WO2020254612A1 - Composés inhibiteurs de tyrosine kinases à libération contrôlée présentant des propriétés pharmacodynamiques localisées - Google Patents

Composés inhibiteurs de tyrosine kinases à libération contrôlée présentant des propriétés pharmacodynamiques localisées Download PDF

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WO2020254612A1
WO2020254612A1 PCT/EP2020/067160 EP2020067160W WO2020254612A1 WO 2020254612 A1 WO2020254612 A1 WO 2020254612A1 EP 2020067160 W EP2020067160 W EP 2020067160W WO 2020254612 A1 WO2020254612 A1 WO 2020254612A1
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certain embodiments
cancer
formula
tki
ixi
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PCT/EP2020/067160
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Luis Zuniga
Juha Punnonen
Mohammad A TABRIZIFARD
Nicola BISEK
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Ascendis Pharma Oncology Division A/S
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6903—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a water-insoluble controlled-release TKI compound for use in the treatment of a cell-proliferation disorder, wherein said water-insoluble controlled-release TKI compound releases one or more TKI drug, wherein upon intra-tissue administration of a single dose of the water-insoluble controlled-release TKI compound anti-tumor activity is observed between 7 and 21 days following administration of the water-insoluble controlled- release TKI compound, and wherein the change in mean arterial blood pressure as measured in mmHg is less than 50% of the change in mean arterial blood pressure observed in the same animal species treated with a daily equimolar dose of the corresponding free TKI drug; and to related aspects.
  • the present invention relates to a water-insoluble controlled-release tyrosine kinase inhibitor (“TKI”) compound for use in the treatment of a cell-proliferation disorder, wherein said water-insoluble controlled-release TKI compound releases one or more TKI drug, wherein the water-insoluble controlled-release TKI compound is administered by intra-tissue administration and wherein the total amount of TKI moieties and TKI drug molecules remaining locally in such tissue 3 days after said intra-tissue administration is at least 25% of the amount of TKI moieties or TKI drug molecules administered by said intra-tissue administration; and to related aspects.
  • TKI water-insoluble controlled-release tyrosine kinase inhibitor
  • Tyrosine kinases are a sub-class of protein kinases that mediate transfer of a phosphate group from adenosine triphosphate (ATP) to specific tyrosine residues of target proteins. This protein phosphorylation serves to modulate protein activity and protein signaling involved in processes such as cell proliferation, differentiation, migration, function, or metabolism.
  • Two types of TKs exist - non-receptor tyrosine kinases (NRTKs) and receptor tyrosine kinases (RTKs).
  • NRTKs are intracellular TKs that propagate signaling cascades induced by RTKs or by other cell surface receptors (e.g. immune cell-associated receptors or G protein-coupled receptors).
  • RTKs are transmembrane glycoproteins that bind extracellular ligands (e.g. VEGF, FGF, EGF, PDGF). Following ligand binding, they become activated, and either auto- phosphorylate tyrosine residues on their intracellular domains or phosphorylate intracellular protein substrates (Hubbard and Hill. Annu Rev Biochem. 2000; 69:373-98). Tyrosine kinases regulate many different signaling pathways depending on the cell type and have been implicated in several disease indications, which make them widely pursued for therapeutic purposes. For example, vascular endothelial growth factor (VEGF) receptors (VEGFRs) are a type of RTK involved in angiogenesis and vascularization of tissues.
  • VEGF vascular endothelial growth factor
  • VEGF Aberrant expression of VEGF in the tumor environment may promote tumor vascularization via VEGFR signaling.
  • TKIs small tyrosine kinase inhibitors
  • Small molecule TKIs have typically been orally administered while biologic tyrosine kinase antagonists are administered intravenously, leading to systemic exposure of the inhibitor/antagonist.
  • efficacy, toxicity, bioavailability and other pharmacokinetic parameters vary greatly depending on the route of administration, systemic inhibition of tyrosine kinases can lead to adverse events, thus limiting their tolerability.
  • VEGFR inhibition is associated with dose limiting hypertension which can lead to sub-optimal drug exposure for cancer treatment (Agarwal el al. Curr Oncol Rep. 2018 Jun 21;20(8):65. doi: 10.1007/sl 1912-018-0708-8).
  • TKIs or TK antagonists may be related to a failure of delivering the drug to the proposed site of action at efficacious concentrations.
  • drug distribution following systemic administration may only serve to exacerbate global side effects due to undesirable systemic exposure to active drug while limiting bioavailability of the active compound in the tumor environment, thus precluding robust anti-tumor benefit. This may be particularly true for small molecule TKIs, which often have broad kinase inhibiting activity, thus affecting multiple kinase pathways (Agarwal et al. Curr Oncol Rep. 2018 Jun 21;20(8):65. doi: 10.1007/sl 1912-018-0708-8).
  • TKIs and biologic tyrosine kinase antagonists that have better specificity for their intended target
  • TKI or biologic tyrosine kinase antagonist treatment regimens such that they overcome the shortcomings of prior art compounds and their related treatment methodologies whilst also providing a favorable anti-tumoral response and reducing adverse events related to systemic exposure.
  • a water-insoluble controhed-release TKI compound for use in the treatment of a cell-proliferation disorder, wherein said water-insoluble controhed-release TKI compound releases one or more TKI drug, wherein upon intra-tissue administration of a single dose of the water-insoluble controhed-release TKI compound anti-tumor activity is observed between 7 and 21 days following administration of the water-insoluble controhed- release TKI compound, and wherein the change in mean arterial blood pressure as measured in mmHg is less than 50% of the change in mean arterial blood pressure observed in the same animal species treated with a daily equimolar dose of the corresponding free TKI drug.
  • the present invention relates to a water-insoluble controhed-release TKI compound for use in the treatment of a cell-proliferation disorder, wherein the conjugate is administered by intra-tissue administration, and wherein such intra-tissue administration results in local inhibition of angiogenesis.
  • the water-insoluble controlled-release TKI compounds of the present invention result in high local and low systemic TKI drug concentrations that provide an improved treatment option for cell-proliferation disorders with a reduced risk of side- effects, such as hypertension.
  • Such lower systemic exposure allows for more aggressive multi-agent therapies, facilitates treatment with otherwise poorly tolerated drug combinations and enables treatment of also hard-to-inject tumors that cannot be injected frequently enough with the corresponding free drug molecules.
  • local inhibition of angiogenesis refers to an inhibition of angiogenesis that is restricted to an area near the site of administration of the water-insoluble controlled-release TKI compound.
  • tissue samples are to be taken for determining the presence of a specific set of markers for angiogenesis inhibition. Flowever, this does not mean that expression of said angiogenesis inhibition markers outside a volume of 2 times r may not be disregulated, meaning up- or downregulated, by at least a factor of 1.5.
  • angiogenesis inhibition intensity decreases with increasing distance from the administration site.
  • tyrosine kinase inhibitor refers to a molecule that binds to and inhibits one or more cell-associated receptor or non-receptor tyrosine kinases that are activated via polypeptide growth factors, cytokines, hormones, or phosphorylation, and are involved in cellular signaling, cellular development, cellular proliferation, cellular maturation, cellular metabolism, angiogenesis, and in certain instances, tumorigenesis. Tyrosine kinases are ubiquitously expressed by virtually all cells.
  • TKIs inhibit activation of tyrosine kinases by multiple mechanisms such as competing with, or allosterically antagonizing, binding of adenosine triphosphate (ATP) to the tyrosine kinase ATP-binding site, or by inhibiting enzymatic phosphorylation of said binding site, or inhibiting enzymatic kinase activity.
  • ATP adenosine triphosphate
  • receptor TKIs may bind one or more RTKs and inhibit RTK activation as described above or by antagonizing activating ligand interactions, thus preventing receptor tyrosine kinase activation.
  • controlled-release tyrosine kinase inhibitor compound or “controlled-release TKI compound” refers to any matrix with embedded TKI drug or TKI conjugates that comprise at least one TKI moiety and from which at least one TKI drug is released with an in vitro release half-life under physiological conditions (aqueous buffer, pH 7.4, 37°C) of at least 2 days, such as of at least 3 days, at least 7 days, at least 10 days, at least 14 days, at least 21 days, at least one month or at least two months.
  • the maximal release half-life under physiological conditions is 3 months.
  • PRRA pattern recognition receptor agonist
  • PRRA refers to a molecule that binds to and activates one or more immune cell-associated receptor that recognizes pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), leading to immune cell activation and/or pathogen- or damage-induced inflammatory responses.
  • Pattern recognition receptors are typically expressed by cells of the innate immune system such as monocytes, macrophages, dendritic cells (DCs), neutrophils, and epithelial cells, as well as cells of the adaptive immune system.
  • cytotoxic agent and “chemotherapeutic agent” are used synonymously and refer to compounds that are toxic to cells, which prevent cellular replication or growth, leading to cellular destruction/death.
  • cytotoxic agents include chemotherapeutic agents and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including synthetic analogues and derivatives thereof.
  • immune checkpoint inhibitor and“immune checkpoint antagonist” are used synonymously and refer to compounds that interfere with the function of, or inhibit binding of ligands that induce signaling through, cell-membrane expressed receptors that inhibit immune cell function upon receptor activation.
  • Such compounds may for example be biologies, such as antibodies, nanobodies, probodies, anticalins or cyclic peptides, or small molecule inhibitors.
  • immune agonist refers to compounds that directly or indirectly activate cell-membrane expressed receptors that stimulate immune cell function upon receptor activation.
  • multi-specific and“multi-specific drugs” refer to compounds that simultaneously bind to two or more different antigens and can mediate antagonistic, agonistic, or specific antigen binding activity in a target-dependent manner.
  • ADC antibody-drug conjugate
  • radionuclides refers to radioactive isotopes that emit ionizing radiation leading to cellular destruction/death. Radionuclides conjugated to tumor targeting carriers are referred to as“targeted radionuclide therapeutics”.
  • DNA damage repair inhibitor refers to a drug that targets DNA damage repair elements, such as for example CHK1, CHK2, ATM, ATR and PARP. Certain cancers are more susceptive to targeting these pathways due to existing mutations, such as BRCA1 mutated patients to PARP inhibitors due to the concept of synthetic lethality.
  • tumor metabolism inhibitor refers to a compound that interferes with the function of one or more enzymes expressed in the tumor environment that produce metabolic intermediates that may inhibit immune cell function.
  • protein kinase inhibitor refers to compounds that inhibit the activity of one or more protein kinases. Protein kinases are enzymes that phosphorylate proteins, which in turn can modulate protein function. It is understood that a protein kinase inhibitor may target more than one kinase and any classification for protein kinase inhibitors used herein refers to the main or most characterized target.
  • chemokine receptor and chemoattractant receptor agonist refers to compounds that activate chemokine or chemoattractant receptors, a subset of G-protein coupled receptors or G-protein coupled-like receptors that are expressed on a wide variety of cells and are primarily involved in controlling cell motility (chemo taxis or chemokinesis). These receptors may also participate in non-cell migratory processes, such as angiogenesis, cell maturation or inflammation.
  • cytokine receptor agonist refers to soluble proteins which control immune cell activation and proliferation.
  • Cytokines include for example interferons, interleukins, lymphokines, and tumor necrosis factor.
  • the term "death receptor agonist” refers to a molecule which is capable of inducing pro-apoptotic signaling through one or more of the death receptors, such as DR4 (TRAIL-R1) or DR5 (TRAIL-R2).
  • the death receptor agonist may be selected from the group consisting of antibodies, death ligands, cytokines, death receptor agonist expressing vectors, peptides, small molecule agonists, cells (such as for example stem cells) expressing the death receptor agonist, and drugs inducing the expression of death ligands.
  • intra-tissue administration refers to a type of administration, for example local injection, of a drug into a tissue of interest such as intra- tumoral, intra muscular, subdermal or subcutaneous injections or injection into or adjacent to a normal or diseased tissue or organ.
  • intra-tissue administration is intraveneous administration.
  • intra-tumoral administration refers to a mode of administration, in which the drug is administered directly into tumor tissue.
  • intra-tumoral administration also refers to administration pre- or post-resection into or onto the tumor bed.
  • intra-tumoral administration includes administration to tissue adjacent to the tumor cells (“peritumoral administration”).
  • Exemplary tumors for intra-tumoral administration are solid tumors and lymphomas. Administration may occur via injection.
  • the term“baseline tissue” refers to a tissue sample taken from, or adjacent to, the area to be treated prior to treatment. For example, a biopsy of tissue to be treated can be taken immediately prior to treatment. It is understood that it may not always be possible to take a reference sample from the respective area prior to treatment, so the term“baseline tissue” may also refer to a non-treated control tissue that may be taken from a comparable location from the same animal or may be taken from a comparable location of a different animal of the same species. It is understood that in general the term“animal” also covers human and in certain embodiments means mouse, rat, non-human primate or human.
  • the term“local” or“locally” refers to a volume of tissue within a distance of 2 times the radius (r) from an injection site in any direction, wherein r is the distance in centimeters (cm) calculated from the volume (V) of water-insoluble controlled-release TKI compound injected in cubic centimeters (cm ) following the spheroid equation
  • V— x nr 3 V— x nr 3 .
  • a sample of tissue weighing at least 0.025g taken within 0.98 cm in any direction of the injection site is referred to as a local sample.
  • anti-tumor activity means the ability to reduce the speed of tumor growth by at least 20%, such as by at least 25%, by at least 30%, by at least 35%, by at least 40%, by at least 45%, or by at least 50%; the ability to inhibit tumors from growing larger, i.e. tumor growth inhibition or tumor stasis; or the ability to cause a reduction in the size of a tumor, i.e. tumor regression.
  • Anti-tumor activity may be determined by comparing the mean relative tumor volumes between control and treatment conditions.
  • Relative volumes of individual tumors (individual RTVs) for day“x” may be calculated by dividing the absolute individual tumor volume on day“x” (T x ) following treatment initiation by the absolute individual tumor volume of the same tumor on the day treatment started (To) multiplied by 100: 100
  • Anti-tumor activity may be observed between 7 to 21 days following treatment initiation.
  • Tumor size reported in mm , may be measured physically by measuring the length ( L ) measured in mm and width ( W) measured in mm of the tumors, which may include injected and non-injected tumors.
  • Tumor volume can be determined by methods such as ultrasound imaging, magnetic resonance imaging, computed tomography scanning, or approximated by using the equation V— x
  • Tumor burden i.e. the total number of cancer cells in an individuum
  • Tumor burden can also be measured in the case of an experimental tumor model that expresses a reporter, such as luciferase enzyme or a fluorescent protein or another measurable protein or enzyme, by measuring the reporter element, i.e. luminescence or fluorescence, or the expressed reporter protein or enzyme product as a measure of the total number of tumor cells present and total tumor size.
  • a reporter such as luciferase enzyme or a fluorescent protein or another measurable protein or enzyme
  • the latter reporter models can be useful for tumors that are not readily measurable on the surface of the animals (i.e. orthotopic tumors).
  • the term“animal” also covers human and in certain embodiments means mouse, rat, non-human primate or human. In certain embodiments“animal” means human.
  • the term“systemic molar concentration of TKI drug” refers to the molar concentration of TKI drug present in plasma.
  • TKI drug molecules may be bound to plasma proteins, such as for example albumin
  • the amount of TKI drug in plasma refers to the total amount of both unbound TKI molecules, i.e. TKI molecules not bound to plasma proteins, and bound TKI molecules, i.e. TKI molecules bound to plasma proteins.
  • the concentration of total TKI drug in plasma may for example be determined by digesting a plasma sample with one or more proteases or other relevant methods that degrade plasma and/or tissue proteins and subsequently determining the concentration of TKI molecules present in the sample using suitable assays.
  • the term“a p-electron-pair-donating heteroaromatic N-comprising moiety” refers to the moiety which after cleavage of the linkage between -D and -L 1 - results in a drug D-H and wherein the drug moiety -D and analogously the corresponding D-H comprises at least one, such as one, two, three, four, five, six, seven, eight, nine or ten heteroaromatic nitrogen atoms that donate a p-electron pair to the aromatic 7r-system. Examples of chemical structures comprising such hetero aromatic nitrogens that donate a p-electron pair to the aromatic
  • p-system include, but are not limited to, pyrrole, pyrazole, imidazole, isoindazole, indole, indazole, purine, tetrazole, triazole and carbazole.
  • imidazole imidazole
  • isoindazole indole
  • indazole purine
  • tetrazole triazole
  • carbazole carbazole.
  • the heteroaromatic nitrogen which donates a p-electron pair to the aromatic 7r-system is marked with“#”:
  • the 7T-electron-pair-donating heteroaromatic nitrogen atoms do not comprise heteroaromatic nitrogen atoms which only donate one electron (i.e. not a pair of 7r-electrons) to the aromatic p-system, such as for example the nitrogen that is marked with“ ⁇ ” in the abovementioned imidazole ring structure.
  • the drug D-H may exist in one or more tautomeric forms, such as with one hydrogen atom moving between at least two heteroaromatic nitrogen atoms. In all such cases, the linker moiety is covalently and reversibly attached at a heteroaromatic nitrogen that donates a 7r-electron pair to the aromatic p-system.
  • drug refers to a substance used in the treatment, cure, prevention or diagnosis of a disease or used to otherwise enhance physical or mental well-being of a patient. If a drug is conjugated to another moiety, the moiety of the resulting product that originated from the drug is referred to as“drug moiety”.
  • any reference to a biologic drug herein i.e. to a drug manufactured in, extracted from, or semisynthesized from biological sources such as a protein drug, also covers biosimilar versions of said drug.
  • prodrug refers to a drug moiety reversibly and covalently connected to a specialized protective group through a reversible prodrug linker moiety which is a linker moiety comprising a reversible linkage with the drug moiety and wherein the specialized protective group alters or eliminates undesirable properties in the parent molecule. This also includes the enhancement of desirable properties in the drug and the suppression of undesirable properties.
  • the specialized non-toxic protective group may also be referred to as “carrier”.
  • a prodrug releases the reversibly and covalently bound drug moiety in the form of its corresponding drug.
  • a prodrug is a conjugate comprising a drug moiety, which is covalently and reversibly conjugated to a carrier moiety via a reversible linker moiety, which covalent and reversible conjugation of the carrier to the reversible linker moiety is either directly or through a spacer.
  • the reversible linker may also be referred to as “reversible prodrug linker”.
  • Such conjugate may release the formerly conjugated drug moiety in the form of a free drug, in which case the reversible linker or reversible prodrug linker is a traceless linker.
  • free form of a drug means the drug in its unmodified, pharmacologically active form.
  • spacer or“linker” refers to a moiety that connects at least two other moieties with each other.
  • the term“reversible”,“reversibly”,“degradable” or“degradably” with regard to the attachment of a first moiety to a second moiety means that the linkage that connects said first and second moiety is cleavable under physiological conditions, which physiological conditions are aqueous buffer at pH 7.4 and 37°C, with a half-life ranging from two days to three months, such as from two days to two months, such as from three days to one month. Such cleavage is in certain embodiments non-enzymatically, i.e. independent of enzymatic activity. Accordingly, the term“stable” with regard to the attachment of a first moiety to a second moiety means that the linkage that connects said first and second moiety exhibits a half-life of more than three months under physiological conditions.
  • reagent means a chemical compound, which comprises at least one functional group for reaction with the functional group of another chemical compound or drug. It is understood that a drug comprising a functional group is also a reagent.
  • the term“moiety” means a part of a molecule, which lacks one or more atom(s) compared to the corresponding reagent. If, for example, a reagent of the formula “H-X-H” reacts with another reagent and becomes part of the reaction product, the corresponding moiety of the reaction product has the structure“H-X-” or“-X-”, whereas each indicates attachment to another moiety. Accordingly, a drug moiety, such as a TKI moiety, is released from a reversible linkage as a drug, such as TKI drug.
  • substituted means that one or more -H atom(s) of a molecule or moiety are replaced by a different atom or a group of atoms, which are referred to as “substituent”.
  • the term“substituent” in certain embodiments refers to a moiety selected from the group consisting of halogen, -CN, -COOR xl , -OR xl , -C(0)R xl , -C(0)N(R xl R xla ), - S (0) 2 N (R X 1 R x 1 a ) , -S(0)N(R xl R xla ), -S(0) 2 R x1 , -S(0)R x1 , -N(R xl )S(0) 2 N(R xla R xlb ), -SR xl , -N(R xl R xla ), -N0 2 , -0C(0)R x1 , -N(R xl )C(0)R xla , -N(R xl )S(0) 2 R xla , -N(R xl )S(0) 2 R
  • Ci_5o alkyl, C 2 _so alkenyl, and C 2 _5o alkynyl are optionally substituted with one or more -R x2 , which are the same or different and wherein Ci_5o alkyl, C 2 _so alkenyl, and C 2 _so alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T°-, -C(0)0-, -O-, -C(O)-, -C(0)N(R x3 )-, -S(0) 2 N(R x3 )-, -S(0)N(R x3 )-, -S(0) 2 -, -SCO)-, -N(R x3 )S(0) 2 N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R x3a
  • Ci_ o alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T°-, -C(0)0-, -0-, -C(O)-, -C(0)N(R x3 )-, -S(0) 2 N(R x3 )-, -S(0)N(R x3 )-; -S(0) 2 -, -SCO)-, -N(R x3 )S(0) 2 N(R x3a )-, -S-, -N(R x3 )-, -OC(OR x3 )(R
  • each -R x3 , -R x3a , -R x4 , -R x4a , -R x4b is independently selected from the group consisting of -H and Ci - 6 alkyl; wherein Ci_ 6 alkyl is optionally substituted with one or more halogen, which are the same or different.
  • a maximum of 6 -H atoms of an optionally substituted molecule are independently replaced by a substituent, e.g. 5 -H atoms are independently replaced by a substituent, 4 -H atoms are independently replaced by a substituent, 3 -H atoms are independently replaced by a substituent, 2 -H atoms are independently replaced by a substituent, or 1 -H atom is replaced by a substituent.
  • hydrogel means a hydrophilic or amphiphilic polymeric network composed of homopolymers or copolymers, which is insoluble due to the presence of hydrophobic interactions, hydrogen bonds, ionic interactions and/or covalent chemical crosslinks.
  • the crosslinks provide the network structure and physical integrity.
  • the hydrogel is insoluble due to the presence of covalent chemical crosslinks.
  • crossl inker refers to a moiety that is a connection between different elements of a hydrogel, such as between two or more backbone moieties or between two or more hyaluronic acid strands.
  • continuous gel refers to a hydrogel in a flexible shape, i.e. a shape that is not pre-formed, but adjusts its shape to fit its surrounding.
  • continuous gel may in certain embodiments fragment into smaller sized particles.
  • continuous gel does not fragment upon administration, such as via injection, and remains essentially the same volume, but may temporarily or permanently change its shape as required to pass through a needle, for example.
  • the term“about” in combination with a numerical value is used to indicate a range ranging from and including the numerical value plus and minus no more than 25% of said numerical value, such as no more than plus and minus 20% of said numerical value or such as no more than plus and minus 10% of said numerical value.
  • the phrase “about 200” is used to mean a range ranging from and including 200 +/- 25%, i.e. ranging from and including 150 to 250; such as 200 +/- 20%, i.e. ranging from and including 160 to 240; such as ranging from and including 200 +/-10%, i.e. ranging from and including 180 to 220.
  • the term“polymer” means a molecule comprising repeating structural units, i.e. the monomers, connected by chemical bonds in a linear, circular, branched, crosslinked or dendrimeric way or a combination thereof, which may be of synthetic or biological origin or a combination of both.
  • the monomers may be identical, in which case the polymer is a homopolymer, or may be different, in which case the polymer is a heteropolymer.
  • a heteropolymer may also be referred to as a “copolymer” and includes, for example, alternating copolymers in which monomers of different types alternate, periodic copolymers, in which monomers of different types are arranged in a repeating sequence; statistical copolymers, in which monomers of different types are arranged randomly; block copolymers, in which blocks of different homopolymers consisting of only one type of monomers are linked by a covalent bond; and gradient copolymers, in which the composition of different monomers changes gradually along a polymer chain.
  • a soluble polymer has a molecular weight of at least 0.5 kDa, e.g.
  • the polymer is soluble, it preferably has a molecular weight of at most 1000 kDa, such as at most 750 kDa, such as at most 500 kDa, such as at most 300 kDa, such as at most 200 kDa, such as at most 100 kDa. It is understood that a polymer may also comprise one or more other moieties, such as, for example, one or more functional groups.
  • polymer also relates to a peptide or protein, even though the side chains of individual amino acid residues may be different. It is understood that for covalently crosslinked polymers, such as hydrogels, no meaningful molecular weight ranges can be provided.
  • polymeric refers to a reagent or a moiety comprising one or more polymers or polymer moieties.
  • a polymeric reagent or moiety may optionally also comprise one or more other moieties, which in certain embodiments are selected from the group consisting of:
  • Ci_ 5 o alkyl C 2-50 alkenyl, C 2-50 alkynyl, C 3 _io cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl;
  • dashed lines indicate attachment to the remainder of the moiety or reagent
  • -R and -R a are independently of each other selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2- dimethylbutyl,
  • the molecular weight ranges, molecular weights, ranges of numbers of monomers in a polymer and numbers of monomers in a polymer as used herein refer to the number average molecular weight and number average of monomers, i.e. to the arithmetic mean of the molecular weight of the polymer or polymeric moiety and the arithmetic mean of the number of monomers of the polymer or polymeric moiety.
  • any integer given for“x” therefore corresponds to the arithmetic mean number of monomers.
  • Any range of integers given for“x” provides the range of integers in which the arithmetic mean numbers of monomers lies.
  • An integer for“x” given as“about x” means that the arithmetic mean numbers of monomers lies in a range of integers of x +/- 25%, such as x +/- 20% or such as x +/- 10%.
  • the term“number average molecular weight” means the ordinary arithmetic mean of the molecular weights of the individual polymers.
  • PEG-based in relation to a moiety or reagent means that said moiety or reagent comprises PEG.
  • PEG-based moiety or reagent comprises at least 10% (w/w) PEG, such as at least 20% (w/w) PEG, such as at least 30% (w/w) PEG, such as at least 40% (w/w) PEG, such as at least 50% (w/w), such as at least 60% (w/w) PEG, such as at least 70% (w/w) PEG, such as at least 80% (w/w) PEG, such as at least 90% (w/w) PEG, or such as at least 95% (w/w) PEG.
