene.
  • alkyl or "aryl-alkyl” refers to a radical of the formula -R c -aryl, where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • Carbocyclyl or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. A carbocyclyl can comprise three to ten carbon atoms.
  • a carbocyclyl can comprise five to seven carbon atoms.
  • the carbocyclyl is attached to the rest of the molecule by a single bond.
  • Carbocyclyl or cycloalkyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds).
  • saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • Carbocyclylalkyl refers to a radical of the formula –R c -carbocyclyl, where R c is an alkylene chain as defined above.
  • Halo or “halogen” refers to a bromo, chloro, fluoro or iodo substituent.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • heteroalkyl refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies – for example, -CH 2 - may be replaced with -NH- or -O-).
  • each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, selenium, or other suitable heteroatom.
  • each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 18 heteroalkyl.
  • a heteroalkyl is a C 1 -C 12 heteroalkyl.
  • a heteroalkyl is a C1-C6 heteroalkyl.
  • a heteroalkyl is a C1-C4 heteroalkyl.
  • Heteroalkyl can include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl, as defined herein.
  • Heteroalkylene refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that can comprise two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes aromatic, fused, and/or bridged ring systems.
  • the heteroatoms in the heterocyclyl radical are optionally oxidized.
  • the heterocyclyl radical is partially or fully saturated.
  • Heterocyclyl is intended to include independent recitations of heterocyclyl comprising aromatic and non-aromatic ring structures, unless otherwise stated.
  • the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, indolinyl, isoindolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl
  • N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1- piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that can comprise two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • the conjugates can contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds are contemplated. When the conjugates contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring. Further, it is understood that replacement of one or more hydrogen atoms with deuterium can significantly lower the rate of metabolism of a drug and, therefore, increase its half-life.
  • Clause A A method of treating fibrosis in a subject, which method comprises administering to the subject an effective amount of a conjugate of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a conjugate of formula I, wherein formula I is: wherein A has the structure: wherein: represents a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R1 and R2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C
  • Clause B The method of Clause A, wherein L is attached to A at any carbon atom of the functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl.
  • Clause C The method of Clause A, wherein L is attached to A at any carbon atom of the functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl.
  • each R2 is selected from the group consisting of -H, -D, -OH, -F, -Cl, -Br, I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl
  • R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl
  • R 5 and R 6 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl
  • R 7 is selected from the group consisting of H, D,
  • Clause D The method of any of the foregoing Clauses, wherein the PI3k inhibitor or the PI3k/mTOR inhibitor is a radical of any one of the following structures:
  • Clause E The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula: , wherein n is an integer from 0 to 10.
  • Clause F The method of any one of the foregoing Clauses, where L is or comprises a moiety of the formula: , wherein n is an integer from 0 to 10.
  • Clause G The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula: [0119] Clause H.
  • Clause K The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula: wherein n is an integer from 0 to 20.
  • Clause L The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula: , wherein n is an integer from 0 to 20.
  • Clause M The method of Clause A, wherein L is a linker that can be cleaved under physiological conditions.
  • Clause N The method of Clause M, wherein L can be cleaved reductively, oxidatively, or enzymatically.
  • Clause O The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula: wherein n is an integer from 0 to 20.
  • Clause T The method of any one of the foregoing Clauses, wherein L comprises a structure selected from a group consisting of: , wherein: R 27 and R 28 are each independently selected from the group consisting of H and C 1 -C 6 alkyl; and Z is an integer from 1 to 8.
  • Clause U The method of any one of the foregoing Clauses, wherein L comprises the structure: wherein: R 31 is H or C 1 -C 6 alkyl; and R29a, R29b, R30a, and R30b are each independently selected from the group consisting of H and C 1 -C 6 alkyl.
  • Clause V The method of Clause A, wherein the conjugate is selected from: [0134] Clause W. The method of Clause A, wherein the conjugate is selected from: . [0135] Clause X. The method of Clause A, wherein the conjugate is selected from: . [0136] Clause Y. The method of Clause A, wherein the conjugate of formula I further comprises a pharmacokinetic extender C and has the formula (II): [0137] Clause Z. The method of Clause Y, wherein C is an albumin binder, a plasma protein binder, or a hapten. [0138] Clause AA.
  • Clauses Y or Z wherein C is an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti- albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06).
  • C is an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti- albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06).
  • Clause BB The method of any one of Clauses Y-AA, wherein C is or comprises: .
  • Clause CC The method of any one of Clauses
  • Clause Z wherein the hapten is recognized by an autologous antibody.
  • Clause KK The method of Clause Z, wherein the hapten is selected from the group consisting of rhamnose, an ⁇ -galactosyl moiety, a dinitrophenyl (DNP) moiety, and a trinitrophenyl (TNP) moiety.
  • Clause LL wherein L is or comprises a moiety of the formula: wherein n is an integer from 0 to 10.
  • Clause QQ The method of Clause LL, wherein L is or comprises a moiety of the formula: .
  • Clause RR The method of Clause LL, wherein L is or comprises a moiety of the formula:
  • Clause SS The method of Clause LL, wherein L is or comprises a moiety of the formula: wherein n is an integer from 0 to 20.
  • Clause TT The method of Clause LL, wherein L is or comprises a moiety of the formula: , wherein n is an integer from 0 to 20.
  • Clause UU The method of Clause LL, wherein L is a linker that can be cleaved under physiological conditions.
  • Clause VV The method of Clause UU, wherein L can be cleaved reductively, oxidatively, or enzymatically.
  • Clause WW The method of Clause UU, wherein L can be cleaved reductively, oxidatively, or enzymatically.
  • Clause LL The method of Clause LL, wherein L comprises an oxime ester.
  • Clause XX The method of Clause LL, wherein L comprises a hydrazone.
  • Clause ZZ The method of Clause LL, wherein L comprises a peptide, a peptidoglycan, an alkyl, or a sugar.
  • Clause AAA The method of Clause LL, wherein L is or comprises: .
  • Clause BBB Clause BBB.
  • Clause LL wherein L is or comprises a structure selected from: , wherein: R 27 and R 28 are each independently selected from the group consisting of H and C 1 -C 6 alkyl; and Z is an integer from 1 to 8.
  • Clause CCC The method of Clause LL, wherein L comprises the structure: wherein: R31 is H or C1-C6 alkyl; and R 29a , R 29b , R 30a, and R 30b are independently selected from the group consisting of H and C1-C6 alkyl.
  • Clause DDD The method of Clause LL, wherein the conjugate is selected from:
  • conjugate of formula I is: wherein A has the structure: wherein: represents a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R1 and R2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH,
  • Clause FFF The use of Clause EEE, wherein the conjugate of formula I further comprises a pharmacokinetic extender C and has the formula (II): [0170] Clause GGG. The use of Clause EEE, wherein C is an albumin binder, a plasma protein binder, or a hapten. [0171] Clause HHH.
  • Clauses FFF or GGG wherein C is an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti- albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06).
  • C is an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti- albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06).
  • a conjugate of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a conjugate of formula I, wherein formula I is: wherein A has the structure: wherein: represents a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R 1 and R 2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl; R 3 and R 4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 al
  • Clause JJJ The conjugate of Clause III, wherein L is attached to A at any carbon atom of the functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi- cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl.
  • each R2 is selected from the group consisting of -H, -D, -OH, -F, -Cl, -Br, I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • R5 and R6 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C 1-6 alkyl, -O-C 1-6 alkyl, and -S-C 1-6 alkyl;
  • R7 is
  • Clause LLL The conjugate of any one of Clauses III-LLL, wherein the PI3k inhibitor or the PI3k/mTOR inhibitor is a radical of any one of the following structures:
  • Clause UUU The conjugate of any one of Clauses III-NNN, wherein L is a linker that can be cleaved under physiological conditions.
  • Clause VVV The conjugate of Clause UUU, wherein L can be cleaved reductively, oxidatively, or enzymatically.
  • Clause WWW The conjugate of Clause UUU, wherein L can be cleaved reductively, oxidatively, or enzymatically.
  • Clause AAAA The conjugate of Clause III selected from:
  • Clause BBBB The conjugate Clause III selected from: .
  • Clause CCCC The conjugate of Clause III selected from: . [0193] Clause DDDD. The conjugate of Clause III, wherein the conjugate of formula I further comprises a pharmacokinetic extender C and has the formula (II): . [0194] Clause EEEE. The conjugate of Clause DDDD, wherein C is an albumin binder, a plasma protein binder, or a hapten. [0195] Clause FFFF.
  • Clause GGGG The conjugate of any one of Clauses DDDD-GGGG, wherein C is or comprises: .
  • Clause HHHH The conjugate of any one of Clauses DDDD-GGGG, wherein C is or comprises: .
  • Clause KKKK The conjugate of any one of DDDD-GGGG, wherein C is or comprises: .
  • Clause MMMM The conjugate of any one of DDDD-GGGG, wherein C is or comprises: .
  • Clause NNNN The conjugate of any one of DDDD-GGGG, wherein C is or comprises .
  • Clause OOOO The conjugate of any one of DDDD-GGGG, wherein C is or comprises:
  • Clause EEEE wherein the hapten is recognized by an autologous antibody.
  • Clause PPPP The conjugate of Clause EEEE, wherein the hapten is selected from the group consisting of rhamnose, an ⁇ -galactosyl moiety, a DNP moiety, and a TNP moiety.
  • Clause QQQQ The conjugate of Clause DDDD, wherein the compound has a structure selected from: , wherein L comprises at least one carbon atom; and p is 0-3.
  • Clause RRRR The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula: , wherein n is an integer from 0 to 10.
  • Clause SSSS The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula: , wherein n is an integer from 0 to 10.
  • Clause TTTT The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula: .
  • Clause UUUU The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula: wherein n is an integer from 0 to 10.
  • Clause VVVV The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula: .
  • Clause WWWW The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula: .
  • Clause ZZZZZ wherein L can be cleaved reductively, oxidatively, or enzymatically.
  • Clause CCCCC The conjugate of Clause DDDD, wherein L is or comprises: [0219] Clause DDDDD.
  • Clause DDDD wherein L is or comprises a structure selected from: , wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8.
  • Clause EEEEE The conjugate of Clause DDDD, wherein L comprises the structure: wherein: R31 is H or C1-C6 alkyl; and R 29a , R 29b , R 30a, and R 30b are independently selected from the group consisting of H and C1-C6 alkyl.
  • Clause FFFFF The conjugate of Clause DDDD, wherein the conjugate is selected from:
  • Clause GGGGG A method of inhibiting the progression of fibrosis in a subject comprising administering to the subject an effective amount of a conjugate of any one of Clauses III-FFFFF, or a stereoisomer or a pharmaceutically acceptable salt thereof, whereupon progression of a fibrotic disease state (e.g., fibrosis) in the subject is inhibited.
  • a fibrotic disease state e.g., fibrosis
  • EXAMPLES [0223] The following examples serve to illustrate the present disclosure. The examples are not intended to limit the scope of the claimed invention.
  • Example 1 Scheme-1 Synthesis of FAP8-PI3K conjugate.
  • FIG.1 depicts the synthesis scheme of a FAP8-PI3K conjugate, which is further described below.
  • reaction mixture was stirred at 55 °C, for 4 hours and, thereafter, KOH (3 eq. with respect to dialkylated product) and H2O (5.0 mL) were added to the same reaction mixture, which was continuously stirred for an additional 12 hours. The progress of the reaction was monitored by LC-MS. [0229] The reaction mixture was carefully neutralized with 1N HCl and extracted multiple times with EtOAc, combined organic extracts were evaporated under reduced pressure, and obtained crude residue was purified by CombiFlash using EtOAc+Hexanes system and provided the desired compound 8 as white solid (500 mg, 81%). [0230] Synthesis of compound (9).
