IL323019A - Compounds of drugs with an albumin binding moiety - Google Patents

Compounds of drugs with an albumin binding moiety

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Publication number
IL323019A
IL323019A IL323019A IL32301925A IL323019A IL 323019 A IL323019 A IL 323019A IL 323019 A IL323019 A IL 323019A IL 32301925 A IL32301925 A IL 32301925A IL 323019 A IL323019 A IL 323019A
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certain embodiments
formula
moiety
group
independently
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IL323019A
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Ascendis Pharma As
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A61K47/595—Polyamides, e.g. nylon
    • 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
    • A61K47/56—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
    • A61K47/61—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 the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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  • Pharmacology & Pharmacy (AREA)
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  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Description

WO 2024/184351 PCT/EP2024/055724 Compounds of drugs with an albumin binding moiety The present application relates to compounds or pharmaceutically acceptable salts thereof, wherein the compounds comprise at least one polymeric moiety, to which at least two drug moieties are covalently and reversibly conjugated, which drug moieties are conjugated to an albumin binding moiety. The application also relates to pharmaceutical composition comprising at least one such compound and their medical uses.
Whereas some classes of therapeutic proteins, including antibodies, have long inherent half- lives, many other molecules, particularly protein or peptide hormones are often susceptible to enzymatic degradation, renal clearance and/or rapid receptor-mediated clearance, which leads to a short plasma elimination half-life. Furthermore, due to the challenges associated with oral delivery, most peptide- or protein-based drugs require parenteral administration, which combined with a short half-life necessitates frequent injections, resulting in discomfort and inconvenience for the patient. This may negatively impact adherence and, ultimately, limit treatment efficacy and outcomes.
Injecting lipidated peptides has been demonstrated to have slower absorption from the subcutaneous tissue compared to the non-derivatized peptide as well as longer circulatory half- life due to reversible binding to albumin. The half-life of endogenous albumin in the circulation is approximately 3 weeks. This long half-life can be attributed both to its large molecular size, which minimizes renal clearance, as well as to recycling via the neonatal Fc receptor (FeRn). In the circulation, the large molecular size protects the bound peptide from renal clearance and reduces the rate of distribution to the extravascular compartment.
The slower absorption is thought to be due to a reduced rate of diffusion in the tissue by a mechanism involving interaction of the fatty acid side chain with cell membranes and/or proteins such as albumin present at the injection site. The rate of diffusion in the tissue following injection and the passage over the capillary wall would expectedly be reduced due to the large molecular size of the albumin-peptide complex. Molecules with a molecular size greater than approximately 16 kDa are preferentially alternatively be absorbed via a lymphatic route compared to direct absorption into blood across the capillary wall. 1 WO 2024/184351 PCT/EP2024/055724 Thus, slower absorption and reversible albumin binding has enabled extension of dosing intervals for drugs, such as peptide drugs, to up to a week. However, an even further extension of the dosing intervals would be desirable.
It is an object of the present invention to overcome the shortcomings of current therapies at least partially.
This object is achieved with a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises at least one polymeric moiety, to which at least two moieties of formula (I) are conjugated and/or to which at least one moiety of formula (T) is conjugated, wherein formula (I) and (T) areL2-L1-D-AB -؛- -I-l 2-l 1'4d-ab ]a (I ),whereineach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety; andeach a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
Applicant discovered that the compounds of the present invention are capable of further extending half-life and dosing frequency. It was surprisingly found that a compound of two or more drugs comprising an albumin binding moiety may coordinate more than one albumin molecule, resulting in a large molecular size of the albumin-drug complex.
This results in compounds exhibiting a further increased albumin binding and slowed absorption of the macromolecular drug-albumin complex. Such compounds also demonstrate a reduced absorption from the site of administration, such as from subcutaneous tissue, 2 WO 2024/184351 PCT/EP2024/055724 compared to administration of the corresponding unconjugated drugs. Consequently, such compounds have a prolonged half-life compared to the corresponding unconjugated drugs.
Within the present invention the terms are used having the meaning as follows.
As used herein, the term "GLP-1 receptor agonist ” refers to agonists of the GLP-1 receptor (GLPIR) and optionally in addition agonists of one or more other receptors, such as for example a receptor for gastric inhibitory polypeptide (GIPR), a receptor for glucagon (GCGR), a receptor for amylin, a receptor for peptide YY (PYYR) or a receptor for glucagon-like peptide-2 (GLP2R). An “agonist ” of a receptor, such as an agonist of the GLP-1 receptor, is a chemical compound that activates such receptor to produce a biological response. If a GLP-receptor agonist is in addition to being a GLPIR agonist also an agonist of one receptor other than GLPIR, such as an agonist of GIPR, GCGR, an amylin receptor, a PYYR or GLP2R, such GLP-1 receptor agonist is also referred to as being a “dual GLP-1 receptor agonist ” or short “dual agonist ”. Likewise, if a GLP-1 receptor agonist is in addition to being a GLPIR agonist also an agonist of two other receptors, which may be selected from the group consisting of GIPR, GCGR, an amylin receptor, a PYYR or GLP2R, such GLP-1 receptor agonist is also referred to as being a “triple GLP-1 receptor agonist ” or short “triple agonist ”.
As used herein, the term “peptide ” as used herein 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. 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 cyclic peptides may be mono-, bi-, tri- or tetracyclic peptides. The term “peptide ” also includes lasso peptides.
As used herein, 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 20amino acid monomer moieties. 3 WO 2024/184351 PCT/EP2024/055724 As used herein, the term “small molecule drug ” refers to drugs that are organic compounds with a molecular weight of less than 1000 Da, such as less than 900 Da or less than 800 Da. It is understood that nucl eobase-based drug moieties, such as adenine or guanine analogues, may also be a type of small molecule drugs.
As used herein, the terms “medium molecule drug ” or “medium size molecule drug ” refer to drugs that are organic compounds which are not peptides and which are not proteins and have a molecular weight ranging from and including 1 kDa to 7.5 kDa.
As used herein, the term “oligonucleotide ” refers to double- or single-stranded RNA and DNA with preferably 2 to 1000 nucleotides and any modifications thereof. Modifications include, for example, those which provide other chemical groups that incorporate additional charge, polarizability, hydrogen bonding, electrostatic interaction, and fluxionality to the nucleic acid ligand bases or to the nucleic acid ligand as a whole. Such modifications include for example, to 2’-position sugar modifications, 5-position pyrimidine modifications, 8-position purine modifications, modifications at exocyclic amines, substitution of 4-thiouridines, substitution of 5-bromo or 5-iodo-uracil; backbone modifications, methylations, unusual base-pairing combinations such as the isobases isocytidine and isoguanidine. Modifications can also include 3’ and 5’ modifications such as capping and change of stereochemistry. The term also includes aptamers.
As used herein, the term “peptide nucleic acids ” refers to organic polymers having a peptidic backbone, i.e., a backbone in which the monomers are connected to each other through peptide linkages, to which nucleobases such as adenine, cytosine, guanine, thymine and uracil, are attached. In certain embodiments, the peptide backbone comprises N-(2-aminoethyl)-glycine.
As used herein, the term "random coil" relates to any conformation of a polymeric molecule, including proteins, in which the individual monomeric elements that form said polymeric structure are essentially randomly oriented towards the adjacent monomeric elements while still being chemically bound to said adjacent monomeric elements. In particular, a polypeptide or protein having random coil conformation substantially lacks a defined secondary and tertiary structure. The nature of polypeptide random coils and their methods of experimental identification are known to the person skilled in the art. In particular, the lack of secondary and 4 WO 2024/184351 PCT/EP2024/055724 tertiary structure of a protein may be determined by circular dichroism (CD) measurements. CD spectroscopy represents a light absorption spectroscopy method in which the difference in absorbance of right- and left-circularly polarized light by a substance is measured. The secondary structure of a protein can be determined by CD spectroscopy using far-ultraviolet spectra with a wavelength between approximately 190 and 250 nm. At these wavelengths the different secondary structures commonly found in conformations each give rise to a characteristic shape and magnitude of the CD spectrum. Accordingly, by using CD spectrometry the skilled artisan is readily capable of determining whether an amino acid polymer adopts random coil conformation at physiological conditions.
When determining whether a peptide or protein adopts random coil conformation under experimental conditions using the methods as described herein, the biophysical parameters such as temperature, pH, osmolarity and protein content may be different to the physiological conditions normally found in vivo. Temperatures between 1 °C and 42 °C or preferably 4 °C to 25 °C may be considered useful to test and/or verify the biophysical properties and biological activity of a peptide or protein under physiological conditions in vitro.
Several buffers, in particular in experimental settings (for example in the determination of protein structures, in particular in circular dichroism (CD) measurements and other methods that allow the person skilled in the art to determine the structural properties of a protein/polypeptide or peptide stretch) or in buffers, solvents and/or excipients for pharmaceutical compositions, are considered to represent "physiological solutions" or "physiological conditions" in vitro. Examples of such buffers are, e.g. phosphate-buffered saline (PBS: 115 mM NaCl, 4 mM KHPO4, 16 mM Na 2HPO4 pH 7.4), Tris buffers, acetate buffers, citrate buffers or similar buffers such as those used in the appended examples. Generally, the pH of a buffer representing physiological conditions should lie in a range from 6.5 to 8.5, preferably in a range from 7.0 to 8.0, most preferably in a range from 7.2 to 7.7 and the osmolarity should lie in a range from 10 to 1000 mmol/kg H2O, more preferably in a range from 50 to 500 mmol/kg H20 and most preferably in a range from 200 to 350 mmol/kg H2O. Optionally, the protein content of a buffer representing physiological conditions may lie in a range from 0 to 100 g/1, neglecting the protein with biological activity itself, whereby typical stabilizing proteins may be used, for example human or bovine serum albumin.
WO 2024/184351 PCT/EP2024/055724 Other established biophysical methods for determining random coil conformation include nuclear magnetic resonance (NMR) spectroscopy, absorption spectrometry, infrared and Raman spectroscopy, measurement of the hydrodynamic volume via size exclusion chromatography, analytical ultracentrifugation and dynamic/static light scattering as well as measurements of the frictional coefficient or intrinsic viscosity.
As used herein the term “physiological conditions ” refers to aqueous buffer at pH 7.4, 37°C.
As used herein the term “pharmaceutical composition ” refers to a composition containing one or more active ingredients, such as for example at least one compound of the present invention, and one or more excipients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients of the composition, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, a pharmaceutical composition of the present invention encompasses any composition made by admixing one or more compound of the present invention and one or more pharmaceutically acceptable excipient.
As used herein, the term "excipient" refers to a diluent, adjuvant, or vehicle with which the therapeutic, such as a drug or prodrug, 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 an example for an excipient when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are examples of excipients when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are in certain embodiments 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, water, ethanol and the like. The pharmaceutical composition, if desired, can also contain minor amounts of wetting or emulsifying agents, pH buffering agents, like, for example, acetate, succinate, tris, carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid), MES (2-(A-morpholino)ethanesulfonic acid), or can contain detergents, like Tween, poloxamers, poloxamines, CHAPS, Igepal, or amino acids like, for example, glycine, lysine, 6 WO 2024/184351 PCT/EP2024/055724 or histidine. These pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, or sustained-release formulations. 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 compositionswill contain a therapeutically effective amount of the drug or drug moiety, 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.