  • the remaining weight percentage of the PEG-based moiety or reagent may be other moieties, such as those selected from the group consisting of:
  • Ci_ 5 o alkyl C 2-50 alkenyl, C 2-50 alkynyl, C 3 _io cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl; • branching points, such as -CR ⁇ , >C ⁇ or -N ⁇ ; and
  • dashed lines indicate attachment to the remainder of the moiety or reagent, and -R and -R a are independently of each other selected from the group consisting of -H, and Ci_ 6 alkyl; and
  • the term“interrupted” means that a moiety is inserted between two carbon atoms or - if the insertion is at one of the moiety’s ends - between a carbon or heteroatom and a hydrogen atom.
  • Ci_4 alkyl alone or in combination means a straight-chain or branched alkyl moiety having 1 to 4 carbon atoms. If present at the end of a molecule, examples of straight-chain or branched C M alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. When two moieties of a molecule are linked by the C alkyl, then examples for such C M alkyl groups are -CH2-, -CH2-CH2-,
  • Each hydrogen of a C M alkyl carbon may optionally be replaced by a substituent as defined above.
  • a C M alkyl may be interrupted by one or more moieties as defined below.
  • C M alkyl alone or in combination means a straight-chain or branched alkyl moiety having 1 to 6 carbon atoms. If present at the end of a molecule, examples of straight-chain and branched CM alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
  • CM alkyl groups are -C3 ⁇ 4-, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )- and -C(CH 3 ) 2 -.
  • Each hydrogen atom of a CM carbon may optionally be replaced by a substituent as defined above.
  • a CM alkyl may be interrupted by one or more moieties as defined below.
  • “Ci_io alkyl”,“Ci_ 2 o alkyl” or“Ci_ 5 o alkyl” means an alkyl chain having 1 to 10, 1 to 20 or 1 to 50 carbon atoms, respectively, wherein each hydrogen atom of the C 0 , C 1.20 or Ci - 50 carbon may optionally be replaced by a substituent as defined above.
  • a C O or Ci_ 5 o alkyl may be interrupted by one or more moieties as defined below.
  • C 2-10 alkenyl C 2-20 alkenyl or “C 2-50 alkenyl” alone or in combination mean a straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon double bond having 2 to 10, 2 to 20 or 2 to 50 carbon atoms, respectively.
  • Each hydrogen atom of a C 2-10 alkenyl, C 2-20 alkenyl or C 2-50 alkenyl group may optionally be replaced by a substituent as defined above.
  • a C 2-10 alkenyl, C 2-20 alkenyl or C 2-50 alkenyl may be interrupted by one or more moieties as defined below.
  • C 2-6 alkynyl alone or in combination means a straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon triple bond having 2 to 6 carbon atoms. If present at the end of a molecule, examples are -CoCH, -CH 2 -CoCH, CH 2 -CH 2 -CoCH and CH 2 -CoC-CH 3 . When two moieties of a molecule are linked by the alkynyl group, then an example is -CoC-. Each hydrogen atom of a C2-6 alkynyl group may optionally be replaced by a substituent as defined above. Optionally, one or more double bond(s) may occur. Optionally, a C2-6 alkynyl may be interrupted by one or more moieties as defined below.
  • C2-10 alkynyl C2-20 alkynyl
  • C2-50 alkynyl alone or in combination means a straight- chain or branched hydrocarbon moiety comprising at least one carbon-carbon triple bond having 2 to 10, 2 to 20 or 2 to 50 carbon atoms, respectively.
  • Each hydrogen atom of a C2-10 alkynyl, C2-20 alkynyl or C2-50 alkynyl group may optionally be replaced by a substituent as defined above.
  • one or more double bond(s) may occur.
  • a C2-10 alkynyl, C2-20 alkynyl or C2-50 alkynyl may be interrupted by one or more moieties as defined below.
  • Ci_4 alkyl, Ci_ 6 alkyl, C HO alkyl, Ci_2o alkyl, Ci_5o alkyl, C2-6 alkenyl, C2-10 alkenyl, C2-20 alkenyl, C2-50 alkenyl, C2-6 alkynyl, C2-10 alkynyl, C2-20 alkenyl or C2-50 alkynyl may optionally be interrupted by one or more moieties which may be selected from the group consisting of
  • dashed lines indicate attachment to the remainder of the moiety or reagent; and -R and -R a are independently of each other selected from the group consisting of -H and Ci_ 6 alkyl.
  • C3_io cycloalkyl means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.
  • Each hydrogen atom of a C3_io cycloalkyl carbon may be replaced by a substituent as defined above.
  • the term “C3_io cycloalkyl” also includes bridged bicycles like norbomane or norbomene.
  • the term“8- to 30-membered carbopolycyclyl” or“8- to 30-membered carbopolycycle” means a cyclic moiety of two or more rings with 8 to 30 ring atoms, where two neighboring rings share at least one ring atom and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated).
  • a 8- to 30-membered carbopolycyclyl means a cyclic moiety of two, three, four or five rings.
  • a 8- to 30-membered carbopolycyclyl means a cyclic moiety of two, three or four rings.
  • 3- to 10-membered heterocycles include but are not limited to aziridine, oxirane, thiirane, azirine, oxirene, thiirene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetra
  • Examples for an 8- to 11-membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine and pteridine.
  • 8- to 11-membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane.
  • Each hydrogen atom of an 8- to 11-membered heterobicyclyl or 8- to 11-membered heterobicycle carbon may be replaced by a substituent.
  • R x and R y form the following structure:
  • R is a C 3.10 cycloalkyl or a 3- to 10-membered heterocyclyl.
  • n is selected from the group consisting of 1, 2, 3 and 4” in relation with a moiety of the structure:
  • R 1 and the adjacent -R 2 form the following structure:
  • wavy bond means that -R la and -R 2a may be either on the same side of the double bond, i.e. in cis configuration, or on opposite sides of the double bond, i.e. in trans configuration and wherein the term“adjacent” means that -R 1 and -R 2 are attached to carbon atoms that are next to each other.
  • each -R 2a may be either on the same side of the double bond, i.e. in cis configuration, or on opposite sides of the double bond, i.e. in trans configuration and wherein the term“adjacent” means that two -R are attached to carbon atoms that are next to each other.
  • N + in the phrases“an electron-donating heteroaromatic N + -comprising moiety” and“attachment to the N + of -D + ” refers to a positively charged nitrogen atom.
  • halogen means fluoro, chloro, bromo or iodo. In certain embodiments halogen is fluoro or chloro.
  • alkali metal ion refers to Na + , K + , Li + , Rb + and Cs + .
  • “alkali metal ion” refers to Na + , K + and Li +
  • alkaline earth metal ion refers to Mg , Ca , Sr and In certain embodiments an alkaline earth metal ion is Mg 2+ or Ca 2+ .
  • the term“functional group” means a group of atoms which can react with other groups of atoms.
  • Exemplary functional groups are carboxylic acid, primary amine, secondary amine, tertiary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, sulfonamides, sulfuric acid, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, and aziridine.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the present invention comprising acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine, amino acids, and quartemary ammonium salts, like tetrabutylammonium or cetyl trimethylammonium.
  • Compounds of the present invention comprising one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, trifluoroacetic acid, and other acids
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines zwitterions
  • the respective salts can be obtained by customary methods, which are known to the person skilled in the art like, for example by contacting these prodrugs with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable means a substance that does not cause harm when administered to a patient and in certain embodiments means approved by a regulatory agency, such as the EMA (Europe), the FDA (US) or any other national regulatory agency for use in animals, such as for use in humans.
  • excipient refers to a diluent, adjuvant, or vehicle with which the therapeutic, such as a drug or the water-insoluble controlled-release TKI compound, is administered.
  • Such pharmaceutical excipient may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred excipient when the pharmaceutical composition is administered orally.
  • Saline and aqueous dextrose are preferred excipients when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid excipients for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, hyaluronic acid, propylene glycol, water, ethanol and the like.
  • the pharmaceutical composition may also contain minor amounts of wetting or emulsifying agents, pEI buffering agents, like, for example, acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid), MES (2-(/V-morpholino)ethanesulfonic acid), or may contain detergents, like Tween ® , poloxamers, poloxamines, CHAPS, Igepal ® , or amino acids like, for example, glycine, lysine, or histidine.
  • pEI buffering agents like, for example, acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid), MES (2-(/V-morpholino)ethanesulfonic acid
  • detergents like Tween ® , poloxamers, poloxamine
  • compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the pharmaceutical composition may be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • Oral formulation can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such compositions may contain a therapeutically effective amount of the drug, such as the water-insoluble controlled-release TKI compound of the present invention, together with a suitable amount of excipient so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • peptide refers to a chain of at least 2 and up to and including 50 amino acid monomer moieties, which may also be referred to as“amino acid residues”, linked by peptide (amide) linkages, which may be linear, branched or cyclic.
  • the amino acid monomers may be selected from the group consisting of proteinogenic amino acids and non- proteinogenic amino acids and may be D- or L-amino acids.
  • the term“peptide” also includes peptidomimetics, such as peptoids, beta-peptides, cyclic peptides and depsipeptides and covers such peptidomimetic chains with up to and including 50 monomer moieties.
  • the term“protein” refers to a chain of more than 50 amino acid monomer moieties, which may also be referred to as“amino acid residues”, linked by peptide linkages, in which preferably no more than 12000 amino acid monomers are linked by peptide linkages, such as no more than 10000 amino acid monomer moieties, no more than 8000 amino acid monomer moieties, no more than 5000 amino acid monomer moieties or no more than 2000 amino acid monomer moieties.
  • small molecule drug refers to drugs that are organic compounds with a molecular weight of no more than 1 kDa, such as up to 900 Da.
  • biologicals or“biopharmaceutical” refers to any pharmaceutical drug manufactured in, extracted from, or semi-synthesized from biological sources. Different from totally synthesized pharmaceuticals, they may include vaccines, blood, blood components, allergenics, somatic cells, gene therapies, tissues, recombinant therapeutic protein, and living cells used in cell therapy. Biologies may be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living cells or tissues. They or their precursors or components are isolated from living sources, such as from human, animal, plant, fungal or microbial sources.
  • the present invention relates to a water-insoluble controlled-release TKI compound for use in the treatment of a cell-proliferation disorder, wherein said water- insoluble controlled-release TKI compound releases one or more TKI drug, wherein upon intra-tissue administration of a single dose of the water-insoluble controlled-release TKI compound anti-tumor activity is observed between 7 and 21 days following administration of the water-insoluble controlled-release TKI compound, and wherein the change in mean arterial blood pressure as measured in mmHg is less than 50% of the change in mean arterial blood pressure observed in the same animal species treated with a daily equimolar dose of the corresponding free TKI drug.
  • the change in mean arterial blood pressure, as measured in mmHg, is less than 50% of the change in mean arterial blood pressure, such as no more than 40%, no more than 30% or no more than 25%.
  • the amount of drug present in a single dose depends on a number of parameters, such as the specific drug for example. In general, it is a dose that achieves an anti tumor activity between 7 and 21 days after administration.
  • the present invention relates to a water-insoluble controlled-release TKI compound for use in the treatment of a cell-proliferation disorder, wherein the water-insoluble controlled-release TKI compound is administered by intra-tissue administration, and wherein such intra-tissue administration results in local inhibition of angiogenesis.
  • Local inhibition of angiogenesis may be measured in several ways, such as for example by taking a local tissue sample and measuring certain markers, such as protein or mRNA markers.
  • the at least five mRNAs are selected from the group consisting of Ac lb, Aggfl, Angptl, Angpt2, Angptll, Angptl3, AngptU, Anpep, B2m, Bail, Btgl, Cell 1, Cd55, Cd59b, Cdh5, Cga, Chga, Citedl, Coll8al, Col4a3, Crhr2, Cs/3, Ctgf, Cxcll 0, Cxcl5, Edil3, Eftial, Efnb2, Egf, Egfl7, Eng, Epasl, Ephb4, Erapl, Erbb2, Ereg, F2, Fgfl, Fgf2, Fgf6, Fgfr3, Figf, Fltl, Fnl, Foxfla, Foxml, Foxo4, Fst, Fzd5, Gapdh, Glmn, Gnal3, Grn, Gusb, Hand2, Heyl, Heyl, Hey
  • the at least five mRNAs are selected from the group consisting of Hifla, Vegfa, Vegfb, Vegfc, Mmpl9, Plau, Ptgs2, Bcl2ll, Nos3, Egr3, Egrl, Adamtsl, Ackr3, Rndl, Hbegf, Cxcl8, Jagl, Dkkl, Ccl2, Amot, BmplO, Rcanl, Vcaml, Rcan2, MmplO, Mmpl4, Cyp2c8, Sod2, Icaml, Sele, Mef2c, Notch4, DU4, Ctnnbl, Ccndl, Dnajb9, Herpudl, Bcl2, Pecaml, 1110, Fos, Zfp36, Duspl, Fosb, Nedd9, Atf3, Tribl, Junb, Bhlhb2, Dusp5, Nr4al, KlflO, K3, Cebpd, Nr4a3, Cx
  • expression levels 24 hours after intra tissue administration of at least five mRNAs selected from the group consisting of Angpt2, Apoldl, D114, Hey2, Ifnbl, Igfbp3, 1112a, Kcnj2, Kdr, Lep, Mycn, Notch4, Stcl, Tgfa and Timp4 are upregulated by at least 50% compared to baseline tissue.
  • expression levels 24 hours after intra-tissue administration of at least five mRNAs selected from the group consisting of AngptU, BmplO, Cga, Chga, Csf3, Cxcl5, Dkkl, F2, Fgf6, Hand2, Ilia, Illb, 116, Myocd, Pig, Ptgs2, Rcan2, Sele, Tbx4, Tdgfl, Thbsl, Tmprss6 and Wtl are downregulated by at least 50% compared to baseline tissue.
  • the term“vary by at least 50%” means that each of the mRNAs may independently of the other mRNAs either be upregulated by at least 50% compared to baseline tissue or may be downregulated by at least 50% compared to baseline tissue.
  • At least five mRNA from the above list of mRNAs vary by at least 50% compared to baseline tissue, such as 5 mRNA, 6 mRNA, 7 mRNAs, 8 mRNAs, 9 mRNAs or 10 mRNAs.
  • the at least five mRNAs from the above list vary by at least 50%, such as by at least 60%, by at least 70%, by at least 80%, by at least 90% or by at least 100%.
  • the total amount of TKI moieties and TKI drug molecules remaining locally 3 days after intra-tissue administration is at least 25% of the amount of TKI moieties or TKI drug molecules administered by intra-tissue administration. ft is understood that the total amount of TKI moieties and TKI drug molecules remaining locally in such tissue includes both the TKI drug molecules released from the water-insoluble controlled-release TKI compound (but remaining in the local tissue) and the TKI moieties and TKI drug molecules not yet released from the water-insoluble controlled-release TKI compound and that the determination of the total amount of TKI moieties and TKI drug molecules remaining locally is made 3 days after said intra-tissue administration.
  • This total amount of TKI moieties and TKI drug molecules may be measured by subjecting a sample to conditions under which unreleased TKI moieties and TKI drug molecules are released from the water-insoluble controlled-release TKI compound (in certain embodiments with an accelerated release half-life) and subsequently determining the amount of TKI drug in said sample, measured in g TKI drug per g tissue.
  • the amount of TKI moieties and TKI drug molecules remaining locally after 3 days is at least 25% of the amount of administered TKI moieties or TKI drug molecules, such as at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% or at least 60%.
  • the maximum systemic molar concentration in plasma of TKI drug released from the water-insoluble controlled-release TKI compound within 24 hours after intra-tissue administration is at least 50% lower than the maximum systemic molar concentration in plasma of TKI drug within 24 hours after intra-tissue administration of an equimolar dose of the corresponding free TKI drug.
  • the maximum systemic molar concentration of TKI drug in serum within 24 hours after administration may be determined by taking multiple serum samples within a time period ranging from 0 to 24 hours, determining the TKI drug content in each of them, plotting the TKI drug concentrations as a function of time and determining the maximum concentration using suitable mathematical models.
  • Exemplary time points for taking of the samples may be 1 hour, 3 hours, 6 hours, 12 hours and 24 hours after intra-tissue administration.
  • the maximum systemic molar concentration of TKI drug released from the water-insoluble controlled-release TKI compound in plasma within 24 hours after said intra-tissue administration is at least 50% lower than the maximum systemic molar concentration of TKI drug in plasma within 24 hours after intra-tissue administration of an equimolar dose of the corresponding free TKI drug, such as at least 55% lower, at least 60% lower, at least 65% lower or at least 70% lower.
  • anti-tumor activity is present 7 to 21 days post intra-tissue administration and the maximum systemic concentration of TKI drug measured in plasma within 24 hours after said intra-tissue administration that is less than 50%, such as no more than 45%, no more than 40%, no more than 35%, no more than 30%, no more than 25%, no more than 20%, no more than 15% or no more than 10%, than the maximum systemic concentrations of TKI drug measured in plasma within 24h following systemic administration of a dose of the corresponding free TKI drug required to achieve the same level of anti-tumor activity 7 to 21 days post administration.
  • systemic administration of the dose of the corresponding free TKI drug is via oral or intravenous route. In certain said systemic administration is via oral administration. In certain embodiments said systemic administration is via intravenous administration.
  • the water-insoluble controlled-release TKI compound comprises a plurality of TKI drug molecules or TKI moieties.
  • the cell-proliferation disorder to be treated with the water-insoluble controlled-release TKI compound is cancer.
  • Such cancer may be selected from the group consisting of lip and oral cavity cancer, oral cancer, liver cancer/hepatocellular cancer, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastasic squamous neck cancer with occult primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenocortical carcinoma, AIDS
  • lung cancer examples are non-small cell lung cancer and small cell lung cancer.
  • the cancer is a non-small cell lung cancer.
  • the cancer is a small cell lung cancer.
  • lymphomas are AIDS-related lymphoma, primary central nervous system lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, Hodgkin's lymphoma during pregnancy, non-Hodgkin's lymphoma, follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma, non-Hodgkin’s lymphoma during pregnancy and angioimmunoblastic lymphoma.
  • the cancer is a cutaneous T-cell lymphoma.
  • Examples for skin cancer are melanoma and Merkel cell carcinoma.
  • the cancer is a skin cancer.
  • the cancer is a Merkel cell carcinoma.
  • An ovarian cancer may for example be an epithelial cancer, a germ cell tumor or a low malignant potential tumor.
  • the cancer is an epithelial cancer.
  • the cancer is a germ cell tumor.
  • the cancer is a low malignant potential tumor.
  • a pancreatic cancer may for example be an exocrine tumor/adenocarcinoma, pancreatic endocrine tumor (PET) or neuroendocrine tumor (NET).
  • the cancer is an exocrine tumor/adenocarcinoma.
  • the tumor is a pancreatic endocrine tumor.
  • the cancer is a neuroendocrine tumor.
  • a brain and nervous system cancer may be for example be a medulloblastoma, such as a childhood medulloblastoma, astrocytoma, ependymoma, neuroectodermal tumors, schwannoma, meningioma, pituitary adenoma and glioma.
  • the cancer is a medullablastoma.
  • the cancer is a childhood medullablastoma.
  • the cancer is an astrocytoma.
  • the cancer is an ependymoma.
  • the cancer is a neuroectodermal tumor.
  • the tumor is a schwannoma.
  • the cancer is a meningioma.
  • the cancer is a pituitary adenoma.
  • the cancer is a glioma.
  • An astrocytoma may be selected from the group consisting of giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, primary pediatric glioblastoma, oligodendroglial tumor, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytic tumor, oligoastrocytoma, anaplastic oligodendroglioma, oligoastrocytic tumor, oligoastrocytoma, anaplastic oligodendroglioma, oligoastrocytic tumor, oligoastrocytoma, anaplastic oligoastrocytoma, anaplastic astrocytoma, pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma and cerebellar
  • Examples for a neuroectodermal tumor are a pineal primitive neuroectodermal tumor and a supratentorial primitive neuroectodermal tumor.
  • An ependymoma may be selected from the group consisting of subependymoma, ependymoma, myxopapillary ependymoma and anaplastic ependymoma.
  • a meningioma may be an atypical meningioma or an anaplastic meningioma.
  • a glioma may be selected from the group consisting of glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumor (sPNET), brain stem glioma, childhood brain stem glioma, hypothalamic and visual pathway glioma, childhood hypothalamic and visual pathway glioma and malignant glioma.
  • sPNET suprantentorial primordial neuroectodermal tumor
  • breast cancer examples are breast cancer during pregnancy, triple negative breast cancer, ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), tubular carcinoma of the breast, medullary carcinoma of the breast, mucinous carcinoma of the breast, papillary carcinoma of the breast, cribriform carcinoma of the breast, invasive lobular carcinoma (ILC), inflammatory breast cancer, lobular carcinoma in situ (LCIS), male breast cancer, Paget’s disease of the nipple, phyllodes tumors of the breast and metastasic breast cancer.
  • the cancer is a breast cancer during pregnancy.
  • the cancer is a triple negative breast cancer.
  • the cancer is a ductal carcinoma in situ.
  • the cancer is an invasive ductal carcinoma. In certain embodiments the cancer is a tubular carcinoma of the breast. In certain embodiments the cancer is a medullary carcinoma of the breast. In certain embodiments the cancer is a mucinous carcinoma of the breast. In certain embodiments the cancer is a papillary carcinoma of the breast. In certain embodiments the cancer is a cribriform carcinoma of the breast. In certain embodiments the cancer is an invasive lobular carcinoma. In certain embodiments the cancer is an inflammatory breast cancer. In certain embodiments the cancer is a lobular carcinoma in situ. In certain embodiments the cancer is a male breast cancer. In certain embodiments the cancer is a Paget’s disease of the nipple. In certain embodiments the cancer is a phyllodes tumor of the breast. In certain embodiments the cancer is a metastatic breast cancer.
  • a carcinoma examples for a carcinoma are neuroendocrine carcinoma, adrenocortical carcinoma and Islet cell carcinoma.
  • the cancer is a neuroendocrine carcinoma.
  • the cancer is an adrenocortical carcinoma.
  • the cancer is an Islet cell carcinoma.
  • Examples for a colorectal cancer are colon cancer and rectal cancer.
  • the cancer is a colon cancer.
  • the cancer is a rectal cancer.
  • a sarcoma may be selected from the group consisting of Kaposi’s sarcoma, osteosarcoma/malignant fibrous histiocytoma of bone, soft tissue sarcoma, Ewing’s family of tumors/sarcomas, rhabdomyosarcoma, clear cell sarcoma of tendon sheaths, central chondrosarcoma, central and periosteal chondroma, fibrosarcoma and uterine sarcoma.
  • the cancer may be a Kaposi’s sarcoma. In certain embodiments the cancer may be an osteosarcoma/malignant fibrous histiocytoma of bone. In certain embodiments the cancer may be a soft tissue sarcoma. In certain embodiments the cancer may be an Ewing’s family of tumors/sarcomas. In certain embodiments the cancer may be a rhabdomyosarcoma. In certain embodiments the cancer may be a clear cell sarcoma of tendon sheaths. In certain embodiments the cancer may be a central chondrosarcoma. In certain embodiments the cancer may be a central and periosteal chondroma. In certain embodiments the cancer may be a fibrosarcoma. In certain embodiments the cancer may be a uterine sarcoma.
  • Examples for a genitourinary cancer are testicular cancer, urethral cancer, vaginal cancer, cervical cancer, penile cancer and vulvar cancer.
  • the cancer may be a testicular cancer.
  • the cancer may be a urethral cancer.
  • the cancer may be a vaginal cancer.
  • the cancer may be a cervical cancer.
  • the cancer may be a penile cancer.
  • the cancer may be a vaginal cancer.
  • the cell-proliferation disorder is a glioblastoma.
  • intra-tumoral administration has the advantage of bypassing the blood-brain-barrier and the water-insoluble controlled-release allows treatment of these hard-to -inject tumors that otherwise cannot be injected frequently enough with the corresponding free drug molecules.
  • the cell-proliferation disorder is an inoperable or surgically challenging cancer of the lung, liver or pancreas.
  • the water-insoluble controlled-release TKI compound is administered to a patient via intra tissue administration, which in certain embodiments is intra-tumoral administration or an administration into one or more tumor-associated draining lymph nodes.
  • intra tissue administration in certain embodiments is intra-tumoral administration or an administration into one or more tumor-associated draining lymph nodes.
  • intra-tissue administration is an intra-tumoral administration.
  • intra-tissue administration is an administration into one or more tumor- associated draining lymph nodes.
  • an intra-tumoral administration is an administration into a solid tumor.
  • the tumor for intra-tumoral administration or the tumor of the tumor- associated draining lymph nodes is selected from the group consisting of lip and oral cavity cancer, oral cancer, liver cancer/hepatocellular cancer, primary liver cancer, lung cancer, lymphoma, malignant mesothelioma, malignant thymoma, skin cancer, intraocular melanoma, metastasic squamous neck cancer with occult primary, childhood multiple endocrine neoplasia syndrome, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, pheochromocytoma, pituitary tumor, adrenocortical carcinoma, AIDS-related malignancies, anal cancer, bile duct cancer, bladder cancer, brain and nervous system cancer, breast cancer, bronchial adenoma
  • the tumor for intra-tumoral administration or the tumor of the tumor- associated draining lymph nodes is a glioblastoma.
  • intra-tumoral administration has the advantage of bypassing the blood-brain-barrier and the water-insoluble controlled-release allows treatment of these hard-to-inject tumors that otherwise cannot be injected frequently enough with the corresponding free drug molecules.
  • the tumor for intra-tumoral administration or the tumor of the tumor- associated draining lymph nodes is an inoperable or surgically challenging cancer of the lung, liver or pancreas.
  • anti-tumor activity is observed 7 to 21 days after said intra-tissue administration. It is understood that this does not mean that no anti-tumor activity is observed prior to 7 days or later than 21 days after intra-tissue administration.
  • the TKI moiety or TKI drug may be selected from the group consisting of receptor tyrosine kinase inhibitors, intracellular kinase inhibitors, cyclin dependent kinase inhibitors, phosphoinositide-3-kinase (PI3K) inhibitors, mitogen-activated protein kinase inhibitors, inhibitors of nuclear factor kappa-b kinase (IKK), and Wee-1 inhibitors.
  • PI3K phosphoinositide-3-kinase
  • IKK nuclear factor kappa-b kinase
  • -D is selected from the group consisting of receptor tyrosine kinase inhibitors, intracellular kinase inhibitors, cyclin dependent kinase inhibitors, mitogen-activated protein kinase inhibitors, inhibitors of nuclear factor kappa-b kinase (IKK), and Wee-1 inhibitors.