  • Serum-starved confluent HLF cells primary lung fibroblast, normal, human
  • TGF ⁇ 1 transforming growth factor beta 1
  • FAP8-PI3K inhibitor conjugates hereof 1-100 nM
  • membranes are incubated with antibodies to detect pSMAD2Ser465/467 (Cell Signaling Technology, #3101; Danvers, MA) or pAktSer473 (Cell Signaling Technology, #4060; Danvers, MA), and signals are visualized with ECL Western Blot Detection Reagents (GE Healthcare; Chicago, IL). After stripping, membranes are blocked and reprobed with antibodies specific for total SMAD2 (Cell Signaling Technology, #3103; Danvers, MA) or total Akt (Cell Signaling Technology, #4060; Danvers, MA).
  • SDS sodium dodecyl sulfate
  • lungs are harvested at 7, 14, and 21 days after bleomycin instillation and assayed as described below.
  • induction of idiopathic pulmonary fibrosis (IPF) is initiated as described above, and a FAP8-PI3K conjugate (2 mmol/kg) is intravenously injected every other day beginning on day 10.
  • Lungs are harvested on day 21 and assayed as described below (day 0 was taken as the day of bleomycin administration).
  • Total lung collagen is determined by the analysis of hydroxyproline as described in published articles using a known and standardized method. The right lung is consistently set aside for this assay.
  • harvested right lung is homogenized in PBS (pH 7.4), and digested with 12 N HCl at 120 °C for 3 hours.
  • Citrate/acetate buffer (pH 6.0) and chloramine-T solution are added at room temperature for 20 minutes, and the samples are incubated with Ehrlich’s solution for 15 minutes at 65 °C.
  • Samples are cooled to room temperature and read at 550 nm. Hydroxyproline standards (Sigma-Aldrich; St. Louis, MO) at concentrations between 0 and 400 mg/ml are used to construct a standard curve.

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Abstract

Conjugates comprising a fibroblast activation protein α (FAP-α)-targeted ligand, a bifunctional or trifunctional linker, and a phosphatidylinositol-3-kinase (PI3k) inhibitor; uses of the conjugates in the manufacture of a medicament for inhibiting progression of fibrosis in a subject; and a method of use in inhibiting progression of fibrosis in a subject.

Description

KETO-AMIDE-BASED FIBROBLAST ACTIVATION PROTEIN-TARGETED LIGAND LINKED TO A PI3K INHIBITOR, COMPOSITIONS AND METHODS OF USE PRIORITY [0001] This patent application is related to and claims the priority benefit of U.S. Provisional Patent Application No. 63/548,098 filed November 10, 2023. The content of the foregoing application is hereby incorporated by reference in its entirety into this disclosure. TECHNICAL FIELD [0002] The present disclosure relates to conjugates comprising a fibroblast activation protein α (FAP-α)-targeted ligand, a bifunctional or trifunctional linker, and a phosphatidylinositol-3-kinase (PI3k) inhibitor; and methods of use of the conjugates as a pharmaceutical composition in the inhibiting the progression of a fibrosis in a subject. BACKGROUND [0003] Fibrotic diseases constitute a major health problem affecting a large number of individuals worldwide. Extracellular matrix can be over-produced and disrupts normal organ architecture, ultimately leading to organ failure. [0004] Virtually every organ in the human body can be affected. The lungs, kidneys, liver, skin, heart, and bladder, however, are the most commonly affected. [0005] Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease. It is believed to be caused by repetitive environmental injury to the lining of the lungs and resulting abnormal wound- healing responses. When lung tissues experience prolonged activation of wound healing responses, the result is typically permanent scarring, organ malfunction, and death. [0006] It is estimated that there are about 128,000 people living with IPF, with 48,000 new cases diagnosed annually in the United States alone. About 40,000 patients die each year. The median survival age after diagnosis is approximately 2-3 years. Owing to the widespread and multi-organ occurrence of fibrotic diseases, it can be difficult to determine their total incidence. It has been estimated, however, that as much as 45% of the mortality in western developed countries is caused by their collective occurrence. [0007] Until recently, there have been no curative therapies for IPF. Treatment options have been limited to lung rehabilitation and oxygen therapy. [0008] In 2014, the U.S. Food and Drug Administration approved pirfenidone and nintedanib for the treatment of IPF. Both drugs show limited and inconsistent efficacy. More recently, several kinase inhibitors have been introduced into human clinical trials in hopes of blocking essential steps in the fibrotic process. The inhibitors, however, target enzymes in healthy tissues as well as diseased tissues, raising concerns about systemic toxicity. In more advanced cases, lung transplantation can be an option. Finding an HLA match, however, is often difficult and avoiding transplant rejection can be challenging. [0009] In view of the above, there is a long-felt and unmet need for therapies that can slow, if not halt, the progression of IPF. In view of the foregoing, it is an object to provide a new method of treating fibrosis. This and other objects and advantages, as well as inventive features, will be apparent from the detailed description provided herein. SUMMARY [0010] Conjugates are provided. The conjugate can have or comprise a conjugate of formula I, or be a stereoisomer or a pharmaceutically acceptable salt thereof. Formula I can be or comprise:
Figure imgf000003_0001
wherein A has the structure:
Figure imgf000003_0002
wherein:
Figure imgf000003_0003
represents a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R1 and R2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH-, (CH3)3C-, -CH2Ph, and substituted -CH2Ph; R8-R10 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; and R11 is selected from the group consisting of H, D, Cl-Cl0 alkyl, C3-Cl0 cycloalkyl,
Figure imgf000004_0001
unsubstituted aryl, and substituted or unsubstituted C7-C20 alkyl aryl, wherein the aryl is:
Figure imgf000004_0002
wherein: R12 and R16 are each independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R13, R14 and R15 are each independently selected from the group consisting of H, D, halogen, -OMe, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R17, R18, R20, and R21 are each independently selected from H and CH3; and R19 and R22 are each independently selected from the group consisting of phenyl, dimethoxyphenyl, and aryl; L is a bifunctional or trifunctional linker; and B is a phosphatidylinositol-3-kinase (PI3K) inhibitor or a dual inhibitor of the PI3K/mTOR signaling pathway. [0011] L can be attached to A at any carbon atom of the functionalized 5- to 10-membered N- containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl. “A” can have the formula IV or V:
Figure imgf000004_0003
wherein: each R2 is independently selected from the group consisting of -H, -D, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH-, and (CH3)3C-; R11 is selected from the group consisting of
Figure imgf000005_0001
Figure imgf000006_0001
R23-R26 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -CF3, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH-, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl. [0012] As noted above, B can be or comprise a radical of a PI3k inhibitor or a dual PI3k/mTOR inhibitor. The PI3k/mTOR inhibitor can be a radical of a compound selected from:
Figure imgf000007_0002
. [0013] The PI3k inhibitor can be a radical o
Figure imgf000007_0001
wherein X is or comprises a structure selected from:
Figure imgf000008_0001
. [0014] In certain embodiments, the PI3k inhibitor is a radical of
Figure imgf000008_0002
. [0015] The PI3k inhibitor is a radical of
Figure imgf000008_0005
(GSK1059615), or
Figure imgf000008_0006
(BEZ235, NVP-BEZ235 or dactolisib). [0016] L of the conjugate can be or can comprise a moiety of the formula:
Figure imgf000008_0003
, wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula: ,
Figure imgf000008_0004
wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula:
Figure imgf000009_0001
. [0017] L can be or can comprise a moiety of the formula:
Figure imgf000009_0002
wherein n is an integer from 0 to 20. L can be or can comprise a moiety of the formula:
Figure imgf000009_0003
. [0018] L can be or can comprise a moiety of the formula:
Figure imgf000009_0004
Figure imgf000010_0001
[0019] L can be or can comprise a moiety of the formula:
Figure imgf000010_0002
wherein n is an integer from 0 to 20. L can be or can comprise a moiety of the formula:
Figure imgf000010_0003
, wherein n is an integer from 0 to 20. L can be a linker that can be cleaved (e.g., under physiological conditions). L can be cleaved reductively, oxidatively, or enzymatically. L can comprise an oxime ester. L can comprise a hydrazone. L can comprise polyethylene glycoln (PEG)n, wherein n = 0-36. L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar. L can be or can comprise
Figure imgf000011_0001
. [0020] L can be or comprise:
Figure imgf000011_0002
wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8. [0021] L can comprise the structure:
Figure imgf000011_0003
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are each independently selected from the group consisting of H and C1-C6 alkyl. [0022] The conjugate can be selected from:
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
. [0023] The conjugate can be selected from:
Figure imgf000014_0002
Figure imgf000015_0001
. [0024] The conjugate can be selected from:
Figure imgf000015_0002
Figure imgf000016_0001
. [0025] The conjugate of formula I can, in certain embodiments, further comprise a pharmacokinetic extender C (e.g., a radical of a pharmacokinetic extender C). In certain embodiments, the conjugate of formula I has the formula (II): A, B, and L of
Figure imgf000016_0002
formula (II) can be or comprise any A, B, or L, respectively, described in connection with formula (I). C can be an albumin binder, a plasma protein binder, or a hapten. C can be an albumin binder, a plasma protein binder, or a hapten. The albumin binder can be or can comprise albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti-albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06). C can be or can comprise any of the following structures:
Figure imgf000017_0001
[0026] C can be or can comprise:
Figure imgf000017_0002
Figure imgf000018_0001
wherein: each of R12-19 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, or -SO2F; and each of R20 and R21 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -O-C1-6 alkyl, -CN, -CHO, -B(OH)2, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, -SO2F, [
Figure imgf000019_0001
. [0028] C can be or can comprise: H
Figure imgf000019_0002
. [0029] C can comprise a radical of polyethylene glycoln (PEG)n, wherein n = 0-32, a peptide, a petidoglycan, or a saccharide. C can be or can comprise:
Figure imgf000020_0001
The hapten can be recognized (or recognizable) by an autologous antibody. The hapten can be selected from the group consisting of rhamnose, an α-galactosyl moiety, a dinitrophenyl (DNP) moiety, and a trinitrophenyl (TNP) moiety. [0030] The conjugate can have a structure selected from:
Figure imgf000020_0002
Figure imgf000021_0001
, wherein L is or comprises at least one carbon atom, and p is 0-3. L can be or can comprise a moiety of the formula:
Figure imgf000021_0002
, wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula:
Figure imgf000021_0003
, wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula:
Figure imgf000021_0004
[0031] L can be or can comprise a moiety of the formula:
Figure imgf000021_0005
wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula:
Figure imgf000022_0001
. L can be or can comprise a moiety of the formula:
Figure imgf000022_0002
[0032] L can be or can comprise a moiety of the formula:
Figure imgf000022_0003
wherein n is an integer from 0 to 20. L can be or can comprise a moiety of the formula:
Figure imgf000023_0001
wherein n is an integer from 0 to 20. L can be a linker that can be cleaved (e.g., under physiological conditions). L can be cleaved reductively, oxidatively, or enzymatically. L can comprise an oxime ester. L can comprise a hydrazone. L can comprise (PEG)n, wherein n = 0- 36. L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar. L can be or can comprise:
Figure imgf000023_0002
. [0033] L can be or comprise a structure selected from:
Figure imgf000024_0001
wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8. [0034] L can comprise the structure:
Figure imgf000024_0002
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are each independently selected from the group consisting of H and C1-C6 alkyl. [0035] Still further provided is a conjugate having a structure selected from:
Figure imgf000024_0003
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