As used herein the term “liquid composition ” refers to a mixture comprising a water-soluble compound and one or more solvents, such as water.
The term “suspension composition ” relates to a mixture comprising at least one water-insoluble compound and one or more solvents, such as water.
As used herein, the term “dry composition ” means that a pharmaceutical composition is provided in a dry form. Suitable methods for drying are spray-drying and lyophilization, i.e., freeze-drying. Such dry composition has a residual water content of a maximum of 10%, such as less than 5% or less than 2%, determined according to Karl Fischer. In certain embodiments such dry pharmaceutical composition is dried by lyophilization.
The term “drug ” as used herein 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. 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 ”.
As used herein the term “prodrug ” refers to a covalent conjugate in which a drug moiety is reversibly and covalently connected to a specialized protective group through a reversible linker moiety, also referred to as “reversible prodrug linker moiety ” or “reversible linker moiety ”, which is conjugated through a reversible linkage to 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 is referred to as “carrier ”. A 7 WO 2024/184351 PCT/EP2024/055724 prodrug releases the reversibly and covalently bound drug moiety in the form of its corresponding drug. In other words, a prodrug is a compound 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. Such compound releases the formerly conjugated drug moiety in the form of a free unmodified drug.
A “reversible linkage ” is a linkage that is degradable, i.e., cleavable, in the absence of enzymes under physiological conditions (aqueous buffer at pH 7.4, 37OC) with a half-life ranging from hour to three months. A “stable linkage ” is a linkage having a half-life under physiological conditions (aqueous buffer at pH 7.4, 37OC) in the absence of enzymes of more than three months.
As used herein, the terms “traceless prodrug linker ” or “traceless linker ” means a reversible prodrug linker, i.e., a linker moiety reversibly and covalently connecting a drug moiety with a carrier, which upon cleavage releases the drug in its free form. As used herein, the term “free form ” of a drug means the drug in its unmodified, pharmacologically active form.
As used herein, the term “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, such as a primary or secondary amine or hydroxyl functional group, is also a reagent.
As used herein, 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 is released from a prodrug as a drug.
If a chemical structure of a group of atoms is provided, which group of atoms is attached to at least one other moiety, said chemical structure may be attached to the at least one other moiety in either orientation, unless explicitly stated otherwise. For example, a moiety “-C(O)N(R1)-” may be attached to two moieties either as “-C^j^R1)-” or as ،،-N(R1)C(O)-”. Similarly, a moiety 8 WO 2024/184351 PCT/EP2024/055724 may be attached to two moieties either as As used herein, the term “functional group ” means a group of atoms which can react with other groups of atoms. Functional groups are for example selected from the group consisting of carboxylic acid, primary or secondary 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.
As used herein, the term “pharmaceutically acceptable salt(s) thereof ’ refers to salts that retain the biological effectiveness or properties of the compound and that typically are not biologically or otherwise undesirable. In certain embodiments, the compound is capable of forming acid/or base salts by virtue of the presence of amino and/or carboxylic functional groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllinate, citrate, ethanedi sulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, 9 WO 2024/184351 PCT/EP2024/055724 for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine. The pharmaceutically acceptable salts can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
The term "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) and/or the FDA (US) and/or any other national regulatory agency for use in animals, in particular for use in humans.
As used herein the terms “about ” or “approx. ” 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 10% of said numerical value. For example, the phrases “about 200” or “approx. 200” is used to mean a range ranging from and including 200 +/- 10%, i.e. ranging from and including 180 to 220. It is understood that a percentage given as “about 20%” or “approx. 20%” does not mean “20% +/- 10%”, i.e. ranging from and including 10 to 30%, but “about 20%” or “approx. 20%” means ranging from and including 18 to 22%, i.e. plus and minus 10% of the numerical value which is 20.
As used herein, 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. It is understood that a polymer may also comprise one or more other chemical groups and/or moieties, such as, for example, one or more functional groups. In WO 2024/184351 PCT/EP2024/055724 certain embodiments a soluble polymer has a molecular weight of at least 0.5 kDa, e.g., a molecular weight of at least 1 kDa, a molecular weight of at least 2 kDa, a molecular weight of at least 3 kDa or a molecular weight of at least 5 kDa. If the polymer is soluble, it in certain embodiments 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, or such as at most 100 kDa. It is understood that for water-insoluble polymers, such as hydrogels, no meaningful molecular weight ranges can be provided. It is understood that also a peptide or protein is a polymer in which the amino acids are the repeating structural units, even though the side chains of each amino acid may be different.
As used herein, the term “polymeric ” means 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 moiety/moieties, which are in certain embodiments selected from the group consisting of:• Ci ٠5o alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl; and• linkages selected from the group comprising and —N whereindashed lines indicate attachment to the remainder of the moiety or reagent, and-R and -Ra 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, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
N- WO 2024/184351 PCT/EP2024/055724 The person skilled in the art understands that the polymerization products obtained from a polymerization reaction do not all have the same molecular weight, but rather exhibit a molecular weight distribution. Consequently, 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.
Accordingly, in a polymeric moiety comprising “x ” monomer units 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 lie. An integer for “x ” given as “about x ” means that the arithmetic mean numbers of monomers lie in a range of integers of x +/- 10%, in certain embodiments x +/- 8%, in certain embodiments x +/- 5% and in certain embodiments x +/- 2%.
As used herein, the term “number average molecular weight ” means the ordinary arithmetic mean of the molecular weights of the individual polymers.
As used herein the term “water-soluble ” with reference to the compound of the present invention means that at least 1 g of the compound may be dissolved in one liter of water at 20°C to form a homogeneous solution. Accordingly, the term “water-insoluble ” with reference to the compound means that less than 1 g of the compound may be dissolved in one liter of water at 20°C to form a homogeneous solution.
As used herein, the term “PEG-based ” in relation to a moiety or reagent means that said moiety or reagent comprises PEG. In certain embodiments a 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, such as at least 95%. The remaining weight percentage of the PEG-based moiety or reagent are other moieties that in certain embodiments are selected from the following moieties and linkages: 12 WO 2024/184351 PCT/EP2024/055724 • Ci ٠5o alkyl, C2-50 alkenyl, C2-50 alkynyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl; and• linkages selected from the group comprising R OR NR O NR 0 0———— —— —— +-0— —o-c-N —O R whereindashed lines indicate attachment to the remainder of the moiety or reagent, and-R and -Ra 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, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
The term “substituted ” as used herein 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 ”.
In certain embodiments the one or more further optional substituents are independently of each other selected from the group consisting of halogen, -CN, -COORxl , -ORxl , -C(O)Rxl , -C(O)N(Rxl Rxla ), -S(O)2N(Rxl Rxla ), -S(O)N(Rxl Rxla ), -S(O)2Rxl , -S(O)Rxl ,- N(RX)S(O)2N(RlaR*10), -SRX1, -N(RXRX1a), -NO2, -OC(O)Rx1, -N(Rxl )C(O)Rxla , -N(RX)S(O)2Rxla, -N(Rxl )S(O)Rxla , -N(Rx)C(O)ORxla, -N(Rx)C(O)N(RXaR*1b),- OC(O)N(RXR*1a), -T°, Ci ٠5o alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T°, C1.50 alkyl, C2٠5o alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Rx2 , which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T0-, -C(O)O-, -0-, 13 WO 2024/184351 PCT/EP2024/055724 - C(O)-, -C(O)N(Rx3 )-, -S(O)2N(Rx3 )-, -S(O)N(Rx3)-, -S(O)2-, -S(O)-, -N(Rx3 )S(O)2N(Rx3a )-, -S-, -N(Rx3 )-, -OC(ORx3 )(Rx3a )-, -N(Rx3 )C(O)N(Rx3a )-, and -OC(O)N(Rx3 )-;- Rxl , -Rxla , -Rxlb are independently of each other selected from the group consisting of -H, -T0, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T°, C1-50 alkyl, C2-50 alkenyl, and C2-alkynyl are optionally substituted with one or more -R*2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T0-, -C(O)O-, -O-, -C(O)-, -C(O)N(Rx3 )-, -S(O)2N(Rx3)-, -S(O)N(Rx3)-; -S(O)2-, -S(O)-, -N(Rx3 )S(O)2N(Rx3a )-, -S-, -N(Rx3 )-, -OC(ORx3 )(Rx3a )-, -N(Rx3 )C(O)N(Rx3a )-, and -OC(O)N(Rx3 )-;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 -Rx2 , which are the same or different;each -Rx2 is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00Rx4 , -ORx4 , -C(0)Rx4 , -C(O)N(Rx4 Rx4a ), -S(O)2N(Rx4 Rx4a ), -S(O)N(Rx4 Rx4a ), -S(O)2Rx4, -S(O)Rx4, -N(Rx4 )S(O)2N(Rx4a Rx4b ), -SRx4 , -N(Rx4 Rx4a ), -NO2, -0C(0)Rx4 , -N(Rx4 )C(O)Rx4a , -N(Rx4 )S(O)2Rx4a , -N(Rx4 )S(O)Rx4a , -N(Rx4 )C(O)ORx4a , -N(Rx4 )C(O)N(Rx4a Rx4b ), -OC(O)N(Rx4 Rx4a ), and Cm alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;each -Rx3 , -Rx3a , -Rx4 , -Rx4a , -Rx4b is independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments the one or more further optional substituents are independently of each other selected from the group consisting of halogen, -CN, -COORxl , -ORxl , -C(O)Rxl , -C(0)N(Rxl Rxla ), -S(0)2N(Rxl Rxla ), -S(0)N(Rxl Rxla ), -S(O)2Rxl , -S(O)Rxl ,- N(Rxl )S(0)2N(Rxla Rxlb ), -SRX1, -N(Rxl Rxla ), -NO2, -OC(O)Rxl , -N(Rxl )C(0)Rxla , -N(Rxl )S(0)2Rxla , -N(Rxl )S(0)Rxla , -N(Rxl )C(0)0Rxla , -N(Rxl )C(0)N(Rxla Rxlb ),- 0C(0)N(Rxl Rxla ), -T°, Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein -T°, Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally substituted with one or more -Rx2 , which are the same or different and wherein Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T0-, -C(O)O-, -0-, -C(O)-, -C(0)N(Rx3 )-, -S(O)2N(Rx3)-, -S(O)N(Rx3)-, -S(O)2-, -S(O)-, 14 WO 2024/184351 PCT/EP2024/055724 - N(Rx3 )S(O)2N(Rx3a )-, -S-, -N(Rx3 )-, -OC(ORx3 )(Rx3a )-, -N(Rx3 )C(O)N(Rx3a )-,and -OC(O)N(Rx3 )-;each -Rxl , -Rxla , -Rxlb , -Rx3 , -Rx3a is independently selected from the group consisting of -H, halogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;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 -Rx2 , which are the same or different;each -Rx2 is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00Rx4 , -ORx4 , -C(0)Rx4 , -C(O)N(Rx4 Rx4a ), -S(O)2N(Rx4 Rx4a ), -S(O)N(Rx4 Rx4a ), -S(O)2Rx4, -S(O)Rx4, -N(Rx4 )S(O)2N(Rx4a Rx4b ), -SRx4 , -N(Rx4 Rx4a ), -NO2, -0C(0)Rx4 , -N(Rx4 )C(O)Rx4a , -N(Rx4 )S(O)2Rx4a , -N(Rx4 )S(O)Rx4a , -N(Rx4 )C(O)ORx4a , -N(Rx4 )C(O)N(Rx4a Rx4b ), -OC(O)N(Rx4 Rx4a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;each -Rx4 , -Rx4a , -Rx4b is independently selected from the group consisting of -H, halogen, C1-alkyl, C2-6 alkenyl, and C2-6 alkynyl; In certain embodiments the one or more further optional substituents are independently of each other selected from the group consisting of halogen, -CN, -C00Rxl , -ORxl , -C(0)Rxl , -C(0)N(Rxl Rxla ), -S(0)2N(Rxl Rxla ), -S(0)N(Rxl Rxla ), -S(O)2Rxl , -S(O)Rxl ,- N(Rxl )S(0)2N(Rxla Rxlb ), -SRX1, -N(Rxl Rxla ), -NO2, -0C(0)Rxl , -N(Rxl )C(0)Rxla , -N(Rxl )S(0)2Rxla , -N(Rxl )S(0)Rxla , -N(Rxl )C(0)0Rxla , -N(Rxl )C(0)N(Rxla Rxlb ),- 0C(0)N(Rxl Rxla ), -T°, C1-6 alkyl, C26 alkenyl, and C24 alkynyl; wherein -T°, C1-6 alkyl, Calkenyl, and C2-6 alkynyl are optionally substituted with one or more -Rx2 , which are the same or different and wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T0-, -C(O)O-, -0-, -C(O)-, -C(0)N(Rx3 )-, -S(O)2N(Rx3)-, -S(O)N(Rx3)-, -S(O)2-, -S(O)-, -N(Rx3 )S(O)2N(Rx3a )-, -S-, -N(Rx3 )-, -OC(ORx3 )(Rx3a )-, -N(Rx3 )C(O)N(Rx3a )-, and -0C(0)N(Rx3 )-;each -Rxl , -Rxla , -Rxlb , -Rx2 , -Rx3 , -Rx3a is independently selected from the group consisting of -H, halogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;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 -Rx2 , which are the same or different.