  • the TKI moiety or TKI drug is a receptor tyrosine kinase inhibitor.
  • receptor tyrosine kinase inhibitors are EGF receptor inhibitors, VEGF receptor inhibitors, C-KIT Receptor inhibitors, ERBB2 (HER2) inhibitors, ERBB3 receptor inhibitors, FGF receptor inhibitors, AXL receptor inhibitors and MET receptor inhibitors.
  • the TKI moiety or TKI drug is an EGF receptor inhibitor, such as afatinib, cetuximab, erlotinib, gefitinib, pertuzumab and margetuximab.
  • the TKI moiety or TKI drug is a VEGF receptor inhibitor, such as axitinib, lenvatinib, pegaptanib and linifanib (ABT-869).
  • the TKI moiety or TKI drug is axitinib.
  • the TKI moiety or TKI drug is lenvatinib.
  • the TKI moiety or TKI drug is a C-KIT Receptor inhibitor such as CDX0158 (KTN0158).
  • the TKI moiety or TKI drug is an ERBB2 (HER2) inhibitor, such as herceptin (trastuzumab).
  • the TKI moiety or TKI drug is an ERBB3 receptor inhibitor, such as CDX3379 (MEDI3379, KTN3379) and AZD8931 (sapitinib).
  • the TKI moiety or TKI drug is an FGF receptor inhibitor such as erdafitinib.
  • the TKI moiety or TKI drug is an AXL receptor inhibitor such as BGB324 (BGB 324, R 428, R428, bemcentinib) and SLC391.
  • the TKI moiety or TKI drug is a MET receptor inhibitor, such as CGEN241 or tivantinib. In certain embodiments the TKI moiety or drug is tivantinib.
  • the TKI moiety or TKI drug is an intracellular kinase inhibitor.
  • intracellular kinase inhibitors are Bruton’s tyrosine kinase (BTK) inhibitors, spleen tyrosine kinase inhibitors, Bcr-Abl tyrosine kinase inhibitors, Janus kinase inhibitors and multi-specific tyrosine kinase inhibitors.
  • the TKI moiety or TKI drug is a BTK inhibitor, such as ibrutinib, acalabrutinib, GS-4059, spebrutinib, BGB-3111, HM71224, zanubrutinib, ARQ531, BI- BTK1 and vecabrutinib.
  • BTK inhibitor such as ibrutinib, acalabrutinib, GS-4059, spebrutinib, BGB-3111, HM71224, zanubrutinib, ARQ531, BI- BTK1 and vecabrutinib.
  • the TKI moiety or TKI drug is a spleen tyrosine kinase inhibitor, such as fostamatinib.
  • the TKI moiety or TKI drug is a Bcr-Abl tyrosine kinase inhibitor, such as imatinib and nilotinib.
  • the TKI moiety or TKI drug is a Janus kinase inhibitor, such as ruxolitinib, tofacitinib and fedratinib.
  • the TKI moiety or TKI drug is a multi-specific tyrosine kinase inhibitor, such as bosutinib, crizotinib, cabozantinib, dasatinib, entrectinib, lapatinib, mubritinib, pazopanib, sorafenib, sunitinib, SU6656 and vandetanib.
  • the TKI moiety or drug is crizotinib.
  • the TKI moiety or drug is cabozantinib which is an inhibitor of c-Met, VEGFR2, AXL and RET.
  • the TKI moiety or TKI drug is a cyclin dependent kinase inhibitor.
  • cyclin dependent kinase inhibitors are copanlisib, ribociclib, palbociclib, abemaciclib, trilaciclib, purvalanol A, olomucine II and MK-7965.
  • the TKI moiety or drug is copanlisib.
  • the TKI moiety or TKI drug is a phophoinositide-3 -kinase inhibitor.
  • phophoinositide-3 -kinase inhibitors are IPI549, GDc-0326, pictilisib, serabelisib, IC-87114, AMG319, seletalisib, idealisib and CUDC907.
  • the TKI moiety or TKI drug is a mitogen-activated protein kinase inhibitor.
  • mitogen-activated protein kinase inhibitors are Ras/famesyl transferase inhibitors, Raf inhibitors, MEK inhibitors and ERK inhibitors.
  • the TKI moiety or TKI drug is a Ras/famesyl transferase inhibitor, such as tipirafinib and LB42708.
  • the TKI moiety or TKI drag is a Raf inhibitor, such as regorafenib, encorafenib, vemurafenib, dabrafenib, sorafenib, PLX-4720, GDC-0879, AZ628, lifirafenib, PLX7904 and R05126766.
  • Raf inhibitor such as regorafenib, encorafenib, vemurafenib, dabrafenib, sorafenib, PLX-4720, GDC-0879, AZ628, lifirafenib, PLX7904 and R05126766.
  • the TKI moiety or TKI drag is a MEK inhibitor, such as cobimetinib, trametinib, binimetinib, selumetinib, pimasertib, refametinib and PD0325901. In certain embodiments the TKI moiety or drag is cobimetinib.
  • the TKI moiety or TKI drag is an ERK inhibitor, such as MK-8353, GDC-0994, ulixertinib and SCH772984.
  • the TKI moiety or TKI drag is an inhibitors of nuclear factor IKK.
  • inhibitors of nuclear factor kappa-b kinase (IKK) are BPI-003 and AS602868.
  • TKI moiety or TKI drug is a Wee-1 inhibitor.
  • An example of a Wee-1 inhibitor is adavosertib.
  • the TKI drug molecules or TKI moieties are selected from the group consisting of lenvatinib, axitinib, cobimetinib, crizotinib, tivantinib, copanlisib and cabozantinib.
  • -D is a non-indolinone-based tyrosine kinase inhibitor.
  • the water-insoluble controlled-release TKI compound comprises one type of TKI drug or TKI moiety, i.e. all TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound have the same structure. It is understood that this does not exclude the occurrence of changes in the chemical structure of individual TKI drug molecules or TKI moieties due to for example molecular rearrangements or degradation, as may for example occur during storage.
  • the water-insoluble controlled- release TKI compound comprises two types of TKI drug molecules or TKI moieties.
  • the water-insoluble controlled-release TKI compound comprises three types of TKI drug molecules or TKI moieties.
  • the water-insoluble controlled-release TKI compound comprises four types of TKI drug molecules or TKI moieties. In certain embodiments the water-insoluble controlled-release TKI compound comprises five types of TKI drug molecules or TKI moieties. In certain embodiments the water-insoluble controlled-release TKI compound comprises at least one type of TKI drug and at least one type of TKI moiety, i.e. a combination of non-covalently embedded TKI drug molecules and covalently conjugated TKI moieties.
  • At least 10% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are lenvatinib, such as at least 20% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are lenvatinib, such as at least 30% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release compound TKI are lenvatinib, such as at least 40% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are lenvatinib, such as at least 50% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are lenvatinib, such as at least 60% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are lenvatinib, such as at least 70% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are lenvatin
  • At least 10% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are axitinib, such as at least 20% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are axitinib, such as at least 30% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are axitinib, such as at least 40% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are axitinib, such as at least 50% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are axitinib, such as at least 60% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are axitinib, such as at least 70% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are axitin
  • At least 10% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are cobimetinib, such as at least 20% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are cobimetinib, such as at least 30% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are cobimetinib, such as at least 40% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are cobimetinib, such as at least 50% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are cobimetinib, such as at least 60% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are cobimetinib, such as at least 70% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI
  • At least 10% of the TKI drug molecules or TKI moieties drug or moiety of the water-insoluble controlled-release TKI compound are crizotinib, such as at least 20% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are crizotinib, such as at least 30% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are crizotinib, such as at least 40% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are crizotinib, such as at least 50% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are crizotinib, such as at least 60% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are crizotinib, such as at least 70% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI
  • At least 10% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are tivantinib, such as at least 20% of TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are tivantinib, such as at least 30% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are tivantinib, such as at least 40% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are tivantinib, such as at least 50% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are tivantinib, such as at least 60% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are tivantinib, such as at least 70% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are tivantini
  • At least 10% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are copanlisib, such as at least 20% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are copanlisib, such as at least 30% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are copanlisib, such as at least 40% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are copanlisib, such as at least 50% of the TKI drug molecules or TKI moieties y of the water- insoluble controlled-release TKI compound are copanlisib, such as at least 60% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are copanlisib, such as at least 70% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound
  • At least 10% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are cabozantinib, such as at least 20% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are cabozantinib, such as at least 30% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are cabozantinib, such as at least 40% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are cabozantinib, such as at least 50% of the TKI drug molecules or TKI moieties of the water- insoluble controlled-release TKI compound are cabozantinib, such as at least 60% of the TKI drug molecules or TKI moieties of the water-insoluble controlled-release TKI compound are cabozantinib, such as at least 70% of the TKI drug molecules or TKI moieties of the
  • the water-insoluble controlled-release TKI compound comprises at least one type of TKI drug or TKI moiety and at least one additional drug or drug moiety of a class other than TKIs.
  • such at least one additional drug or drug moiety of a different class is selected from the group consisting of cytotoxic/chemotherapeutic agents, immune checkpoint inhibitors or antagonists, immune agonists, multi-specific drugs, antibody-drug conjugates (ADC), radionuclides or targeted radionuclide therapeutics, DNA damage repair inhibitors, tumor metabolism inhibitors, pattern recognition receptor agonists, chemokine and chemoattractant receptor agonists, chemokine or chemokine receptor antagonists, cytokine receptor agonists, death receptor agonists, CD47 or SIRPa antagonists, oncolytic drugs, signal converter proteins, epigenetic modifiers, tumor peptides or tumor vaccines, heat shock protein (HSP) inhibitors, proteolytic enzymes, ubiquitin and proteasome inhibitors, adhe
  • HSP heat
  • the at least one additional drug or drug moiety is a cytotoxic/chemotherapeutic agent. In certain embodiments the at least one additional drug or drug moiety is an immune checkpoint inhibitor or antagonist. In certain embodiments the at least one additional drug or drug moiety is a multi-specific drug. In certain embodiments the at least one additional drug or drug moiety is an antibody-drug conjugate (ADC). In certain embodiments the at least one additional drug or drug moiety is a targeted radionuclide therapeutic. In certain embodiments the at least one additional drug or drug moiety is a DNA damage repair inhibitor. In certain embodiments the at least one additional drug or drug moiety is a tumor metabolism inhibitor. In certain embodiments the at least one additional drug or drug moiety is a pattern recognition receptor agonist.
  • the at least one additional drug or drug moiety is a chemokine or chemoattractant receptor agonist. In certain embodiments the at least one additional drug or drug moiety is a cytokine receptor agonist. In certain embodiments the at least one additional drug or drug moiety is a death receptor agonist. In certain embodiments the at least one additional drug or drug moiety is a CD47 antagonist. In certain embodiments the at least one additional drug or drug moiety is a SIRPa antagonist. In certain embodiments the at least one additional drug or drug moiety is an oncolytic drug. In certain embodiments the at least one additional drug or drug moiety is a signal converter protein. In certain embodiments the at least one additional drug or drug moiety is an epigenetic modifier.
  • the at least one additional drug or drug moiety is a tumor peptide or tumor vaccine. In certain embodiments the at least one additional drug or drug moiety is a heat shock protein (HSP) inhibitor. In certain embodiments the at least one additional drug or drug moiety is a proteolytic enzyme. In certain embodiments the at least one additional drug or drug moiety is a ubiquitin and proteasome inhibitor. In certain embodiments the at least one additional drug or drug moiety is an adhesion molecule antagonist. In certain embodiments the at least one additional drug or drug moiety is a hormone including hormone peptides and synthetic hormones.
  • HSP heat shock protein
  • cytotoxic or chemotherapeutic agent examples include alkylating agents, anti-metabolites, anti-microtubule agents, topoisomerase inhibitors, cytotoxic antibiotics, auristatins, enediynes, lexitropsins, duocarmycins, cyclopropylpyrroloindoles, puromycin, dolastatins, maytansine derivatives, alkylsufonates, triazenes and piperazine.
  • Example for an alkylating agent are nitrogen mustards, such as mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan; nitrosoureas, such as N-nitroso-N-methylurea, carmustine, lomustine, semustine, fotemustine and streptozotocin; tetrazines, such as dacarbazine, mitozolomide and temozolomide; ethylenimines, such as altretamine; aziridines, such as thiotepa, mitomycin and diaziquone; cisplatin and derivatives, such as cisplatin, carboplatin, oxaliplatin; and non-classical alkylating agents, such as procarbazine and hexamethylmelamine.
  • nitrogen mustards such as mechlorethamine, cyclophosphamide, melphalan, chlorambucil
  • anti-metabolite examples include anti-folates, such as methotrexate and pemetrexed; fluoropyrimidines, such as fluorouracil and capecitabine; deoxynucleoside analogues, such as cytarabine, gemcitabine, decitabine, azacytidine, fludarabine, nelarabine, cladribine, clofarabine and pentostatin; and thiopurines, such as thioguanine and mercaptopurine.
  • fluoropyrimidines such as fluorouracil and capecitabine
  • deoxynucleoside analogues such as cytarabine, gemcitabine, decitabine, azacytidine, fludarabine, nelarabine, cladribine, clofarabine and pentostatin
  • thiopurines such as thioguanine and mercaptopurine.
  • Examples for an anti-microtubule agent are Vinca alkaloids, such as vincristine, vinblastine, vinorelbine, vindesine and vinflunine; taxanes, such as paclitaxel and docetaxel; podophyllotoxins and derivatives, such as podophyllotoxin, etoposide and teniposide; stilbenoid phenol and derivatives, such as zybrestat (CA4P); and BNC105.
  • Vinca alkaloids such as vincristine, vinblastine, vinorelbine, vindesine and vinflunine
  • taxanes such as paclitaxel and docetaxel
  • podophyllotoxins and derivatives such as podophyllotoxin, etoposide and teniposide
  • stilbenoid phenol and derivatives such as zybrestat (CA4P)
  • BNC105 BNC105.
  • topoisomerase inhibitors examples include topoisomerase I inhibitors, such as irinotecan, topotecan and camptothecin; and topoisomerase II inhibitors, such as etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, merbarone and aclarubicin.
  • cytotoxic antibiotic examples include anthracyclines, such as doxorubicin, daunorubicin, epirubicin and idarubicin; pirarubicin, aclarubicin, bleomycin, mitomycin C, mitoxantrone, actinomycin, dactinomycin, adriamycin, mithramycin and tirapazamine.
  • anthracyclines such as doxorubicin, daunorubicin, epirubicin and idarubicin
  • pirarubicin aclarubicin
  • bleomycin mitomycin C
  • mitoxantrone actinomycin
  • actinomycin actinomycin
  • dactinomycin adriamycin
  • mithramycin mithramycin and tirapazamine.
  • auristatin examples include monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF).
  • Examples for an enediyne are neocarzinostatin, lidamycin (C-1027), calicheamicins, esperamicins, dynemicins and golfomycin A.
  • Examples for a maytansine derivative are ansamitocin, mertansine (emtansine, DM1) and ravtansine (soravtansine, DM4).
  • an immune checkpoint inhibitor or antagonist examples include inhibitors of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), such as ipilimumab, tremelimumab, MK- 1308, FPT155, PRS010, BMS-986249, BPI-002, CBT509, JS007, ONC392, TE1254, IBI310, BR02001, CG0161, KN044, PBI5D3H5, BCD145, ADU1604, AGEN1884, AGEN1181, CS1002 and CP675206; inhibitors of PD-1 (programmed death 1), such as pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS-936559, cemiplimab and PDR001; inhibitors of PD-L1 (programmed cell death protein 1), such as MDX-1105, MEDI4736, atezolizumab, avelumab, BMS-936559 and
  • said one or more further drug is an inhibitor of PD-1. In certain embodiments said one or more further drug is an inhibitor of PD-L1.
  • an immune agonist examples include CD27, such as recombinant CD70, such as HERA- CD27L, and varlilumab (CDX-1127); agonists of CD28, such as recombinant CD80, recombinant CD86, TGN1412 and FPT155; agonists of CD40, such as recombinant CD40L, CP-870,893, dacetuzumab (SGN-40), Chi Lob 7/4, ADC-1013 and CDX1140; agonists of 4- 1BB (CD 137), such as recombinant 4-1BBL, urelumab, utomilumab and ATOR-1017; agonists of 0X40, such as recombinant OX40L, MEDI0562, GSK3174998, MOXR0916 and PF-04548600; agonists of GITR, such as recombinant GITRL, TRX518, MEDI1873, INCAGN01876, MK-12
  • Examples for a multi-specific drug are biologies and small molecule immune checkpoint inhibitors.
  • Examples for biologies are multi-specific immune checkpoint inhibitors, such as CD137/HER2 lipocalin, PD1/LAG3, FS118, XmAb22841 and XmAb20717; and multi- specific immune agonists.
  • Such multi-specific immune agonists may be selected from the group consisting of Ig superfamily agonists, such as ALPN-202; TNF superfamily agonists, such as ATOR-1015, ATOR-1144, ALG.APV-527, lipocalin/PRS-343, PRS344/ONC0055, FAP-CD40 DARPin, MP0310 DARPin, FAP-0X40 DARPin, EGFR-CD40 DARPin, EGFR41BB/CD137 DARPin, EGFR-0X40/DARFPin, HER2-CD40 DARPin, HER2- 41BB/CD137 DARPin, HER2-0X40 DARPin, FIBRONECTIN ED-B-CD40 DARPin, FIBRONECTIN ED-B-41BB/CD137 and FIBRONECTIN ED-B-0X40 DARPin; CD3 multispecific agonists, such as blinatumomab, solit
  • CD16 multispecific agonists such as 1633 BiKE, 161533 TriKE, OXS-3550, OXS-C3550, AFM13 and AFM24.
  • An example for a small molecule immune checkpoint inhibitor is CA-327 (TIM3/PD-L1 antagonist).
  • Examples for an antibody-drug conjugate are ADCs targeting hematopoietic cancers, such as gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, SAR3419, BT062, SGN-CD19A, IMGN529, MDX-1203, polatuzumab vedotin (RG7596), pinatuzumab vedotin (RG7593), RG7598, milatuzumab-doxorubicin and OXS-1550; and ADCs targeting solid tumor antigens, such as trastuzumab emtansine, glembatumomab vedotin, SAR56658, AMG- 172, AMG-595, BAY-94-9343, BIIB015, vorsetuzumab mafodotin (SGN-75), ABT-414, ASG-5ME, enfor
  • radionuclides examples include b-emitters, such as 177 Lutetium, 166 Holmium, 186 Rhenium, 188 Rhenium, 67 Copper, 149 Promethium, 199 Gold, 77 Bromine, 153 Samarium, 105 Rhodium,
  • Astatine and Auger electron-emitters, such as Bromine, Indium, Iodine and 125 Iodine.
  • Examples for targeted radionuclide therapeutics are zevalin ( 90 Y-ibritumomab tiuxetan), bexxar ( 131 I-tositumomab), oncolym ( 131 I-Lym 1), lymphocide ( 90 Y-epratuzumab), cotara ( 131 I-chTNT-l/B), labetuzumab ( 90 Y or 131 I-CEA), theragyn ( 90 Y-pemtumomab), licartin ( 131 I- metuximab), radretumab ( I-L19) PAM4 ( Y-clivatuzumab tetraxetan), xofigo ( Ra dichloride), lutathera ( 177 Lu-DOTA-Tyr 3 -Octreotate) and 131 I-MIBG.
  • zevalin 90 Y-ibritumomab tiuxe
  • DNA damage repair inhibitor examples include poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, rucaparib, niraparib, veliparib, CEP 9722 and E7016; CHK1/CHK2 dual inhibitors, such as AZD7762, V158411, CBP501 and XL844; CHK1 selective inhibitors, such as PF477736, MK8776/SCH900776, CCT244747, CCT245737, LY2603618, LY2606368/prexasertib, AB-IsoG, ARRY575, AZD7762, CBP93872, ESP01, GDC0425, SAR020106, SRA737, V158411 and VER250840; CHK2 inhibitors, such as CCT241533 and PV1019; ATM inhibitors, such as AZD0156, AZD1390, KU55933, M3541 and SX-RDS
  • Examples for a tumor metabolism inhibitor are inhibitors of the adenosine pathway, inhibitors of the tryptophan metabolism and inhibitors of the arginine pathway.
  • Examples for an inhibitor of the adenosine pathway are inhibitors of A2AR (adenosine A2A receptor), such as ATL-444, istradefylline (KW-6002), MSX-3, preladenant (SCH-420,814), SCH-58261, SCH412,348, SCH-442,416, ST-1535, caffeine, VER-6623, VER-6947, VER- 7835, vipadenant (BIIB-014), ZM-241,385, PBF-509 and V81444; inhibitors of CD73, such as IPH53 and SRF373; and inhibitors of CD39, such as IPH52.
  • A2AR adenosine A2A receptor
  • ATL-444 istradefylline
  • MSX-3 preladenant
  • SCH-420,814 SCH-58261
  • SCH412,348, SCH-442,416, ST-1535 caffeine, VER-6623, VER-6947, VER- 7835, vi
  • an inhibitor of the tryptophane metabolism examples include inhibitors of IDO, such as indoximod (NLG8189), epacadostat, navoximod, BMS-986205 and MK-7162; inhibitors of TDO, such as 680C91; and IDO/TDO dual inhibitors.
  • inhibitors of the arginine pathway are inhibitors of arginase, such as INCBOOl 158.
  • Examples for a pattern recognition agonist are Toll-like receptor agonists, NOD-like receptors, RIG-I-like receptors, cytosolic DNA sensors, STING, and aryl hydrocarbon receptors (AhR).
  • Toll-like receptor agonists are agonists of TLR1/2, such as peptidoglycans, lipoproteins, Pam3CSK4, Amplivant, SLP-AMPLIVANT, HESPECTA, ISA101 and ISA201; agonists of TLR2, such as LAM-MS, LPS-PG, LTA-BS, LTA-SA, PGN-BS, PGN-EB, PGN- EK, PGN-SA, CL429, FSL-1, Pam2CSK4, Pam3CSK4, zymosan, CBLB612, SV-283, ISA204, SMP105, heat killed Listeria monocytogenes ; agonists of TLR3, such as poly(A:U), poly(EC) (poly-ICLC), rintatolimod, apoxxim, IPH3102, poly-ICR, PRV300, RGCL2, RGIC.l, Riboxxim (RGCIOO, RGICIOO), Riboxxol (RGIC50) and Ribox
  • the agonist of TLR7/8 is a conjugate as described in EP 19150384.
  • the agonist of TLR7/8 is in certain embodiments of formula (1) wherein the dashed line indicates attachment to a PEG hydrogel. It is understood that a multitude of the moieties of formula (1) are conjugated to said hydrogel. Examples for CpG ODN are ODN 1585, ODN 2216, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN 2007, ODN BW006, ODN D-SL01, ODN 2395, ODN M362 and ODN D- SL03.
  • NOD-like receptors examples include agonists of NODI, such as C12-iE-DAP, C14-Tri- LAN-Gly, iE-DAP, iE-Lys, and Tri-DAP; and agonists of NOD2, such as L18-MDP, MDP, M-TriLYS, murabutide and N-glycolyl-MDP.
  • RIG-I-like receptors examples include 3p-hpRNA, 5’ppp-dsRNA, 5’ppp RNA (M8), 5 ⁇ H RNA with kink (CBS-13-BPS), 5’PPP SLR, KIN100, KIN 101, KIN1000, KIN1400, KIN 1408, KIN 1409, KIN1148, KIN131A, poly(dA:dT), SB9200, RGT100 and hiltonol.
  • Examples for cytosolic DNA sensors are cGAS agonists, dsDNA-EC, G3-YSD, HSV-60, ISD, ODN TTAGGG (A151), poly(dG:dC) and VACV-70.
  • Examples for STING are MK-1454, ADU-S100 (MIW815), 2’3’-cGAMP, 3’3’-cGAMP, c-di-AMP, c-di-GMP, cAIMP (CL592), cAIMP difluor (CL614), cAIM(PS) 2 difluor (Rp/Sp) (CL656), 2’2’-cGAMP, 2’3’-cGAM(PS)2 (Rp/Sp), 3 ‘ 3'-cGAM fluorinated, c-di-AMP fluorinated, 2’3'-c-di-AMP, 2’3’-c-di-AM(PS)2 (Rp,Rp), c-d
  • Examples for an aryl hydrocarbon receptor (AhR) are of FICZ, ITE and L-kynurenine.
  • Examples for a chemokine receptor and chemoattractant receptor agonist are CXC chemokine receptors, CC chemokine receptors, C chemokine receptors, CX3C chemokine receptors and chemoattractant receptors.
  • Examples for a CXC chemokine receptor are CXCR1 agonists, such as recombinant CXCL8 and recombinant CXCL6; CXCR2 agonists, such as recombinant CXCL8, recombinant CXCL1, recombinant CXCL2, recombinant CXCL3, recombinant CXCL5, recombinant CXCL6, MGTA 145 and SB251353; CXCR3 agonists, such as recombinant CXCL9, recombinant CXCL10, recombinant CXCL11 and recombinant CXCL4; CXCR4 agonists, such as recombinant CXCL12, ATI2341, CTCE0214, CTCE0324 and NNZ4921; CXCR5 agonists, such as recombinant CXCL13; CXCR6 agonists, such as recombinant CXCL16; and CXCL7
  • Examples for a CC chemokine receptor are CCR1 agonists, such as recombinant CCL3, ECI301, recombinant CCL4, recombinant CCL5, recombinant CCL6, recombinant CCL8, recombinant CCL9/10, recombinant CCL14, recombinant CCL15, recombinant CCL16, recombinant CCL23, PB103, PB105 and MPIF1; CCR2 agonists, such as recombinant CCL2, recombinant CCL8, recombinant CCL16, PB103 and PB105; CCR3 agonists, such as recombinant CCL11, recombinant CCL26, recombinant CCL7, recombinant CCL13, recombinant CCL15, recombinant CCL24, recombinant CCL5, recombinant CCL28 and recombinant CCL18;
  • C chemokine receptors are XCR1 agonist, such as recombinant XCL1 or recombinant XCL2.
  • CX3C chemokine receptors are CX3CR1 agonist, such as recombinant CX3CL1.
  • chemoattractant receptors examples include formyl peptide receptor agonists, such as N- formyl peptides, N-formylmethionine-leucyl-phenylalanine, enfuvirtide, T21/DP107, annexin Al, Ac2-26 and Ac9-25; C5a receptor agonists; and chemokine-like receptor 1 agonists, such as chemerin.