. [0036] Uses of a conjugate hereof, or a stereoisomer or a pharmaceutically acceptable salt thereof, or optionally a pharmaceutical composition comprising an effective amount of such a conjugate, stereoisomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of the progression of fibrosis in a subject are also provided. The conjugate can be any conjugate hereof. In certain embodiments, the conjugate comprises an albumin binder, a plasma protein binder, or a hapten. The C can be an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti-albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06). [0037] Methods are also provided for inhibiting the progression of fibrosis in a subject. Such am ethod can comprise administering to the subject an effective amount of a conjugate hereof, or a stereoisomer or a pharmaceutically acceptable salt thereof, whereupon the progression of fibrosis in the subject is inhibited or otherwise alleviated. DESCRIPTION OF THE DRAWINGS [0001] The disclosed embodiments and other features, advantages, and aspects contained herein, and the matter of attaining them, will become apparent in light of the following detailed description of various exemplary embodiments of the present disclosure. Such detailed description will be better understood when taken in conjunction with the accompanying drawings, wherein: [0002] FIG.1 is a synthesis scheme for conjugates hereof (further described in Example 1 below); and [0003] FIG.2 shows data from a liquid chromatography-mass spectrometry (LC-MS) analysis of conjugates hereof. [0004] While the present disclosure is susceptible to various modifications and alternative forms, exemplary embodiments thereof are shown by way of example in the drawings and are herein described in detail. DETAILED DESCRIPTION [0038] Conjugates are provided that comprise a phosphatidylinositol-3-kinase (PI3K) inhibitor or a dual inhibitor of the PI3K/mTOR signaling pathway. Such conjugates can further comprise a linker and a FAP8 payload. In certain embodiments, the conjugates are useful for inhibiting progression of fibrosis in a subject. “Inhibiting” and its formatives means hindering, retarding, abrogating, or reversing the onset or progression of fibrosis or related symptoms. The subject can be a human or a mammal of economic importance and/or social importance to humans, for instance, carnivores other than humans (e.g., cats and dogs), swine (e.g., pigs, hogs, and wild boars), ruminants (e.g., cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), horses, and birds including those kinds of birds that are endangered and kept in zoos, and fowl, more particularly domesticated fowl, e.g., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economic importance to humans. The term "subject" does not denote a particular age. Thus, adult, juvenile and newborn subjects are covered. The terms "subject, " "individual" and "patient" may be used interchangeably herein. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. [0039] A method of treating fibrosis in a subject is also provided. The terms "treat," "treatment," and "treating" refer to any and all uses which remedy a condition or symptom, or otherwise prevent, hinder, retard, abrogate or reverse the onset or progression of fibrosis or other undesirable symptoms in any way whatsoever. Thus, the term "treating," and the like, is to be considered in its broadest possible context. For example, treatment does not necessarily imply that a subject is treated until total recovery or cure. In conditions that display or are characterized by multiple signs or symptoms, the treatment need not necessarily remedy, prevent, hinder, retard, abrogate or reverse all signs or symptoms, but can remedy, prevent, hinder, retard, abrogate or reverse one or more signs or symptoms. [0040] The method can comprise administering to the subject an effective amount of a conjugate hereof or a stereoisomer or pharmaceutically acceptable salt thereof, whereupon the subject is treated for fibrosis. [0041] The conjugate can be or comprise formula I or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the conjugate of formula I Formula I can be or comprise:
Figure imgf000039_0004
wherein A has the structure:
Figure imgf000039_0001
wherein:
Figure imgf000039_0002
a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R1 and R2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH-, (CH3)3C-, -CH2Ph, and substituted -CH2Ph; R8-R10 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; and R11 is selected from the group consisting of H, D, Cl-Cl0 alkyl, C3-Cl0 cycloalkyl, adamantyl,
Figure imgf000039_0005
substituted or unsubstituted aryl, and substituted or unsubstituted C7-C20 alkyl aryl, wherein the aryl is:
Figure imgf000039_0003
wherein: R12 and R16 are each independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R13, R14 and R15 are each independently selected from the group consisting of H, D, halogen, -OMe, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R17, R18, R20, and R21 are each independently selected from H and CH3; and R19 and R22 are each independently selected from the group consisting of phenyl, dimethoxyphenyl, and aryl; L is a bifunctional or trifunctional linker; and B is a PI3K inhibitor or a dual inhibitor of the PI3K/mTOR signaling pathway. The conjugate can optionally be formulated as a pharmaceutical composition, for example, further comprising a pharmaceutically acceptable carrier. [0042] "Administration" of the conjugate or composition to a subject means that the conjugate or composition is presented such that the conjugate can be transferred to the subject. There is no particular limitation on the mode of administration. In certain embodiments, the mode of administration can be by way of oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intracerebrally, intranasally, intrathecal, and intraspinal), inhalation (including nebulisation), topical, rectal or vaginal modes. The conjugate or composition can also be administered directly into a tumor and/or into tissue adjacent to one or more segments of a tumor or administered directly into blood vessels. [0043] The conjugate can be administered in, as appropriate, a treatment or diagnostic effective amount. A treatment or diagnostic effective amount is intended to include an amount which, when administered according to the desired dosing regimen, achieves a desired therapeutic or diagnostic effect, including one or more of: alleviating the symptoms of, preventing or delaying the onset of, inhibiting or slowing the progression of, diagnosing, or halting or reversing altogether the onset or progression of a particular condition being treated and/or assessed. [0044] The expressions “effective amount” and "therapeutically effective amount" mean the amount of conjugate when administered to a mammal, in particular a human, in need of such treatment, is sufficient to treat cancer. The precise amount of conjugate to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the subject. [0045] Suitable dosage amounts and dosing regimens to achieve this can be determined by the attending physician and can depend on the particular condition being treated or diagnosed, the severity of the condition as well the general age, health and weight of the subject. [0046] Dosing can occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages of the particulate material per se can lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. The dosage can be in the range of 1 µg to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage can be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 400 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 350 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 300 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 275 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 250 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 200 mg per kg of body weight per dosage. In another embodiment, the dosage can be in the range of 1 mg to 150 mg per kg of body weight per dosage. In yet another embodiment, the dosage can be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage. All ranges set forth in this paragraph are inclusive of their stated end points and all 1 mg increments encompassed thereby. [0047] Conjugates or compositions can be administered in a single dose or a series of doses. [0048] Referring back to the conjugate comprising formula I, L can be attached to A at any carbon atom of the functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl. “A” can have the formula IV or V:
Figure imgf000041_0001
wherein: each R2 is selected from the group consisting of -H, -D, -OH, -F, -Cl, -Br, I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH-, and (CH3)3C-; R11 is selected from the group consisting of
Figure imgf000042_0001
Figure imgf000043_0001
; R23-R26 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -CF3, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH-, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1- 6 alkyl. [0049] PI3k kinases are members of a unique and conserved family of intracellular lipid kinases that can phosphorylate the 3'-OH group on phosphatidylinositols or phosphoinositides. PI3k kinases are key signaling enzymes that rcan relay signals from cell surface receptors to downstream effectors. The PI3k signaling pathway can be highly mutated in human cancers, and PI3k signaling can be a key factor in disease states including inflammatory disease states and fibrosis. [0050] Downstream mediators of the PI3k signal transduction pathway include Akt and mammalian target of rapamycin (mTOR). mTOR is a serine-threonine kinase related to the lipid kinases of the PI3k family and has been implicated in a wide range of biological processes including cell growth, cell proliferation, cell motility and survival. Disregulation of the mTOR pathway can occur in various disease states, including cancer. [0051] B of formula I can be or comprise a PI3k inhibitor or a dual PI3k/mTOR inhibitor, or a radical of a PI3k inhibitor or a radical of a dual PI3k/mTOR inhibitor. The PI3k/mTOR inhibitor can be or comprise a compound selected from:
Figure imgf000044_0002
[0052] The PI3k inhibitor can be a radical o
Figure imgf000044_0001
wherein X is or comprises a structure selected from:
Figure imgf000045_0001
. In certain embodiments, the PI3k inhibitor is a radical of
Figure imgf000045_0002
. The PI3k inhibitor is a radical o
Figure imgf000045_0003
Figure imgf000045_0004
[0053] L of the conjugates can be a bifunctional or trifunctional linker. L of the conjugates can be a linker that can be cleaved or a “releasable” linker. L of the compounds hereof can be a non- releasable linker. [0054] The term “releasable linker” is a linker that includes at least one bond that can be broken or cleaved under physiological conditions, such as reductive, acidic, basic, oxidative, metabolic, biochemical, enzymatic (e.g., cathepsin B-cleavable), or other conditions (e.g., p-aminobenzylic- based multivalent releasable bond (see, e.g., International Patent Application Publication Number WO 2017/0205661)). In other words, a “releasable linker” is a linker that can be cleaved to varying degrees under certain conditions and, in particular, can be fragmented or cleaved in less than about 1 week when under, or otherwise exposed to, certain metabolic, physiological, or cellular conditions that can initiate a cascade of fragmentation or bond cleavage (which may, for example, result in the release of one or more moieties connected through one or more portions of the linker (e.g., A and B)). Bond cleavage can occur by standard chemical hydrolysis reactions that occur, for example, at physiological pH, or as a result of compartmentalization into a cellular organelle such as an endosome having a lower pH than cytosolic pH. Bond cleavage can also occur by acid catalyzed elimination. Alternatively, fragmentation can be initiated by a nucleophilic attack on a disulfide group of the quick-release linker, causing cleavage to form a thiolate, for example. In any of these cases, the quick-release nature of such linkers can be realized by whatever mechanism may be relevant to the chemical, metabolic, physiological, or biological conditions present. In certain embodiments, a releasable linker comprises one or more sulfide bridges. [0055] In contrast, a non-releasable linker means a linker that includes at least one bond that is not easily or quickly broken (i.e. the bond does not cleave) and, while potentially cleavable or fragmentable to varying degrees under certain conditions, does not cleave, fragment, or otherwise release one or more of the moieties connected through one or more portions of the linker (e.g., A and B) when subjected to certain metabolic, physiological, or cellular conditions that may initiate a cascade of fragmentation (e.g., after administration to a subject) for more than about 1 week (e.g., 1 week), more than about 1 month (e.g., 1 month), more than about 4 months (e.g., 4 months), more than about 6 months (e.g., 6 months), or more than about 1 year (e.g., 1 year). In certain embodiments, a non-releasable linker comprises one or more amides, esters, ethers, amines, or thioethers (e.g., thio-maleimide), for example. [0056] In some embodiments, the linker comprises an ester, phosphate, oxime, acetal, pyrophosphate, polyphosphate, disulfide, sulfate, hydrazide, imine, carbonate, carbamate or enzyme-cleavable amino acid sequence. L can comprise an oxime ester. L can comprise a hydrazone. L can comprise polyethylene glycol (PEG). L can comprise (PEG)n, wherein n = 0-36. L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar. [0057] The linker(s) can comprise a self-immolative disulfide group. An example of a self- immolative disulfide also includes a sterically protected disulfide bond. The steroid can be attached to the linker via any other suitable self-immolative bond, including via a self-immolative cathepsin cleavable amino acid sequence; via a self-immolative furin cleavable amino acid sequence; via a self-immolative