WO 2024/184351 PCT/EP2024/055724 In certain embodiments 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.
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, in certain embodiments between a carbon and a hydrogen atom.
As used herein, 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.
As used herein, 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.
As used herein, the term “cleavable triggering moiety (-Tr)” refers to a moiety that may undergo chemical or enzymatic cleavage under physiological conditions (aqueous buffer at pH 7.4, 37OC), wherein upon cleavage of said cleavable triggering moiety a compound will release at least two drug moieties comprising an albumin-binding moiety. 16 WO 2024/184351 PCT/EP2024/055724 As used herein, the term “Cm 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 Cm 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 Cm alkyl, then examples for such Cm alkyl groups are -CH2-, -CH2-CH2-, -CH(CH3)-,-CH-CH-CH- -CH(C2H5)-, -C(CH3)2-. Each hydrogen of a Cm alkyl carbon may optionally be replaced by a substituent as defined above. Optionally, a Cm alkyl may be interrupted by one or more moieties as defined below.
As used herein, the term “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.
As used herein, the term “Cm 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. When two moieties of a molecule are linked by the Cm alkyl group, then examples for such Cm alkyl groups are -CH)-, -CH-CH)-, -CH(CH3)-, -CH-CH-CH)-,-CH(C2H5)- and -C(CH3)2-. Each hydrogen atom of a Cm carbon may optionally be replaced by a substituent as defined above. Optionally, a Cm alkyl may be interrupted by one or more moieties as defined below.
Accordingly, “Cmo alkyl ”, “C1-20 alkyl ” or “Cmo alkyl ” means an alkyl chain having 1 to 10, to 20 or 1 to 50 carbon atoms, respectively, wherein each hydrogen atom of the Cmo, C1-or Cmo carbon may optionally be replaced by a substituent as defined above. Optionally, a Cmo or Cmo alkyl may be interrupted by one or more moieties as defined below.
As used herein, the term “C2-6 alkenyl ” alone or in combination means a straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon double bond having 2 to carbon atoms. If present at the end of a molecule, examples are -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CHCH2-CH3 and -CH=CH-CH=CH2. When two moieties of a molecule are linked by the C2-6 alkenyl group, then an example for such C2-6 alkenyl is -CH=CH-. Each 17 WO 2024/184351 PCT/EP2024/055724 hydrogen atom of a C2-6 alkenyl moiety may optionally be replaced by a substituent as defined above. Optionally, a C2-6 alkenyl may be interrupted by one or more moieties as defined below.
Accordingly, the term “C2-10 alkenyl ”, "C2-20 alkenyl ” or "C2-50 alkenyl ” alone or in combination means 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. Each hydrogen atom of a C2-10 alkenyl, C2-20 alkenyl or C2-50 alkenyl group may optionally be replaced by a substituent as defined above. Optionally, a C2-10 alkenyl, C2-20 alkenyl or C2-50 alkenyl may be interrupted by one or more moieties as defined below.
As used herein, the term "C2-6 alkynyl" alone or in combination means straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon triple bond having 2 to carbon atoms. If present at the end of a molecule, examples are -C=CH, -CH2-C=CH, CH2-CH2-C=CH and CH2-C=C-CH3. When two moieties of a molecule are linked by the alkynyl group, then an example is -C=C-. 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.
Accordingly, as used herein, the term “C2-10 alkynyl ”, "C2-20 alkynyl ” and "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. Optionally, one or more double bond(s) may occur. Optionally, a C2-10 alkynyl, C2-20 alkynyl or C2-50 alkynyl may be interrupted by one or more moieties as defined below.
As mentioned above, a Cm alkyl, C1-6 alkyl, Cho alkyl, C1-20 alkyl, C1-50 alkyl, C2-6 alkenyl, C2-10 alkenyl, C2-20 alkenyl, C2-50 alkenyl, C2-6 alkynyl, C2-10 alkynyl, C2-20 alkenyl or C2-alkynyl may optionally be interrupted by one or more moieties which in certain embodiments are selected from the group consisting of 18 WO 2024/184351 PCT/EP2024/055724 dashed lines indicate attachment to the remainder of the moiety or reagent; and-R and -Ra 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, 2,3-dimethylbutyl and 3,3-dimethylpropyl.
As used herein, the term "C3-10 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 C3-10 cycloalkyl carbon may be replaced by a substituent as defined above. The term "C3-10 cycloalkyl" also includes bridged bicycles like norbornane or norbornene.
The term “8- to 30-membered carbopoly cyclyl" or “8- to 30-membered carbopoly cycle ” 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). In certain embodiments an 8- to 30-membered carbopoly cyclyl means a cyclic moiety of two, three, four or five rings, in certain embodiments of two, three or four rings.
As used herein, the term "3- to 10-membered heterocyclyl" or "3- to 10-membered heterocycle" means a ring with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un- saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen 19 WO 2024/184351 PCT/EP2024/055724 (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for 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, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine and homopiperazine. Each hydrogen atom of a 3- to 10-membered heterocyclyl or 3- to 10-membered heterocyclic group may be replaced by a substituent as defined below.
As used herein, the term "8- to 11-membered heterobicyclyl" or "8- to 11-membered heterobicycle" means a heterocyclic moiety of two rings with 8 to 11 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. 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. The term 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 as defined below.
Similary, the term “8- to 30-membered heteropolycyclyl" or “8- to 30-membered heteropoly cycle ” means a heterocyclic moiety of more than two rings with 8 to 30 ring atoms, in certain embodiments of three, four or five rings, 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 unsaturated), wherein at least one ring atom up to WO 2024/184351 PCT/EP2024/055724 ring atoms are replaced by a heteroatom selected from the group of sulfur (including -S(O)- and -S(O)2-), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of a molecule via a carbon or nitrogen atom.
It is understood that the phrase “the pair Rx /Ry is joined together with the atom to which they are attached to form a C3-10 cycloalkyl or a 3- to 10-membered heterocyclyl" in relation with a moiety of the structure means that Rx and Ry form the following structure: I r ]יwherein R is C3-10 cycloalkyl or 3- to 10-membered heterocyclyl.
It is also understood that the phrase “the pair Rx /Ry is joint together with the atoms to which they are attached to form a ring A” in relation with a moiety of the structure means that Rx and Ry form the following structure: As used herein, "halogen" means fluoro, chloro, bromo or iodo. In certain embodiments halogen is fluoro or chloro.
In general, the term “comprise ” or “comprising ” also encompasses “consist of ’ or “consisting of ’.
WO 2024/184351 PCT/EP2024/055724 The compounds of the present invention release a compound H-D-AB upon cleavage of the linkage between -L1- and -D-, wherein H- is hydrogen. If a compound of the present invention for example comprises semaglutide in bound form, such as conjugated to -L1- or -L1 -, the semaglutide moiety -D-AB may for simplification be referred to herein as semaglutide, even though it strictly speaking would be a “semaglutide moiety ”.
The compounds release the corresponding free drug of the moiety -D-AB, which is H-D-AB, wherein H- is hydrogen.
In certain embodiments the compound comprises at least one polymeric moiety, to which at least two moieties of formula (I) are conjugated, wherein formula (I) isL2-L1-D-AB -؛- whereineach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety.
In certain embodiments the compound comprises at least one polymeric moiety, to which at least one moiety of formula (T) is conjugated, wherein formula (T) is -I-l 2-l 1'4d-ab ]a (I ),whereineach -L2- is independently a spacer moiety or is absent;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety; andeach a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
In certain embodiments the compound comprises two moieties of formula (I). In certain embodiments the compound comprises three moieties of formula (1). In certain embodiments 22 WO 2024/184351 PCT/EP2024/055724 the compound comprises four moieties of formula (I). In certain embodiments the compound comprises five moieties of formula (I). In certain embodiments the compound comprises six moieties of formula (I). In certain embodiments the compound comprises seven moieties of formula (1). In certain embodiments the compound comprises eight moieties of formula (I).
In certain embodiments the at least one polymeric moiety of the compounds of the present invention is a linear polymeric moiety -P-.
In certain embodiments a moiety of formula (I) or (F) is conjugated to each of the two ends of such linear moiety -P-.
In certain embodiments the compound is of formula (1-a) or (I-a ‘) ab-d-l 1-l 2-p—l 2-l 1-d-ab (Ia) ab-d-l 1'-l 2-p—l 2-l 1'--d-ab-a L Ja(I-a ’),whereineach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety;-P- is a polymeric moiety; andeach a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
In certain embodiments the compound is of formula (I-a). In certain embodiments the compound is of formula (I-a ’).