  • chemokine antagonists are inhibitors of CXCL chemokines, such as UNBS5162; inhibitors of CXCL8, such as BMS986253 and PA620; inhibitors of CXCL10, such as TM110, eldelumab and NI0801; inhibitors of CXCL12, such as NOX-A12 and JVS100; inhibitors of CXCL13, such as VX5; inhibitors of CCL2, such as PA508, ABN912, AF2838, BN83250, BN83470, C243, CGEN54, CNTO888, NOXE36, VT224 and SSR150106; inhibitors of CCL5, such as HGS1025 and NI0701; inhibitors of CCL2/CCL5, such as BKTP46; inhibitors of CCL5/FMLP receptor, such as RAP 160; inhibitors of CCL11, such as bertilimumab and RAP701; inhibitors of CCL5/CXCL4, such as CT2008 and CT2009; inhibitors of
  • chemokine receptor antagonists are inhibitors of CXCR1, such as repertaxin, CCX832, FX68 and KB03; inhibitors of CXCR2, such as AZD5069, AZD5122, AZD8309, GSK1325756, GSK1325756H, PS291822, SB332235 and SB656933; inhibitors of CXCR1/CXCR2, such as DF1970, DF2156A, DF2162, DF2755A, reparixin, SX576, SX682, PACG31P, AZD4721 and PA401; inhibitors of CXCR3; inhibitors of CXCR4, such as BL8040; inhibitors of CXCR4/E-selectin, such as GMI1359; inhibitors of CXCR6, such as CCX5224; inhibitors of CCR1, such as AZD4818, BAY865047, BMS817399, CCX354, CCX634, CCX9588, CP48
  • Examples for a cytokine receptor agonist are mRNAs, DNAs or plasmids encoding the genes for IL-2, IL-15, IL-7, IL-10, IL-12, IL-21, IFNa 1-17, IFNp, IFNy, IL-18, IL-27, TNFa, GM- CSF, FLT3L and TRAIL and recombinant proteins, such as agonists of IL-2/IL-15 b/g receptors, agonists of IL-10 receptor, agonists of IL-12 receptor, agonists of IL-18 receptor, agonists of IL-21 receptor, agonists of IL-7 receptor, agonists of IFNa/b receptor, agonists of IFN g receptor, agonists of FLT3 receptor and agonists of TNFa receptor.
  • Examples for agonists of IL-2/IL-15 b/g receptor are recombinant IL-2, recombinant IL-15, ALKS4230, ALT803, APN301, MDNA109, NKTR214, RG7461, RG7813, AM0015, NIZ985, NKTR255, RTX-212, SO-C101, XmAb24306, L19-IL2, THOR-707700 and PB101.
  • an agonist of IL-2 is as described in PCT/EP2019/057709, which is herewith incorporated by reference in its entirety.
  • the agonist of IL-2 is in certain embodiments a conjugate comprising an IL-2 protein of SEQ ID NO:l
  • n is about 113 or about 226; and wherein the nitrogen of the amine of the side chain of any one of the lysine residues, i.e. one of the lysine residues selected from the group consisting of the lysine residues at position 7, 8, 31, 34, 42, 47, 48, 53, 63, 75 and 96 of SEQ ID NO:l, is conjugated to a moiety of formula (3)
  • pi, p2, p3 and p4 are independently an integer ranging from 200 to 250.
  • sequence of the IL-2 protein varies by at least one amino acid from the sequence of SEQ ID NO:l, such as by one amino acid, by two amino acids, by three amino acids, by four amino acids or by five amino acids.
  • sequence of the IL-2 protein is of SEQ ID NO:2:
  • a non-TKI moiety -D is in certain embodiments a conjugate comprising an IL-2 protein of SEQ ID NO:2
  • n is about 113 or about 226; and wherein the nitrogen of the amine of the side chain of any one of the lysine residues, i.e. one of the lysine residues selected from the group consisting of the lysine residues at position 8, 9, 32, 35, 43, 48, 49, 54, 64, 76 and 97 of SEQ ID NO:2, is conjugated to a moiety of formula (3)
  • pi, p2, p3 and p4 are independently an integer ranging from 200 to 250.
  • n of formula (2) is 113. In certain embodiments n of formula (2) is 226. In certain embodiments pi, p2, p3 and p4 of formula (3) are independently an integer ranging from 220 to 240. In certain embodiments pi, p2, p3 and p4 of formula (3) are the same integer.
  • Examples for agonists of IL-10 receptor are AG011, dekavil, EG10, ILlONanocap, Ilodecakin, AM0010, tenovil and VT310 VIRON.
  • Examples for agonists of IL-12 receptor are AM0012, AS 1409, dodekin, HemaMax, LipoVIL12, MSB0010360N and NHS-IL12.
  • An example for an agonist of IL-18 receptor is SB485232.
  • An example for an agonist of IL-21 receptor is BMS982470 (denenicokin).
  • Examples for agonists of IL-7 receptor are CYT107, CYT99007 and GX-I7.
  • TNFa receptor examples include L19-TNFa, aurimune, beromun, BreMel/TNFa, fibromun, refnot and TNFPEG20.
  • Examples for death receptor agonists are TRAILR1/DR4 agonists, such as AMG951 (dulanermin), APG350, APG880, HGSETR1 (mapatumumab) and SL231; and
  • TRAILR2/DR5 agonists such as AMG655, DS8273, HGSETR2 (lexatumumab), HGSTR2J, IDD004/ GEN 1029, INBRX109, LBY135, MEDI3039, PRO95780, RG7386 and TAS266.
  • CD47 antagonists are ALX148, CC-90002, Hu5F9G4, SRF231, TI061, TTI- 621, TTI-622, A0176, IBI188, IMC002 and LYN00301.
  • SIRPa antagonist An example for a SIRPa antagonist is FSI89.
  • Examples for oncolytic drugs are CAVATAK, BCG, mobilan, TG4010, Pexa-Vec (JX-594), JX-900, JX-929 and JX-970.
  • Examples for signal converter proteins are Fnl4-TRAIL (KAHR101), CTLA4-FasL (KAHR102), PD1-41BBL (DSP 105), PD1-CD70 (DSP 106) and SIRPa-41BBL (DSP 107).
  • Examples for epigenetic modifiers are DNA methyltransferase inhibitors, lysine-specific demethylase 1 inhibitors, Zeste homolog 2 inhibitors, bromodomain and extra-terminal motif (BET) protein inhibitors such as GSK525762, and histone deacetylase (HDAC) inhibitors such as beleodaq, SNDX275 and CKD-M808.
  • BET bromodomain and extra-terminal motif
  • HDAC histone deacetylase
  • tumor peptides/vaccines examples include NY-ESO, WT1, MART-1, 10102 and PF- 06753512.
  • HSP heat shock protein
  • PF- 04929113 SNX-5422
  • proteolytic enzymes are recombinant hyaluronidase, such as rHuPH20 and PEGPH20.
  • ubiquitin and proteasome inhibitors examples include ubiquitin-specific protease (USP) inhibitors, such as P005091; 20S proteasome inhibitors, such as bortezimib, carfilzomib, ixazomib, oprozomib, delanzomib and celastrol; and immunoproteasome inhibitors, such as ONX-0914.
  • USP ubiquitin-specific protease
  • 20S proteasome inhibitors such as bortezimib, carfilzomib, ixazomib, oprozomib, delanzomib and celastrol
  • immunoproteasome inhibitors such as ONX-0914.
  • adhesion molecule antagonists examples include p2-intcgrin antagonists, such as imprime PGG; and selectin antagonists.
  • hormones are hormone receptor agonists and hormone receptor antagonists.
  • hormone receptor agonist examples include somatostatin receptor agonists, such as somatostatin, lanreotide, octreotide, FX125L, FX141L and FX87L.
  • hormone receptor antagonists are anti-androgens, anti-estrogens and anti- progestogens.
  • anti-androgens are steroidal antiandrogens, such as cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, oxendolone and osaterone acetate; nonsteroidal anti-androgens, such as flutamide, bicalutamide, nilutamide, topilutamide, enzalutamide and apalutamide; androgen synthesis inhibitors, such as ketoconazole, abiraterone acetate, seviteronel, aminoglutethimide, finasteride, dutasteride, epristeride and alfatradiol.
  • anti-estrogens examples include selective estrogen receptor modulators (SERMs), such as tamoxifen, clomifene, Fareston and raloxifene; ER silent antagonists and selective estrogen receptor degrader (SERD), such as fulvestrant; aromatase inhibitors, such as anastrozole, letrozole, exemestane, vorozole, formestane and fadrozole; and anti-gonadotropins, such as testosterone, progestogens and GnRH analogues.
  • SERMs selective estrogen receptor modulators
  • SESD selective estrogen receptor degrader
  • aromatase inhibitors such as anastrozole, letrozole, exemestane, vorozole, formestane and fadrozole
  • anti-gonadotropins such as testosterone, progestogens and GnRH analogues.
  • anti-progestogens examples are mifepristone, lilopristone and on
  • such cytotoxic or chemotherapeutic agents are selected from the group consisting of alkylating agents, anti-metabolites, anti-microtubule agents, topoisomerase inhibitors, cytotoxic antibiotics, auristatins, enediynes, lexitropsins, duocarmycins, cyclopropylpyrroloindoles, puromycin, dolastatins, maytansine derivatives, alkylsufonates, triazenes and piperazine.
  • the alkylating agent is in certain embodiments selected from the group consisting of nitrogen mustards, such as mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan; nitrosoureas, such as N-nitroso-N-methylurea, carmustine, lomustine, semustine, fotemustine and streptozotocin; tetrazines, such as dacarbazine, mitozolomide and temozolomide; ethylenimines, such as altretamine; aziridines, such as thiotepa, mitomycin and diaziquone; cisplatin and derivatives, such as cisplatin, carboplatin, oxaliplatin; and non- classical alkylating agents, such as procarbazine and hexamethylmelamine.
  • nitrogen mustards such as mechlorethamine, cyclophosphamide, mel
  • the anti-metabolite is in certain embodiments selected from the group consisting of anti folates, such as methotrexate and pemetrexed; fluoropyrimidines, such as fluorouracil and capecitabine; deoxynucleoside analogues, such as cytarabine, gemcitabine, decitabine, azacytidine, fludarabine, nelarabine, cladribine, clofarabine and pentostatin; and thiopurines, such as thioguanine and mercaptopurine.
  • anti folates such as methotrexate and pemetrexed
  • fluoropyrimidines such as fluorouracil and capecitabine
  • deoxynucleoside analogues such as cytarabine, gemcitabine, decitabine, azacytidine, fludarabine, nelarabine, cladribine, clofarabine and pentostatin
  • the anti-microtubule agent is in certain embodiments selected from the group consisting of Vinca alkaloids, such as vincristine, vinblastine, vinorelbine, vindesine and vinflunine; taxanes, such as paclitaxel and docetaxel; podophyllotoxins and derivatives, such as podophyllotoxin, etoposide and teniposide; stilbenoid phenol and derivatives, such as zybrestat (CA4P); and BNC105.
  • Vinca alkaloids such as vincristine, vinblastine, vinorelbine, vindesine and vinflunine
  • taxanes such as paclitaxel and docetaxel
  • podophyllotoxins and derivatives such as podophyllotoxin, etoposide and teniposide
  • stilbenoid phenol and derivatives such as zybrestat (CA4P)
  • BNC105 BNC105.
  • the topoisomerase inhibitor is in certain embodiments selected from the group consisting of topoisomerase I inhibitors, such as irinotecan, topotecan and camptothecin; and topoisomerase II inhibitors, such as etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, merbarone and aclarubicin.
  • topoisomerase I inhibitors such as irinotecan, topotecan and camptothecin
  • topoisomerase II inhibitors such as etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, merbarone and aclarubicin.
  • the cytotoxic antibiotic is in certain embodiments selected from the group consisting of anthracyclines, such as doxorubicin, daunorubicin, epirubicin and idarubicin; pirarubicin, aclarubicin, bleomycin, mitomycin C, mitoxantrone, actinomycin, dactinomycin, adriamycin, mithramycin and tirapazamine.
  • anthracyclines such as doxorubicin, daunorubicin, epirubicin and idarubicin
  • pirarubicin aclarubicin
  • bleomycin mitomycin C
  • mitoxantrone actinomycin
  • actinomycin actinomycin
  • dactinomycin dactinomycin
  • adriamycin mithramycin and tirapazamine.
  • the auristatin is in certain embodiments selected from the group consisting of monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF).
  • MMAE monomethyl auristatin E
  • MMAF monomethyl auristatin F
  • the enediyne is in certain embodiments selected from the group consisting of neocarzinostatin, lidamycin (C-1027), calicheamicins, esperamicins, dynemicins and golfomycin A.
  • the maytansine derivative is in certain embodiments selected from the group consisting of ansamitocin, mertansine (emtansine, DM1) and ravtansine (soravtansine, DM4).
  • the immune checkpoint inhibitor or antagonist is in certain embodiments selected from the group consisting of inhibitors of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), such as ipilimumab, tremelimumab, MK-1308, FPT155, PRS010, BMS-986249, BPI-002, CBT509, JS007, ONC392, TE1254, IBI310, BR02001, CG0161, KN044, PBI5D3H5, BCD145, ADU 1604, AGEN1884, AGEN1181, CS1002 and CP675206; inhibitors of PD-1 (programmed death 1), such as pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS- 936559, cemiplimab and PDR001; inhibitors of PD-L1 (programmed cell death protein 1), such as MDX-1105, MED 14736, atezolizumab, a
  • the immune agonist is in certain embodiments selected from the group consisting of agonists of CD27, such as recombinant CD70, such as HERA-CD27L, and varlilumab (CDX-1127); agonists of CD28, such as recombinant CD80, recombinant CD86, TGN1412 and FPT155; agonists of CD40, such as recombinant CD40L, CP-870,893, dacetuzumab (SGN-40), Chi Lob 7/4, ADC-1013 and CDX1140; agonists of 4-1BB (CD137), such as recombinant 4- 1BBL, urelumab, utomilumab and ATOR-1017; agonists of 0X40, such as recombinant OX40L, MEDI0562, GSK3174998, MOXR0916 and PF-04548600; agonists of GITR, such as recombinant GITRL, TRX518,
  • the multi-specific drug is in certain embodiments selected from the group consisting of biologies and small molecule immune checkpoint inhibitors.
  • biologies are multi-specific immune checkpoint inhibitors, such as CD137/HER2 lipocalin, PD1/LAG3, FS 118, XmAb22841 and XmAb20717; and multi-specific immune agonists.
  • Such multi specific immune agonists may be selected from the group consisting of Ig superfamily agonists, such as ALPN-202; TNF superfamily agonists, such as ATOR-1015, ATOR-1144, ALG.APV-527, lipocalin/PRS-343, PRS344/ONC0055, FAP-CD40 DARPin, MP0310 DARPin, FAP-0X40 DARPin, EGFR-CD40 DARPin, EGFR41BB/CD137 DARPin, EGFR- 0X40/DARFPin, HER2-CD40 DARPin, HER2-41BB/CD137 DARPin, HER2-0X40 DARPin, FIBRONECTIN ED-B-CD40 DARPin, FIBRONECTIN ED-B-41BB/CD137 and FIBRONECTIN ED-B-0X40 DARPin; CD3 multispecific agonists, such as blinatumomab, solit
  • Such immune checkpoint inhibitor or antagonist is in certain embodiments selected from the group consisting of inhibitors of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), such as ipilimumab, tremelimumab, MK-1308, FPT155, PRS010, BMS-986249, BPI-002, CBT509, JS007, ONC392, TE1254, IBI310, BR02001, CG0161, KN044, PBI5D3H5, BCD145, ADU 1604, AGEN1884, AGEN1181, CS1002 and CP675206; inhibitors of PD-1 (programmed death 1), such as pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS- 936559, cemiplimab and PDR001; inhibitors of PD-L1 (programmed cell death protein 1), such as MDX-1105, MED 14736, atezolizumab, a
  • said one or more further drug is an inhibitor of PD-1. In certain embodiments said one or more further drug is an inhibitor of PD-L1.
  • the water-insoluble controlled-release TKI compound comprises at least one TKI drug non-covalently embedded in the water-insoluble controlled-release TKI compound. In certain embodiments the water-insoluble controlled-release TKI compound comprises at least one TKI moiety covalently and reversibly conjugated to another moiety.
  • the water-insoluble controlled-release TKI compound is selected from the group consisting of crystals, nanoparticles, microparticles, nanospheres, microspheres, particles with a diameter larger than about 1 mm and continuous gels.
  • the water-insoluble controlled-release TKI compound is a crystal.
  • the water-insoluble controlled-release TKI compound is a nanoparticle, such as a nanoparticle with an average diameter ranging from 5 to 800 nm, a nanoparticle with an average diameter ranging from 10 to 600 nm or a nanoparticle with an average diameter ranging from 20 to 500 nm.
  • the water-insoluble controlled-release TKI compound is a microparticle, such as microparticle with an average diameter ranging from 10 to 950 pm, such as a microparticle with an average diameter ranging from 20 to 500 pm, such as a microparticle with an average diameter ranging from 25 to 250 pm, such as a microparticle with an average diameter ranging from 30 to 250 pm or a microparticle with a n average diameter ranging from 35 to 150 pm.
  • the water-insoluble controlled- release TKI compound is a nanosphere, such as a nanosphere with an average diameter ranging from 5 to 800 nm, a nanosphere with an average diameter ranging from 10 to 600 nm or a nanosphere with an average diameter ranging from 20 to 500 nm.
  • the water-insoluble controlled-release TKI compound is a microsphere, such as microsphere with an average diameter ranging from 10 to 700 pm, such as a microsphere with an average diameter ranging from 20 to 500 pm, such as a microsphere with an average diameter ranging from 25 to 250 pm, such as a microsphere with an average diameter ranging from 30 to 250 pm or a microsphere with a n average diameter ranging from 35 to 150 pm.
  • the water-insoluble controlled-release TKI compound is a particle with an average diameter larger than about 1 mm, such as with an average diameter of at least 2 mm, with an average diameter of at least 4 mm or with an average diameter of at least 5 mm. In certain embodiments the water-insoluble controlled-release TKI compound is a continuous gel.
  • the water-insoluble controlled-release TKI compound is a vesicle comprising at least one TKI moiety or TKI drug, such as a micelle, liposome or polymersome. In one embodiment the water-insoluble controlled-release TKI compound is a micelle comprising at least one TKI moiety or TKI drug.
  • the water-insoluble controlled-release TKI compound is a liposome comprising at least one TKI moiety or TKI drug, such as a liposome selected from the group consisting of aquasomes; non-ionic surfactant vesicles, such as niosomes and proniosomes; cationic liposomes, such as LeciPlex; transfersomes; ethosomes; ufasomes; sphingosomes; and pharmacosomes.
  • the water-insoluble controlled-release TKI compound is a polymersome comprising at least one TKI moiety or TKI drug.
  • the water-insoluble controlled-release TKI compound comprises at least one TKI drug non-covalently embedded in a water-insoluble polymer.
  • a water-insoluble polymer comprises a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethacryloxide
  • the water-insoluble controlled-release TKI compound is a poly(lactic- co-glycolic acid) (PLGA) crystal comprising at least one TKI drug non-covalently embedded in said PLGA crystal.
  • PLGA poly(lactic- co-glycolic acid)
  • the water-insoluble controlled-release TKI compound comprises at least one TKI moiety covalently and reversibly conjugated to a water-insoluble polymer.
  • such water-insoluble polymer comprises a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly
  • the water-insoluble controlled-release TKI compound comprises at least one TKI moiety covalently and reversibly conjugated to a hydrogel.
  • a plurality of TKI moieties is covalently conjugated to such hydrogel.
  • such hydrogel comprises a polymer selected from the group consisting of 2-methacryloyl- oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates),
  • the hydrogel is a PEG-based or hyaluronic acid-based hydrogel. In certain embodiments the hydrogel is a PEG-based hydrogel. In certain embodiments the hydrogel is a hyaluronic acid-based hydrogel.
  • Such hydrogel may be degradable or non- degradable, i.e. stable. In certain embodiments such hydrogel is degradable. In certain embodiments such hydrogel is non-degradable.
  • such water-insoluble controlled-release TKI compound is a conjugate or a pharmaceutically acceptable salt thereof, wherein said conjugate comprises at least one
  • TKI moiety -D covalently conjugated via at least one moiety -L'-L 2 - to a polymeric moiety Z, wherein -L - is covalently and reversibly conjugated to -D and -L - is covalently conjugated to Z and wherein -L 1 - is a linker moiety and -L 2 - is a chemical bond or a spacer moiety.
  • a plurality of moieties -D is covalently conjugated to Z. It is understood that each moiety -D is covalently conjugated via at least one moiety -L -L - to a polymeric moiety Z.
  • -D is selected from the group consisting of receptor tyrosine kinase inhibitors, intracellular kinase inhibitors, cyclin dependent kinase inhibitors, phosphoinositide-3-kinase (PI3K) inhibitors, mitogen-activated protein kinase inhibitors, inhibitors of nuclear factor kappa-b kinase (IKK), and Wee-1 inhibitors.
  • receptor tyrosine kinase inhibitors intracellular kinase inhibitors
  • cyclin dependent kinase inhibitors cyclin dependent kinase inhibitors
  • PI3K phosphoinositide-3-kinase
  • IKK nuclear factor kappa-b kinase
  • -D is a receptor tyrosine kinase inhibitor.
  • receptor tyrosine kinase inhibitors are EGF receptor inhibitors, VEGF receptor inhibitors, C-KIT Receptor inhibitors, ERBB2 (HER2) inhibitors, ERBB3 receptor inhibitors, FGF receptor inhibitors, AXE receptor inhibitors and MET receptor inhibitors.
  • -D is an EGF receptor inhibitor, such as afatinib, cetuximab, erlotinib, gefitinib, pertuzumab and margetuximab.
  • -D is a VEGF receptor inhibitor, such as axitinib, lenvatinib, pegaptanib and linifanib (ABT-869). In certain embodiments -D is axitinib. In certain embodiments -D is lenvatinib.
  • -D is a C-KIT Receptor inhibitor such as CDX0158 (KTN0158).
  • -D is an ERBB2 (HER2) inhibitor, such as herceptin (trastuzumab).
  • -D is an ERBB3 receptor inhibitor, such as CDX3379 (MEDI3379, KTN3379) and AZD8931 (sapitinib).
  • -D is an FGF receptor inhibitor such as erdafitinib.
  • -D is an AXL receptor inhibitor such as BGB324 (BGB 324, R 428, R428, bemcentinib) and SLC391.
  • -D is a MET receptor inhibitor, such as CGEN241 or tivantinib. In certain embodiments -D is tivantinib.
  • -D is an intracellular kinase inhibitor.
  • intracellular kinase inhibitors are Bruton’s tyrosine kinase (BTK) inhibitors, spleen tyrosine kinase inhibitors, Bcr-Abl tyrosine kinase inhibitors, Janus kinase inhibitors and multi-specific tyrosine kinase inhibitors.
  • BTK ton’s tyrosine kinase
  • spleen tyrosine kinase inhibitors spleen tyrosine kinase inhibitors
  • Bcr-Abl tyrosine kinase inhibitors Janus kinase inhibitors
  • multi-specific tyrosine kinase inhibitors multi-specific tyrosine kinase inhibitors.
  • -D is a BTK inhibitor, such as ibrutinib, acalabrutinib, GS-4059, spebrutinib, BGB-3111, HM71224, zanubrutinib, ARQ531, BI-BTK1 and vecabrutinib.
  • BTK inhibitor such as ibrutinib, acalabrutinib, GS-4059, spebrutinib, BGB-3111, HM71224, zanubrutinib, ARQ531, BI-BTK1 and vecabrutinib.
  • -D is a spleen tyrosine kinase inhibitor, such as fostamatinib.
  • -D is a Bcr-Abl tyrosine kinase inhibitor, such as imatinib and nilotinib.
  • -D is a Janus kinase inhibitor, such as ruxolitinib, tofacitinib and fedratinib.
  • -D is a multi-specific tyrosine kinase inhibitor, such as bosutinib, crizotinib, cabozantinib, dasatinib, entrectinib, lapatinib, mubritinib, pazopanib, sorafenib, sunitinib, SU6656 and vandetanib.
  • -D is crizotinib.
  • -D is cabozantinib which is an inhibitor of c-Met, VEGFR2, AXL and RET.
  • -D is a cyclin dependent kinase inhibitor.
  • cyclin dependent kinase inhibitors are copanlisib, ribociclib, palbociclib, abemaciclib, trilaciclib, purvalanol A, olomucine II and MK-7965.
  • -D is copanlisib.
  • -D is a phophoinositide-3-kinase inhibitor.
  • phophoinositide-3 -kinase inhibitors are IPI549, GDc-0326, pictilisib, serabelisib, IC-87114, AMG319, seletalisib, idealisib and CUDC907.
  • -D is a mitogen-activated protein kinase inhibitor.
  • mitogen-activated protein kinase inhibitors are Ras/famesyl transferase inhibitors, Raf inhibitors, MEK inhibitors and ERK inhibitors.
  • -D is a Ras/famesyl transferase inhibitor, such as tipirafinib and LB42708.
  • -D is a Raf inhibitor, such as regorafenib, encorafenib, vemurafenib, dabrafenib, sorafenib, PLX-4720, GDC-0879, AZ628, lifirafenib, PLX7904 and R05126766.
  • Raf inhibitor such as regorafenib, encorafenib, vemurafenib, dabrafenib, sorafenib, PLX-4720, GDC-0879, AZ628, lifirafenib, PLX7904 and R05126766.
  • -D is a MEK inhibitor, such as cobimetinib, trametinib, binimetinib, selumetinib, pimasertib, refametinib and PD0325901.
  • -D or drag is cobimetinib.
  • -D is an ERK inhibitor, such as MK-8353, GDC-0994, ulixertinib and SCH772984.
  • -D is an inhibitors of nuclear factor IKK. Examples for inhibitors of nuclear factor kappa-b kinase (IKK) are BPI-003 and AS602868.
  • -D is a Wee-1 inhibitor.
  • An example of a Wee-1 inhibitor is adavosertib.
  • all moieties -D of a water-insoluble controlled-release TKI compound are identical. It is understood that this does not exclude the occurrence of changes in the chemical structure of individual TKI drug molecules or TKI moieties due to for example molecular rearrangements or degradation, as may for example occur during storage.
  • the water-insoluble controlled-release TKI compound comprises more than one type of -D, i.e. two or more different types of -D, such as two different types of -D, three different types of -D, four different types of -D or five different types of -D.