β-glucuronidase cleavable moiety; via a self-immolative phosphatase cleavable moiety; or via a self-immolative sulfatase cleavable moiety. Multiple self- immolative linkages are also contemplated. [0058] In some embodiments, the linker comprises a self-immolative moiety. In some embodiments, the linker comprises a self-immolative disulfide and or sterically protected disulfide bond. In some embodiments, the linker comprises a self-immolative cathepsin-cleavable amino acid sequence. In some embodiments, the linker comprises a self-immolative furin-cleavable amino acid sequence. In some embodiments, the linker comprises a self-immolative β- glucuronidase-cleavable moiety. In some embodiments, the linker comprises a self-immolative phosphatase-cleavable moiety. In some embodiments, the linker comprises a self-immolative sulfatase-cleavable moiety. [0059] In some embodiments, the linker comprises a phosphate or pyrophosphate group. In some embodiments, the linker comprises a cathepsin B cleavable group. In some embodiments, the cathepsin B cleavable group is Valine-Citrulline. In some embodiments, the linker comprises a carbamate moiety. In some embodiments, the linker comprises a β-glucuronide. [0060] In some embodiments, L comprises one or more spacer linkers (e.g., S1). Spacer linkers can be hydrophilic spacer linkers comprising a plurality of hydroxyl functional groups. A spacer can comprise any stable arrangement of atoms. Each spacer can be independently selected from the group consisting an amide, ester, urea, carbonate, carbamate, disulfide, amino acid, amine, ether, alkyl, alkene, alkyne, heteroalkyl (e.g., PEG), cycloakyl, aryl, heterocycloalkyl, heteroaryl, carbohydrate, glycan, peptidoglycan, polypeptide, or any combination thereof. In some embodiments, a spacer comprises any one or more of the following units: an amide, ester, urea, carbonate, carbamate, disulfide, amino acid, amine, ether, alkyl, alkene, alkyne, heteroalkyl (e.g., PEG), cycloakyl, aryl, heterocycloalkyl, heteroaryl, carbohydrate, glycan, peptidoglycan, polypeptide, or any combination thereof. In some embodiments, a spacer comprises one or more monosaccharide, disaccharide, polysaccharide, glycan, or peptidoglycan. In some embodiments, a spacer comprises a releasable moiety (e.g., a disulfide bond, an ester, or other moieties that can be cleaved in vivo). In some embodiments, a spacer comprises one or more units such as ethylene (e.g., polyethylene), ethylene glycol (e.g., PEG), ethanolamine, ethylenediamine, and the like (e.g., propylene glycol, propanolamine, propylenediamine). In some embodiments, a spacer comprises an oligoethylene, PEG, alkyl chain, oligopeptide, polypeptide, rigid functionality, peptidoglycan, oligoproline, oligopiperidine, or any combination thereof. In some embodiments, a spacer comprises an oligoethylene glycol or a PEG. A spacer can comprise an oligoethylene glycol. In some embodiments, a spacer comprises a PEG. In some embodiments, a spacer comprises an oligopeptide or polypeptide. In some embodiments, a spacer comprises an oligopeptide. In some embodiments, a spacer comprises a polypeptide. In some embodiments, a spacer comprises a peptidoglycan. In some embodiments, a spacer does not comprise a glycan. In some embodiments, a spacer does not comprise a sugar. In some embodiments, a rigid functionality is an oligoproline or oligopiperidine. In some embodiments, a rigid functionality is an oligoproline. In some embodiments, a rigid functionality is an oligopiperidine. In some embodiments, a rigid functionality is an oligophenyl. In some embodiments, a rigid functionality is an oligoalkyne. In some embodiments, an oligoproline or oligopiperidine has about two up to and including about fifty, about two to about forty, about two to about thirty, about two to about twenty, about two to about fifteen, about two to about ten, or about two to about six repeating units (e.g., prolines or piperidines). [0061] L can be or can comprise a moiety of the formula:
Figure imgf000048_0001
, wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula: ,
Figure imgf000048_0002
. [0062] L can be or can comprise a moiety of the formula:
Figure imgf000048_0003
wherein n is an integer from 0 to 20. L can be or can comprise a moiety of the formula:
Figure imgf000048_0004
[0063] L can be or can comprise a moiety of the formula:
Figure imgf000049_0001
[0064] L can be or can comprise a moiety of the formula:
Figure imgf000049_0002
, wherein n is an integer from 0 to 20. L can be or can comprise a moiety of the formula:
Figure imgf000049_0003
Figure imgf000050_0001
, wherein n is an integer from 0 to 20. L can be a linker that can be cleaved (e.g., under physiological conditions). L can be cleaved reductively, oxidatively, or enzymatically. L can comprise an oxime ester. L can comprise a hydrazone. L can comprise (PEG)n, wherein n = 0-36. L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar. L can be or can comprise
Figure imgf000050_0003
. [0065] L can comprise a structure selected from:
Figure imgf000050_0002
wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8. [0066] L can comprise the structure:
Figure imgf000051_0001
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are each independently selected from the group consisting of H and C1-C6 alkyl. [0067] The conjugate can be selected from:
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000053_0001
[0068] The conjugate can be selected from:
Figure imgf000054_0001
[0069] The conjugate can be selected from:
Figure imgf000055_0001
. [0070] The conjugate of formula I further comprises a pharmacokinetic extender C and has the formula (II):
Figure imgf000055_0002
. C can be an albumin binder, a plasma protein binder, or a hapten. The albumin binder can be or can comprise albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide- stabilized Fv fragment (dsFv), an anti-albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06). C can be or can comprise:
Figure imgf000056_0001
. [0071] C can be or can comprise:
Figure imgf000056_0002
Figure imgf000057_0001
wherein: each of R12-19 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, or -SO2F; and each of R20 and R21 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -O-C1-6 alkyl, -CN, -CHO, -B(OH)2, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, -SO2F,
Figure imgf000058_0001
. [0072] C can be or can comprise:
Figure imgf000058_0002
Figure imgf000059_0001
. H [0073] C can be or can comprise:
Figure imgf000059_0002
. [0074] C can comprise a radical of (PEG)n, wherein n = 0-32, a peptide, a petidoglycan, or a saccharide. C can be or can comprise:
Figure imgf000059_0003
. The hapten is recognized by an autologous antibody. The hapten can be selected from the group consisting of rhamnose, an α-galactosyl moiety, a dinitrophenyl (DNP) moiety, and a trinitrophenyl (TNP) moiety. [0075] The conjugate can have a structure selected from:
Figure imgf000059_0004
Figure imgf000060_0001
, wherein L comprises at least one carbon atom; and p is 0-3. L can be or can comprise a moiety of the formula:
Figure imgf000060_0002
, wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula:
Figure imgf000060_0003
, wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula:
Figure imgf000060_0004
[0076] L can be or can comprise a moiety of the formula:
Figure imgf000061_0001
wherein n is an integer from 0 to 10. L can be or can comprise a moiety of the formula:
Figure imgf000061_0002
. L can be or can comprise a moiety of the formula:
Figure imgf000061_0003
[0077] L can be or can comprise a moiety of the formula:
Figure imgf000062_0001
wherein n is an integer from 0 to 20. L can be or can comprise a moiety of the formula:
Figure imgf000062_0002
wherein n is an integer from 0 to 20. L can be a linker that can be cleaved (e.g., under physiological conditions). L can be cleaved reductively, oxidatively, or enzymatically. L can comprise an oxime ester. L can comprise a hydrazone. L can comprise polyethylene glycoln (PEGn), wherein n = 0-36. L can comprise a peptide, a peptidoglycan, an alkyl, or a sugar. L can be or can comprise:
Figure imgf000062_0003
Figure imgf000063_0001
. [0078] L can comprise a structure selected from:
Figure imgf000063_0002
wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8. L can comprise the structure:
Figure imgf000063_0003
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are independently selected from the group consisting of H and C1-C6 alkyl.
[0079] The conjugate can have a structure selected from:
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
. [0080] The conjugates can be synthesized as described herein or otherwise by one of ordinary skill in the art having the benefit of this disclosure via standard synthesis methods generally known in the art using commercially available starting materials and reagents. [0081] As noted above, optionally, the conjugate (or stereoisomer or pharmaceutical salt therof) can be formulated into a pharmaceutical composition. The pharmaceutical composition can comprise any conjugate hereof and a pharmaceutically acceptable carrier, such as a composition comprising a conjugate dispersed in a pharmaceutically acceptable liquid carrier. The pharmaceutical composition can comprise a plurality of conjugates and a pharmaceutically acceptable carrier. The composition is suitable for administration to a subject for diagnostic, mapping, and/or therapeutic applications. By "suitable" for administration is meant that administration of the conjugate/composition to a subject will not result in unacceptable toxicity, including allergenic responses and disease states. [0082] Liquids within which the conjugate may be dispersed include a carrier liquid or an in vivo liquid. By the conjugate being "dispersed" throughout or in a liquid is meant that the conjugate presents as a dispersed phase within the liquid which itself, relative to the conjugate, presents as a continuous liquid medium or phase. The term "liquid" in the context of a liquid carrier is intended to mean a vehicle in which the conjugate is dispersed and which is in a liquid state at least at the temperature of intended use. [0083] A liquid carrier used in accordance with the invention can be made up of one or more different liquids. Suitable pharmacologically acceptable liquid carriers are described in Martin, Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA, (1990), and include, but are not limited to, liquids that may be sterilized, such as water and oils, including those of petroleum, animal, vegetable, mineral or synthetic origin, such as peanut oil, soya bean oil, mineral oil, sesame oil, and the like. Other liquid carriers include methylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, ethanol, isopropyl alcohol, and benzyl alcohol. Water or soluble saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers, particularly for injectable solutions. [0084] In practice, the conjugate can be taken up by a subject in vivo, for example, when the conjugate is administered orally or parenterally. In that case, a liquid carrier originally carrying the conjugate can become so dilute in vivo that the surrounding liquid environment throughout which the conjugate is dispersed becomes more representative of an in vivo liquid (i.e., a biological liquid/fluid within the subject) than the original liquid carrier. For example, once administered parenterally, the conjugate might more aptly be described as being dispersed throughout blood rather than an original liquid carrier. Under those circumstances, it can be convenient to refer to the conjugate as being dispersed throughout an in vivo liquid carrier (i.e., a biological liquid/fluid within the subject). [0085] Compositions can comprise one or more pharmacologically acceptable additives known to those in the art. For example, the liquid carrier may comprise one or more additives such as wetting agents, de-foaming agents, surfactants, buffers, electrolytes, preservatives, colourings, flavourings, and sweeteners. [0086] The particular nature of a liquid carrier and any additive (if present) will in part depend upon the intended application of the composition. A suitable liquid carrier and additive (if present) can be selected for the intended application of the composition. [0087] Where the conjugate or compositions are suitable for parenteral administration, they will generally be in the form of an aqueous or non-aqueous isotonic sterile injection solution that may contain one or more of an anti-oxidant, buffer, bactericide or solute which renders the composition isotonic with the blood of the intended subject. Such compositions can be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials. [0088] The term "about" or "approximately" means within an acceptable range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Unless otherwise stated, the term "about" means within an acceptable error range for the particular value, such as ± 1-20%, preferably ± 1-10% and more preferably ±1-5%. [0089] Where a range of values is provided, it is understood that each intervening value, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both limits, ranges excluding either or both of those limits are also included. [0090] A phrase referring to "at least one of" a list of items refers to any combination of those items, including single members. As an example, "at least one of a, b, or c" is intended to cover: a, b, c, a-b, a-c, b-c, and a-b-c. [0091] "Oxo" refers to the =O