It is understood that a moiety -L1 - is conjugated to more than one moiety -D- and that all linkages between -L1 - and a moiety -D- are covalent and reversible. 23 WO 2024/184351 PCT/EP2024/055724 In certain embodiments both a of formula (I-a ‘) are the same integer. In certain embodiments both a of formula (I-a ‘) are 2. In certain embodiments both a of formula (I-a ‘) are 3. In certain embodiments both a of formula (I-a ‘) are 4. In certain embodiments both a of formula (I-a ‘) are 5. In certain embodiments both a of formula (I-a ‘) are 6. In certain embodiments both a of formula (I-a ‘) are 7. In certain embodiments both a of formula (I-a ‘) are 8. In certain embodiments both a of formula (I-a ‘) are 9. In certain embodiments both a of formula (I-a ‘) are 10. In certain embodiments both a of formula (I-a ‘) are 11. In certain embodiments both a of formula (I-a ‘) are 12. In certain embodiments both a of formula (I-a ‘) are 13. In certain embodiments both a of formula (I-a ‘) are 14. In certain embodiments both a of formula (I-a ‘) are 15. In certain embodiments both a of formula (I-a ‘) are 16.
Optionally, further moieties of formula (I) or (F) are conjugated to -P- of formula (I-a) or (I- a ’)• In certain embodiments no further moieties of formula (I) or (F) are conjugated to -P- of formula (1-a) or (I-a ’).
A moiety -P- of formula (I-a) or (I-a ’) comprises one or more polymer, such as a polymer selected from the group consisting of poly(2-methacryloyl-oxyethyl phosphoyl cholines), poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkoxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(hydroxybutyrate), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethylene phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl- oxazolines), poly(2-hydroxyethyl methacrylates), poly(N-(2-hydroxypropyl)methacrylamides), poly(hydroxypropyl methacrylates),poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co- glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), polypropylene glycols), poly(siloxanes), polyprethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), celluloses, carboxymethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, 24 WO 2024/184351 PCT/EP2024/055724 rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof.
In certain embodiments -P- of formula (1-a) or (I-a ‘) comprises one or more polymer selected from the group consisting of 2-methacryloyl-oxy ethyl 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(hydroxyethyl acrylates), poly(hydroxyethyl- oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), polypropylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), polypinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof.
In certain embodiments -P- of formula (la) or (I-a ‘) is a PEG-based or hyaluronic acid-based moiety. In certain embodiments -P- of formula (la) or (I-a ‘) is a PEG-based moiety. In certain embodiments -P- of formula (la) or (I-a ‘) is a hyaluronic acid-based moiety.
In certain embodiments -P- of formula (la) or (I-a ‘) is of formula (I-ai) x’o' X2 J n (I-ai), whereindashed lines indicate attachment to -L2-;n is an integer such that the molecular weight of the PEG moiety ranges from about about 20 kDa; WO 2024/184351 PCT/EP2024/055724 - X1- and -X2- are independently of each other selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-,- N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-,- S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-,- N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;each -Ry2 is independently selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), -S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -N 02, -0C(0)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(0)0Ry 5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and each -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments n of formula (I-ai) ranges from 2 to 22. 26 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -X1- and -X2- of formula (I-ai) are independently of each other selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-,- N(Ry1)-, -OC(ORyl )(Ryla )-, -N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, Cmo alkyl, C250 alkenyl, and C2-50 alkynyl; wherein -T-, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-20 alkyl, C2-alkenyl, and C2-20 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein -T, Cmo alkyl, C2-10 alkenyl, and C2-alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;- Ry2 is selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), -S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)ORy5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and Cm alkyl; wherein Cm alkyl is optionally substituted with one or more halogen, which are the same or different; andeach -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other 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. 27 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -X1- and -X2- of formula (I-ai) are independently of each other selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-,- S(O)2N(Ryl )-,-S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-,- N(Ry1)-, -OC(ORyl )(Ryla )-, -N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C250 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -8(0)2-, -8(0)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently selected from the group consisting of -H, -T, Cmo alkyl, C2-alkenyl, and C2-10 alkynyl;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; each -Ry2 is independently selected from the group consisting of halogen, and C1-6 alkyl; and each -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -P- of formula (1-a) or (I-a ‘) is of formula (I-ai-i) whereindashed lines indicate attachment to -L2-;each -XA- is independently selected from the group consisting of 28 WO 2024/184351 PCT/EP2024/055724 29 WO 2024/184351 PCT/EP2024/055724 s's<(x-46), (x-47), (x-48), (x-49), (x-53), (x-60), R04 R°4a R°A׳ A V104 ।04bR R (x-57), (x-50), (x-52), (x-54) (x-51), (x-61), O R״ (x-58), (x-62), 04a ״ 04 ״RR x O p o p ,P^ v(x-63), WO 2024/184351 PCT/EP2024/055724 04 04a 04״bRR XR (x-64), OOOO04a ״ 04 ״RXR 04״c 04״aR XR o x 0 px 0'p 'p >O' X04״b/V04cR R (x-66), R°x R°4t .r 04c R°t R°4xR°t R°4x (x-68), (x-67), 0 0 0 0O' O X 'q' x O' ,0 / ' 's' > ^N< < 's' > N ^o 31 WO 2024/184351 PCT/EP2024/055724 (x-106), (x-109), (x-97), 0 0 o x 0'jK 's،< o >' (x-98), O O o x p '5' '8' > ° ° ° ' (x-99), (x-107), (x-110), (x-114), (x-117), 32 WO 2024/184351 PCT/EP2024/055724 (x-121), (x-122), (x-123), 33 WO 2024/184351 PCT/EP2024/055724 34 WO 2024/184351 PCT/EP2024/055724 wherein a dashed line indicates attachment to -L2- or the remainder of the moiety of formula (I-ai-i);each -R04, -R04a , -R04b and -R04c is independently selected from the group consisting of halogen, -H, -CN, -T°, Ci-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T°, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -R06, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T0-, -C(O)O-, -0-, -C(O)-, -C(O)N(R07)-, -S(O)2N(R07)-, -S(O)N(R07)-, -S(O)2-, -S(O)-, -N(R07)S(O)2N(R07a )-, -S-,-N(R07)-, -OC(OR07)(R07a )-, -N(R07)C(O)N(R07a )-, and -OC(O)N(R07)-;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 -R06, which are the same or different; andeach -R06, -R07 and -R07a is independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or differenteach b is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;each c is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; and WO 2024/184351 PCT/EP2024/055724 n is an integer such that the molecular weight of the PEG moiety ranges from about kDa to about 20 kDa.
In certain embodiments n of formula (I-ai-i) ranges from 2 to 22, i.e., n is in certain embodiments selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22. In general, based on the number of ethylene glycol units the molecular weight of a PEG moiety can be calculated by multiplying the number of ethylene glycol units with 0.044 kDa.
In certain embodiments both moieties -XA- are identical. In certain embodiments the moieties -XA- are different from each other.
In certain embodiments a moiety -XA- is selected from the group consisting of formula (x-1), (x-2), (x-3), (x-4), (x-5), (x-6), (x-7), (x-8), (x-9), (x-10), (x-11), (x-12), (x-13), (x-14), (x-15), (x-16), (x-17), (x-18), (x-19), (x-20), (x-21), (x-22) and (x-23). In certain embodiments a moiety -XA- is selected from the group consisting of formula (x-1), (x-2), (x-3), (x-5), (x-6), (x-7), (x-8), (x-12), (x-13), (x-14), (x-15), (x-16), (x-17), (x-18), (x-19), (x-20), (x-21), (x-22) and (x-23). In certain embodiments a moiety -XA- is selected from the group consisting of formula (x-1), (x-2), (x-3), (x-5), (x-6), (x-7), (x-8), (x-12), (x-13), (x-14), (x-15), (x-16), (x- 17), (x-18), (x-19), (x-20) and (x-21). In certain embodiments a moiety -XA- is selected from the group consisting of formula (x-1), (x-2), (x-3), (x-5), (x-12), (x-13), (x-14), (x-15), (x-16), (x-17) and (x-18).
In certain embodiments -R04 of formula is -H. In certain embodiments -R04a is -H. In certain embodiments -R04b is -H. In certain embodiments -R04c is -H.
In certain embodiments both -XA- are of formula (x-1), in particular of formula (x-1 ‘) A.•X{(x-1 ‘),wherein the dashed line marked with the asterisk indicates attachment to -L2- and the unmarked dashed line indicates attachment to the remainder of -P-. In certain embodiments the dashed line marked with the asterisk indicates attachment to a moiety of formula (x-2) of -L2-. 36 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -P- of formula (1-a) or (I-a ‘) is of formula (I-aii) whereindashed lines indicate attachment to -L2-;each b is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;each c is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; andn is used as defined for n of formula (I-ai).
In certain embodiments -P- of formula (1-a) or (I-a ‘) is of formula (I-aii ’) whereindashed lines indicate attachment to -L2-; andn is an integer such that the molecular weight of the PEG moiety ranges from about about 20 kDa.
In certain embodiments -P- of formula (1-a) or (I-a ’) is selected from the group consisting of 37 WO 2024/184351 PCT/EP2024/055724 ס ס (I-aii ’-xi), 38 WO 2024/184351 PCT/EP2024/055724 NR04(I-aii ’-xiv), NR04(I-aii ’-xv) andRlkNAR04 (I-aii ’-xvi), whereindashed lines indicate attachment to -L2-;-R04 is defined as above; andn is an integer such that the molecular weight of the PEG moiety ranges from about 1about 20 kDa.
In certain embodiments -R04 of formula (I-aii ’-xiii), (I-aii ’-xiv), (I-aii ’-xv) or (I-aii ’-xvi) is -H.
In certain embodiments n of formulas (I-aii ’-i), (I-aii ’-ii), (I-aii ’-iii), (I-aii ’-iv), (I-aii ’-v), (I- aii ’vi), (I-aii ’-vii), (I-aii ’-viii), (I-aii ’-ix), (I-aii ’-x), (I-aii ’-xi), (I-aii ’-xii), (I-aii ’-xiii), (I-aii ‘- xiv), (I-aii ’-xv) and (I to (I-aii ’-xvi) ranges from 2 to 22, i.e., n is in certain embodiments selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 32 and 22.
A dashed line in any one of formulas (I-aii ’-i), (I-aii ’-ii), (I-aii ’-iii) and (I-aii ’-vi) suitably indicates attachment to -L2- via a moiety of formula (x-2), resulting in a moiety of formula (x-162’) O (x-162 ’), wherein the dashed line marked with the asterisk indicates attachment to the remainder of -L2- and the unmarked dashed line indicates attachment to the remainder of-P-. 39 WO 2024/184351 PCT/EP2024/055724 A dashed line in any one of formulas (I-aii ’-v), (I-aii ’-vi), (I-aii ’-vii) and (I-aii ’-viii) suitably indicates attachment to -L2- via a moiety of formula (x-1), resulting in a moiety of formula (x-162”) n s'° (x-162"), wherein the dashed line marked with the asterisk indicates attachment to the remainder of -L2- and the unmarked dashed line indicates attachment to the remainder of-P-.