  • all -D may be connected to the same type of -L 1 - or may be connected to different types of -L 1 -, i.e. a first type of -D may be connected to a first type of -L 1 -, a second type of -D may be connected to a second type of -L 1 - and so on.
  • Using different types of -L 1 - may in certain embodiments allow different release kinetics for different types of -D, such as for example a faster release for a first type of -D, a medium release for a second type of -D and a slow release for a third type of -D.
  • the conjugates of the present invention comprise one type of -L 1 -. In certain embodiments the conjugates of the present invention comprise two types of -L 1 -. In certain embodiments the conjugates of the present invention comprise three types of -L 1 -. In certain embodiments the conjugates of the present invention comprise four types of -L 1 -. In certain embodiments the conjugates of the present invention comprise five types of -L 1 -.
  • the conjugates of the present invention comprise one type of -D and one type of -L 1 -. In certain embodiments the conjugates of the present invention comprise two types of -D and two types of -L 1 -. In certain embodiments the conjugates of the present invention comprise three types of -D and three types of -L 1 -. In certain embodiments the conjugates of the present invention comprise four types of -D and four types of -L 1 -. In certain embodiments the conjugates of the present invention comprise two types of -D and one type of -L 1 -. In certain embodiments the conjugates of the present invention comprise three types of -D and one or two types of -L 1 -.
  • At least 10% of all moieties -D of the water-insoluble controlled- release TKI compound are axitinib, such as at least 20% of all moieties -D, such as at least 30% of all moieties -D, such as at least 40% of all moieties -D, such as at least 50% of all moieties -D, such as at least 60% of all moieties -D, such as at least 70% of all moieties -D, such as at least 80% of all moieties -D, such as at least 90% of all moieties -D.
  • all moieties -D of the water-insoluble controlled-release TKI compound are axitinib.
  • At least 10% of all moieties -D of the water-insoluble controlled- release TKI compound are lenvatinib, such as at least 20% of all moieties -D, such as at least 30% of all moieties -D, such as at least 40% of all moieties -D, such as at least 50% of all moieties -D, such as at least 60% of all moieties -D, such as at least 70% of all moieties -D, such as at least 80% of all moieties -D, such as at least 90% of all moieties -D.
  • all moieties -D of the water-insoluble controlled-release TKI compound are lenvatinib.
  • At least 10% of all moieties -D of the water-insoluble controlled- release TKI compound are cobimetinib, such as at least 20% of all moieties -D, such as at least 30% of all moieties -D, such as at least 40% of all moieties -D, such as at least 50% of all moieties -D, such as at least 60% of all moieties -D, such as at least 70% of all moieties -D, such as at least 80% of all moieties -D, such as at least 90% of all moieties -D.
  • all moieties -D of the water-insoluble controlled-release TKI compound are cobimetinib.
  • At least 10% of all moieties -D of the water-insoluble controlled- release TKI compound are crizotinib, such as at least 20% of all moieties -D, such as at least 30% of all moieties -D, such as at least 40% of all moieties -D, such as at least 50% of all moieties -D, such as at least 60% of all moieties -D, such as at least 70% of all moieties -D, such as at least 80% of all moieties -D, such as at least 90% of all moieties -D.
  • all moieties -D of the water-insoluble controlled-release TKI compound are crizotinib.
  • At least 10% of all moieties -D of the water-insoluble controlled- release TKI compound are tivantinib, such as at least 20% of all moieties -D, such as at least 30% of all moieties -D, such as at least 40% of all moieties -D, such as at least 50% of all moieties -D, such as at least 60% of all moieties -D, such as at least 70% of all moieties -D, such as at least 80% of all moieties -D, such as at least 90% of all moieties -D.
  • all moieties -D of the water-insoluble controlled-release TKI compound are tivantinib.
  • At least 10% of all moieties -D of the water-insoluble controlled- release TKI compound are copanlisib, such as at least 20% of all moieties -D, such as at least 30% of all moieties -D, such as at least 40% of all moieties -D, such as at least 50% of all moieties -D, such as at least 60% of all moieties -D, such as at least 70% of all moieties -D, such as at least 80% of all moieties -D, such as at least 90% of all moieties -D.
  • all moieties -D of the water-insoluble controlled-release TKI compound are copanlisib.
  • At least 10% of all moieties -D of the water-insoluble controlled- release TKI compound are cabozantinib, such as at least 20% of all moieties -D, such as at least 30% of all moieties -D, such as at least 40% of all moieties -D, such as at least 50% of all moieties -D, such as at least 60% of all moieties -D, such as at least 70% of all moieties -D, such as at least 80% of all moieties -D, such as at least 90% of all moieties -D.
  • all of moieties -D are cabozantinib of the water-insoluble controlled- release TKI compound.
  • the conjugate further comprises non-TKI moieties -D, i.e. the conjugate comprises at least one moiety -D in the form of a TKI moiety and one or more drug moieties -D of at least one different class of drugs, such that some of the moieties -D of the conjugate are TKI moieties as described above and in addition the conjugate comprises moieties -D that are from one or more different classes of drugs or non-TKI moieties.
  • these moieties -D in the form of a different class of drugs are selected from the group consisting of cytotoxic/chemotherapeutic agents, immune checkpoint inhibitors or antagonists, immune agonists, multi-specific drugs, antibody-drug conjugates (ADC), radionuclides or targeted radionuclide therapeutics, DNA damage repair inhibitors, tumor metabolism inhibitors, pattern recognition receptor agonists, chemokine and chemoattractant receptor agonists, chemokine or chemokine receptor antagonists, cytokine receptor agonists, death receptor agonists, CD47 or SIRPa antagonists, oncolytic drugs, signal converter proteins, epigenetic modifiers, tumor peptides or tumor vaccines, heat shock protein (HSP) inhibitors, proteolytic enzymes, ubiquitin and proteasome inhibitors, adhesion molecule antagonists, and hormones including hormone peptides and synthetic hormones.
  • ADC antibody-drug conjugates
  • the one or more non-TKI moieties -D are cytotoxic/chemotherapeutic agents. In certain embodiments the one or more non-TKI moieties -D are immune checkpoint inhibitors or antagonists. In certain embodiments the one or more non-TKI moieties -D are multi-specific drugs. In certain embodiments the one or more non-TKI moieties -D are antibody-drug conjugates (ADC). In certain embodiments the one or more non-TKI moieties -D are targeted radionuclide therapeutics. In certain embodiments the one or more non-TKI moieties -D are DNA damage repair inhibitors. In certain embodiments the one or more non-TKI moieties -D are tumor metabolism inhibitors.
  • the one or more non-TKI moieties -D are pattern recognition receptor agonists. In certain embodiments the one or more non-TKI moieties -D are chemokines and chemoattractant receptor agonists. In certain embodiments the one or more non-TKI moieties -D are chemokines or chemokine receptor antagonists. In certain embodiments the one or more non- TKI moieties -D are cytokine receptor agonists. In certain embodiments the one or more non- TKI moieties -D are death receptor agonists. In certain embodiments the one or more non- TKI moieties -D are CD47 antagonists.
  • the one or more non-TKI moieties -D are SIRPa antagonists. In certain embodiments the one or more non-TKI moieties -D are oncolytic drugs. In certain embodiments the one or more non-TKI moieties -D are signal converter proteins. In certain embodiments the one or more non-TKI moieties -D are epigenetic modifiers. In certain embodiments the one or more non-TKI moieties -D are tumor peptides or tumor vaccines. In certain embodiments the one or more non-TKI moieties -D are heat shock protein (HSP) inhibitors. In certain embodiments the one or more non-TKI moieties -D are proteolytic enzymes.
  • HSP heat shock protein
  • the one or more non-TKI moieties -D are ubiquitin and proteasome inhibitors. In certain embodiments the one or more non-TKI moieties -D are adhesion molecule antagonists. In certain embodiments the one or more non-TKI moieties -D are hormones including hormone peptides and synthetic hormones.
  • cytotoxic/chemotherapeutic agents examples include cytotoxic/chemotherapeutic agents, immune checkpoint inhibitors or antagonists, immune agonists, multi-specific drugs, antibody-drug conjugates (ADC), radionuclides or targeted radionuclide therapeutics, DNA damage repair inhibitors, tumor metabolism inhibitors, pattern recognition receptor agonists, chemokine and chemoattractant receptor agonists, chemokine or chemokine receptor antagonists, cytokine receptor agonists, death receptor agonists, CD47 or SIRPa antagonists, oncolytic drugs, signal converter proteins, epigenetic modifiers, tumor peptides or tumor vaccines, heat shock protein (HSP) inhibitors, proteolytic enzymes, ubiquitin and proteasome inhibitors, adhesion molecule antagonists, and hormones including hormone peptides and synthetic hormones are as described elsewhere herein.
  • ADC antibody-drug conjugates
  • the one or more non-TKI moieties -D are an inhibitor of PD-1. In certain embodiments the one or more non-TKI moieties -D are an inhibitor of PD-L1.
  • a moiety -L 1 - is conjugated to -D via a functional group of -D, which functional group is in certain embodiments selected from the group consisting of carboxylic acid, primary amine, secondary amine, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isothiocyanate, phosphoric acid, phosphonic acid, acryloyl, hydroxylamine, sulfate, vinyl sulfone, vinyl ketone, diazoalkane, guanidine, aziridine, amide, imide, imine, urea, amidine, guanidine, sulfonamide, phosphonamide, phosphoramide, hydrazide and selenol.
  • a functional group of -D which functional group is in certain embodiments selected from the group consisting of carboxylic acid, primary amine, secondary amine, thiol, sulfonic acid,
  • -L 1 - is conjugated to -D via a functional group of -D selected from the group consisting of carboxylic acid, primary amine, secondary amine, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isothiocyanate, phosphoric acid, phosphonic acid, acryloyl, hydroxylamine, sulfate, vinyl sulfone, vinyl ketone, diazoalkane, guanidine, amidine and aziridine.
  • -L 1 - is conjugated to -D via a functional group of -D selected from the group consisting of hydroxyl, primary amine, secondary amine, amidine and carboxylic acid.
  • -L 1 - is conjugated to -D via a hydroxyl group of -D. In certain embodiments -L 1 - is conjugated to -D via a primary amine group of -D.
  • -L 1 - is conjugated to -D via a secondary amine group of -D.
  • -L 1 - is conjugated to -D via a carboxylic acid group of -D.
  • -L 1 - is conjugated to -D via an amidine group of -D.
  • the moiety -L 1 - may be connected to -D through any type of linkage, provided that it is reversible.
  • -L 1 - is connected to -D through a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide, acylguanidine, acylamidine, carbonate, phosphate, sulfate, urea, hydrazide, thioester, thiophosphate, thiosulfate, sulfonamide, sulfoamidine, sulfaguanidine, phosphoramide, phosphoamidine, phosphoguanidine, phosphonamide, phosphonamidine, phosphonguanidine, phosphonate, borate and imide.
  • -L 1 - is connected to -D through a linkage selected from the group consisting of amide, ester, carbonate, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide, acylamidine and acylguanidine.
  • -L 1 - is connected to -D through a linkage selected from the group consisting of amide, ester, carbonate, acylamide and carbamate. It is understood that some of these linkages may not be reversible per se, but that in the present invention neighboring groups present in -L 1 - render these linkages reversible.
  • -L 1 - is connected to -D through an ester linkage.
  • -L 1 - is connected to -D through a carbonate linkage.
  • -L 1 - is connected to -D through an acylamidine linkage.
  • -L 1 - is connected to -D through a carbamate linkage.
  • -L 1 - is connected to -D through an amide linkage.
  • the moiety -L 1 - is a linker moiety from which -D is released in its free form, i.e. frequently in the form of D-H or D-OH.
  • Such moieties are also referred to as“prodrug linkers” or “reversible prodrug linkers” and are known in the art, such as for example the reversible linker moieties disclosed in WO 2005/099768 A2, WO 2006/136586 A2, WO 2011/089216 Al, WO 2013/024053 Al, WO 2011/012722 Al, WO 2011/089214 Al, WO 2011/089215 Al, WO 2013/024052 Al and WO 2013/160340 Al, which are incorporated by reference herewith.
  • the moiety -L 1 - is as disclosed in WO 2009/095479 A2. Accordingly, in certain embodiments the moiety -L 1 - is of formula (I):
  • -X- is selected from the group consisting of -C(R 4 R 4a )-, -N(R 4 )-, -0-, -C(R 4 R 4a )-C(R 5 R 5a )-, -C(R 5 R 5a )-C(R 4 R 4a )-, -C(R 4 R 4a )-N(R 6 )-,
  • X 1 is selected from the group consisting of C and S(O);
  • -X 2 - is selected from the group consisting of -C(R 8 R 8a )- and -C(R 8 R 8a )-C(R 9 R 9a )-;
  • -R 1 , -R la , -R 2 , -R 2a , -R 4 , -R 4a , -R 5 , -R 5a , -R 6 , -R 8 , -R 8a , -R 9 and -R 9a are independently selected from the group consisting of -H and Ci_ 6 alkyl;
  • -R 3 and -R 3a are independently selected from the group consisting of -H and C i alkyl, provided that in case one or both of -R 3 and -R 3a are other than -H they are connected to N to which they are attached through an sp -hybridized carbon atom;
  • -R 7a , -R 10 , -R 10a and -R 11 are independently selected from the group consisting of -H and Ci_ 6 alkyl;
  • one or more of the pairs -R la /-R 4a , -R la /-R 5a , -R la /-R 7a , -R 4a /-R 5a and -R 8a /-R 9a form a chemical bond;
  • one or more of the pairs -RV-R la , -R 2 /-R 2a , -R 4 /-R 4a , -R 5 /-R 5a , -R 8 /-R 8a and -R 9 /-R 9a are joined together with the atom to which they are attached to form a C3_io cycloalkyl or 3- to 10-membered heterocyclyl; alternatively, one or more of the pairs -RV-R 4 , -RV-R 5 , -RV-R 6 , -R’/-R 7a , -R 4 /-R 5 , -R 4 /-R 6 , -R 8 /-R 9 and -R 2 /-R 3 are joined together with the atoms to which they are attached to form a ring A;
  • R 3 /R 3a are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle
  • A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; C 3.10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; and
  • the ring comprises 3 to 10 atoms comprising at least one nitrogen
  • R # and R ## represent an sp 3 -hydridized carbon atom.
  • Exemplary embodiments of suitable 3- to 10-membered heterocycles formed by -R 3 /-R 3a of formula (I) together with the nitrogen atom to which they are attached are the following: wherein
  • -R is selected from the group consisting of -H and Ci_ 6 alkyl.
  • -L 1 - of formula (I) may optionally be further substituted.
  • any substituent may be used as far as the cleavage principle is not affected, i.e. the hydrogen marked with the asterisk in formula (I) is not replaced and the nitrogen of the moiety
  • -X- of formula (I) is -C(R 4 R 4a )-. In certain embodiments -X- of formula (I) is -N(R 4 ). In certain embodiments -X- of formula (I) is -0-. In certain embodiments -X- of formula (I) is C(R 4 R 4a )-C(R 5 R 5a )-. In certain embodiments -X- of formula (I) is -C(R 5 R 5a )-C(R 4 R 4a )-. In certain embodiments -X- of formula (I) is -C(R 4 R 4a )- N(R 6 )-.
  • -X- of formula (I) is -N(R 6 )-C(R 4 R 4a )-. In certain embodiments -X- of formula (I) is -C(R 4 R 4a )-0-. In certain embodiments -X- of formula (I) is - -0-C(R 4 R 4a )- In certain embodiments -X- of formula (I) is -0-C(R 4 R 4a )-. In certain embodiments -X- of formula (I) is -C(R 7 R 7a )-.
  • X 1 of formula (I) is C. In certain embodiments X 1 of formula (I) is S(O).
  • -R 1 of formula (I) is -H. In certain embodiments -R 1 of formula (I) is methyl. In certain embodiments -R 1 of formula (I) is ethyl. In certain embodiments -R la of formula (I) is -H. In certain embodiments -R la of formula (I) is methyl. In certain embodiments -R la of formula (I) is ethyl. In certain embodiments -R 2 of formula (I) is -H. In certain embodiments -R 2 of formula (I) is methyl. In certain embodiments -R 2 of formula (I) is ethyl. In certain embodiments -R 2a of formula (I) is -H.
  • -R 2a of formula (I) is methyl. In certain embodiments -R 2a of formula (I) is ethyl. In certain embodiments -R of formula (I) is -H. In certain embodiments -R of formula (I) is methyl. In certain embodiments -R 3 of formula (I) is ethyl. In certain embodiments -R 3a of formula (I) is -H. In certain embodiments -R 3a of formula (I) is methyl. In certain embodiments -R 3a of formula (I) is ethyl. In certain embodiments -R 4 of formula (I) is -H. In certain embodiments -R 4 of formula (I) is methyl.
  • -R 4 of formula (I) is ethyl. In certain embodiments -R 4a of formula (I) is -H. In certain embodiments -R 4a of formula (I) is methyl. In certain embodiments -R 4a of formula (I) is ethyl. In certain embodiments -R 5 of formula (I) is -H. In certain embodiments -R 5 of formula (I) is methyl. In certain embodiments -R 5 of formula (I) is ethyl. In certain embodiments -R 5a of formula (I) is -H. In certain embodiments -R 5a of formula (I) is methyl. In certain embodiments -R 5a of formula (I) is ethyl.
  • -R of formula (I) is methyl. In certain embodiments -R of formula (I) is ethyl. In certain embodiments -R of formula (I) is -H. In certain embodiments -R 8a of formula (I) is methyl. In certain embodiments -R 8a of formula (I) is ethyl. In certain embodiments -R 9 of formula (I) is -H. In certain embodiments -R 9 of formula (I) is methyl. In certain embodiments -R 9 of formula (I) is ethyl. In certain embodiments -R 9a of formula (I) is -H. In certain embodiments -R 9a of formula (I) is methyl.
  • -R 9a of formula (I) is ethyl. In certain embodiments -R 10 of formula (I) is -H. In certain embodiments -R 10 of formula (I) is methyl. In certain embodiments -R 10 of formula (I) is ethyl. In certain embodiments -R 10a of formula (I) is -H. In certain embodiments -R 10a of formula (I) is methyl. In certain embodiments -R 10a of formula (I) is ethyl. In certain embodiments -R n of formula (I) is -H. In certain embodiments -R 11 of formula (I) is methyl. In certain embodiments -R 11 of formula (I) is ethyl.
  • -R of formula (I) is -H, which -H is substituted with -L
  • -R la of formula (I) is -H, which -H is substituted with -L 2
  • -R 2 of formula (I) is -H, which -H is substituted with -L 2 ⁇
  • -R 2a of formula (I) is -H, which -H is substituted with -L 2 -
  • -R of formula (I) is -H, which -H is substituted with -L -
  • -R 3a of formula (I) is -H, which -H is substituted with -L 2 -
  • -R 4 of formula (I) is -H, which -H is substituted with -L 2 -
  • -R5 of formula (I) is -H, which -H is substituted with -L 2 In certain embodiments -R
  • -R 1 of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R la of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R of formula (I) is -H, which -H is substituted with -L
  • -R 2a of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R of formula (I) is -H, which -H is substituted with -L
  • -R 3a of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R of formula (I) is -H, which -H is substituted with -L
  • -R5 of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R 5a of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R 6 of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R 7 of formula (I) is -H, which -H is substituted with -L 2
  • -R 7a of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R of formula (I) is -H, which -H is substituted with -L
  • -R 8a of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R of formula (I) is -H, which -H is substituted with -L
  • -R 9a of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R 10 of formula (I) is -H, which -H is substituted with -L 2 -.
  • -R 11 of formula (I) is -H, which -H is substituted with -L 2 -.
  • the dashed line indicates attachment to a primary or secondary amine or hydroxyl of -D by forming an amide or ester linkage, respectively;
  • -R 4 , -R 5 and -R 5a are independently of each other selected from the group consisting of -H, -C(R 9 R 9a R 9b ) and -T;
  • al and a2 are independently of each other 0 or 1 ;
  • each -R 6 , -R 6a , -R 7 , -R 7a , -R 8 , -R 8a , -R 8b , -R 9 , -R 9a , -R 9b are independently of each other selected from the group consisting of -H, halogen, -CN, -COOR 10 , -OR 10 , -C(0)R 10 , -C(O)N(R 10 R 10a ), -S(O) 2 N(R 10 R 10a ), -S(O)N(R 10 R 10a ), -S(0) 2 R 10 , -S(0)R 10 , -N(R 10 )S(O) 2 N(R 10a R 10b ), -SR 10 , -N(R 10 R 10a ), -N0 2 , -OC(0)R 10 , -N(R 10 )C(O)R 10a , -N (R 1 °)
  • each -R 10 , -R 10a , -R 10b is independently selected from the group consisting of -H, -T, Ci_ 2 o alkyl, C 2-2 o alkenyl, and C 2-2 o alkynyl; wherein -T, Ci_ 2 o alkyl, C 2-2 o alkenyl, and C 2-2 o alkynyl are optionally substituted with one or more -R n , which are the same or different and wherein C i _?o alkyl, C 2.2 o alkenyl, and C 2.2 o alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(0)0-, -0-, -C(O)-, -C(0)N(R 12 )-, -S(0) 2 N(R 12 )-, -S(0)N(R 12 )-, -S(0) 2 -, -S(O)-, -
  • each T is independently of each other selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl; wherein each T is independently optionally substituted with one or more -R 11 , which are the same or different;
  • Ci_ 6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • each -R 12 , -R 12a , -R 13 , -R 13a , -R 13b is independently selected from the group consisting of -H, and Ci_ 6 alkyl; wherein C i _ f , alkyl is optionally substituted with one or more halogen, which are the same or different;
  • one or more of the pairs -RV-R la , -R 2 /-R 2a , -R 3 /-R 3a , -R 6 /-R 6a , -R 7 /-R 7a are joined together with the atom to which they are attached to form a C3.10 cycloalkyl or a 3- to 10-membered heterocyclyl;
  • A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; C3_io cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; and
  • the dashed line indicates attachment to -D through a functional group of -D selected from the group consisting of -OH, -SH and -NH2;
  • n 0 or 1 ;
  • -R 1 and -R 2 is/are independently of each other selected from the group consisting of -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(0)R 3 , -S(0)R 3 , -S(0) 2 R 3 , and -SR 4 ,
  • one and only one of -R 1 and -R 2 is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl;
  • -R is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 )2;
  • -R 4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted hetero arylalkyl;
  • each -R 5 is independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;
  • -R 9 is selected from the group consisting of -H and optionally substituted alkyl
  • -Y- is absent and -X- is -O- or -S-;
  • -Y- is -N(Q)CH2- and -X- is -O-;
  • Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;
  • -R 1 and -R 2 may be joined to form a 3 to 8-membered ring;
  • both -R 9 together with the nitrogen to which they are attached form a heterocyclic ring
  • alkyl as used herein includes linear, branched or cyclic saturated hydrocarbon groups of 1 to 8 carbon atoms, or in some embodiments 1 to 6 or 1 to 4 carbon atoms.
  • alkoxy includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar.
  • alkenyl includes non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds.
  • alkynyl includes non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds.
  • aryl includes aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl.
  • heteroaryl includes aromatic rings comprising 3 to 15 carbons containing at least one N, O or S atom, preferably 3 to 7 carbons containing at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar.
  • alkenyl, alkynyl, aryl or heteroaryl moieties may be coupled to the remainder of the molecule through an alkylene linkage.
  • the substituent will be referred to as alkenylalkyl, alkynylalkyl, arylalkyl or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl or heteroaryl is coupled.
  • halogen includes bromo, fluoro, chloro and iodo.
  • heterocyclic ring refers to a 4 to 8 membered aromatic or non-aromatic ring comprising 3 to 7 carbon atoms and at least one N, O, or S atom.
  • Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term“heteroaryl” above.
  • suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or an additional ring, each optionally further substituted.
  • Optional substituents on any group, including the above, include halo, nitro, cyano, -OR, -SR, -NR 2 , -OCOR, -NRCOR, -COOR, -CONR 2 , -SOR, -S0 2 R, -SONR 2 , -S0 2 N R 2 , wherein each R is independently alkyl, alkenyl, alkynyl, aryl or heteroaryl, or two R groups taken together with the atoms to which they are attached form a ring.
  • -R 1 is selected from the group consisting of optionally substituted Ci- , linear, branched, or cyclic alkyl; optionally substituted aryl; optionally substituted heteroaryl; alkoxy; and -NR 5 2;
  • -R 2 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;
  • -R is selected from the group consisting of -H; optionally substituted Ci-Ce alkyl; optionally substituted aryl; and optionally substituted heteroaryl;
  • -R 4 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; each -R 5 is independently of each other selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or when taken together two -R 5 can be cycloalkyl or cycloheteroalkyl; and
  • Alkyl “alkenyl”, and“alkynyl” include linear, branched or cyclic hydrocarbon groups of 1-8 carbons or 1-6 carbons or 1-4 carbons wherein alkyl is a saturated hydrocarbon, alkenyl includes one or more carbon-carbon double bonds and alkynyl includes one or more carbon- carbon triple bonds. Unless otherwise specified these contain 1-6 C.
  • Aryl includes aromatic hydrocarbon groups of 6-18 carbons, preferably 6-10 carbons, including groups such as phenyl, naphthyl, and anthracene“Heteroaryl” includes aromatic rings comprising 3-15 carbons containing at least one N, O or S atom, preferably 3-7 carbons containing at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiszolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar.
  • substituted means an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group comprising one or more substituent groups in place of one or more hydrogen atoms.
  • Substituents may generally be selected from halogen including F, Cl, Br, and I; lower alkyl including linear, branched, and cyclic; lower haloalkyl including fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; OH; lower alkoxy including linear, branched, and cyclic; SH; lower alkylthio including linear, branched and cyclic; amino, alkylamino, dialkylamino, silyl including alkylsilyl, alkoxysilyl, and arylsilyl; nitro; cyano; carbonyl; carboxylic acid, carboxylic ester, carboxylic amide, aminocarbonyl; aminoacyl; carbamate; urea;
  • the dashed line indicates attachment to -D through an amine functional group of -D;
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, aralkyl, halogen, nitro, -SO3H, -SO2NHR 5 , amino, ammonium, carboxyl, PO3H2, and OPO3H2;
  • R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
  • Suitable substituents for formulas (V) are alkyl (such as Ci_ 6 alkyl), alkenyl (such as C2-6 alkenyl), alkynyl (such as C2-6 alkynyl), aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (such as aromatic 4 to 7 membered heterocycle) or halogen moieties.