radical. [0092] "Alkyl" generally refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C1- C15 alkyl). "Alkyl" is intended to include independent recitations of a saturated "alkyl, " unless otherwise stated. An alkyl can comprise one to thirteen carbon atoms (e.g., C1-C13 alkyl). An alkyl can comprise one to eight carbon atoms (e.g., C1-C8 alkyl). An alkyl can comprise one to five carbon atoms (e.g., C1-C5 alkyl). An alkyl can comprise one to four carbon atoms (e.g., C1- C4 alkyl). An alkyl can comprise one to three carbon atoms (e.g., C1-C3 alkyl). An alkyl can comprise one to two carbon atoms (e.g., C1-C2 alkyl). An alkyl can comprise one carbon atom (e.g., C1 alkyl). An alkyl can comprise five to fifteen carbon atoms (e.g., C5-C15 alkyl). An alkyl can comprise five to eight carbon atoms (e.g., C5-C8 alkyl). An alkyl can comprise two to five carbon atoms (e.g., C2-C5 alkyl). An alkyl can comprise three to five carbon atoms (e.g., C3-C5 alkyl). In various embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n- propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2- methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. [0093] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above. [0094] "Alkylene" or "alkylene chain" generally refers to a straight or branched divalent alkyl group linking the rest of the molecule to a radical group, such as having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, i-propylene, n-butylene, and the like. [0095] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring systems from which aryl groups are derived include, but are not limited to, benzene, fluorene, indane, indene, tetralin and naphthalene. [0096] "Aralkyl" or "aryl-alkyl" refers to a radical of the formula -Rc-aryl, where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. [0097] "Carbocyclyl" or "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. A carbocyclyl can comprise three to ten carbon atoms. A carbocyclyl can comprise five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). Examples of saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl. " Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. [0098] "Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl, where Rc is an alkylene chain as defined above. [0099] "Halo" or "halogen" refers to a bromo, chloro, fluoro or iodo substituent. [0100] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. [0101] The term "heteroalkyl" refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies – for example, -CH2- may be replaced with -NH- or -O-). For example, each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, selenium, or other suitable heteroatom. In some instances, each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or -N(aryl)- or having another substituent contemplated herein), or sulfur (e.g. - S-, -S(=O)-, or -S(=O)2-). A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. A heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. A heteroalkyl is a C1-C18 heteroalkyl. A heteroalkyl is a C1-C12 heteroalkyl. A heteroalkyl is a C1-C6 heteroalkyl. A heteroalkyl is a C1-C4 heteroalkyl. Heteroalkyl can include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl, as defined herein. [0102] "Heteroalkylene" refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule. [0103] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that can comprise two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes aromatic, fused, and/or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. The heterocyclyl radical is partially or fully saturated. "Heterocyclyl" is intended to include independent recitations of heterocyclyl comprising aromatic and non-aromatic ring structures, unless otherwise stated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, indolinyl, isoindolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. [0104] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1- piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. [0105] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that can comprise two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). [0106] The conjugates can contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds are contemplated. When the conjugates contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring. Further, it is understood that replacement of one or more hydrogen atoms with deuterium can significantly lower the rate of metabolism of a drug and, therefore, increase its half-life. [0107] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those in the art to which the disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference. [0108] The invention illustratively described herein may be suitably practiced in the absence of any element(s) or limitation(s), which is/are not specifically disclosed herein. Thus, for example, each instance herein of any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms. Likewise, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, where a compound/composition is substituted with “an” alkyl or aryl, the compound/composition is optionally substituted with at least one alkyl and/or at least one aryl. [0109] The terms and expressions, which have been employed, are used as terms of description and not of limitation. Where certain terms are defined and are otherwise described or discussed elsewhere in the "Detailed Description," all such definitions, descriptions, and discussions are intended to be attributed to such terms. There also is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof. Furthermore, while subheadings may be used in the "Detailed Description," such use is solely for ease of reference and is not intended to limit any disclosure made in one section to that section only; rather, any disclosure made under one subheading is intended to constitute a disclosure under each and every other subheading. [0110] It is recognized that various modifications are possible within the scope of the claimed invention. Thus, although the present invention has been specifically disclosed in the context of preferred embodiments and optional features, those skilled in the art may resort to modifications and variations of the concepts disclosed herein. Such modifications and variations are considered within the scope of the invention as claimed herein. EMBODIMENTS [0111] The following enumerated embodiments, represented by clauses, are non-limiting aspects according to the present disclosure and describe particular embodiments hereof: [0112] Clause A. A method of treating fibrosis in a subject, which method comprises administering to the subject an effective amount of a conjugate of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a conjugate of formula I, wherein formula I is: wherein A has the structure:
Figure imgf000083_0001
wherein:
Figure imgf000083_0002
represents a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R1 and R2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH- , (CH3)3C-, -CH2Ph, and substituted -CH2Ph; R8-R10 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; and R11 is selected from the group consisting of H, D, Cl-Cl0 alkyl, C3-Cl0 cycloalkyl, adamantyl,
Figure imgf000083_0003
, , substituted or unsubstituted aryl, substituted or unsubstituted C7-C20 alkyl aryl, wherein the aryl is:
Figure imgf000083_0004
wherein: R12 and R16 are each independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R13, R14 and R15 are each independently selected from the group consisting of H, D, halogen, -OMe, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R17, R18, R20, and R21 are each independently selected from H and CH3; and R19 and R22 are independently selected from the group consisting of phenyl, dimethoxyphenyl, and aryl; L is a bifunctional or trifunctional linker; and B is a phosphatidylinositol-3-kinase (PI3K) inhibitor or a dual inhibitor of the PI3K/ mammalian target of rapamycin (mTOR) signaling pathway. [0113] Clause B. The method of Clause A, wherein L is attached to A at any carbon atom of the functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl. [0114] Clause C. The method of Clauses A or B, wherein A has the formula IV or V:
Figure imgf000084_0001
wherein: each R2 is selected from the group consisting of -H, -D, -OH, -F, -Cl, -Br, I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH-, and (CH3)3C-; R11 is selected from the group consisting of
Figure imgf000085_0001
Figure imgf000086_0001
R23-R26 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -CF3, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH-, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl. [0115] Clause D. The method of any of the foregoing Clauses, wherein the PI3k inhibitor or the PI3k/mTOR inhibitor is a radical of any one of the following structures:
Figure imgf000086_0002
Figure imgf000087_0001
, comprises a structure selected from:
Figure imgf000087_0002
. [0116] Clause E. The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula:
Figure imgf000087_0003
, wherein n is an integer from 0 to 10. [0117] Clause F. The method of any one of the foregoing Clauses, where L is or comprises a moiety of the formula:
Figure imgf000087_0004
, wherein n is an integer from 0 to 10. [0118] Clause G. The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula:
Figure imgf000088_0001
[0119] Clause H. The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula:
Figure imgf000088_0002
wherein n is an integer from 0 to 20. [0120] Clause I. The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula:
Figure imgf000088_0003
. [0121] Clause J. The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula:
Figure imgf000088_0004
Figure imgf000089_0001
[0122] Clause K. The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula:
Figure imgf000089_0002
wherein n is an integer from 0 to 20. [0123] Clause L. The method of any one of the foregoing Clauses, wherein L is or comprises a moiety of the formula:
Figure imgf000089_0003
Figure imgf000090_0001
, wherein n is an integer from 0 to 20. [0124] Clause M. The method of Clause A, wherein L is a linker that can be cleaved under physiological conditions. [0125] Clause N. The method of Clause M, wherein L can be cleaved reductively, oxidatively, or enzymatically. [0126] Clause O. The method of any one of the foregoing Clauses, wherein L comprises an oxime ester. [0127] Clause P. The method of any one of the foregoing Clauses, wherein L comprises a hydrazone. [0128] Clause Q. The method of any one of the foregoing Clauses, wherein L comprises polyethylene glycoln (PEG)n, wherein n = 0-36. [0129] Clause R. The method of any one of the foregoing Clauses, wherein L comprises a peptide, a peptidoglycan, an alkyl, or a sugar. [0130] Clause S. The method of any one of the foregoing Clauses, wherein L is or comprises:
Figure imgf000090_0002
Figure imgf000091_0003
. [0131] Clause T. The method of any one of the foregoing Clauses, wherein L comprises a structure selected from a group consisting of:
Figure imgf000091_0001
, wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8. [0132] Clause U. The method of any one of the foregoing Clauses, wherein L comprises the structure:
Figure imgf000091_0002
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are each independently selected from the group consisting of H and C1-C6 alkyl.
[0133] Clause V. The method of Clause A, wherein the conjugate is selected from:
Figure imgf000092_0001
[0134] Clause W. The method of Clause A, wherein the conjugate is selected from:
Figure imgf000093_0001
. [0135] Clause X. The method of Clause A, wherein the conjugate is selected from:
Figure imgf000093_0002
. [0136] Clause Y. The method of Clause A, wherein the conjugate of formula I further comprises a pharmacokinetic extender C and has the formula (II):
Figure imgf000093_0003
[0137] Clause Z. The method of Clause Y, wherein C is an albumin binder, a plasma protein binder, or a hapten. [0138] Clause AA. The method of Clauses Y or Z, wherein C is an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti- albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06). [0139] Clause BB. The method of any one of Clauses Y-AA, wherein C is or comprises: .
Figure imgf000094_0001
[0140] Clause CC. The method of any one of Clauses Y-AA, wherein C is or comprises:
Figure imgf000095_0001
Figure imgf000096_0001
wherein: each of R12-19 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, or -SO2F; and each of R20 and R21 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -O-C1-6 alkyl, -CN, -CHO, -B(OH)2, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, -SO2F,
Figure imgf000096_0002
[0141] Clause DD. The method of any one Clause Y-A, wherein C is or comprises:
Figure imgf000096_0003
. [0142] Clause EE. The method of Clause Y, wherein C is or comprises: .
Figure imgf000096_0004
[0143] Clause FF. The method of Clause Y, wherein C is or comprises:
Figure imgf000097_0001
. [0144] Clause GG. The method of Clause Y, wherein C comprises a radical of (PEG)n, wherein n = 0-32, a peptide, a petidoglycan, or a saccharide. [0145] Clause HH. The method of Clause Y, wherein C is or comprises:
Figure imgf000097_0002
[0146] Clause II. The method of Clause Y, wherein C is or comprises
Figure imgf000097_0003
. [0147] Clause JJ. The method of Clause Z, wherein the hapten is recognized by an autologous antibody. [0148] Clause KK. The method of Clause Z, wherein the hapten is selected from the group consisting of rhamnose, an α-galactosyl moiety, a dinitrophenyl (DNP) moiety, and a trinitrophenyl (TNP) moiety.