A dashed line in any one of formulas (I-aii ”-ix), (I-aii ”-x), (I-aii ”-xi) and (I-aii ”-xii) suitably indicates attachment to -L2- via a moiety of formula (x-1 3), resulting in a moiety of formula (x-12 ’)R04 ° (x-12 ‘), wherein the dashed line marked with the asterisk indicates attachment to the remainder of -L2- and the unmarked dashed line indicates attachment to the remainder of -P-, with -R04 being used as defined in formula (I-ai-i). Suitably, -R04 of formula (x-12 ’) is -H.
A dashed line in any one of formulas (I-aii ”-xiii), (I-aii ”-xiv), (I-aii ”-xv) and (I-aii ”-xvi) suitably indicates attachment to -L2- via a moiety of formula (x-1 4), resulting in a moiety of formula (x-12 ”) R04 (x-12 ”), wherein the dashed line marked with the asterisk indicates attachment to the remainder of -L2- and the unmarked dashed line indicates attachment to the remainder of -P-, with -R04 being used as defined in formula (I-ai-i). Suitably, -R04 of formula (x-12 ”) is -H.
In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ‘) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety ranges from 1 to 15 kDa. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety ranges from 1 to 10 kDa. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 1 kDa. In certain embodiments n of 40 WO 2024/184351 PCT/EP2024/055724 formula (I-ai), (I-ai-i), (I-aii), (I-aii ‘) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 2 kDa. In certain embodiments n of formula (I- ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 2.5 kDa. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 3 kDa. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 4 kDa. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 5 kDa. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 7.5 kDa. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 10 kDa. In certain embodiments n of formula (I- ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 15 kDa. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer such that the molecular weight of the PEG moiety is about 20 kDa.
In general, the conversion of the molecular weight of a PEG moiety to the number of ethylene glycol units, such as n in formula (I-ai), (I-ai-i), (I-aii), (I-aii ’), (I-aii ’-i), (I-aii ’-ii), (I-aii ’-iii), (I-aii ’-iv), (I-aii ’-v), (I-aii ’-vi), (I-aii ’-vii), (I-aii ’-viii), (I-aii ’-ix), (I-aii ’-x), (I-aii ’-xi), (I- aii ’-xii), (I-aii ’-xiii), (I-aii ’-xiv), (I-aii ’-xv) and (I-aii ’-xvi), can easily be made by dividing the molecular weight of the PEG moiety in kDa by 0.044 (molecular weight of one ethylene glycol unit: 44 Da).
In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer ranging from and including about 22 to about 450. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is about 22. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii) or (I-aii ’) is about 23. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is about 45. In certain embodiments n of formula (I-ai) is about 57. In certain embodiments n of formula (I-ai), (I-ai- i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is about 68. In certain embodiments n of formula (I- ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is about 90. In certain embodiments n of formula (I-ai) is about 113. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) 41 WO 2024/184351 PCT/EP2024/055724 or (I-aii ’-i) to (I-aii ’-xvi) is about 170. In certain embodiments n of formula (I-ai), (I-ai-i), (I- aii), (I-aii ‘) or (I-aii ’-i) to (I-aii ’-xvi) is about 230. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ‘) or (I-aii ’-i) to (I-aii ’-xvi) is about 340. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is about 450.
In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is an integer ranging from and including 2 to 21. In certain embodiments n of formula (I-ai), (I- ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is 2. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is 2. In certain embodiments n of formula (I- ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is 3. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is 4. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is 5. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is 6. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is 7. In certain embodiments n of formula (I-ai), (I-ai-i), (I-aii), (I-aii ’) or (I-aii ’-i) to (I-aii ’-xvi) is 2. whereindashed lines indicate attachment to -L2-, and n ranges from 50 to 200.
In certain embodiments -P- of formula (I-a) or (I-a ’) is of formula (P-ii) ,O whereindashed lines indicate attachment to -L2-; and n ranges from 50 to 200.
In certain embodiments -P- of formula (1-a) or (I-a ’) is of formula (P-i) WO 2024/184351 PCT/EP2024/055724 In certain embodiments n of formula (P-i) and (P-ii) ranges 60 to 180, from 70 to 160, from to 160, from 90 to 140, from 95 to 130 or from 100 to 125. In certain embodiments n of formula (P-i) and (P-ii) n is selected such that P has a molecular weight of about 5 kDa.
In certain embodiments n of formulas (P-i) or (P-ii) ranges from 2 to 22, i.e., n is in certain embodiments 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22.
In certain embodiments n of formulas (P-i) or (P-ii) ranges from 23 to 49, i.e., n is in certain embodiments 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49.
In certain embodiments -P- of formula (1-a) or (I-a ‘) is of formula (I-aiv)O O whereinthe dashed lines indicate attachment to -BP-;each -XA- is independently used as defined in formula (I-ai-i);d, e, f and g are independently an integer selected from the group consisting of 1, 2,3, 4, 5, 6, 7, 8, 9 and 10;each m is independently an integer ranging from 1 to 100; andn is an integer such that the molecular weight of the PEG moiety ranges from about 1 about kDa.
In certain embodiments d of formula (I-aiv) is an integer ranging from 1 to 8. In certain embodiments d of formula (I-aiv) is an integer ranging from 1 to 6. In certain embodiments d of formula (I-aiv) is 1. In certain embodiments d of formula (I-aiv) is 2. In certain embodiments d of formula (I-aiv) is 3. In certain embodiments d of formula (I-aiv) is 4. In certain embodiments d of formula (I-aiv) is 5. In certain embodiments d of formula (I-aiv) is 6.
In certain embodiments g of formula (I-aiv) is an integer ranging from 1 to 8. In certain embodiments g of formula (I-aiv) is an integer ranging from 1 to 6. In certain embodiments g of formula (I-aiv) is 1. In certain embodiments g of formula (I-aiv) is 2. In certain embodiments 43 WO 2024/184351 PCT/EP2024/055724 g of formula (I-aiv) is 3. In certain embodiments g of formula (I-aiv) is 4. In certain embodiments g of formula (I-aiv) is 5. In certain embodiments g of formula (I-aiv) is 6.
In certain embodiments d and g of formula (I-aiv) are the same integer. In certain embodiments both d and g of formula (I-aiv) are 1. In certain embodiments both d and g of formula (I-aiv) are 2. In certain embodiments both d and g of formula (I-aiv) are 3. In certain embodiments both d and g of formula (I-aiv) are 4.
In certain embodiments e of formula (I-aiv) is an integer ranging from 1 to 8. In certain embodiments e of formula (I-aiv) is an integer ranging from 1 to 6. In certain embodiments e of formula (I-aiv) is 1. In certain embodiments e of formula (I-aiv) is 2. In certain embodiments e of formula (I-aiv) is 3. In certain embodiments e of formula (I-aiv) is 4. In certain embodiments e of formula (I-aiv) is 5. In certain embodiments e of formula (I-aiv) is 6.
In certain embodiments f of formula (I-aiv) is an integer ranging from 1 to 8. In certain embodiments f of formula (I-aiv) is an integer ranging from 1 to 6. In certain embodiments f of formula (I-aiv) is 1. In certain embodiments f of formula (I-aiv) is 2. In certain embodiments f of formula (I-aiv) is 3. In certain embodiments f of formula (I-aiv) is 4. In certain embodiments f of formula (I-aiv) is 5. In certain embodiments f of formula (I-aiv) is 6.
In certain embodiments e and f of formula (I-aiv) are the same integer. In certain embodiments both e and f of formula (I-aiv) are 1. In certain embodiments both e and f of formula (I-aiv) are 2. In certain embodiments both e and f of formula (I-aiv) are 3. In certain embodiments both e and f of formula (I-aiv) are 4.
In certain embodiments n of formula (I-aiv) is an integer such that the molecular weight of the PEG moiety ranges from 1 to 15 kDa. In certain embodiments n of formula (I-aiv) is an integer such that the molecular weight of the PEG moiety ranges from 1 to 10 kDa. In certain embodiments n of formula (I-aiv) is an integer such that the molecular weight of the PEG moiety is about 1 kDa. In certain embodiments n of formula (I-aiv) is an integer such that the molecular weight of the PEG moiety is about 2 kDa. In certain embodiments n of formula (I- aiv) is an integer such that the molecular weight of the PEG moiety is about 2.5 kDa. In certain embodiments n of formula (I-aiv) is an integer such that the molecular weight of the PEG moiety is about 3 kDa. In certain embodiments n of formula (I-aiv) is an integer such that the 44 WO 2024/184351 PCT/EP2024/055724 molecular weight of the PEG moiety is about 4 kDa. In certain embodiments n of formula (I- aiv) is an integer such that the molecular weight of the PEG moiety is about 5 kDa. In certain embodiments n of formula (I-aiv) is an integer such that the molecular weight of the PEG moiety is about 7.5 kDa. In certain embodiments n of formula (I-aiv) is an integer such that the molecular weight of the PEG moiety is about 10 kDa. In certain embodiments n of formula (I- aiv) is an integer such that the molecular weight of the PEG moiety is about 15 kDa. In certain embodiments n of formula (I-aiv) is an integer such that the molecular weight of the PEG moiety is about 20 kDa.
In certain embodiments n of formula (I-aiv) is an integer ranging from and including about to about 450. In certain embodiments n of formula (I-aiv) is about 22. In certain embodiments n of formula (I-aiv) is about 23. In certain embodiments n of formula (I-aiv) is about 45. In certain embodiments n of formula (I-ai) is about 57. In certain embodiments n of formula (I- aiv) is about 68. In certain embodiments n of formula (I-aiv) is about 90. In certain embodiments n of formula (I-ai) is about 113. In certain embodiments n of formula (I-aiv) is about 170. In certain embodiments n of formula (I-aiv) is about 230. In certain embodiments n of formula (I-aiv) is about 340. In certain embodiments n of formula (I-aiv) is about 450.
In certain embodiments the at least one polymeric moiety is a linear polymeric moiety -P- comprising a first and a second end and the at least two moieties of formula (I) and/or the at least one moiety of formula (F) is/are conjugated to -P- at sites selected from the group consisting of internal sites, the first end and the second end.