  • alkyl alkoxy
  • alkoxyalkyl aryl
  • alkaryl alkaryl
  • aralkyl mean alkyl radicals of 1-8, preferably 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl and butyl, and aryl radicals of 6-10 carbon atoms, e.g. phenyl and naphthyl.
  • halogen includes bromo, fluoro, chloro and iodo.
  • -L 1 - is as disclosed in W02002/089789A1, which is herewith incorporated by reference in its entirety. Accordingly, in certain embodiments -L 1 - is of formula (VI):
  • the dashed line indicates attachment to -D through an amine functional group of -D;
  • Li is a bifunctional linking group
  • Y l and Y2 are independently O, S or NR 7 ;
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, Ci_ 6 alkyls, C ⁇ -n branched alkyls, C3_8 cycloalkyls, Ci_ 6 substituted alkyls, C3.8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, Ci_6 heteroalkyls, substituted Ci_ 6 heteroalkyls, Ci_ 6 alkoxy, phenoxy, and Ci_ 6 heteroalkoxy;
  • Ar is a moiety which when included in formula (VI) forms a multisubstituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
  • X is a chemical bond or a moiety that is actively transported into a target cell, a hydrophobic moiety, or a combination thereof,
  • y is 0 or 1 ;
  • alkyl shall be understood to include, e.g. straight, branched, substituted C 2 alkyls, including alkoxy, C3_8 cycloalkyls or substituted cycloalkyls, etc.
  • substituted shall be understood to include adding or replacing one or more atoms contained within a functional group or compounds with one or more different atoms.
  • Substituted alkyls include carboxyalkyls, aminoalkyls, dialkylaminos, hydroxyalkyls and mercaptoalkyls; substtued cycloalkyls include moieties such as 4-chlorocyclohexyl; aryls include moieties such as napthyl; substituted aryls include moieties such as 3-bromo-phenyl; aralkyls include moieties such as toluyl; heteroalkyls include moieties such as ethylthiophene; substituted heteroalkyls include moieties such as 3-methoxythiophone; alkoxy includes moieities such as methoxy; and phenoxy includes moieties such as 3-nitrophenoxy.
  • Halo- shall be understood to include fluoro, chloro, iodo and bromo.
  • -L 1 - comprises a substructure of formula (VII)
  • the dashed line marked with the asterisk indicates attachment to a nitrogen of -D by forming an amide bond
  • the unmarked dashed lines indicate attachment to the remainder of -L 1 -; and wherein -L - is substituted with -L - and wherein -L - is optionally further substituted.
  • -L 1 - comprises a substructure of formula (VIII) wherein
  • the dashed line marked with the asterisk indicates attachment to a nitrogen of -D by forming a carbamate bond
  • the unmarked dashed lines indicate attachment to the remainder of -L 1 -; and wherein -L 1 - is substituted with -L 2 - and wherein -L 1 - is optionally further substituted.
  • -L 1 - is of formula (Vlll-a):
  • the dashed line marked with the asterisk indicates attachment to a nitrogen of -D and the unmarked dashed line indicates attachment to -L 2 -;
  • n 0, 1, 2, 3, or 4;
  • -Y 3 - is selected from the group consisting of -O- and -S-;
  • -Y 4 - is selected from the group consisting of -0-, -NR 5 - and -C(R 6 R 6a )-;
  • -R 3 , -R 5 , -R 6 , -R 6a are independently of each other selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,
  • -R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl;
  • -W- is selected from the group consisting of C1.20 alkyl optionally interrupted by one or more groups selected from the group consisting of C 3.10 cycloalkyl, 8- to 30-membered carbopolycyclyl, 3- to 10-membered heterocyclyl, -C(O)-, -C(0)N(R 7 )-, -0-, -S- and -N(R 7 )-;
  • -Nu is a nucleophile selected from the group consisting of -N(R 7 R 7a ), -N(R 7 OH), -N(R 7 )-N(R 7a R 7b ), -S(R 7 ),-COOH,
  • -Ar- is selected from the group consisting of
  • dashed lines indicate attachment to the remainder of -L 1 1 7
  • -Z - is selected from the group consisting of -O-, -S- and -N(R )-, and
  • -R 7 , -R 7a , -R 7b are independently of each other selected from the group consisting of -H, Ci - 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • the dashed line marked with the asterisk indicates attachment to a nitrogen of -D and the unmarked dashed line indicates attachment to -L 2 -;
  • n 0, 1 , 2, 3, or 4;
  • -Y 2 - is selected from the group consisting of -O- and -S-;
  • -Y 3 - is selected from the group consisting of -O- and -S-;
  • -Y 4 - is selected from the group consisting of -0-, -NR 5 - and -C(R 6 R 6a )-;
  • -R 2 , -R 3 , -R 5 , -R 6 , -R 6a are independently of each other selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,
  • -R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and
  • -W- is selected from the group consisting of C 1.20 alkyl optionally interrupted by one or more groups selected from the group consisting of C 3 _io cycloalkyl, 8- to 30-membered carbopolycyclyl, 3- to 10-membered heterocyclyl, -C(O)-, -C(0)N(R 7 )-, -O-, -S- and -N(R 7 )-;
  • -Nu is a nucleophile selected from the group consisting of -N(R 7 R 7a ), -N(R 7 OH), -N(R 7 )-N(R 7a R 7b ), -S(R 7 ), -COOH,
  • -Ar- is selected from the group consisting of
  • dashed lines indicate attachment to the remainder of -L 1 -
  • -Z - is selected from the group consisting of -0-, -S- and -N(R )-, and
  • -R 7 , -R 7a , -R 7b are independently of each other selected from the group consisting of -H, C i _ f , alkyl, C2-6 alkenyl and C2-6 alkynyl;
  • -L 1 - is optionally further substituted. In one embodiment -L 1 - of formula (Vlll-b) is not further substituted.
  • the dashed line indicates the attachment to the p-electron-pair-donating heteroaromatic N of -D;
  • n is an integer selected from the group consisting of 0, 1, 2, 3 and 4;
  • -X 2 - is selected from the group consisting of -0-, -S-, -N(R 5 )- and -C(R 6 )(R 6a )-;
  • Ci_ 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more -R , which are the same or different; and wherein C i _ f , alkyl, C 2.6 alkenyl and C 2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(0)0-, -0-, -C(O)-, -C(0)N(R 14 )-, -S(0) 2 N(R 14 )-,
  • -R 3 , -R 4 , -R 5 , -R 7 , -R 8 and -R 9 are independently selected from the group consisting of -H, -T, -CN, Ci_ 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl; wherein Ci_ 6 alkyl, C 2.6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more
  • C 2-6 alkenyl and C 2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(0)0-, -0-, -C(O)-, -C(0)N(R 14 )-, each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3.10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 1 1-membered heterobicyclyl; wherein each T is independently optionally substituted with one or more -R , which are the same or different;
  • -R is selected from the group consisting of -H, -NO2, -OCH3, -CN, -N(R 14 )(R 14a ), -OH, -C(0)0H and C, _ 6 alkyl; wherein Ci_ 6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • -R 14 and -R 14a are independently selected from the group consisting of -H and Ci_6 alkyl; wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different; optionally, one or more of the pairs -RV-R la , -R 2 /-R 2a , two adjacent -R 2 , -R 6 /- R 6a , -R 10 /-R 10a , -R u /-R lla , -R 12 /-R 12a and -R 3 /-R 9 are joined together with the atom to which they are attached to form a C3_io cycloalkyl, 3- to 10-membered heterocyclyl or an 8- to 1 1-membered heterobicyclyl;
  • one or more of the pairs -RV-R 2 , -RV-R 5 , -RV-R 6 , -RV-R 9 , -RV-R 10 , -R 2 /-R 5 , -R 3 /-R 6a , -R 4 /-R 5 , -RVR 6 , -R 5 /-R 10 , -R 6 /-R 10 and -R u /-R 12 are joined together with the atoms to which they are attached to form a ring -A-;
  • -A- is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3.10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl;
  • -R 1 and an adjacent -R 2 form a carbon-carbon double bond provided that n is selected from the group consisting of 1, 2, 3 and 4;
  • n is selected from the group consisting of 2, 3 and 4;
  • -X 2 - is -N(R 5 )-
  • -X 3 - is selected from the group consisting of the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) is 5, 6 or 7 atoms and if present the carbon-carbon double bond formed between -R 1 and -R2 or two adjacent -R 2 is in a cis configuration; and wherein -L 1 - is substituted with -L 2 - and wherein -L 1 - is optionally further substituted.
  • the dashed line indicates the attachment to a 7r-electron-pair-donating heteroaromatic N of -D;
  • n is an integer selected from the group consisting of 0, 1, 2, 3 and 4;
  • -X 2 - is selected from the group consisting of -0-, -S-, -N(R 5 )- and -C(R 6 )(R 6a )-;
  • Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more -R , which are the same or different; and wherein Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(0)0-, -0-, -C(O)-, -C(0)N(R 14 )-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -S(0) 2 -, -SCO)-,
  • -R 3 , -R 4 , -R 5 , -R 7 , -R 8 and -R 9 are independently selected from the group consisting of -H, -T, -CN, Ci- 6 alkyl, C2-6 alkenyl and C2-6 alkynyl; wherein C e alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more -R , which are the same or different; and wherein Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(0)0-, -0-, -C(O)-, -C(0)N(R 14 )-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -S(0) 2 -, -S(O)-, -N(R 14 )S(0) 2 N
  • each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl; wherein each T is independently optionally substituted with one or more -R , which are the same or different;
  • -R is selected from the group consisting of -H, -N0 2 , -OCH3, -CN, -N(R 14 )(R 14a ), -OH, -C(0)OH and Ci_6 alkyl; wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • -R 14 and -R 14a are independently selected from the group consisting of -H and Ci-6 alkyl; wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • R 2 , -R 6 /-R 6a , -R 10 /-R 10a , -R u /-R lla and -R 12 /-R 12a are joined together with the atom to which they are attached to form a C3.10 cycloalkyl, 3- to 10-membered heterocyclyl or an 8- to 1 1-membered heterobicyclyl;
  • one or more of the pairs -RV-R 2 , -RV-R 5 , -RV-R 6 , -RV-R 9 , -RV-R 10 , -R 3 /-R 6a , -R 4 /-R 5 , -R 4 /-R 6 , -R 5 /-R 10 , and -R 6 /-R 10 are joined together with the atoms to which they are attached to form a ring -A-;
  • -A- is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11- membered heterobicyclyl;
  • -R 1 and an adjacent -R 2 form a carbon-carbon double bond provided that n is selected from the group consisting of 1, 2, 3 and 4;
  • n is selected from the group consisting of 2, 3 and 4;
  • -X 2 - is -N(R 5 )-
  • -X 3 - is selected from the group consisting of the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IX) is 5, 6 or 7 atoms and if present the carbon-carbon double bond formed between -R 1 and -R or two adjacent -R is in a cis configuration; and wherein -L 1 - is substituted with -L 2 - and wherein -L 1 - is optionally further substituted.
  • the expression“distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk” refers to the total number of atoms in the shortest distance between the nitrogen and carbon atoms marked with the asterisk and also includes the nitrogen and carbon atoms marked with the asterisk.
  • n is 1 and the distance between the nitrogen marked with an asterisk and the carbon marked with an asterisk is 5:
  • n 2, -R 1 and -R la form a cyclohexyl and the distance between the nitrogen marked with an asterisk and the carbon marked with an asterisk is 6:
  • -X 2 - of formula (IXi) or (IX) is -0-. In certain embodiments -X 2 - of formula (IXi) or (IX) is -S-. In certain embodiments -X - of formula (IXi) or (IX) is -N(R )-. In certain embodiments, -X 2 - of formula (IXi) or (IX) is -C(R 6 )(R 6a )-. In certain embodiments -X - of formula
  • -X 3 - of formula (IXi) or (IX) is -C(R 10 )(R 10a )-. In certain embodiments -X 3 - of formula (IXi) or (IX) is -C(R u )(R lla )-C(R 12 )(R 12a )- . In certain embodiments -X - of formula (IXi) or (IX) is -0-. In certain embodiments -X - of formula (IXi) or (IX) is -0.
  • the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) or (IX) is 5 atoms.
  • the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) or (IX) is 6 atoms.
  • -X 2 - of formula the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) or (IX) is 7 atoms. In certain embodiments -X 2 - of formula the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) or (IX) is 5 atoms.
  • -X 2 - of formula (IXi) or (IX) is -N(R 5 )-, -X 3 - is O and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) or (IX) is 6 atoms.
  • -X 2 - of formula (IXi) or (IX) is -N(R 5 )-, -X 3 - is O and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) or (IX) is 7 atoms.
  • -X 2 - of formula (IXi) or (IX) is -N(R 5 )-, -X 3 - is H and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) or (IX) is 5 atoms.
  • -X 2 - of formula (IXi) or (IX) is -N(R 5 )-, -X 3 - is H and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) or (IX) is 6 atoms.
  • -X 2 - of formula (IXi) or (IX) is -N(R 5 )-, -X 3 - is H and the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (IXi) or (IX) is 7 atoms.
  • -X - of formula the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 5 atoms. In certain embodiments, -X 2 - of formula the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 6 atoms.
  • -X - of formula the distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk in formula (I) is 7 atoms.
  • -R 1 , -R la , -R 6 , -R 6a , -R 10 , -R 10a , -R n , -R l la , -R 12 , -R 12a and each of -R 2 and -R 2a of formula (IXi) or (IX) are independently selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, C i _ f , alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 1 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 1 of formula (IXi) or (IX) is selected from the group consisting of -H, - C(0)OH, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 1 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci _ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 1 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl. In certain embodiments -R 1 of formula (IXi) or (IX) is -H. In certain embodiments -R 1 of formula (IXi) or (IX) is -C(0)OH.
  • -R 1 of formula (IXi) or (IX) is halogen. In certain embodiments -R 1 of formula (IXi) or (IX) is -F. In certain embodiments -R 1 of formula (IXi) or (IX) is -CN. In certain embodiments -R 1 of formula (IXi) or (IX) is -OH. In certain embodiments -R 1 of formula (IXi) or (IX) is Ci_ 6 alkyl. In certain embodiments -R 1 of formula (IXi) or (IX) is C2-6 alkenyl. In certain embodiments -R 1 of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R 1 of formula (IXi) or (IX) is selected from the group consisting of - H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1- dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl.
  • -R’/-R la may optionally be joined together with the atom to which they are attached to form a C3.10 cycloalkyl and that one or more of the pairs -RV-R 2 , -RV-R 5 , -RV-R 6 , -RV-R 9 and -RV-R 10 may optionally be joined together with the atoms to which they are attached to form a ring -A-, wherein -A- is used as defined for formula (IXi) or (IX).
  • -R la of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R la of formula (IXi) or (IX) is selected from the group consisting of -H, - C(0)OH, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R la of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci _ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R la of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl.
  • -R la of formula (IXi) or (IX) is -H.
  • -R la of formula (IXi) or (IX) is -C(0)OH.
  • -R la of formula (IXi) or (IX) is halogen. In certain embodiments -R la of formula (IXi) or (IX) is -F. In certain embodiments -R la of formula (IXi) or (IX) is -CN. In certain embodiments -R la of formula (IXi) or (IX) is -OH. In certain embodiments -R la of formula (IXi) or (IX) is Ci_ 6 alkyl. In certain embodiments -R la of formula (IXi) or (IX) is C2-6 alkenyl. In certain embodiments -R la of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R la of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl.
  • -R 6 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 6 of formula (IXi) or (IX) is selected from the group consisting of -H, - C(0)OH, -CN, -OH, Ci _ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 6 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 6 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl. In certain embodiments -R 6 of formula (IXi) or (IX) is -H. In certain embodiments -R 6 of formula (IXi) or (IX) is -C(0)OH.
  • -R 6 of formula (IXi) or (IX) is halogen. In certain embodiments -R 6 of formula (IXi) or (IX) is -F. In certain embodiments -R 6 of formula (IXi) or (IX) is -CN. In certain embodiments -R 6 of formula (IXi) or (IX) is -OH. In certain embodiments -R 6 of formula (IXi) or (IX) is Ci_ 6 alkyl. In certain embodiments -R 6 of formula (IXi) or (IX) is C2-6 alkenyl. In certain embodiments -R 6 of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R 6 of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1 -methylbutyl and 1- ethylpropyl.
  • -R 6a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 6a of formula (IXi) or (IX) is selected from the group consisting of -H, - C(0)OH, -CN, -OH, Ci _ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 6a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 6a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl. In certain embodiments -R 6a of formula (IXi) or (IX) is -H. In certain embodiments -R 6a of formula (IXi) or (IX) is -C(0)OH.
  • -R 6a of formula (IXi) or (IX) is halogen. In certain embodiments -R 6a of formula (IX) is -F. In certain embodiments -R 6a of formula (IXi) or (IX) is -CN. In certain embodiments -R 6a of formula (IXi) or (IX) is -OH. In certain embodiments -R 6a of formula (IXi) or (IX) is Ci_ 6 alkyl. In certain embodiments -R 6a of formula (IXi) or (IX) is C2-6 alkenyl. In certain embodiments -R 6a of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R 6a of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,
  • -R 10 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 10 of formula (IXi) or (IX) is selected from the group consisting of -H, - C(0)OH, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 10 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 10 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl. In certain embodiments -R 10 of formula (IXi) or (IX) is -H. In certain embodiments -R 10 of formula (IXi) or (IX) is -C(0)OH.
  • -R 10 of formula (IXi) or (IX) is halogen. In certain embodiments -R 10 of formula (IXi) or (IX) is -F. In certain embodiments -R 10 of formula (IXi) or (IX) is -CN. In certain embodiments -R 10 of formula (IX) is -OH. In certain embodiments -R 10 of formula (IXi) or (IX) is Ci_ 6 alkyl. In certain embodiments -R 10 of formula (IXi) or (IX) is C2-6 alkenyl. In certain embodiments -R 10 of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R 10 of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1 -methylbutyl and 1- ethylpropyl.
  • -R 10a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 10a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 10a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci - 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 10a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl. In certain embodiments -R 10a of formula (IXi) or (IX) is -H. In certain embodiments -R 10a of formula (IXi) or (IX) is -C(0)OH.
  • -R 10a of formula (IXi) or (IX) is halogen. In certain embodiments -R 10a of formula (IXi) or (IX) is -F. In certain embodiments -R 10a of formula (IXi) or (IX) is -CN. In certain embodiments -R 10a of formula (IXi) or (IX) is -OH. In certain embodiments -R 10a of formula (IXi) or (IX) is Ci_ 6 alkyl. In certain embodiments -R 10a of formula (IXi) or (IX) is C2-6 alkenyl.
  • -R 10a of formula (IXi) or (IX) is C2-6 alkynyl. In certain embodiments -R 10a of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1 -methylbutyl and 1 -ethylpropyl.
  • -R 11 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R n of formula (IXi) or (IX) is selected from the group consisting of -H, - C(0)OH, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R n of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci _ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 11 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl.
  • -R 1 1 of formula (IXi) or (IX) is -H.
  • -R n of formula (IXi) or (IX) is -C(0)OH.
  • -R 11 of formula (IXi) or (IX) is halogen. In certain embodiments -R 11 of formula (IXi) or (IX) is -F. In certain embodiments -R 11 of formula (IXi) or (IX) is -CN. In certain embodiments -R 1 1 of formula (IXi) or (IX) is -OH. In certain embodiments -R n of formula (IXi) or (IX) is Ci_ 6 alkyl. In certain embodiments -R 11 of formula (IXi) or (IX) is C2-6 alkenyl. In certain embodiments -R 11 of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R 11 of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1 -methylbutyl and 1- ethylpropyl.
  • -R l la of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R l la of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -CN, -OH, Ci _ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R l la of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R l la of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl.
  • -R l la of formula (IXi) or (IX) is -H.
  • -R lla of formula (IXi) or (IX) is -C(0)OH.
  • -R l la of formula (IXi) or (IX) is halogen. In certain embodiments -R l la of formula (IXi) or (IX) is -F. In certain embodiments -R 1 la of formula (IXi) or (IX) is -CN. In certain embodiments -R 1 la of formula (IXi) or (IX) is -OH. In certain embodiments -R l la of formula (IXi) or (IX) is C ⁇ .e alkyl. In certain embodiments -R l la of formula (IXi) or (IX) is C2-6 alkenyl.
  • -R l la of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R Ua of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1 -methylbutyl and 1 -ethylpropyl.
  • -R 12 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 12 of formula (IXi) or (IX) is selected from the group consisting of -H, - C(0)OH, -CN, -OH, C I _ f , alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 12 of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl. In certain embodiments -R 12 of formula (IXi) or (IX) is -H. In certain embodiments -R 12 of formula (IXi) or (IX) is -C(0)OH.
  • -R of formula (IXi) or (IX) is halogen. In certain embodiments -R of formula (IXi) or (IX) is -F. In certain embodiments -R of formula (IXi) or (IX) is -CN. In certain embodiments -R 12 of formula (IX) is -OH. In certain embodiments -R 12 of formula (IXi) or (IX) is C ⁇ .e alkyl. In certain embodiments -R of formula (IXi) or (IX) is C2-6 alkenyl. In certain embodiments -R of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1 -methylbutyl and 1- ethylpropyl.
  • -R 12a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 12a of formula (IXi) or (IX) is selected from the group consisting of -H, - C(0)OH, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 12a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci _ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 12a of formula (IXi) or (IX) is selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl. In certain embodiments -R 12a of formula (IXi) or (IX) is -H. In certain embodiments -R 12a of formula (IXi) or (IX) is -C(0)OH.
  • -R 12a of formula (IXi) or (IX) is halogen. In certain embodiments -R 12a of formula (IXi) or (IX) is -F. In certain embodiments -R 12a of formula (IXi) or (IX) is -CN. In certain embodiments -R 12a of formula (IXi) or (IX) is -OH. In certain embodiments -R 12a of formula (IXi) or (IX) is Ci_ 6 alkyl. In certain embodiments -R 12a of formula (IXi) or (IX) is C2-6 alkenyl.
  • -R 12a of formula (IXi) or (IX) is C2-6 alkynyl. In certain embodiments -R 12a of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1 -ethylpropyl.
  • each of -R 2 of formula (IXi) or (IX) is independently selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • each of -R of formula (IXi) or (IX) is independently selected from the group consisting of -H, -C(0)OH, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2- 6 alkynyl.
  • each of -R 2 of formula (IXi) or (IX) is independently selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • each of -R of formula (IXi) or (IX) is independently selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl.
  • each of -R 2 of formula (IXi) or (IX) is -H.
  • each of -R 2 of formula (IXi) or (IX) is -C(0)OH.
  • each of -R of formula (IXi) or (IX) is halogen. In certain embodiments each of -R of formula (IXi) or (IX) is -F. In certain embodiments each of -R 2 of formula (IXi) or (IX) is -CN. In certain embodiments each of -R 2 of formula (IXi) or (IX) is -OH. In certain embodiments each of -R 2 of formula (IXi) or (IX) is Ci_ 6 alkyl. In certain embodiments each of -R of formula (IXi) or (IX) is C2-6 alkenyl.
  • each of -R 2 of formula (IXi) or (IX) is C2-6 alkynyl. In certain embodiments each of -R 2 of formula (IXi) or (IX) is selected from the group consisting of -H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1- dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1- ethylpropyl.
  • pairs -R 2 /-R 2a and two adjacent -R 2 may optionally be joined with the atom to which they are attached to form a C3.10 cycloalkyl and that the pair -R 2 /-R 5 may optionally be joined together with the atoms to which they are attached to form a ring -A-, wherein -A- is used as defined in formula (IX) or (IXi).
  • each of -R 2a of formula (IXi) or (IX) is independently selected from the group consisting of -H, -C(0)OH, halogen, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • each of -R 2a of formula (IXi) or (IX) is independently selected from the group consisting of -H, -C(0)OH, -CN, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2- 6 alkynyl.
  • each of -R 2a of formula (IXi) or (IX) is independently selected from the group consisting of -H, -C(0)OH, halogen, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • each of -R 2a of formula (IXi) or (IX) is independently selected from the group consisting of -H, -C(0)OH, -OH and Ci_ 6 alkyl.
  • each of -R 2a of formula (IXi) or (IX) is -H.
  • each of -R 2a of formula (IXi) or (IX) is -C(0)OH.
  • each of -R 2a of formula (IXi) or (IX) is halogen. In certain embodiments each of -R 2a of formula (IXi) or (IX) is -F. In certain embodiments each of -R 2a of formula (IXi) or (IX) is -CN. In certain embodiments each of - R 2a of formula (IXi) or (IX) is -OH. In certain embodiments each of -R 2a of formula (IXi) or (IX) is Ci- 6 alkyl. In certain embodiments each of -R 2a of formula (IXi) or (IX) is C2-6 alkenyl.
  • each of -R 2a of formula (IXi) or (IX) is C2-6 alkynyl. In certain embodiments each of -R 2a of formula (IXi) or (IX) is selected from the group consisting of - H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-methylbutyl and 1-ethylpropyl.
  • -R 3 , -R 4 , -R 5 , -R 7 , -R 8 and -R 9 of formula (IXi) or (IX) are independently selected from the group consisting of -H, -T, -CN, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 3 , -R 4 , -R 5 , -R 7 , -R 8 and -R 9 of formula (IXi) or (IX) are independently selected from the group consisting of -H, -T, -CN, Ci_ 6 alkyl and C2-6 alkenyl.
  • -R , -R , -R , -R , -R and -R of formula (IXi) or (IX) are independently selected from the group consisting of -H, -T, -CN and Ci_ 6 alkyl. In certain embodiments -R ,
  • -R 4 , -R 5 , -R 7 , -R 8 and -R 9 of formula (IXi) or (IX) are independently selected from the group consisting of -H, -T and Ci_ 6 alkyl.
  • -R , -R , -R , -R and -R of formula (IXi) or (IX) are independently selected from the group consisting of -H and Ci_ 6 alkyl.
  • -R of formula (IXi) or (IX) is selected from the group consisting of -H, -T, -CN, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R of formula (IXi) or (IX) is -H.
  • -R of formula (IXi) or (IX) is -T.
  • -R of formula (IXi) or (IX) is -CN.
  • -R of formula (IX) is Ci_ 6 alkyl.
  • -R of formula (IXi) or (IX) is C2-6 alkenyl.