[0149] Clause LL. The method of Clause A, wherein the compound has a structure selected from:
Figure imgf000098_0001
wherein L comprises at least one carbon atom; and p is 0-3. [0150] Clause MM. The method of Clause LL, wherein L is or comprises a moiety of the formula:
Figure imgf000098_0002
, wherein n is an integer from 0 to 10. [0151] Clause NN. The method of Clause LL, wherein L is or comprises a moiety of the formula:
Figure imgf000098_0003
, wherein n is an integer from 0 to 10. [0152] Clause OO. The method of Clause LL, wherein L is or comprises a moiety of the formula:
Figure imgf000099_0001
. [0153] Clause PP. The method of Clause LL, wherein L is or comprises a moiety of the formula:
Figure imgf000099_0002
wherein n is an integer from 0 to 10. [0154] Clause QQ. The method of Clause LL, wherein L is or comprises a moiety of the formula:
Figure imgf000099_0003
. [0155] Clause RR. The method of Clause LL, wherein L is or comprises a moiety of the formula:
Figure imgf000099_0004
Figure imgf000100_0001
[0156] Clause SS. The method of Clause LL, wherein L is or comprises a moiety of the formula:
Figure imgf000100_0002
wherein n is an integer from 0 to 20. [0157] Clause TT. The method of Clause LL, wherein L is or comprises a moiety of the formula:
Figure imgf000100_0003
, wherein n is an integer from 0 to 20. [0158] Clause UU. The method of Clause LL, wherein L is a linker that can be cleaved under physiological conditions. [0159] Clause VV. The method of Clause UU, wherein L can be cleaved reductively, oxidatively, or enzymatically. [0160] Clause WW. The method of Clause LL, wherein L comprises an oxime ester. [0161] Clause XX. The method of Clause LL, wherein L comprises a hydrazone. [0162] Clause YY. The method of Clause LL, wherein L comprises (PEG)n, wherein n = 0-36. [0163] Clause ZZ. The method of Clause LL, wherein L comprises a peptide, a peptidoglycan, an alkyl, or a sugar. [0164] Clause AAA. The method of Clause LL, wherein L is or comprises:
Figure imgf000101_0002
. [0165] Clause BBB. The method of Clause LL, wherein L is or comprises a structure selected from:
Figure imgf000101_0001
, wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8. [0166] Clause CCC. The method of Clause LL, wherein L comprises the structure:
Figure imgf000102_0001
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are independently selected from the group consisting of H and C1-C6 alkyl. [0167] Clause DDD. The method of Clause LL, wherein the conjugate is selected from:
Figure imgf000102_0002
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
. [0168] Clause EEE. Uses of conjugate of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a conjugate of formula I in the manufacture of a medicament for inhibiting the progression of a fibrotic disease state (e.g., fibrosis) in a subject, wherein formula I is: wherein A has the structure:
Figure imgf000111_0002
wherein:
Figure imgf000111_0003
represents a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R1 and R2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH- , (CH3)3C-, -CH2Ph, and substituted -CH2Ph; R8-R10 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; and R11 is selected from the group consisting of H, D, C1-C10 alkyl, C3-C10 cycloalkyl, adamantyl,
Figure imgf000112_0001
, , substituted or unsubstituted aryl, substituted or unsubstituted C7-C20 alkyl aryl, wherein the aryl is:
Figure imgf000112_0002
wherein: R12 and R16 are each independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R13, R14 and R15 are each independently selected from the group consisting of H, D, halogen, -OMe, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R17, R18, R20, and R21 are each independently selected from H and CH3; and R19 and R22 are independently selected from the group consisting of phenyl, dimethoxyphenyl, and aryl; L is a bifunctional or trifunctional linker; and B is a phosphatidylinositol-3-kinase (PI3K) inhibitor or a dual inhibitor of the PI3K/ mammalian target of rapamycin (mTOR) signaling pathway. [0169] Clause FFF. The use of Clause EEE, wherein the conjugate of formula I further comprises a pharmacokinetic extender C and has the formula (II):
Figure imgf000112_0003
[0170] Clause GGG. The use of Clause EEE, wherein C is an albumin binder, a plasma protein binder, or a hapten. [0171] Clause HHH. The use of Clauses FFF or GGG wherein C is an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti- albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06). [0172] Clause III. A conjugate of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a conjugate of formula I, wherein formula I is: wherein A has the structure:
Figure imgf000113_0001
wherein:
Figure imgf000113_0002
represents a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R1 and R2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH-, (CH3)3C-, -CH2Ph, and substituted -CH2Ph; R8-R10 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; and R11 is selected from the group consisting of H, D, Cl-Cl0 alkyl, C3-Cl0 cycloalkyl, adamantyl,
Figure imgf000114_0001
, , substituted or unsubstituted aryl, substituted or unsubstituted C7-C20 alkyl aryl, wherein the aryl is:
Figure imgf000114_0002
wherein: R12 and R16 are each independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R13, R14 and R15 are each independently selected from the group consisting of H, D, halogen, -OMe, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R17, R18, R20, and R21 are each independently selected from H and CH3; and R19 and R22 are independently selected from the group consisting of phenyl, dimethoxyphenyl, and aryl; L is a bifunctional or trifunctional linker; and B is a PI3K inhibitor or a dual inhibitor of the PI3K/mTOR signaling pathway; wherein the conjugate is optionally provided as a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. [0173] Clause JJJ. The conjugate of Clause III, wherein L is attached to A at any carbon atom of the functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi- cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl.
[0174] Clause KKK. The conjugate of Clauses III or JJJ, wherein A has the formula IV or V:
Figure imgf000115_0001
wherein: each R2 is selected from the group consisting of -H, -D, -OH, -F, -Cl, -Br, I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH-, and (CH3)3C-; R11 is selected from the group consisting of
Figure imgf000115_0002
Figure imgf000116_0001
Figure imgf000117_0001
; and R23-R26 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -CF3, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH-, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl. [0175] Clause LLL. The conjugate of any one of Clauses III-LLL, wherein the PI3k inhibitor or the PI3k/mTOR inhibitor is a radical of any one of the following structures:
Figure imgf000117_0002
,
Figure imgf000118_0001
Figure imgf000118_0002
, wherein X is or comprises a structure selected from:
Figure imgf000118_0003
. [0176] Clause MMM. The conjugate of any one of Clauses III-LLL wherein L is or comprises a moiety of the formula:
Figure imgf000118_0004
, wherein n is an integer from 0 to 10. [0177] Clause NNN. The conjugate of any one of Clauses III-MMM, where L is or comprises a moiety of the formula:
Figure imgf000119_0001
, wherein n is an integer from 0 to 10. [0178] Clause OOO. The conjugate of any one of Clauses III-NNN, wherein L is or comprises a moiety of the formula:
Figure imgf000119_0002
[0179] Clause PPP. The conjugate of any one of Clauses III-NNN, wherein L is or comprises a moiety of the formula:
Figure imgf000119_0003
wherein n is an integer from 0 to 20. [0180] Clause QQQ. The conjugate of any one of Clauses III-NNN, wherein L is or comprises a moiety of the formula:
Figure imgf000119_0004
. [0181] Clause RRR. The conjugate of any one of Clauses III-NNN, wherein L is or comprises a moiety of the formula:
Figure imgf000120_0001
[0182] Clause SSS. The conjugate of any one of Clauses III-NNN, wherein L is or comprises a moiety of the formula:
Figure imgf000120_0002
wherein n is an integer from 0 to 20. [0183] Clause TTT. The conjugate of any one of Clauses III-NNN, wherein L is or comprises a moiety of the formula:
Figure imgf000120_0003
Figure imgf000121_0001
, wherein n is an integer from 0 to 20. [0184] Clause UUU. The conjugate of any one of Clauses III-NNN, wherein L is a linker that can be cleaved under physiological conditions. [0185] Clause VVV. The conjugate of Clause UUU, wherein L can be cleaved reductively, oxidatively, or enzymatically. [0186] Clause WWW. The conjugate of any one of Clauses III-NNN, wherein L comprises an oxime ester, a hydrazone, a (PEG)n, wherein n = 0-36, a peptide, a peptidoglycan, an alkyl, and/or a sugar. [0187] Clause XXX. The conjugate of any one of Clauses III-NNN, wherein L is or comprises:
Figure imgf000121_0002
Figure imgf000122_0001
. [0188] Clause YYY. The conjugate of any one of Clauses III-NNN, wherein L comprises a structure selected from a group consisting of:
Figure imgf000122_0002
, wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8. [0189] Clause ZZZ. The conjugate of any one Clauses III-NNN, wherein L comprises the structure:
Figure imgf000122_0003
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are each independently selected from the group consisting of H and C1-C6 alkyl.
[0190] Clause AAAA. The conjugate of Clause III selected from:
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
.
[0191] Clause BBBB. The conjugate Clause III selected from:
Figure imgf000126_0001
.
[0192] Clause CCCC. The conjugate of Clause III selected from:
Figure imgf000127_0001
. [0193] Clause DDDD. The conjugate of Clause III, wherein the conjugate of formula I further comprises a pharmacokinetic extender C and has the formula (II):
Figure imgf000127_0002
. [0194] Clause EEEE. The conjugate of Clause DDDD, wherein C is an albumin binder, a plasma protein binder, or a hapten. [0195] Clause FFFF. The conjugate of Clauses DDDD or EEEE, wherein C is an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti-albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06). [0196] Clause GGGG. The conjugate of any one of Clauses DDDD-GGGG, wherein C is or comprises:
Figure imgf000128_0001
. [0197] Clause HHHH. The conjugate of any one of Clauses DDDD-GGGG, wherein C is or comprises:
Figure imgf000128_0002
Figure imgf000129_0001
wherein: each of R12-19 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, or -SO2F; and each of R20 and R21 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -O-C1-6 alkyl, -CN, -CHO, -B(OH)2, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, -SO2F,
Figure imgf000130_0001
[0198] Clause IIII. The conjugate of any one of Clauses DDDD-GGGG, wherein C is or comprises:
Figure imgf000130_0002
. [0199] Clause JJJJ. The conjugate of any one of DDDD-GGGG, wherein C is or comprises:
Figure imgf000130_0003
.