In certain embodiments the at least one polymeric moiety of the compounds of the present invention comprises a plurality of linearly connected units selected from the group consisting wherein WO 2024/184351 PCT/EP2024/055724 an unmarked dashed line indicates a point of attachment to an adjacent unit at a dashed line marked with # or to a hydrogen,a dashed line marked with # indicates a point of attachment to an adjacent unit at an unmarked dashed line or to a hydroxyl;a dashed line marked with the asterisk indicates attachment to -L2-;the total number of units Z2 in -P- is at least 2;the total number of units Z1 and Z2 is at least 5;- Ra 1 and -Ra 2 are each independently selected from the group consisting of hydrogen; Cm alkyl; an alkali metal ion, an ammonium ion, an alkaline earth metal ion, or other suitable counterion;- X3- is selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-, -N(Ryl )C(0)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;each -Ry2 is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00Ry5, -ORy5, -C(0)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), 46 WO 2024/184351 PCT/EP2024/055724 - S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)ORy5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; andeach -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -X3- is selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-,- S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-, -N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-50 alkenyl, and C2.50 alkynyl; wherein -T-, C1-20 alkyl, C2- alkenyl, and C2-20 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -8(0)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein -T, C1-10 alkyl, C2-alkenyl, and C2-10 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -8(0)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;- Ry2 is selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), 47 WO 2024/184351 PCT/EP2024/055724 - S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)O Ry5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and each -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -X3- is selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ryl )-,-S(O)N(Ry1)-, -S(O)2-,- S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-,- N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-,- S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-,- N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;-Ryl and -Ryla are independently selected from the group consisting of -H, -T, Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropolycyclyl;each -Ry2 is independently selected from the group consisting of halogen, and C1-6 alkyl; andeach -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight ranging from about 1 about 20 kDa. In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight ranging from about 1 about 15 kDa. In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight of 48 WO 2024/184351 PCT/EP2024/055724 about 1 kDa. In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight of about 2 kDa. In certain embodiments the total number of units Z1 and Zis such that -P- has a molecular weight of about 3 kDa. In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight of about 4 kDa. In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight of about 5 kDa. In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight of about 7.5 kDa. In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight of about 10 kDa. In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight of about 15 kDa. In certain embodiments the total number of units Z1 and Z2 is such that -P- has a molecular weight of about 20 kDa. whereinthe unmarked dashed line indicates attachment to the carbonyl of Z2;the dashed line marked with the asterisk indicates attachment to -L2-;dl is independently an integer selected from the group consisting of 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;d2 is independently an integer selected from the group consisting of 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
In certain embodiments dl of formula (1-b) is 1. In certain embodiments dl of formula (1-b) is 2. In certain embodiments dl of formula (1-b) is 3. In certain embodiments dl of formula (1-b) is 4. In certain embodiments dl of formula (1-b) is 5. In certain embodiments dl of formula (I- b) is 6.
In certain embodiments d2 of formula (1-b) is 1. In certain embodiments d2 of formula (1-b) is 2. In certain embodiments d2 of formula (1-b) is 3. In certain embodiments d2 of formula (1-b) is 4. In certain embodiments d2 of formula (1-b) is 5. In certain embodiments d2 of formula (I- b) is 6.
In certain embodiments -X3- is of formula (1-b) WO 2024/184351 PCT/EP2024/055724 In certain embodiments -X3- is of formula (I-b ’) (I-b ’), whereinthe unmarked dashed line indicates attachment to the carbonyl of Z2; and the dashed line marked with the asterisk indicates attachment to -L2-.
In certain embodiments the compound is of formula (1-c) or (I-c ’) AB—D-L1— L2־־BP—P-BP--L2—L1—D־ABq (1-c), [aB—d ]־L1'־ L2־־bP—P-BP--L2—L1l 4d-Ab a J n L Jq (1-c ’), whereineach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugatedto -D-;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety;-P- is a polymeric moiety;each BP is independently a branching point;each a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; andp and q are independently an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
In certain embodiments the compound is of formula (1-c). In certain embodiments the compound is of formula (1-c ’).
' * WO 2024/184351 PCT/EP2024/055724 It is understood that a moiety -L1 - is conjugated to more than one moiety -D- and that all linkages between -L1 - and a moiety -D- are covalent and reversible.
In certain embodiments both a of formula (I-c ’) are the same integer. In certain embodiments both a of formula (I-c ’) are 2. In certain embodiments both a of formula (I-c ’) are 3. In certain embodiments both a of formula (I-c ’) are 4. In certain embodiments both a of formula (I-c ’) are 5. In certain embodiments both a of formula (I-a ’) are 6. In certain embodiments both a of formula (I-c ’) are 7. In certain embodiments both a of formula (I-c ’) are 8. In certain embodiments both a of formula (I-c ’) are 9. In certain embodiments both a of formula (I-c ’) are 10. In certain embodiments both a of formula (I-c ’) are 11. In certain embodiments both a of formula (I-c ’) are 12. In certain embodiments both a of formula (I-c ’) are 13. In certain embodiments both a of formula (I-c ’) are 14. In certain embodiments both a of formula (I-c ’) are 15. In certain embodiments both a of formula (I-c ’) are 16.
In certain embodiments p and q of formula (I-c) or (I-c ’) are the same integer. In certain embodiments p and q of formula (I-c) or (I-c ’) are a different integer.
Embodiments for -P- are as described for formula (I-a) and (I-a ’) elsewhere herein.
Each BP of formula (I-c) and (I-c ’) is independently a branching point. In certain embodiments both BP are identical. In certain embodiments both BP are different. BP point may be a single atom, such as a nitrogen or carbon atom, or may be a group of atoms, such as a di-, tri- or tetraamino acid. A diamino acid may be selected from the group consisting of lysine, ornithine, 2,3-diaminoproprionic acid and 2,4-diaminobutyric acid, each either in R- and S-configuration.
In certain embodiments BP of formula (I-c ’) comprises a lysine, in particular a lysine in S- configuration. In certain moieties both moieties BP of formula (I-c ’) comprise a lysine, in particular a lysine in S-configuration.
In certain embodiments both moieties BP have the structure of formula (l-c-i) 51 WO 2024/184351 PCT/EP2024/055724 whereinthe unmarked dashed lines indicate attachment to -L2-;the dashed line marked with the asterisk indicates attachment to -P-; andeach h is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; andeach i is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
In certain embodiments both h of formula (I-c-i) are the same integer. In certain embodiments both h of formula (I-c-i) are 2 and i of formula (I-c-i) is 4. In certain embodiments both h of formula (I-c-i) are 3 and i of formula (I-c-i) is 4. In certain embodiments both h of formula (I- c-i) are 4 and i of formula (I-c-i) is 4.
In certain embodiments both moieties BP have the structure of formula (I-c-i ’) whereinthe unmarked dashed lines indicate attachment to -L2-; andthe dashed line marked with the asterisk indicates attachment to -P-. 52 WO 2024/184351 PCT/EP2024/055724 In certain embodiments one BP of formula (I-c ’) is lysine, in particular lysine in S configuration. In certain embodiments both moeities BP of formula (I-c ’) are lysine, in particular lysine in S configuration.
In certain embodiments the moiety BP-P-BP is of formula (I-d ’) (I-d ’),whereinthe dashed lines indicate attachment to -L2-;each m is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, and 8;n is an integer ranging from 2 to 200;each o is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, and 8; andeach p is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, and 8.
In certain embodiments the moiety BP-P-BP is of formula (I-d) 53 WO 2024/184351 PCT/EP2024/055724 (I-d),whereinthe dashed lines indicate attachment to -L2-;each m is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 5 and 8;each p is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, and 8; andn is an integer ranging from 2 to 200.
In certain embodiments n of formula (I-d) and (I-d ’) ranges 60 to 180, from 70 to 160, from to 160, from 90 to 140, from 95 to 130 or from 100 to 125. In certain embodiments n of formula (1-d) and (I-d ’) is selected such that P has a molecular weight of about 5 kDa.
In certain embodiments the moiety BP-P-BP is of formula (I-e) (I-e),wherein dashed lines indicate attachment to -L2-; and n is an integer ranging from 2 to 200.
In certain embodiments n of formula (I-e) ranges 60 to 180, from 70 to 160, from 80 to 160, from 90 to 140, from 95 to 130 or from 100 to 125. In certain embodiments n of formula (I-e) is selected such that P has a molecular weight of about 5 kDa.
In certain embodiments the at least one polymeric moiety of the compound of the present invention is a multi-arm polymeric moiety. Such multi-arm polymeric moiety comprises at least one branching point. Accordingly, in certain embodiments the compound comprises at 54 WO 2024/184351 PCT/EP2024/055724 least one branching point B, to which at least two moieties of formula (1b) and/or at least one moiety of formula (Ib ’) are conjugated, wherein formula (Ib) and (Ib ’) are( b ״ L’-D-AB ־- A-L -؛- -:-a-l ^-l ^d-ab ], (Ib-) whereinthe dashed line indicates attachment to a branching point B;- A- is a polymeric moietyeach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety; andeach a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
In certain embodiments the compound comprises at least one branching point B, to which at least two moieties of formula (Ib) are conjugated, wherein formula (Ib) is A l 2 l 1 d ab (Ib) whereinthe dashed line indicates attachment to a branching point B;- A- is a polymeric moietyeach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety; andeach -AB is independently an albumin-binding moiety.
In certain embodiments the compound comprises at least one branching point B, to which at least one moiety of formula (Ib ’) is conjugated, wherein formula (Ib ’) is-I-a-l 2-i_4d-ab ]1 a (Ib ), 55 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line indicates attachment to a branching point B;- A- is a polymeric moietyeach -L2- is independently a spacer moiety or is absent;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety; andeach a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
The moiety -A- of formula (Ib) or (Ib ’) comprises one or more polymer, such as a polymer selected from the group consisting of 2-methacryloyl-oxy ethyl 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(hydroxyethyl acrylates), poly(hydroxyethyl- oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), polypropylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), polypinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof.
In certain embodiments -A- of formula (Ib) or (Ib ’) comprises a PEG-based polymer or a hyaluronic acid-based polymer. In certain embodiments -A- of formula (Ib) or (Ib ’) comprises a PEG-based polymer. In certain embodiments -A- of formula (Ib) or (Ib ’) comprises a hyaluronic acid-based polymer. 56 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -A- of formula (1b) or (Ib ’) is of formula (I-ba) z (I-ba),whereinthe unmarked dashed line indicates attachment to the branching point B;the dashed line marked with the asterisk indicates attachment to -L2-;z is an integer selected such that the molecular weight of -A- ranges from about 0.5 kDa to about 10 kDa;- X8- is selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-, -N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;each -Ry2 is independently selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), -S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -N 57 WO 2024/184351 PCT/EP2024/055724 02, -OC(O)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)ORy 5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and each -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -X8- is selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-,- N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-, -N(Ryl )C(0)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-50 alkenyl, and C2.50 alkynyl; wherein -T-, C1-20 alkyl, C2- alkenyl, and C2-20 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein -T, C1-10 alkyl, C2-alkenyl, and C2-10 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein Ci-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;- Ry2 is selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), -S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)ORy5a , 58 WO 2024/184351 PCT/EP2024/055724 - N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and each -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -X8- is selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ryl )-,-S(O)N(Ry1)-, -S(O)2-,- S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-,- N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-,- S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-,- N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;-Ryl and -Ryla are independently selected from the group consisting of -H, -T, Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropolycyclyl;each -Ry2 is independently selected from the group consisting of halogen, and C1-6 alkyl; andeach -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -A- of formula (1b) or (Ib ’) is of formula (1-bb) or (I-bb ‘)U P 59 WO 2024/184351 PCT/EP2024/055724 whereinthe unmarked dashed line indicates attachment to the branching point B;the dashed line marked with the asterisk indicates attachment to -L2-;z is an integer selected such that the molecular weight of -A- ranges from about 0.5 kDa to about 10 kDa;zl is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16; andz2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16.