  • -R of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R 4 of formula (IXi) or (IX) is selected from the group consisting of -H, -T, -CN, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R 4 of formula (IXi) or (IX) is -H. In certain embodiments -R 4 of formula (IXi) or (IX) is -T. In certain embodiments -R 4 of formula (IXi) or (IX) is -CN. In certain embodiments -R 4 of formula (IXi) or (IX) is Ci_6 alkyl. In certain embodiments -R 4 of formula (IXi) or (IX) is C 2-6 alkenyl. In certain embodiments -R 4 of formula (IXi) or (IX) is C2-6 alkynyl.
  • -R 5 of formula (IXi) or (IX) is selected from the group consisting of -H, -T, -CN, Ci _6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl.
  • -R 5 of formula (IXi) or (IX) is -H.
  • -R 5 of formula (IXi) or (IX) is -T.
  • -R 5 of formula (IXi) or (IX) is -CN.
  • -R 5 of formula (IXi) or (IX) is Ci_6 alkyl.
  • -R 5 of formula (IXi) or (IX) is C 2-6 alkenyl.
  • -R 5 of formula (IXi) or (IX) is C 2-6 alkynyl.
  • -R of formula (IXi) or (IX) is selected from the group consisting of -H, -T, -CN, Ci_6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl.
  • -R of formula (IXi) or (IX) is -H.
  • -R 7 of formula (IXi) or (IX) is -T.
  • -R 7 of formula (IXi) or (IX) is -CN.
  • -R 7 of formula (IXi) or (IX) is Ci_6 alkyl.
  • -R of formula (IXi) or (IX) is C 2-6 alkenyl.
  • -R of formula (IXi) or (IX) is C 2-6 alkynyl.
  • -R of formula (IXi) or (IX) is selected from the group consisting of -H, -T, -CN, Ci_6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl.
  • -R of formula (IXi) or (IX) is -H.
  • -R of formula (IXi) or (IX) is -T.
  • -R of formula (IXi) or (IX) is -CN.
  • -R of formula (IXi) or (IX) is Ci_6 alkyl.
  • -R of formula (IXi) or (IX) is C 2-6 alkenyl.
  • -R of formula (IXi) or (IX) is C 2-6 alkynyl.
  • -R 9 of formula (IXi) or (IX) is selected from the group consisting of -H, -T, -CN, Ci -6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl. In certain embodiments -R 9 of formula (IXi) or (IX) is -H. In certain embodiments -R 9 of formula (IXi) or (IX) is -T. In certain embodiments -R 9 of formula (IXi) or (IX) is -CN. In certain embodiments -R 9 of formula (IXi) or (IX) is Ci_6 alkyl.
  • -R 9 of formula (IXi) or (IX) is C 2-6 alkenyl. In certain embodiments -R 9 of formula (IXi) or (IX) is C 2-6 alkynyl. In certain embodiments T of formula (IXi) or (IX) is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl. In certain embodiments T of formula (IXi) or (IX) is phenyl.
  • T of formula (IXi) or (IX) is naphthyl. In certain embodiments T of formula (IXi) or (IX) is indenyl. In certain embodiments T of formula (IXi) or (IX) is indanyl. In certain embodiments T of formula (IXi) or (IX) is tetralinyl. In certain embodiments T of formula (IXi) or (IX) is C3.10 cycloalkyl. In certain embodiments T of formula (IXi) or (IX) is 3- to 10-membered heterocyclyl. In certain embodiments T of formula (IXi) or (IX) is 8- to 11-membered heterobicyclyl.
  • T of formula (IX) is substituted with one or more -R of formula (IXi) or (IX), which are the same or different.
  • T of formula (IX) is substituted with one -R of formula (IXi) or (IX).
  • T of formula (IX) is not substituted with -R of formula (IXi) or (IX).
  • -R of formula (IXi) or (IX) is selected from the group consisting of - H, -NO2, -OCH3, -CN, -N(R 14 )(R 14a ), -OH, -C(0)OH and Ci_ 6 alkyl.
  • -R of formula (IXi) or (IX) is -H. In certain embodiments -R of formula (IXi) or (IX) is -NO2. In certain embodiments -R 13 of formula (IXi) or (IX) is -OCH3.
  • -R of formula (IXi) or (IX) is -CN. In certain embodiments -R of formula (IXi) or (IX) is -N(R 14 )(R 14a ). In certain embodiments -R 13 of formula (IXi) or (IX) is -OH. In certain embodiments -R of formula (IXi) or (IX) is -C(0)OH. In certain embodiments -R of formula (IXi) or (IX) is C ⁇ . e alkyl.
  • -R 14 and -R 14a of formula (IXi) or (IX) are independently selected from the group consisting of -H and Ci_6 alkyl.
  • -R 14 of formula (IXi) or (IX) is -H.
  • -R 14 of formula (IXi) or (IX) is C ⁇ . e alkyl.
  • -R 14a of formula (IXi) or (IX) is -H.
  • -R 14a of formula (IXi) or (IX) is Ci_6 alkyl.
  • -R 3 /-R 9 of formula (IXi) are joined with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclyl.
  • -R /-R of formula (IXi) are joined with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocyclyl or an 8- to 11- membered heterobicyclyl, wherein the attachment of the 3- to 10-membered heterocyclyl or 8- to 11-membered heterobicyclyl to the rest of the linker moiety of formula (IXi) takes place via a sp 3 -hybridized nitrogen.
  • -R /-R of formula (IXi) are joined with the nitrogen atom to which they are attached to form a ring selected from the group consisting of aziridine, azetidine, pyrroline, imidazoline, pyrazoline, 4-thiazoline, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, piperazine, piperidine, morpholine, triazolidine, tetrazolidine, diazepane, homopiperazine, indoline, benzimidazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, decahydroisoquinoline, tetrahydroisoquinoline and dihydroisoquinoline.
  • Each hydrogen atom of such rings may be replaced by a substituent as defined above.
  • n of formula (IX) or (IX) is selected from the group consisting of 0, 1, 2 and 3. In certain embodiments n of formula (IX) or (IX) is selected from the group consisting of 0, 1 and 2. In certain embodiments n of formula (IX) or (IX) is selected from the group consisting of 0 and 1. In certain embodiments n of formula (IX) or (IX) is 0. In certain embodiments n of formula (IX) or (IX) is 1. In certain embodiments n of formula (IX) or (IX) is 2. In certain embodiments n of formula (IX) or (IX) is 3. In certain embodiments n of formula (IX) or (IX) is 4.
  • -L 1 - of formula (IX) or (IX) is connected to -D through a linkage selected from the group consisting of amide, carbamate, dithiocarbamate, O-thiocarbamate, S-thiocarbamate, urea, thiourea, thioamide, amidine and guanidine. It is understood that some of these linkages may not be reversible per se, but that in the present invention neighboring groups present in -L 1 -, such as for example amide, primary amine, secondary amine and tertiary amine, render these linkages reversible.
  • -L 1 - of formula (IX) or (IX) is conjugated to -D through a thiourea linkage
  • -L 1 - of formula (IX) or (IX) is conjugated to -D through a guanidine linkage
  • X of formula (IX) or (IX) 0 and -X - of formula (IX) or (IX) is -N(R 5 ) with -R 5 being ethyl.
  • x' of formula (IX) or (IX) 0, -X 2 - of formula (IX) or (IX) is -N(R 5 ) with -R 5 being ethyl and both -R 1 and -R la of formula (IX) or (IX) are -H.
  • n of formula (IX) or (IX) is 0 and -X 3 - of formula
  • the pair -RV-R la is joined together with the atom to which they are attached to form a C 3 _io cycloalkyl, 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclyl;
  • the pair -RV-R 5 is joined together with the atoms to which they are attached to form a 3- to 10-membered heterocyclyl or 8- to 11-membered heterobicyclyl.
  • -R 1 and -R la of formula (IX') are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
  • -RV-R la may optionally be joined together with the atom to which they are attached to form a C 3.10 cycloalkyl and that the paird -RV-R 5 may optionally be joined together with the atoms to which they are attached to form a 3- to 10-membered heterocyclyl or 8- to 11-membered heterobicyclyl.
  • -R 1 and -R la of formula (IX ') are both -H.
  • -R 1 of formula (DC) is -H and -R la of formula (DC) is Ci_6 alkyl.
  • -R 1 of formula (G) is -H and -R la of formula (G) is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
  • -R of formula (I X ' ) is Ci_6 alkyl. In certain embodiments -R is T. In certain embodiments -R of formula (DC) is C3_io cycloalkyl, such as C5- or O,-cycloalkyl.
  • -R 5 of formula (DC) is methyl.
  • -R 5 of formula (DC) is ethyl.
  • -R 5 of formula (IX') is -CH 3
  • -R 1 and -R la of formula (DC) are -H
  • -R 3 of formula (IX ') is -H which is replaced by one -L 2 -Z moiety.
  • -R 5 of formula (DC) is -CH 3
  • -R 1 of formula (DC) is -H
  • formula (IX ') is -CH 3 and -R of formula (DC) is -H which is replaced by one -L -Z moiety.
  • -R 5 of formula ( I X ' ) is ethyl
  • -R 1 and -R la of formula (IX ') are -H
  • -RV-R 5 of formula (DC) are joined together with the atoms to which they are attached to form a ring -A- as defined for formula (IXi) or (IX).
  • -RV-R 5 are joined together with the atoms to which they are attached to form a 3- to 10-membered heterocyclyl, such as a 5-membered heterocyclyl.
  • one or more of the pairs -R’/-R la , -R 2 /-R 2a , two adjacent -R 2 are joined together with the atom to which they are attached to form a C 3 _io cycloalkyl, 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclyl;
  • one or more of the pairs -RV-R 2 , -RV-R 5 , -R 2 /-R 5 and -R 4 /-R 5 are joined together with the atoms to which they are attached to form a ring -A-;
  • -A- is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3 _io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl; optionally, -R 1 and an adjacent -R 2 form a carbon-carbon double bond provided that n is selected from the group consisting of 1, 2, 3 and 4;
  • n is selected from the group consisting of 2, 3 and 4;
  • n of formula (IX") is 0. In certain embodiments, n of formula (IX") is 1. In certain embodiments, n of formula (IX") is 2.
  • -R 1 and -R la of formula (IX") are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
  • - R 1 /- R 1 may optionally be joined together with the atom to which they are attached to form a C 3.10 cycloalkyl and that one or more of the pairs -RV-R 2 and -RV-R 5 may optionally be joined together with the atoms to which they are attached to form a ring -A-, wherein -A- is used as defined for formula (IXi) or (IX).
  • -R 2 and -R 2a of formula (IX") are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
  • pairs -R 2 /-R 2a and two adjacent -R 2 may optionally be joined with the atom to which they are attached to form a C3_io cycloalkyl and that the pair -R /-R may optionally be joined together with the atoms to which they are attached to form a ring -A-, wherein -A- is used as defined in formula (IXi) or (IX).
  • -R 1 and -R la of formula (IX") are both -H.
  • -R 1 of formula (IX") is -H and -R la of formula (IX") is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3- methylpentyl,
  • -R of formula (IX) is C ⁇ .e alkyl.
  • -R 5 of formula (IX") is -H. In certain embodiments, -R 5 of formula (IX") is methyl. In certain embodiments, -R 5 of formula (IX") is ethyl.
  • -R 7 of formula (IX") is hydrogen. In certain embodiments, -R 7 of formula (IX") is methyl. In certain embodiments, -R 7 of formula (IX") is ethyl.
  • -L 1 - is of formula (IX'"): wherein the dashed line indicates the attachment to the 7r-electron-pair-donating heteroaromatic N of -D;
  • one or more of the pairs -R’/-R la , -R 2 /-R 2a , two adjacent -R 2 and -R /-R are joined together with the atom to which they are attached to form a C 3.10 cycloalkyl, 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclyl;
  • one or more of the pairs -RV-R 2 , -RV-R 5 , -R 2 /-R 5 and -R 4 /-R 5 are joined together with the atoms to which they are attached to form a ring -A-; wherein -A- is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3 _io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl;
  • -R 1 and an adjacent -R 2 form a carbon-carbon double bond provided that n is selected from the group consisting of 1, 2, and 3;
  • n is selected from the group consisting of 2, and 3;
  • n of formula (IX') is 1. In certain embodiments, n of formula (IX'") is 2. In certain embodiments, n of formula (IX'") is 3.
  • -R 1 and -R la of formula (IX'") are independently selected from the group consisting of -H and Ci_ 6 alkyl. In certain embodiments, -R 1 and -R la of formula (IX'") are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3- dimethylpropyl.
  • -R’/-R la may optionally be joined together with the atom to which they are attached to form a C3_io cycloalkyl and that one or more of the pairs -RV-R 5 , -RV-R 9 and -RV-R 10 may optionally be joined together with the atoms to which they are attached to form a ring -A-, wherein -A- is used as defined for formula (IXi) or (IX).
  • -R 1 and -R la of formula (IX'") are both -H.
  • -R 2 and -R 2a of formula (IX'") are independently selected from the group consisting of -H and Ci_ 6 alkyl. In certain embodiments, -R 2 and -R 2a of formula (IX'") are independently selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3- dimethylpropyl.
  • one or more of the pairs -R 2 /-R 2a and two adjacent -R may optionally be joined with the atom to which they are attached to form a C3_io cycloalkyl and that the pair -R 2 /-R 5 may optionally be joined together with the atoms to which they are attached to form a 3- to 10-membered heterocyclyl or 8- to 11-membered heterobicyclyl.
  • -R 2 and -R 2a of formula (IX'") are both -H.
  • -R of formula (IX') is H. In certain embodiments, -R of formula (IX'") is methyl.
  • -R 5 of formula (IX') is H. In certain embodiments, -R 5 of formula (IX'") is methyl.
  • -L 1 - is selected from the group consisting of
  • the dashed line marked with the asterisk indicates attachment to a p-electron-pair- donating heteroaromatic N of -D and the unmarked dashed line indicates attachment to -L 2 -.
  • -L 1 - is selected from the group consisting of (IX-a), (IX-k), (IX-m), (IX-q) and (IX-t).
  • -L 1 - is of formula (IX-a). In certain embodiments -L 1 - is of formula (IX-b). In certain embodiments -L 1 - is of formula (IX-c). In certain embodiments -L 1 - is of formula (IX-d). In certain embodiments -L 1 - is of formula (IX-e). In certain embodiments -L 1 - is of formula (IX-f). In certain embodiments -L 1 - is of formula (IX-g). In certain embodiments -L 1 - is of formula (IX-h). In certain embodiments -L 1 - is of formula (IX- i). In certain embodiments -L 1 - is of formula (IX-j).
  • -L 1 - is of formula (IX-k). In certain embodiments -L 1 - is of formula (IX-1). In certain embodiments -L 1 - is of formula (IX-m). In certain embodiments -L 1 - is of formula (IX-n). In certain embodiments -L 1 - is of formula (IX-o). In certain embodiments -L 1 - is of formula (IX-p). In certain embodiments -L 1 - is of formula (IX-q). In certain embodiments -L 1 - is of formula (IX- r). In certain embodiments -L 1 - is of formula (IX-s). In certain embodiments -L 1 - is of formula (IX-t).
  • the unmarked dashed line indicates the attachment to a 7r-electron-pair-donating heteroaromatic N of -D;
  • -Y- is selected from the group consisting of -N(R )-, -O- and -S-;
  • -R 1 , -R 2 and -R 3 are independently selected from the group consisting of -H, -T, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl; wherein Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more -R 4 , which are the same or different; and wherein Ci_ 6 alkyl, C alkenyl and C2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(0)0-, -0-, -C(O)-, -C(0)N(R 5 )-, -S(0) 2 N(R 5 )-, -S(0)N(R 5 )-, -S(0) 2 -, -Sic))-, -N(R 5 )S(0) 2 N(R 5a )-, -S-, -N(R 5 )-,
  • each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3.10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl, wherein each T is independently optionally substituted with one or more -R 4 , which are the same or different; wherein -R 4 , -R 5 and -R 5a are independently selected from the group consisting of -H and Ci_ 6 alkyl; wherein Ci_ 6 alkyl is optionally substituted with one or more halogen, which are the same or different; and
  • -Y- of formula (X) is -N(R )-.
  • -Y- of formula (X) is -0-.
  • -Y- of formula (X) is -S-.
  • -R 1 , -R 2 and -R 3 of formula (X) are independently selected from the group consisting of -H, -T, Ci_ 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl.
  • -R 1 of formula (X) is independently selected from the group consisting of -H, -T, Ci_ 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl. In certain embodiments -R 1 of formula (X) is -H. In certain embodiments -R 1 of formula (X) is -T. In certain embodiments -R 1 of formula (X) is Ci_ 6 alkyl. In certain embodiments -R 1 of formula (X) is C 2-6 alkenyl. In certain embodiments -R 1 of formula (X) is C 2-6 alkynyl.
  • -R 2 of formula (X) is independently selected from the group consisting of -H, -T, Ci_ 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl.
  • -R of formula (X) is -H.
  • -R of formula (X) is -T.
  • -R 2 of formula (X) is C ⁇ . e alkyl.
  • -R 2 of formula (X) is C 2-6 alkenyl.
  • -R 2 of formula (X) is C 2-6 alkynyl.
  • -R of formula (X) is independently selected from the group consisting of -H, -T, Ci_ 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl. In certain embodiments -R of formula (X) is -H. In certain embodiments -R of formula (X) is -T. In certain embodiments -R 3 of formula (X) is Ci_ 6 alkyl. In certain embodiments -R 3 of formula (X) is C2-6 alkenyl. In certain embodiments -R of formula (X) is C2-6 alkynyl.
  • T of formula (X) is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11- heterobicyclyl.
  • T of formula (X) is phenyl.
  • T of formula (X) is naphthyl.
  • T of formula (X) is indenyl.
  • T of formula (X) is indanyl.
  • T of formula (X) is tetralinyl.
  • T of formula (X) is C3_io cycloalkyl.
  • T of formula (X) is 3- to 10-membered heterocyclyl.
  • T of formula (X) is 8- to 11 -heterobicyclyl.
  • T of formula (X) is substituted with one or more -R 4 of formula (X).
  • T of formula (X) is substituted with one -R 4 of formula (X).
  • T of formula (X) is not substituted with -R 4 of formula (X).
  • -R 4 , -R 5 and -R 5a of formula (X) are independently selected from the group consisting of -H and Ci_ 6 alkyl.
  • -R 4 of formula (X) is selected from the group consisting of -H and Ci _ 6 alkyl. In certain embodiments -R 4 of formula (X) is -H. In certain embodiments -R 4 of formula (X) is Ci_ 6 alkyl.
  • -R 5 of formula (X) is selected from the group consisting of -H and Ci_ 6 alkyl. In certain embodiments -R 5 of formula (X) is -H. In certain embodiments -R 5 of formula (X) is Ci_ 6 alkyl.
  • -R 5a of formula (X) is selected from the group consisting of -H and Ci_ 6 alkyl. In certain embodiments -R 5a of formula (X) is -H. In certain embodiments -R 5a of formula (X) is Ci_ 6 alkyl.
  • -L 1 - of formula (X) is connected to -D through a heminal linkage. In certain embodiments -L 1 - of formula (X) is connected to -D through an aminal linkage.
  • -L 1 - of formula (X) is connected to -D through a hemithioaminal linkage.
  • -Y- of formula (X) is -O- and -R 2 is C i . (> alkyl.
  • -Y- of formula (X) is -O- and -R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
  • -Y- of formula (X) is -O- and -R of formula (X) is methyl. In certain embodiments, -Y- of formula (X) is -O- and -R 2 of formula (X) is ethyl.
  • -Y- of formula (X) is -O- and -R 2 of formula (X) is C i _ f , alkyl, wherein Ci_ 6 alkyl is interrupted by -C(O)-.
  • -Y- of formula (X) is -N(R )- and -R of formula (X) is Ci_ 6 alkyl, wherein C ⁇ .e alkyl is interrupted by -C(0)0- and -R is as defined in formula (X).
  • -Y- is -N(R 3 )- and -R 2 is Ci_ 6 alkyl, wherein Ci_ 6 alkyl is interrupted by -C(0)0- and -R is selected from the group consisting of -H, methyl, ethyl and propyl.
  • -L 1 - is of formula (Xi)
  • the dashed line marked with an asterisk indicates the attachment to -L 2 - and the unmarked dashed line indicates the attachment to the p-electron-pair-donating heteroaromatic N of -D;
  • -R v is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; and -R 1 is used as defined in formula (X).
  • -R v of formula (Xi) is selected from the group consisting of methyl, ethyl and propyl. In certain embodiments, -R v of formula (Xi) is methyl. In certain embodiments, -R v of formula (Xi) is ethyl. In certain embodiments, -R v of formula (Xi) is propyl.
  • -L 1 - is of formula (Xii)
  • the dashed line marked with an asterisk indicates the attachment to -L 2 - and the unmarked dashed line indicates the attachment to the p-electron-pair-donating heteroaromatic N of -D;
  • -R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
  • -R of formula (Xii) is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R of formula (Xii) is -H. In certain embodiments,
  • -R of formula (Xii) is methyl. In certain embodiments, -R of formula (Xii) is ethyl.
  • -R 1 of formula (Xii) is selected from the group consisting of methyl, ethyl and propyl. In certain embodiments, -R 1 of formula (Xii) is methyl. In certain embodiments, -R 1 of formula (Xii) is ethyl. In certain embodiments, -R 1 of formula (Xii) is propyl.
  • -L 1 - is of formula (Xiii) (Xiii),
  • the dashed line marked with an asterisk indicates the attachment to -L - and the unmarked dashed line indicates the attachment to the p-electron-pair-donating heteroaromatic N of -D;
  • -R z is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
  • -R z of formula (Xiii) is selected from the group consisting of methyl, ethyl and propyl. In certain embodiments, -R z of formula (Xiii) is methyl. In certain embodiments, -R z of formula (Xiii) is ethyl. In certain embodiments, -R z of formula (Xiii) is propyl.
  • a moiety -L 1 - suitable for drugs D that when bound to -L 1 - comprise an electron-donating heteroaromatic N + moiety or a quaternary ammonium cation and becomes a moiety -D + upon linkage with -L 1 - is of formula (XI)
  • the dashed line marked with an asterisk indicates the attachment to -L 2 -, the unmarked dashed line indicates the attachment to the N + of -D + ;
  • -Y # - is selected from the group consisting of -N(R #3 )-, -O- and -S-;
  • Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl are independently selected from the group consisting of -H, -T # , Ci - 6 alkyl, C2-6 alkenyl and C2-6 alkynyl; wherein Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more -R #4 , which are the same or different; and wherein Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T # -, -C(0)0-, -0-, -C(O)-, -C(0)N(R #5 )-, -S(0) 2 N(R #5 )-, -S(0)N(R #5 )-, -S(0) 2 -, -S(O)-, -N(R #5 )S(0) 2 N(R #5
  • each T # is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl, wherein each T # is independently optionally substituted with one or more -R #4 , which are the same or different; and
  • -R , -R and are independently selected from the group consisting of -H and Ci_ 6 alkyl; wherein C i _ f , alkyl is optionally substituted with one or more halogen, which are the same or different; and
  • each -L - is substituted with -L - and optionally further substituted.
  • -D + may comprise both an electron-donating heteroaromatic N + and a quaternary ammonium cation and analogously the corresponding D may comprise both an electron-donating hetero aromatic N and a tertiary amine. It is also understood that if D is conjugated to -L 1 -, then -D + and -L 1 - form a quaternary ammonium cation, for which there may be a counter anion.
  • counter anions include, but are not limited to, chloride, bromide, acetate, bicarbonate, sulfate, bisulfate, nitrate, carbonate, alkyl sulfonate, aryl sulfonate and phosphate.
  • Such drug moiety -D + comprises at least one, such as one, two, three, four, five, six, seven, eight, nine or ten electron-donating heteroaromatic N + or quaternary ammonium cations and analogously the corresponding released drug D comprises at least one, such as one, two, three, four, five, six, seven, eight, nine or ten electron-donating heteroaromatic N or tertiary amines.
  • Examples of chemical structures including heteroaromatic nitrogens i.e.
  • N + or N that donate an electron to the aromatic 7r-system include, but are not limited to, pyridine, pyridazine, pyrimidine, quinoline, quinazoline, quinoxaline, pyrazole, imidazole, isoindazole, indazole, purine, tetrazole, triazole and triazine.
  • pyridine pyridazine
  • pyrimidine quinoline
  • quinazoline quinoxaline
  • pyrazole imidazole
  • isoindazole indazole, purine, tetrazole, triazole and triazine.
  • the heteroaromatic nitrogen which donates one electron to the aromatic p-system is marked with
  • Such electron-donating heteroaromatic nitrogen atoms do not comprise heteroaromatic nitrogen atoms which donate one electron pair (i.e. not one electron) to the aromatic p-system, such as for example the nitrogen that is marked with“#” in the abovementioned imidazole ring structure.
  • the drug D may exist in one or more tautomeric forms, such as with one hydrogen atom moving between at least two heteroaromatic nitrogen atoms. In all such cases, the linker moiety is covalently and reversibly attached at a heteroaromatic nitrogen that donates an electron to the aromatic p-system.
  • -Y # - of formula (XI) is -N(R #3 )-. In certain embodiments -Y # - of formula (XI) is -0-. In certain embodiments -Y # - of formula (XI) is -S-.
  • -R , -R and -R of formula (XI) are independently selected from the group consisting of -H, -T # , Ci_ 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl.
  • -R #1 of formula (XI) is independently selected from the group consisting of -H, -T # , Ci_ 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl. In certain embodiments -R #1 of formula (XI) is -H. In certain embodiments -R #1 of formula (XI) is -T # . In certain embodiments -R #1 of formula (XI) is Ci_ 6 alkyl. In certain embodiments -R #1 of formula (XI) is C 2-6 alkenyl. In certain embodiments -R #1 of formula (XI) is C 2-6 alkynyl.
  • -R #2 of formula (XI) is independently selected from the group consisting of -H, -T # , Ci_ 6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl.
  • -R #2 of formula (XI) is -H.
  • -R 2 of formula (XI) is -T # .
  • -R #2 of formula (XI) is Ci_ 6 alkyl.
  • -R #2 of formula (XI) is C 2-6 alkenyl.
  • -R #2 of formula (XI) is C 2-6 alkynyl.
  • -R #3 of formula (XI) is independently selected from the group consisting of -H, -T # , C i _r, alkyl, C 2-6 alkenyl and C 2-6 alkynyl. In certain embodiments -R #3 of formula (XI) is -H. In certain embodiments -R #3 of formula (XI) is -T # . In certain embodiments, -R #3 is Ci_ 6 alkyl. In certain embodiments -R #3 of formula (XI) is C2-6 alkenyl. In certain embodiments -R #3 of formula (XI) is C2-6 alkynyl.