[0200] Clause KKKK. The conjugate of any one of DDDD-GGGG, wherein C is or comprises:
Figure imgf000131_0001
. [0201] Clause LLLL. The conjugate of any one of DDDD-GGGG, wherein C comprises a radical of (PEG)n, wherein n = 0-32, a peptide, a petidoglycan, or a saccharide. [0202] Clause MMMM. The conjugate of any one of DDDD-GGGG, wherein C is or comprises:
Figure imgf000131_0002
. [0203] Clause NNNN. The conjugate of any one of DDDD-GGGG, wherein C is or comprises
Figure imgf000131_0003
. [0204] Clause OOOO. The conjugate of Clause EEEE, wherein the hapten is recognized by an autologous antibody. [0205] Clause PPPP. The conjugate of Clause EEEE, wherein the hapten is selected from the group consisting of rhamnose, an α-galactosyl moiety, a DNP moiety, and a TNP moiety. [0206] Clause QQQQ. The conjugate of Clause DDDD, wherein the compound has a structure selected from:
Figure imgf000132_0001
, wherein L comprises at least one carbon atom; and p is 0-3. [0207] Clause RRRR. The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula:
Figure imgf000133_0001
, wherein n is an integer from 0 to 10. [0208] Clause SSSS. The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula:
Figure imgf000133_0002
, wherein n is an integer from 0 to 10. [0209] Clause TTTT. The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula:
Figure imgf000133_0003
. [0210] Clause UUUU. The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula:
Figure imgf000133_0004
wherein n is an integer from 0 to 10. [0211] Clause VVVV. The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula:
Figure imgf000134_0001
. [0212] Clause WWWW. The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula:
Figure imgf000134_0002
[0213] Clause XXXX. The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula:
Figure imgf000134_0003
wherein n is an integer from 0 to 20. [0214] Clause YYYY. The conjugate of Clause DDDD, wherein L is or comprises a moiety of the formula:
Figure imgf000135_0001
, wherein n is an integer from 0 to 20. [0215] Clause ZZZZ. The conjugate of Clause DDDD, wherein L is a linker that can be cleaved under physiological conditions. [0216] Clause AAAAA. The conjugate of Clause ZZZZ, wherein L can be cleaved reductively, oxidatively, or enzymatically. [0217] Clause BBBBB. The conjugate of Clause DDDD, wherein L comprises an oxime ester, a hydrazone, (PEG)n, wherein n = 0-36, a peptide, a peptidoglycan, an alkyl, and/or a sugar. [0218] Clause CCCCC. The conjugate of Clause DDDD, wherein L is or comprises:
Figure imgf000135_0002
[0219] Clause DDDDD. The conjugate of Clause DDDD, wherein L is or comprises a structure selected from:
Figure imgf000136_0001
, wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8. [0220] Clause EEEEE. The conjugate of Clause DDDD, wherein L comprises the structure:
Figure imgf000136_0002
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are independently selected from the group consisting of H and C1-C6 alkyl. [0221] Clause FFFFF. The conjugate of Clause DDDD, wherein the conjugate is selected from:
Figure imgf000136_0003
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
. [0222] Clause GGGGG. A method of inhibiting the progression of fibrosis in a subject comprising administering to the subject an effective amount of a conjugate of any one of Clauses III-FFFFF, or a stereoisomer or a pharmaceutically acceptable salt thereof, whereupon progression of a fibrotic disease state (e.g., fibrosis) in the subject is inhibited. EXAMPLES [0223] The following examples serve to illustrate the present disclosure. The examples are not intended to limit the scope of the claimed invention. Example 1 Scheme-1: Synthesis of FAP8-PI3K conjugate. [0224] FIG.1 depicts the synthesis scheme of a FAP8-PI3K conjugate, which is further described below. [0225] Synthesis of compound (2). Et3N was added (5.0 eq) to a stirred solution compound 1 (1.0 g, 5.1 mmol) in dry dichloromethane (DCM) (3.0 mL) at 0 °C, followed by POCl3 (1.5 eq). The reaction continued at same temperature for 1 hour, and progress of the reaction was monitored by thin layer chromatography (TLC). Upon complete depletion of starting materials as indicated on TLC plates, the reaction mixture was further diluted with DCM and absorbed on silica-gel cartridge and purified in CombiFlash using ethyl acetate and hexanes as mobile phase. The desired compound 2 (750 mg, 81%) was obtained as a light-yellow liquid. [0226] Synthesis of compound (5). To a mixture of N-Boc-L-prolinal (1 eq., 200 mg, 0.851 mmol), N-protected glycine (1 eq., 161mg, 0.851mmol) and isocyanide (1 eq., 162 mg, 0.851 mmol) were dissolved in anhydrous DCM (10 mL) and stirred for 4 hours. After complete conversion (liquid chromatography-mass spectrometry (LC-MS)) of starting materials, trifluoroacetic acid (3.0 mL) was added to the reaction mixture and stirring was continued at room tempearture for 1 hour. The volatiles were evaporated under reduced pressure. The oily residue was redissolved in anhydrous DCM (10 mL) and cooled down to 0 °C with ice bath. Triethylamine (5.0 mL) was added dropwise and the stirring continued to full conversion (LC-MS different retention time with same mass), usually less than 2 hours. The liquids were evaporated under reduced pressure, the mixture was redissolved in DCM and washed 3 times with water. Organic phase was washed with brine, dried over sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude residue was purified by using CombiFlash with hexanes and ethyl acetate as mobile phase and the desired α-hydroxyamide (compound 5) was obtained as brown color solid. [0227] Synthesis of compound (6). Compound 5 was dissolved in MeOH+AcOH (10 mL, 1:1) and added with 10% Pd-C (100 mg for 1g of starting material), then stirred under hydrogen atmosphere for 4 hours. The reaction mixture was filtered thorough celite pad and filtrate was evaporated under reduced pressure and obtained crude residue was azeotrope with EtOH, then purified by CombiFlash using MeOH + DCM to obtain the amine 6 as white color solid. [0228] Synthesis of compound (8). Cs2CO3 (2.65 gm, 7.93 mmol) and then tertiary-butyl bromo acetate (7.93 mmol) were added to a solution of compound 7 (500 mg, 2.64mmol) in dimethylformamide (DMF) (10. mL). The reaction mixture was stirred at 55 °C, for 4 hours and, thereafter, KOH (3 eq. with respect to dialkylated product) and H2O (5.0 mL) were added to the same reaction mixture, which was continuously stirred for an additional 12 hours. The progress of the reaction was monitored by LC-MS. [0229] The reaction mixture was carefully neutralized with 1N HCl and extracted multiple times with EtOAc, combined organic extracts were evaporated under reduced pressure, and obtained crude residue was purified by CombiFlash using EtOAc+Hexanes system and provided the desired compound 8 as white solid (500 mg, 81%). [0230] Synthesis of compound (9). To a stirred solution of compound 8 (200 mg, 0.66 mmol) in anhydrous DCM (10.0 mL), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (411 mg, 0.792 mmol) and N,N-diisopropylethylamine (DIPEA) (0.22 mL, 1.32 mmol) were added. The reaction mixture was continuously stirred for 10 minutes, and amine 6 (0.66 mmol) was added to the above reaction mixture and stirring continued there for an additional 2 hours. Thereafter, the reaction mixture was diluted with water, then extracted into DCM (2x20 mL), and the combined organic extracts were dried over anhydrous sodium sulphate, filtered and the filtrate was evaporated under reduced pressure. Obtained crude residue was purified by combiflash using EtOAc+Hexanes for 15 minutes, followed by MeOH+DCM as mobile phase for 25 provided the compound 9 as white solid. [0231] Synthesis of compound (10). To a stirred solution of compound 9 (1.0 eq) dissolved in DCM, DMP (3.0 eq) and water (5.0. eq) was added and stirred at room temperature overnight. Rection mixture was further diluted with saturated with sodium bicarbonate solution and extracted into DCM (2x30 mL), the combined organic extracts were dried over anhydrous sodium sulphate, filtered and filtrate was evaporated under reduced pressure, then the obtained crude residue was purified by CombiFlash using MeOH+CH2Cl2 as mobile phase provided the desired keto compound 10 as white solid. [0232] Synthesis of compound (11). Trifluoroacetic acid (TFA) (2 ml) was added to a stirred solution of compound 10 (200 mg, 0.237 mmol) in CH2Cl2 (5.0 mL) and the reaction mixture was stirred at for 2 hours, and evaporated under reduced pressure. The obtained crude reduce was solidified with diethyl ether, filtered, and the obtained solid was dried and used in further steps without purification or purification by using combiflash with methanol in dichloromethane as mobile phase to provide FAP8 base ligand (compound 11) as white solid. [0233] Synthesis of compound (13). Compound 12 (500 mg, 0.727 mmol) was dissolved in CH2Cl2 (10.0 mL), added with 2-tert-butyl-1,3-diisopropylisourea (5.0 eq, 728 mg, 3.635 mmol) and stirred at room temperature for 18 hours. Upon completion, the reaction mixture was diluted with CH2Cl2, washed with distilled water, and the organic layer was separated and evaporated under vacuum to obtain the crude residue. The crude purified by column chromatography using ethyl acetate in hexane as mobile phase produced the desired compound 13 as yellowish gummy liquid. [0234] Synthesis of compound (14). Compound 11 (200 mg, 0.326 mmol) dissolved in CH2Cl2 (8.0 mL) was added with PyBOP (1.2 eq) and DIPEA (3.0 eq), and allowed to stir for 10 minutes, followed by the addition of compound 13 dissolved in CH2Cl2 (2.0 mL). The reaction mixture was stirred at room temperature for 2 hours, washed with distilled water, the organic layer dried over anhydrous sodium sulfate and evaporated under vacuum to generate the crude extract. Purification of the crude using methanol in dichloromethane mobile phase in CombiFlash afforded white solid of compound 14. [0235] Synthesis of compound (15). Compound 14 (50 mg, 0.049 mmol) was dissolved in CH2Cl2 (1.0 mL), added with TFA (1.0 mL), allowed to stir for 6h, followed by addition of triisopropyl silane (TIPS) (100 μL) and further allowed to stir for 1 hour. Upon complete deprotection of the starting material as confirmed by LC-MS, the reaction mixture was concentrated under vacuum, diluted with minimal amount of dichloromethane, absorbed on celite, and subjected to reverse phase column chromatography using acetonitrile in 20 mM ammonium acetate (pH 5.0) as mobile phase. Lyophilization of the acquired fractions afforded compound 15 as white solid. [0236] Synthesis of compound (18). Compound 16 (1.0 mL, 11.054 mmol) was dissolved in CH3CN (8.0 mL) and cooled to 0°C, followed by dropwise addition of compound 17 dissolved in CH3CN (5.0 mL), and allowed to stir for 30 minutes at 0 °C.2-mercaptopyridine (0.9 eq) dissolved in CH3CN (20.0 mL) was added dropwise to the reaction mixture and refluxed for 2 hours. The appearance of white precipitates into the reaction mixture confirmed the formation of the product. Following reflux, the reaction mixture was cooled to 0 °C, stirred for 1 hour, and filtered, to afford compound 18 as white solid. [0237] Synthesis of compound (19). Compound 18 (500 mg, 2.66 mmol) was dissolved in CH2Cl2 (5.0 mL) along with TEA (1.0 eq) and added dropwise to a solution of triphosgene (0.33 eq) in CH2Cl2 (5.0 mL) cooled at 0 °C. The reaction was stirred for 1.5 hours, followed by dropwise addition of a solution of hydroxybenzotriazole (1.0 eq) in CH2Cl2 (10.0 mL) and TEA (1.0 eq), and further allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (50.0 mL), washed twice with distilled water (100 mL X 2) and brine (100 mL), the combined organic layer dried over anhydrous sodium sulfate and concentrated under vacuum. The crude extract was purified through column chromatography using ethyl acetate in hexane as mobile phase to obtain compound 19 as white solid. [0238] Synthesis of compound (21). Compound 20 (50 mg, 0.094 mmol) dissolved in 1.0 mL DMF was added with compound 19 (1.0 eq) and DIPEA (1.0 eq), stirred at rt for 2h. Completion of the reaction was determined by LC-MS. The reaction mixture was added with distilled water and dichloromethane, organic layer was collected and dried over anhydrous sodium sulfate, concentrated under vacuum, absorbed in celite and subjected to reverse phase chromatography using acetonitrile in 20 mM ammonium acetate (pH 7.0) as mobile phase. Lyophilization of the acquired fractions afforded compound 21 as white solid. [0239] Synthesis of compound (22). Compound 21 (20 mg, 0.027 mmol) was dissolved in DMF (300 μL ) along with 1.0 eq of 4-dimethylaminopyridine (DMAP) under inert conditions, followed by the portion-wise addition of compound 15 dissolved in DMF (200 μL). The reaction was stirred at room temperature for 2 hours and the complete conversion of the starting material was determined by LC-MS. The reaction mixture was subjected to high-performance liquid chromatography (HPLC), and lyophilization of the fractions afforded white solids of compound 22 at 50% purity as evident from LC-MS analysis shown in FIG. 2. Further purification of the compound using ultra performance liquid chromatography can be used to improve the purity of the product. Example 2 Western Blot Analysis of Cultured Fibroblasts. [0240] Serum-starved confluent HLF cells (primary lung fibroblast, normal, human) are coincubated in medium containing transforming growth factor beta 1 (TGFβ1) (10 ng/ml) with or without the indicated concentrations of FAP8-PI3K inhibitor conjugates hereof (1-100 nM) for 24 hours. Afterwards, cells are harvested and lysed for Western blot analysis. After sodium dodecyl sulfate (SDS)–polyacrylamide gel electrophoresis and blocking, membranes are incubated with antibodies to detect pSMAD2Ser465/467 (Cell Signaling Technology, #3101; Danvers, MA) or pAktSer473 (Cell Signaling Technology, #4060; Danvers, MA), and signals are visualized with ECL Western Blot Detection Reagents (GE Healthcare; Chicago, IL). After stripping, membranes are blocked and reprobed with antibodies specific for total SMAD2 (Cell Signaling Technology, #3103; Danvers, MA) or total Akt (Cell Signaling Technology, #4060; Danvers, MA). Example 3 Bleomycin-Induced Lung Fibrosis Studies [0241] Eight- to 10-week-old C57BL/6-NCrl (strain code: 027) male mice (Charles River Laboratories; Wilmington, MA) are anesthetized (mixture of xylazine/ketamine) and then injected intratracheally with freshly prepared bleomycin sulfate (0.75 U/kg) (Cayman Chemical, catalog no.13877; Ann Arbor, MI) in sterile phosphate-buffered saline (PBS) (volume varied between 88 and 108 ml depending on the body weight). Control mice are injected with 50 ml of sterile PBS. Body weights are monitored throughout each study. To quantitate fibrosis development during longitudinal studies, lungs are harvested at 7, 14, and 21 days after bleomycin instillation and assayed as described below. For therapy studies, induction of idiopathic pulmonary fibrosis (IPF) is initiated as described above, and a FAP8-PI3K conjugate (2 mmol/kg) is intravenously injected every other day beginning on day 10. Lungs are harvested on day 21 and assayed as described below (day 0 was taken as the day of bleomycin administration). [0242] Total lung collagen is determined by the analysis of hydroxyproline as described in published articles using a known and standardized method. The right lung is consistently set aside for this assay. [0243] Briefly, harvested right lung is homogenized in PBS (pH 7.4), and digested with 12 N HCl at 120 °C for 3 hours. Citrate/acetate buffer (pH 6.0) and chloramine-T solution are added at room temperature for 20 minutes, and the samples are incubated with Ehrlich’s solution for 15 minutes at 65 °C. Samples are cooled to room temperature and read at 550 nm. Hydroxyproline standards (Sigma-Aldrich; St. Louis, MO) at concentrations between 0 and 400 mg/ml are used to construct a standard curve.