In certain embodiments -A- of formula (Ib) or (Ib ’) is of formula (1-bb). In certain embodiments -A- of formula (Ib) or (Ib ’) is of formula (I-bb ‘).
In certain embodiments -A- of formula (Ib) or (Ib ’) is of formula (1-bc) or (l-bc ’) 0 (I־bc), L Jz L JZ1 H z2 (I-bc ’), whereinthe unmarked dashed line indicates attachment to the branching point B;the dashed line marked with the asterisk indicates attachment to -L2-;z is an integer selected such that the molecular weight of -A- ranges from about 0.5 kDa to about 10 kDa;zl is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16; andz2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16. 60 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -A- of formula (Ib) or (Ib ’) is of formula (I-bc). In certain embodiments -A- of formula (Ib) or (Ib ’) is of formula (I-bc ‘).
In certain embodiments zl of formula (I-bb), (I-bb ‘), 0־bc) or (I-bc ‘) is 1. In certain embodiments zl of formula (I-bb) , (I-bb ’), (1-bc) or (I-bc ’) is 2. In certain embodiments zl of formula (I-bb), (I-bb ’), (1-bc) or (I-bc ’) is 3. In certain embodiments zl of formula (I-bb) , (I- bb ’), (1-bc) or (I-bc ’) is 4. In certain embodiments zl of formula (I-bb), (I-bb ’), (1-bc) or (1-bc) is 5. In certain embodiments zl of formula (I-bb), (I-bb ’), (1-bc) or (I-bc ’) is 6. In certain embodiments zl of formula (I-bb), (I-bb ’), (1-bc) or (I-bc ’) is 7. In certain embodiments zl of formula (I-bb), (I-bb ’), (1-bc) or (1-bc) is 8. In certain embodiments zl of formula (I-bb), (I- bb ’), (1-bc) or (I-bc ’) is 9. In certain embodiments zl of formula (I-bb), (I-bb ’), (1-bc) or (I- be ’) is 10. In certain embodiments zl of formula (I-bb), (I-bb ’), (1-bc) or (I-bc ’) is 11. In certain embodiments zl of formula (I-bb), (I-bb ’), (I-bc) or (1-bc ’) is 12. In certain embodiments zl of formula (I-bb) , (I-bb ’), (I-bc) or (I-bc ’) is 13. In certain embodiments zl of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 14. In certain embodiments zl of formula (I-bb), (I-bb ’), (I-bc) or (I- be ’) is 15. In certain embodiments zl of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 16.
In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 1. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 2. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 3. In certain embodiments z2 of formula (I-bb), (I- bb ’), (I-bc) or (I-bc ’) is 4. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I- be ’) is 5. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 6. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 7. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 8. In certain embodiments z2 of formula (I-bb), (I- bb ’), (I-bc) or (I-bc ’) is 9. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I- be ’) is 10. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 11. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 12. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 13. In certain embodiments z2 of formula (I-bb), (I- bb ’), (I-bc) or (I-bc ’) is 14. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I- be ’) is 15. In certain embodiments z2 of formula (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is 16. 61 WO 2024/184351 PCT/EP2024/055724 In certain embodiments zl of formula (I-bb), (I-bb ‘), 0־bc) or (I-bc ‘) is 3 and z2 of formula (I- bb), (I-bb ’), (1-bc) or (I-bc ‘) is 2. In certain embodiments zl of formula (I-bb), (I-bb ’), (1-bc) or (I-bc ‘) is 2 and z2 of formula (I-bb), (I-bb ’), (1-bc) or (I-bc ’) is 2.
In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- ranges from and includes about 0.5 kDa to about 10 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 0.5 kDa. In certain embodiments z of formula (I- ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 1 kDa. In certain embodiments of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 1.5 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 2 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 2.5 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 3 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 3.5 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 4 kDa. In certain embodiments z of formula (I- ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 5 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 6 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 7 kDa. In certain embodiments of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I- be ’) is an integer such that the molecular weight of the -A- is about 8 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 9 kDa. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer such that the molecular weight of the -A- is about 10 kDa.
In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer ranging from and including about 11 to about 230. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is an integer ranging from and including about 11 to about 225. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is about 11. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is about 12. In certain 62 WO 2024/184351 PCT/EP2024/055724 embodiments z of formula(I-ba), (I-bb), (I-bb ‘), 0־bc) or (I-bc ‘) is about 22. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (1-bc) or (I-bc ‘) is about 23. In certainembodiments z of formula (I-ba), (I-bb), (I-bb ’), (1-bc) or (I-bc ’) is about 34. In certainembodiments z of formula (I-ba), (I-bb), (I-bb ’), (1-bc) or (I-bc ’) is about 45. In certain embodiments z of formula (I-ba), (I-bb) or (-I-bc) is about 57. In certain embodiments z offormula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is about 68. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is about 79. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is about 90. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is about 102. In certain embodiments z of formula (I-ba), (I-bb), (I- bb ’), (I-bc) or (I-bc ’) is about 113. In certain embodiments z of formula (I-bb) or (I-bc) is about 135. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is about 160. In certain embodiments z of formula (I-bb) or (I-bc) is about 180. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is about 205. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (I-bc) or (I-bc ’) is about 225. In certain embodiments z of formula (I-ba), (I-bb), (I-bb ’), (1-bc) or (I-bc ’) is about 230.
In certain embodiments the compound comprises one branching point B, such as a branching point selected from the group consisting of XVXs.X6(I-bl), R1X4 X6X5-!;-X7X4 X6X5-; (I-b2) and (I-b3),whereindashed lines indicate attachment to -A- of formula (lb);-R1 is used as defined for the term “substituent ”; and-X4-, -X5-, -X6- and -X7- are independently used as defined for -X1- and -X2- of formula (I-ai).
In certain embodiments -X4-, -X5- and -X6- of formula (I-bl) and (I-b2) are identical. In certain embodiments -X4-, -X5- and -X6- of formula (I-bl) and (I-b2) are identical and are selected from the group consisting of -CH2-, -CHCH2- and -CHCHCH2- 63 WO 2024/184351 PCT/EP2024/055724 In certain embodiments the compound comprises one branching point of formula (I-bl). In certain embodiments the compound comprises one branching point of formula (I-b2). In certain embodiments the compound comprises one branching point of formula (I-b3). In certain embodiments the compound comprises one branching point of formula (I-b3), wherein -X4-, -X5-, -X6- and -X7- are identical. In certain embodiments the compound comprises one branching point of formula (I-b3), wherein -X4-, -X5-, -X6- and -X7- are selected from the group consisting of -CH2-, -CH2CH2- and -CH2CH2CH2- In certain embodiments the compound comprises one branching point of formula (I-b3), wherein -X4-, -X5-, -X6- and -X7- are -CH2-.
In certain embodiments the compound is of formula (I-b4) x4־a-l 2-l 1-d-abAB—D-L1-L2-A-X7-^X5-A-L2-L1-D-AB X6-A-L2-L1-D-AB (I-b4), whereineach -A- is a polymeric moiety;each -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety;- X4-, -X5-, -X6- and -X7- are independently of each other selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-,- N(Ry1)-, -OC(ORyl )(Ryla )-, -N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C2alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the 64 WO 2024/184351 PCT/EP2024/055724 same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;each -Ry2 is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00Ry5, -ORy5, -C(0)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ),-S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -NO2, -0C(0)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a ,-N(Ry5)C(O)ORy5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; andeach -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -X4-, -X5-, -X6- and -X7- of formula (I-b4) are independently of each other selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-,-C(0)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(0)2N(Ryla )-, -S-, -N(Ry1)-, -0C(0Ryl )(Ryla )-, -N(Ryl )C(0)N(Ryla )-, -0C(0)N(Ryl )-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-20 alkyl, C2-alkenyl, and C2-20 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(0)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -0C(0)N(Ry3)-;-Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein -T, Cmo alkyl, C2-10 alkenyl, and C2-alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and 65 WO 2024/184351 PCT/EP2024/055724 wherein Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;- Ry2 is selected from the group consisting of halogen, -CN, oxo (=0), -C00Ry5, -ORy5, -C(0)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), -S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -NO2, -0C(0)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)ORy5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; andeach -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -X4-, -X5-, -X6- and -X7- of formula (I-b4) are independently of each other selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-,- C(0)N(Ry1)-, -S(O)2N(Ryl )-,-S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(0)2N(Ryla )-, -S-, -N(Ry1)-, -0C(0Ryl )(Ryla )-, -N(Ryl )C(0)N(Ryla )-, -0C(0)N(Ryl )-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(0)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -0C(0)N(Ry3)-;- Ryl and -Ryla are independently selected from the group consisting of -H, -T, Cmo alkyl, C2-alkenyl, and C2-10 alkynyl;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; 66 WO 2024/184351 PCT/EP2024/055724 each -Ry2 is independently selected from the group consisting of halogen, and C1-6 alkyl; and each -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -X4-, -X5-, -X6- and -X7- of formula (I-b3) and (I-b4) are identical. In certain embodiments -X4-, -X5-, -X6- and -X7- of formula (I-b3) and (I-b4) are identical and are selected from the group consisting of -CH2-, -CHCH2- and -CHCHCH2- In certain embodiments the moiety-؛- A ־ X4-;-a-x7—|—x5-a-!-x6-a !- is of formula (I-b5) whereindashed lines indicate attachment to -L2-; and 67 WO 2024/184351 PCT/EP2024/055724 nl, n2, n3 and n4 are independently an inter ranging from and including about 10 to about 300, in certain embodiments from and including about 10 to about 230.
In certain embodiments the moiety-؛- A ־ X4-;-a-x7—|—x5-a־!-x6-a !- is of formula (I-b6) whereindashed lines indicate attachment to -L2-; andnl, n2, n3 and n4 are independently an inter ranging from and including about 10 to about230.
In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are the same integer. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 11. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 12. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 22. In certain embodiments nl, n2, n 68 WO 2024/184351 PCT/EP2024/055724 and n4 of formula (I-b5) or (I-b6) are about 23. . In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 28. In certain embodiments nl, n2, n3 and n4 of formula (I- b5) or (I-b6) are about 29. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I- b6) are about 34. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 45. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 56. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 68. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 80. In certain embodiments nl, n2, nand n4 of formula (I-b5) or (I-b6) are about 90. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 100. In certain embodiments nl, n2, n3 and n4 of formula (I- b5) or (I-b6) are about 115. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I- b6) are about 135. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 160. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 180. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 200. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 225. In certain embodiments nl, n2, n3 and n4 of formula (I-b5) or (I-b6) are about 230.