  • T # of formula (XI) is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11- heterobicyclyl.
  • T # of formula (XI) is phenyl.
  • T # of formula (XI) is naphthyl.
  • T # of formula (XI) is indenyl.
  • T # of formula (XI) is indanyl.
  • T # of formula (XI) is tetralinyl.
  • T # of formula (XI) is C3_io cycloalkyl. In certain embodiments T # of formula (XI) is 3- to 10-membered heterocyclyl. In certain embodiments T # of formula (XI) is 8- to 11 -heterobicyclyl. In certain embodiments T # of formula (XI) is substituted with one or more -R 4 of formula (XI).
  • T # of formula (XI) is substituted with one -R 4 of formula (XI).
  • T # of formula (XI) is not substituted with -R 4 of formula (XI).
  • -R , -R and -R of formula (XI) are independently selected from the group consisting of -H and Ci_ 6 alkyl.
  • -R #4 of formula (XI) is selected from the group consisting of -H and Ci_ 6 alkyl. In certain embodiments -R #4 of formula (XI) is -H. In certain embodiments -R #4 of formula (XI) is Ci_ 6 alkyl.
  • -R #5 of formula (XI) is selected from the group consisting of -H and Ci - 6 alkyl. In certain embodiments -R 5 of formula (XI) is -H. In certain embodiments -R #5 of formula (XI) is Ci_ 6 alkyl.
  • -R #5a of formula (XI) is selected from the group consisting of -H and Ci - 6 alkyl. In certain embodiments -R #5a of formula (XI) is -H. In certain embodiments -R #5a of formula (XI) is Ci_ 6 alkyl.
  • -Y # - of formula (XI) is -O- and -R #2 of formula (XI) is Ci_ 6 alkyl.
  • -Y # - of formula (XI) is -O- and -R #2 of formula (XI) is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
  • -Y* - of formula (XI) is -O- and -R #2 of formula (XI) is methyl. In certain embodiments, -Y*- of formula (XI) is -O- and -R #2 of formula (XI) is ethyl.
  • -Y # - of formula (XI) is -O- and -R #2 of formula (XI) is Ci_ 6 alkyl, wherein Ci_ 6 alkyl is interrupted by -C(O)-.
  • -Y # - of formula (XI) is -N(R 3 )- and -R #2 of formula (XI) is Ci_ 6 alkyl, wherein Ci_ 6 alkyl is interrupted by -C(0)0- and -R #3 is as defined in formula (XI).
  • -Y # - of formula (XI) is -N(R 3 )- and -R #2 of formula (XI) is C i _ f , alkyl, wherein Ci_ 6 alkyl is interrupted by -C(0)0- and -R #3 of formula (XI) is selected from the group consisting of -H, methyl, ethyl and propyl.
  • -L 1 - is of formula (Xli)
  • the dashed line marked with an asterisk indicates the attachment to -L 2 - and the unmarked dashed line indicates the attachment to the p-electron-pair-donating heteroaromatic N of -D;
  • -R #v is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
  • -R #v of formula (Xli) is selected from the group consisting of methyl, ethyl and propyl. In certain embodiments, -R #v of formula (Xli) is methyl. In certain embodiments, -R #v of formula (Xli) is ethyl. In certain embodiments, -R #v of formula (Xli) is propyl. In certain embodiments, -L 1 - of formula (Xlii)
  • the dashed line marked with an asterisk indicates the attachment to -L 2 - and the unmarked dashed line indicates the attachment to the p-electron-pair-donating heteroaromatic N of -D;
  • -R #t is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
  • -R #3 of formula (Xlii) is selected from the group consisting of -H, methyl and ethyl. In certain embodiments, -R #3 of formula (Xlii) is -H. In certain embodiments, -R #3 of formula (Xlii) is methyl. In certain embodiments, -R #3 of formula (Xlii) is ethyl.
  • -R #t of formula (Xlii) is selected from the group consisting of methyl, ethyl and propyl. In certain embodiments, -R #t of formula (Xlii) is methyl. In certain embodiments, -R #t of formula (Xlii) is ethyl. In certain embodiments, -R #t of formula (Xlii) is propyl.
  • -L 1 - is of formula (Xliii)
  • the dashed line marked with an asterisk indicates the attachment to - L 2 - and the unmarked dashed line indicates the attachment to the p-electron-pair-donating heteroaromatic N of -D;
  • -R #z is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
  • -R #z of formula (Xliii) is selected from the group consisting of methyl, ethyl and propyl. In certain embodiments, -R #z of formula (Xliii) is methyl. In certain embodiments, -R #z of formula (Xliii) is ethyl. In certain embodiments, -R #z of formula (Xliii) is propyl.
  • a moiety -L 1 - suitable for drugs D that when bound to -L 1 - comprise an electron-donating heteroaromatic N + moiety or a quaternary ammonium cation and becomes a moiety -D + upon linkage with -L 1 - is of formula (XII)
  • the dashed line indicates the attachment to the N + of -D + ;
  • t is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6;
  • -A- is a ring selected from the group consisting of monocyclic or bicyclic aryl and heteroaryl, provided that -A- is connected to -Y and -C(R 1 )(R la )- via carbon atoms; wherein said monocyclic or bicyclic aryl and heteroaryl are optionally substituted with one or more -R , which are the same or different;
  • -R 1 , -R la and each -R 2 are independently selected from the group consisting of -H, -C(0)0H, -halogen, -N ( 3 ⁇ 4, -CN, -OH, C i _ f , alkyl, C2-6 alkenyl and C2-6 alkynyl; wherein Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more -R , which are the same or different; and wherein Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(0)0-, -0-, -C(O)-, -C(0)N(R 4 )-, -S(0) 2 N(R 4 )-, -S(0)N(R 4 )-, -S(0) 2 -, -S(O)-, -N(
  • each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl, wherein each -T- is independently optionally substituted with one or more -R , which are the same or different;
  • -R is selected from the group consisting of -H, -NO2, -OCH3, -CN, -N(R 4 )(R 4a ), -OH, -C(0)OH and Ci_6 alkyl; wherein CY alkyl is optionally substituted with one or more halogen, which are the same or different;
  • -R 4 and -R 4a are independently selected from the group consisting of -H and CY alkyl; wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • -Y is selected from the group consisting of:
  • -Nu is a nucleophile
  • -Y 1 - is selected from the group consisting of -O-, -C(R 10 )(R 10a )-,
  • -Y - is selected from the group consisting of -O-, -S- and -N(R )-;
  • -E- is selected from the group consisting of Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and -Q-; wherein Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl are optionally substituted with one or more -R 14 , which are the same or different;
  • -R 14 , -R 15 and -R 15a are independently selected from the group consisting of -H and Ci_ 6 alkyl; wherein Ci_ 6 alkyl is optionally substituted with one or more halogen, which are the same or different; and each -L 1 - is substituted with -L 2 - and optionally further substituted.
  • -D + may comprise both an electron-donating heteroaromatic N + and a quaternary ammonium cation and analogously the corresponding D may comprise both an electron-donating hetero aromatic N and a tertiary amine. It is also understood that if D is conjugated to -L 1 -, then -D + and -L 1 - form a quaternary ammonium cation, for which there may be a counter anion.
  • counter anions include, but are not limited to, chloride, bromide, acetate, bicarbonate, sulfate, bisulfate, nitrate, carbonate, alkyl sulfonate, aryl sulfonate and phosphate.
  • Such drug moiety -D + comprises at least one, such as one, two, three, four, five, six, seven, eight, nine or ten electron-donating heteroaromatic N + or quaternary ammonium cations and analogously the corresponding released drug D comprises at least one, such as one, two, three, four, five, six, seven, eight, nine or ten electron-donating heteroaromatic N or tertiary amines.
  • Examples of chemical structures including heteroaromatic nitrogens i.e.
  • N + or N that donate an electron to the aromatic p- system include, but are not limited to, pyridine, pyridazine, pyrimidine, quinoline, quinazoline, quinoxaline, pyrazole, imidazole, isoindazole, indazole, purine, tetrazole, triazole and triazine.
  • pyridine pyridazine
  • pyrimidine quinoline
  • quinazoline quinoxaline
  • pyrazole imidazole
  • isoindazole indazole, purine, tetrazole, triazole and triazine.
  • the heteroaromatic nitrogen which donates one electron to the aromatic p-system is marked with
  • Such electron-donating heteroaromatic nitrogen atoms do not comprise heteroaromatic nitrogen atoms which donate one electron pair (i.e. not one electron) to the aromatic p- system, such as for example the nitrogen that is marked with“#” in the abovementioned imidazole ring structure.
  • the drug D may exist in one or more tautomeric forms, such as with one hydrogen atom moving between at least two heteroaromatic nitrogen atoms. In all such cases, the linker moiety is covalently and reversibly attached at a heteroaromatic nitrogen that donates an electron to the aromatic p-system.
  • the term“monocyclic or bicyclic aryl” means an aromatic hydrocarbon ring system which may be monocyclic or bicyclic, wherein the monocyclic aryl ring consists of at least 5 ring carbon atoms and may comprise up to 10 ring carbon atoms and wherein the bicylic aryl ring consists of at least 8 ring carbon atoms and may comprise up to 12 ring carbon atoms.
  • Each hydrogen atom of a monocyclic or bicyclic aryl may be replaced by a substituent as defined below.
  • the term“monocyclic or bicyclic heteroaryl” means a monocyclic aromatic ring system that may comprise 2 to 6 ring carbon atoms and 1 to 3 ring heteroatoms or a bicyclic aromatic ring system that may comprise 3 to 9 ring carbon atoms and 1 to 5 ring heteroatoms, such as nitrogen, oxygen and sulfur.
  • Examples for monocyclic or bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothiophenyl, furanyl, imidazolyl, indolyl, azaindolyl, azabenzimidazolyl, benzoxazolyl, benzthiazolyl, benzthiadiazolyl, benzotriazolyl, tetrazinyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, thiazolyl and thiophenyl.
  • Each hydrogen atom of a monocyclic or bicyclic heteroaryl may be replaced by a substituent as defined below.
  • nucleophile refers to a reagent or functional group that forms a bond to its reaction partner, i.e. the electrophile by donating both bonding electrons.
  • t of formula (XII) is 0. In certain embodiments t of formula (XII) is 1.
  • t of formula (XII) is 2. In certain embodiments t of formula (XII) is3.
  • t of formula (XII) is 4. In certain embodiments t of formula (XII) is 5.
  • t of formula (XII) is 6.
  • -A- of formula (XII) is a ring selected from the group consisting of monocyclic or bicyclic aryl and heteroaryl, provided that -A- is connected to -Y and - C ( R ' ) ( R 1 a ) - via carbon atoms.
  • -A- of formula (XII) is substituted with one or more -R of formula (XII) which are the same or different.
  • -A- of formula (XII) is not substituted with -R 2 of formula (XII).
  • -A- of formula (XII) is selected from the group consisting of:
  • each V is independently selected from the group consisting of O, S and N.
  • -R 1 , -R la and each -R 2 of formula (XII) are independently selected from the group consisting of -H, -C(0)0H, -halogen, -CN, -NO2, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 1 , -R la and each -R 2 of formula (XII) are independently selected from the group consisting of -H, -C(0)0H, -CN, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • -R 1 of formula (XII) is -H.
  • -R 1 of formula (XII) is -C(0)0H. In certain embodiments -R 1 of formula (XII) is -halogen. In certain embodiments -R 1 of formula (XII) is -F. In certain embodiments -R 1 of formula (XII) is -CN. In certain embodiments -R 1 of formula (XII) is -N(3 ⁇ 4. In certain embodiments -R 1 of formula (XII) is -OH. In certain embodiments -R 1 of formula (XII) is Ci_ 6 alkyl. In certain embodiments -R 1 of formula (XII) is C2-6 alkenyl.
  • -R 1 of formula (XII) is C2-6 alkynyl. In certain embodiments -R la of formula (XII) is -H. In certain embodiments -R la of formula (XII) is -C(0)0H. In certain embodiments -R la of formula (XII) is -halogen. In certain embodiments -R la of formula (XII) is -F. In certain embodiments -R la of formula (XII) is -CN. In certain embodiments -R la of formula (XII) is -NO2. In certain embodiments -R la of formula (XII) is -OH.
  • -R la of formula (XII) is Ci _ 6 alkyl. In certain embodiments -R la of formula (XII) is C2-6 alkenyl. In certain embodiments -R la of formula (XII) is C2-6 alkynyl.
  • each of -R of formula (XII) is independently selected from the group consisting of -H, -C(0)0H, -halogen, -CN, -NO2, -OH, Ci_ 6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
  • each of -R 2 of formula (XII) is -H.
  • each of -R of formula (XII) is -C(0)0H.
  • each of -R of formula (XII) is -halogen.
  • each of -R of formula (XII) is -F.
  • each of -R 2 of formula (XII) is -CN.
  • each of -R 2 of formula (XII) is -NO 2 . In certain embodiments each of -R of formula (XII) is -OH. In certain embodiments each of -R of formula (XII) is Ci_ 6 alkyl. In certain embodiments each of -R of formula (XII) is C2-6 alkenyl. In certain embodiments each of -R 2 of formula (XII) is C2-6 alkynyl.
  • T of formula (XII) is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3.10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl.
  • T of formula (XII) is phenyl.
  • T of formula (XII) is naphthyl.
  • T of formula (XII) is indenyl.
  • T of formula (XII) is indanyl.
  • T of formula (XII) is tetralinyl.
  • T of formula (XII) is C3.10 cycloalkyl. In certain embodiments T of formula (XII) is 3- to 10-membered heterocyclyl. In certain embodiments T of formula (XII) is 8- to 11-membered heterobicyclyl.
  • T of formula (XII) is substituted with one or more -R of formula (XII), which are the same or different. In certain embodiments T of formula (XII) is substituted with one -R of formula (XII). In certain embodiments T of formula (XII) is not substituted with -R of formula (XII).
  • -R of formula (XII) is selected from the group consisting of -H, -NO2, -OCH3, -CN, -N(R 4 )(R 4a ), -OH, -C(0)0H and Ci_6 alkyl.
  • -R 3 of formula (XII) is -H.
  • -R of formula (XII) is -NO2.
  • -R of formula (XII) is -OCH 3 .
  • -R of formula (XII) is -CN.
  • -R 3 of formula (XII) is -N(R 4 )(R 4a ).
  • -R 3 of formula (XII) is -OH. In certain embodiments -R of formula (XII) is -C(0)OH. In certain embodiments -R 3 of formula (XII) is Ci_ 6 alkyl. In certain embodiments -R 4 and -R 4a of formula (XII) are independently selected Ifom the group consisting of -H and Ci_ 6 alkyl. In certain embodiments -R 4 of formula (XII) is -H. In certain embodiments -R 4 is Ci_ 6 alkyl. In certain embodiments -R 4a of formula (XII) is -H. In certain embodiments -R 4a of formula (XII) is Ci_ 6 alkyl.
  • -Nu of formula (XII) is a nucleophile selected from the group consisting of primary, secondary, or tertiary amine and amide. In certain embodiments -Nu of formula (XII) is a primary amine. In certain embodiments -Nu of formula (XII) is a secondary amine. In certain embodiments -Nu of formula (XII) is a tertiary amine. In certain embodiments -Nu of formula (XII) is an amide. In certain embodiments -Y 1 - of formula (XII) is selected from the group consisting of -O-, -C(R 10 )(R 10a )-, -N(R U )- and -S-.
  • -Y - of formula (XII) is selected from the group consisting of -0-, -S- and -N(R 13 ). In certain embodiments -Y 3 - of formula (XII) is -0-. In certain embodiments -Y - of formula (XII) is -S-. In certain embodiments -Y - of formula (XII) is -N(R 13 )-.
  • -E- of formula (XII) is selected from the group consisting of Ci_ 6 alkyl, C2-6 alkenyl, C2-6 alkynyl and -Q-. In certain embodiments -E- of formula (XII) is Ci_ 6 alkyl. In certain embodiments -E- of formula (XII) is C2-6 alkenyl. In certain embodiments -E- of formula (XII) is C2-6 alkynyl. In certain embodiments -E- of formula (XII) is -Q-.
  • Q of formula (XII) is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl.
  • Q of formula (XII) is phenyl.
  • Q of formula (XII) is naphthyl.
  • Q of formula (XII) is indenyl.
  • Q of formula (XII) is indanyl.
  • Q of formula (XII) is tetralinyl.
  • Q of formula (XII) is C3_io cycloalkyl. In certain embodiments Q of formula (XII) is 3- to 10-membered heterocyclyl. In certain embodiments Q of formula (XII) is 8- to 11-membered heterobicyclyl. In certain embodiments Q of formula (XII) is substituted with one or more -R 14 . In certain embodiments Q of formula (XII) is not substituted with -R 14 .
  • each -R 7 , -R 8 , -R 9 , -R 10 , -R 10a , -R 11 , -R 12 and -R 13 of formula (XII) are independently selected from the group consisting of C1.20 alkyl, C2-20 alkenyl, C2-20 alkynyl and -Q.
  • -R 5 of formula (XII) is Ci_ 2 o alkyl.
  • -R 5 of formula (XII) is C 2-20 alkenyl.
  • -R 5 of formula (XII) is C 2-20 alkynyl.
  • -R 5 of formula (XII) is -Q.
  • -R 6 of formula (XII) is Ci_ 2 o alkyl. In certain embodiments -R 6 of formula (XII) is C 2-20 alkenyl. In certain embodiments -R 6 of formula (XII) is C 2-20 alkynyl. In certain embodiments -R 6 is -Q.
  • each of -R of formula (XII) is independently selected from the group consisting of C 1.20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl and -Q. In certain embodiments each of -R 7 of formula (XII) is C 1.20 alkyl. In certain embodiments each of -R 7 of formula (XII) is
  • each of -R of formula (XII) is C 2-20 alkenyl. In certain embodiments each of -R of formula (XII) is C 2-20 alkynyl. In certain embodiments each of -R of formula (XII) is -Q.
  • -R of formula (XII) is C 1.20 alkyl. In certain embodiments -R of formula (XII) is C 2-20 alkenyl. In certain embodiments -R of formula (XII) is C 2-20 alkynyl. In certain embodiments -R of formula (XII) is -Q.
  • -R 9 of formula (XII) is C 1.20 alkyl. In certain embodiments -R 9 of formula (XII) is C 2-20 alkenyl. In certain embodiments -R 9 of formula (XII) is C 2-20 alkynyl. In certain embodiments -R 9 of formula (XII) is -Q.
  • -R 10 of formula (XII) is C 1.20 alkyl. In certain embodiments -R 10 of formula (XII) is C 2-20 alkenyl. In certain embodiments -R 10 of formula (XII) is C 2-20 alkynyl. In certain embodiments -R 10 of formula (XII) is -Q.
  • -R 10a of formula (XII) is C 1.20 alkyl. In certain embodiments -R 10a of formula (XII) is C 2-20 alkenyl. In certain embodiments -R 10a of formula (XII) is C 2-20 alkynyl. In certain embodiments -R 10a of formula (XII) is -Q.
  • -R 1 1 of formula (XII) is C 1.20 alkyl. In certain embodiments -R 1 1 of formula (XII) is C 2-20 alkenyl. In certain embodiments -R 11 of formula (XII) is C 2-20 alkynyl. In certain embodiments -R 1 1 of formula (XII) is -Q. In certain embodiments -R 12 of formula (XII) is Ci_ 2 o alkyl. In certain embodiments -R 1 of formula (XII) is C 2-20 alkenyl. In certain embodiments -R 12 of formula (XII) is C 2-20 alkynyl.
  • -R 12 of formula (XII) is -Q.
  • -R of formula (XII) is Ci_ 2 o alkyl. In certain embodiments -R of formula (XII) is C 2-20 alkenyl. In certain embodiments -R of formula (XII) is C 2-20 alkynyl.
  • -R of formula (XII) is -Q.
  • -R 14 , -R 15 and -R 15a of formula (XII) are selected from the group consisting of -H and Ci_6 alkyl.
  • -R 14 of formula (XII) is -H. In certain embodiments -R 14 of formula (XII) is Ci_6 alkyl.
  • -R 15 of formula (XII) is -H. In certain embodiments -R 15 of formula (XII) is Ci_6 alkyl.
  • -R 15a of formula (XII) is -H. In certain embodiments -R 15a of formula (XII) is Ci-6 alkyl.
  • -Y of formula (XII) is , wherein -R 5 is as defined above and the dashed line marked with an asterisk indicates the attachment to -A-.
  • -Y of formula (XII) is , wherein -R 6 is as defined above and the dashed line marked with an asterisk indicates the attachment to -A-.
  • -R 6 of formula (XII) is of formula (Xlla):
  • -Y 4 - is selected from the group consisting of C3.10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl, which are optionally substituted with one or more -R which are the same or different;
  • -R 16 and -R 17 are independently selected from the group consisting of -H, CMO alkyl, C2-10 alkenyl and C2-10 alkynyl; wherein CM O alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally substituted with one or more -R which are the same or different; and wherein C O alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -A'-, -C(0)0-, -0-, -C(O)-,
  • each A' is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3.10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl, wherein each A' is independently optionally substituted with one or more -R which are the same or different;
  • -R 18 , -R 19 and -R 19a are independently selected from the group consisting of -H and CM alkyl; wherein CM alkyl is optionally substituted with one or more halogen, which are the same or different; and
  • -Y 4 - of formula (Xlla) is selected from the group consisting of C3.10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl. In certain embodiments -Y 4 - of formula (Xlla) is C3_io cycloalkyl. In certain embodiments -Y 4 - of formula (Xlla) is 3- to 10-membered heterocyclyl. In certain embodiments -Y 4 - of formula (Xlla) is 8- to 11-membered heterobicyclyl. In certain embodiments -Y 4 - of formula (Xlla) is substituted with one or more -R which are the same or different. In certain embodiments -Y 4 - of formula (Xlla) is not substituted with -R 18 .
  • -R 16 and -R 17 of formula (Xlla) are selected from the group consisting of CMO alkyl, C 2-i o alkenyl and C 2-i o alkynyl.
  • -R 16 of formula (Xlla) is Ci_io alkyl.
  • -R 16 of formula (Xlla) is C 2-10 alkenyl.
  • -R 16 of formula (Xlla) is C 2-10 alkynyl.
  • -R 17 of formula (Xlla) is Ci. 10 alkyl.
  • -R 17 of formula (Xlla) is C 2-10 alkenyl.
  • -R 17 of formula (Xlla) is C 2-10 alkynyl.
  • A' of formula (Xlla) is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3.10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 1 1-membered heterobicyclyl.
  • A' of formula (Xlla) is phenyl.
  • A' of formula (Xlla) is naphthyl.
  • A' of formula (Xlla) is indenyl.
  • A' of formula (Xlla) is indanyl.
  • A' of formula (Xlla) is tetralinyl.
  • A' of formula (Xlla) is C 3-10 cycloalkyl. In certain embodiments A' of formula (Xlla) is 3- to 10-membered heterocyclyl. In certain embodiments A' of formula (Xlla) is 8- to 1 1-membered heterobicyclyl.
  • A' of formula (Xlla) is substituted with one or more -R , which are the same or different. In certain embodiments A' of formula (Xlla) is not substituted with -R 18 .
  • -R 18 , -R 19 and -R 19a of formula (Xlla) are selected from the group consisting of -H and Ci_ 6 alkyl.
  • -R of formula (Xlla) is -H. In certain embodiments -R of formula (Xlla) is Ci _ 6 alkyl. In certain embodiments -R 19 of formula (Xlla) is -H. In certain embodiments -R 19 of formula (Xlla) is Ci_ 6 alkyl. In certain embodiments -R 19a of formula (Xlla) is -H. In certain embodiments -R 19a of formula (Xlla) is Ci_ 6 alkyl.
  • -R 6 of formula (XII) is of formula (Xllb): (Xllb),
  • -Y 5 - is selected from the group consisting of -Q'-, Ci_io alkyl, C 2-10 alkenyl and C 2-10 alkynyl; wherein CA - 10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl are optionally substituted with one or more -R , which are the same or different; and wherein C O alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -Q'-, -C(0)0-, -0-, -C(O)-, -C(0)N(R 24 )-, -S(0) 2 N(R 24 )-, -S(0)N(R 24 )-, -S(0) 2 -, -SCO)-, -N(R 24 )S(0) 2 N(R 24a )-, -S-, -N(R 24 )-, -OC(OR 24 )R 24
  • -R , -R , -R and -R are independently selected from the group consisting of -H, Ci- 10 alkyl, C 2 _io alkenyl and C 2 _io alkynyl; wherein Ci_io alkyl, C 2 _io alkenyl and C 2 _io alkynyl are optionally substituted with one or more -R which are the same or different; and wherein C MO alkyl, C 2 _io alkenyl and C 2 _io alkynyl are optionally interrupted by one or more groups selected from the group consisting of -Q'-,
  • each Q' is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3_io cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl, wherein each Q' is independently optionally substituted with one or more -R , which are the same or different;
  • -R 23 , -R 24 and -R 24a are independently selected from the group consisting of -H and C M alkyl; wherein C M alkyl is optionally substituted with one or more halogen, which are the same or different;
  • the pair -R 21 /-R 21a is joined together with the atoms to which is attached to form a C3_io cycloalkyl, 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclyl; and

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Abstract

La présente invention concerne un composé de type TKI à libération contrôlée et insoluble dans l'eau, destiné à être utilisé dans le traitement d'anomalies de la prolifération cellulaire et présentant les caractéristiques suivantes : ledit composé de type TKI à libération contrôlée et insoluble dans l'eau libère une ou plusieurs molécules à activité TKI ; lors de l'administration intra-tissulaire d'une dose unique du composé de type TKI à libération contrôlée et insoluble dans l'eau, une activité anti-tumorale est observée entre 7 et 21 jours après l'administration du composé de type TKI à libération contrôlée et insoluble dans l'eau ; et le changement de la pression artérielle moyenne mesurée en mmHg est de moins de 50 % du changement de la pression artérielle moyenne observée chez la même espèce animale traitée avec une dose équimolaire quotidienne du médicament de type TKI sous forme libre correspondant. L'invention concerne également des aspects associés.
PCT/EP2020/067160 2019-06-21 2020-06-19 Composés inhibiteurs de tyrosine kinases à libération contrôlée présentant des propriétés pharmacodynamiques localisées WO2020254612A1 (fr)

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