Claims

WHAT IS CLAIMED IS: 1. A conjugate of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a conjugate of formula I, wherein formula I is: wherein A has the structure:
Figure imgf000154_0001
wherein:
Figure imgf000154_0002
represents a functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, which optionally further comprises 1-3 heteroatoms selected from O, N, and S; R1 and R2 are each independently selected from the group consisting of -H, -D - OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH- , (CH3)3C-, -CH2Ph, and substituted -CH2Ph; R8-R10 are each independently selected from group consisting of -H, -OH, -F, -Cl, -Br, -I, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; and R11 is selected from the group consisting of H, D, Cl-Cl0 alkyl, C3-Cl0 cycloalkyl, adamantyl,
Figure imgf000154_0003
, , substituted or unsubstituted aryl, substituted or unsubstituted C7-C20 alkyl aryl, wherein the aryl is:
Figure imgf000155_0001
wherein: R12 and R16 are each independently selected from the group consisting of H, D, halogen, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R13, R14 and R15 are each independently selected from the group consisting of H, D, halogen, -OMe, C1-C3 alkyl, C1-C3 alkoxy, -CF3, and -C(=O)-OR23, wherein R23 is selected from the group consisting of H, D, halogen, Cl-C4 alkyl, and C1-C3 alkoxy; R17, R18, R20, and R21 are each independently selected from H and CH3; and R19 and R22 are independently selected from the group consisting of phenyl, dimethoxyphenyl, and aryl; L is a bifunctional or trifunctional linker; and B is a phosphatidylinositol-3-kinase (PI3K) inhibitor or a dual inhibitor of the PI3K/ mammalian target of rapamycin (mTOR) signaling pathway; wherein the conjugate is optionally provided as a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
2. The conjugate of claim 1, wherein L is attached to A at any carbon atom of the functionalized 5- to 10-membered N-containing aromatic or non-aromatic mono- or bi-cyclic heterocycle, a 1° amine, a 2° amine, a functionalized alkyl, or a functionalized cycloalkyl.
3. The conjugate of claim 1 or 2, wherein A has the formula IV or V:
Figure imgf000155_0002
wherein: each R2 is selected from the group consisting of -H, -D, -OH, -F, -Cl, -Br, I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R3 and R4 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R5 and R6 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl; R7 is selected from the group consisting of H, D, OH, CH2=, -CH3, CH3CH2-, (CH3)2CH-, and (CH3)3C-; R11 is selected from the group consisting of
Figure imgf000156_0001
Figure imgf000157_0001
R23-R26 are each independently selected from the group consisting of -H, -OH, -F, -Cl, -Br, -I, -CF3, -NO2, -SO3H, -SO2NH2, -NH2, -N3, -NH=NH-, -C1-6 alkyl, -O-C1-6 alkyl, and -S-C1-6 alkyl.
4. The conjugate of claim 1, wherein the PI3k inhibitor or the PI3k/mTOR inhibitor is a radical of any one of the following structures:
,
Figure imgf000158_0001
Figure imgf000159_0001
, wherein X is or comprises a structure selected from:
Figure imgf000159_0002
.
5. The conjugate of any one of claims 1-4, wherein L is or comprises a moiety of the formula:
Figure imgf000159_0003
, wherein n is an integer from 0 to 10.
6. The conjugate of any one of claims 1-4, where L is or comprises a moiety of the formula:
Figure imgf000159_0004
, wherein n is an integer from 0 to 10.
7. The conjugate of any one of claims 1-4, wherein L is or comprises a moiety of the formula:
Figure imgf000159_0005
.
8. The conjugate of any one of claims 1-4, wherein L is or comprises a moiety of the formula:
Figure imgf000160_0001
wherein n is an integer from 0 to 20.
9. The conjugate of any one of claims 1-4, wherein L is or comprises a moiety of the formula:
Figure imgf000160_0002
.
10. The conjugate of any one of claims 1-4, wherein L is or comprises a moiety of the formula:
Figure imgf000160_0003
11. The conjugate of any one of claims 1-4, wherein L is or comprises a moiety of the formula:
Figure imgf000161_0001
wherein n is an integer from 0 to 20.
12. The conjugate of any one of claims 1-4, wherein L is or comprises a moiety of the formula:
Figure imgf000161_0002
, wherein n is an integer from 0 to 20.
13. The conjugate of claim 1, wherein L is a linker that can be cleaved under physiological conditions.
14. The conjugate of claim 13, wherein L can be cleaved reductively, oxidatively, or enzymatically.
15. The conjugate of any one of claims 1-4, wherein L comprises an oxime ester.
16. The conjugate of any one of claims 1-4, wherein L comprises a hydrazone.
17. The conjugate of any one of claims 1-4, wherein L comprises polyethylene glycoln (PEG)n, wherein n = 0-36.
18. The conjugate of any one of claims 1-4, wherein L comprises a peptide, a peptidoglycan, an alkyl, or a sugar.
19. The conjugate of any one of claims 1-4, wherein L is or comprises:
Figure imgf000162_0001
20. The conjugate of any one of claims 1-4, wherein L comprises a structure selected from a group consisting of:
Figure imgf000163_0001
, wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8.
21. The conjugate of any one of claims 1-4, wherein L comprises the structure:
Figure imgf000163_0002
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are each independently selected from the group consisting of H and C1-C6 alkyl.
22. The conjugate of claim 1 selected from:
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
.
23. The conjugate of claim 1 selected from:
Figure imgf000167_0001
.
24. The conjugate of claim 1 selected from:
Figure imgf000168_0001
.
25. The conjugate of claim 1, wherein the conjugate of formula I further comprises a pharmacokinetic extender C and has the formula (II):
Figure imgf000168_0002
.
26. The conjugate of claim 25, wherein C is an albumin binder, a plasma protein binder, or a hapten.
27. The conjugate of claim 25 of claim 26, wherein C is an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti- albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06).
28. The conjugate of any one of claims 25-27, wherein C is or comprises: .
Figure imgf000169_0001
29. The conjugate of any one of claims 25-27, wherein C is or comprises:
Figure imgf000170_0001
wherein: each of R12-19 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, or -SO2F; and each of R20 and R21 is independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -O-C1-6 alkyl, -CN, -CHO, -B(OH)2, -C=C-C(O)aryl, -C=C-S(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, -SO2F,
Figure imgf000171_0001
30. The conjugate of any one of claims 25-27, wherein C is or comprises:
Figure imgf000171_0002
.
31. The conjugate of any one of claims 25-27, wherein C is or comprises:
Figure imgf000171_0003
.
32. The conjugate of any one of claims 25-27, wherein C is or comprises:
Figure imgf000172_0001
.
33. The conjugate of any one of claims 25-27, wherein C comprises a radical of (PEG)n, wherein n = 0-32, a peptide, a petidoglycan, or a saccharide.
34. The conjugate of any one of claims 25-27, wherein C is or comprises:
Figure imgf000172_0002
35. The conjugate of any one of claims 25-27, wherein C is or comprises
Figure imgf000172_0003
.
36. The conjugate of claim 26, wherein the hapten is recognized by an autologous antibody.
37. The conjugate of claim 26, wherein the hapten is selected from the group consisting of rhamnose, an α-galactosyl moiety, a dinitrophenyl (DNP) moiety, and a trinitrophenyl (TNP) moiety.
38. The conjugate of claim 1, wherein the compound has a structure selected from:
Figure imgf000173_0001
, wherein L comprises at least one carbon atom; and p is 0-3.
39. The conjugate of claim 38, wherein L is or comprises a moiety of the formula:
Figure imgf000174_0001
, wherein n is an integer from 0 to 10.
40. The conjugate of claim 38, wherein L is or comprises a moiety of the formula:
Figure imgf000174_0002
, wherein n is an integer from 0 to 10.
41. The conjugate of claim 38, wherein L is or comprises a moiety of the formula:
Figure imgf000174_0003
.
42. The conjugate of claim 38, wherein L is or comprises a moiety of the formula:
Figure imgf000174_0004
wherein n is an integer from 0 to 10.
43. The conjugate of claim 38, wherein L is or comprises a moiety of the formula:
Figure imgf000175_0001
.
44. The conjugate of claim 38, wherein L is or comprises a moiety of the formula:
Figure imgf000175_0002
45. The conjugate of claim 38, wherein L is or comprises a moiety of the formula:
Figure imgf000175_0003
wherein n is an integer from 0 to 20.
46. The conjugate of claim 38, wherein L is or comprises a moiety of the formula:
Figure imgf000176_0001
, wherein n is an integer from 0 to 20.
47. The conjugate of claim 38, wherein L is a linker that can be cleaved under physiological conditions. 48. The conjugate of claim 47, wherein L can be cleaved reductively, oxidatively, or enzymatically. 49. The conjugate of claim 38, wherein L comprises an oxime ester.
48. The conjugate of claim 38, wherein L comprises a hydrazone.
49. The conjugate of claim 38, wherein L comprises (PEG)n, wherein n = 0-36.
50. The conjugate of claim 38, wherein L comprises a peptide, a peptidoglycan, an alkyl, or a sugar.
51. The conjugate of claim 38, wherein L is or comprises:
Figure imgf000176_0002
Figure imgf000177_0001
.
52. The conjugate of claim 38, wherein L is or comprises a structure selected from:
Figure imgf000177_0002
, wherein: R27 and R28 are each independently selected from the group consisting of H and C1-C6 alkyl; and Z is an integer from 1 to 8.
53. The conjugate of claim 38, wherein L comprises the structure:
Figure imgf000177_0003
wherein: R31 is H or C1-C6 alkyl; and R29a, R29b, R30a, and R30b are independently selected from the group consisting of H and C1-C6 alkyl.
54. The conjugate of claim 38, wherein the conjugate is selected from:
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
. 55. Uses of a conjugate of any one of claims 1-54, or a stereoisomer or a pharmaceutically acceptable salt thereof, or optionally a pharmaceutical composition comprising an effective amount of a conjugate, stereoisomer, or pharmaceutically acceptable salt of any oneo f claims 1-54, in the manufacture of a medicament for the inhibition of the progression of fibrosis in a subject. 56. The use of claim 55, wherein the conjugate comprises a pharmacokinetic extender C and has the formula (II):
Figure imgf000190_0002
57. The use of claim 56, wherein C is an albumin binder, a plasma protein binder, or a hapten.
58. The use of claim 56 or 57, wherein C is an albumin binder that is or comprises albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv), an anti-albumin antibody CA645, an anti-human serum albumin nanobody, or variable new antigen receptor E06 (VNAR E06).
59. A method of inhibiting the progression of fibrosis in a subject comprising administering to the subject an effective amount of a conjugate of any one of claims 1-54, or a stereoisomer or a pharmaceutically acceptable salt thereof, whereupon progression of fibrosis in the subject is inhibited.
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US20120115866A1 (en) * 2006-09-15 2012-05-10 Tyrogenex, Inc. Kinase inhibitor compounds
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