In certain embodiments the compound comprises more than one branching point B, such as two or more branching points selected from the group consisting of (I-bl), (I-b2) and (I-b3).
In certain embodiments -D- is a drug moiety selected from the group consisting of small molecule drug moieties, medium size molecule drug moieties, oligonucleotide drug moieties, peptide nucleic acid drug moieties, peptide drug moieties and protein drug moieties.
In certain embodiments -D- is a peptide drug moiety. In certain embodiments -D- is a small molecule drug moiety. In certain embodiments -D- is a medium size drug moiety. In certain embodiments -D- is an oligonucleotide drug moiety. In certain embodiments -D- is a peptide nucleic acid drug moiety. In certain embodiments -D- is a protein drug moiety.
In certain embodiments -D- or -D-AB is a GLP-1 receptor agonist moiety. Accordingly, the compound of the present invention may be a GLP-1 receptor agonist compound.
In certain embodiments -D- or -D-AB is a mono agonist of the GLP-1 receptor, i.e., only activates the GLP-1 receptor. 69 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -D- or -D-AB is an agonist of the GLP-1 receptor and an agonist of a further receptor, i.e., -D- or -D-AB is a dual GLP-1 receptor agonist. Such further receptor may be selected from the group consisting of the GIP receptor, the GCG receptor, an amylin receptor, a PYY receptor and the GLP-2 receptor.
In certain embodiments -D- or -D-AB is an agonist of the GLP-1 receptor and of the GIP receptor. In certain embodiments -D- or -D-AB is an agonist of the GLP-1 receptor and of the GCG receptor. In certain embodiments -D- or -D-AB is an agonist of the GLP-1 receptor and of an amylin receptor. In certain embodiments -D- or -D-AB is an agonist of the GLP-1 receptor and of a PYY receptor. In certain embodiments -D- or -D-AB is an agonist of the GLP-receptor and of the GLP-2 receptor.
In certain embodiments -D- or -D-AB is an agonist of the GLP-1 receptor and growth/differentiation factor 15 (GDF15). In certain embodiments -D- or -D-AB is an agonist of the GLP-1 receptor and fibroblast growth factor 21 (FGF21).
In certain embodiments -D- or -D-AB is an agonist of the GLP-1 receptor and an agonist of two further receptors, i.e., -D- or -D-AB is a triple GLP-1 receptor agonist. These further receptors are in certain embodiments selected from the group consisting of the GIP receptor (GIPR), the GCG receptor (GCGR), an amylin receptor, a PYY receptor (PYYR) and the GLP- receptor (GLP2R).
In certain embodiments -D- or -D-AB is a triple GLP-1 receptor agonist that activates the GLP- receptor, the GIP receptor and the GCG receptor. In certain embodiments -D- or -D-AB is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, the GIP receptor and an amylin receptor. In certain embodiments -D- or -D-AB is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, the GIP receptor and a PYY receptor. In certain embodiments -D- or -D-AB is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, the GIP receptor and the GLP-2 receptor. In certain embodiments -D- or -D-AB is a triple GLP- receptor agonist that activates the GLP-1 receptor, the GCG receptor and an amylin receptor. In certain embodiments -D- or -D-AB is a triple GLP-1 receptor agonist that activates the GLP- receptor, the GCG receptor and a PYY receptor. In certain embodiments -D- or -D-AB is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, the GCG receptor and the GLP- receptor. In certain embodiments -D- or -D-AB is a triple GLP-1 receptor agonist that 70 WO 2024/184351 PCT/EP2024/055724 activates the GLP-1 receptor, an amylin receptor and a PYY receptor. In certain embodiments -D- or -D-AB is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, the amylin receptor and the GLP-2 receptor. In certain embodiments -D- or -D-AB is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, a PYY receptor and the GLP-receptor.
In certain embodiments -D- is a human GLP-1 of SEQ ID NO: 1: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG.
In certain embodiments -D- is human GLP-1 analog of SEQ ID NO: 1, which peptide sequence may comprise one or more amino acid changes compared to SEQ ID NO:1. Such amino acid changes may be the addition of one or more amino acid residues, the deletion of one or more amino acid residues, the substitution of one or more amino acid residues or may be any combination thereof. Such amino acid change may be at the N-terminus, the C-terminus and/or at an internal site of the GLP-1 of SEQ ID NO:1. In certain embodiments such human GLP-analog has a maximum of 3 amino acid changes compared to SEQ ID NO:1, i.e., a maximum of three amino acids are added to, deleted from or substituted compared to the sequence of SEQ IDNO:1.
In certain embodiments -D- has the sequenceHXEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO:2), wherein X! is 2-aminoisobutyric acid (Aib).
In certain embodiments -D- has the sequenceHXEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO:3), wherein X! is Aib and the C-terminal glycine, i.e., the glycine at position 31, is amidated as a C-terminal primary amide.
In certain embodiments -D- is exenatide. Exenatide has the sequenceHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO:4).
In certain embodiments -D- has the sequenceHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO:5), 71 WO 2024/184351 PCT/EP2024/055724 wherein the C-terminal serine, i.e., the serine at position 39, is amidated as a C-terminal primary amide.
In certain embodiments -D- is lixisenatide. Lixisenatide has the sequenceHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK (SEQ ID NO:6), wherein the C-terminal lysine, i.e., the lysine at position 44, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK (SEQ ID NO:7).
In certain embodiments -D- has the sequenceHXEGTFTSDLSKQXEEEAVRLFIEWLKQGGPSSGAPPPC (SEQ ID NO:8), wherein X! is D-alanine and X2 is norleucine (Nie).
In certain embodiments -D- has the sequenceHXEGTFTSDLSKQXEEEAVRLFIEWLKQGGPSSGAPPPC (SEQ ID NO:9), wherein X! is D-alanine, X2 is Nie and the C-terminal cysteine, i.e., the cysteine at position 39, is amidated as a C-terminal primary amide.
In certain embodiments -D- is PEG-loxenatide. PEG-loxenatide has the sequence HXEGTFTSDLSKQXEEEAVRLFIEWLKQGGPSSGAPPPC (SEQ ID NO: 10), wherein X! is D-alanine; X2 is Nie; the cysteine at position 39 is chemically modified through conjugation to the thiol group of the cysteine side-chain with O-mPEG O-mPEGwhereinthe dashed line indicates attachment to the thiol group of the cysteine side chain of the cysteine at position 39, and each mPEG is methoxypoly(ethylene glycol) with a molecular weight of approx. 20 kDa. 72 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -D- has the sequenceHXEGTFTSDLSKQXEEEAVRLFIEWLKQGGPSSGAPPPC (SEQ ID NO: 11),wherein X! is D-alanine; X2 is Nie; the cysteine at position 39 is chemically modified through conjugation to the thiol group of the cysteine side-chain with O-mPEGwherein the dashed line indicates attachment to the thiol group of the cysteine side chain of the cysteine at position 39, each mPEG is methoxypoly(ethylene glycol) with a molecular weight of approx. 20 kDa, and the C-terminal cysteine, i.e., the cysteine at position 39, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO: 12).
In certain embodiments -D- has the sequenceHAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO: 13),and the C-terminal glycine, i.e., the glycine at position 31, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequence HVEGTFTSDVSSYLEEQAAREFIKWLVRGRG (SEQ ID NO: 14).
In certain embodiments -D- has the sequenceHVEGTFTSDVSSYLEEQAAREFIKWLVRGRG (SEQ ID NO: 15),and the C-terminal glycine, i.e., the glycine at position 31, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceHGEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO: 16).
O-mPEG WO 2024/184351 PCT/EP2024/055724 In certain embodiments -D- has the sequenceHGEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO: 17), and the C-terminal glycine, i.e., the glycine at position 31, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceHXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGL (SEQ ID NO: 18), wherein X! is Aib.
In certain embodiments -D- has the sequenceHXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGL (SEQ ID NO: 19), wherein X! is Aib and the C-terminal leucine, i.e., the leucine at position 32, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceYX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO:20), wherein X! is Aib, X2 is Aib and the C-terminal serine, i.e., the serine at position 39, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceYXEGTFTSDYSIXLDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO:21), wherein X! is Aib and X2 is Aib.
In certain embodiments -D- has the sequence HSQGTFTSDKSEYLDSERARDFVAWLEAGG (SEQ ID NO :22).
In certain embodiments -D- has the sequenceHSQGTFTSDKSEYLDSERARDFVAWLEAGG (SEQ ID NO:23), wherein the C-terminal glycine, i.e., the glycine at position 30, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceHXQGTFTSDYSKYLDERAAKDFIKWLESA (SEQ ID NO:24), 74 WO 2024/184351 PCT/EP2024/055724 wherein X! is 1-amino-cyclobutanecarboxylic acid (Ac4c); and the C-terminal alanine, i.e. the alanine at position 29, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceHXQGTFTSDYSKYLDERAAKDFIKWLESA (SEQ ID NO:25), wherein X! is 1-amino-cyclobutanecarboxylic acid (Ac4c).
In certain embodiments -D- has the sequenceHXQGTFTSDYSKYLDEKAAKEFIQWLLQT (SEQ ID NO:26), wherein X! is Aib and the glutamic acid at position 16 and the lysine at position 20 are connected via a lactam bridge.
In certain embodiments -D- has the sequenceHXQGTFTSDYSKYLDEKAAKEFIQWLLQT (SEQ ID NO:27), wherein X! is Aib, the glutamic acid at position 16 and the lysine at position 20 are connected via a lactam bridge and the C-terminal threonine, i.e., the threonine at position 29, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceHXQGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG (SEQ ID NO:28), wherein X! is Aib and the C-terminal glycine, i.e., the glycine at position 34, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceHXQGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG (SEQ ID NO:29), wherein X! is Aib.
In certain embodiments -D- has the sequenceHXEGSFTSELATILDKQAARDFIAWLIQHKITD (SEQ ID NO:30), wherein X! is Aib.
In certain embodiments -D- has the sequenceHXEGSFTSELATILDKQAARDFIAWLIQHKITD (SEQ ID NO:31), 75 WO 2024/184351 PCT/EP2024/055724 wherein X! is Aib and the C-terminal aspartic acid, i.e., the aspartic acid at position 33, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceYXIQGTFTSDYSIXLDKKAQX;AFIEYLLEGGPSSGAPPPS (SEQ IDNO:32), wherein X! is Aib, X2 is a-methyl-leucine (aMeL), X3 is Aib; and the C-terminal serine, i.e. the serine at position 39, is amidated as a C-terminal primary amide.
In certain embodiments -D- has the sequenceYXIQGTFTSDYSIXLDKKAQX;AFIEYLLEGGPSSGAPPPS (SEQ ID NO:33), wherein X! is Aib, X2 is a-methyl-leucine (aMeL) and X3 is Aib.
In certain embodiments -D- has the sequenceHX1EGTFTSDVSSYLEEEAAKEFIAWLVRGGPSSGAPPPSK (SEQ ID NO:54), wherein X! is Aib.
In certain embodiments -D- has the sequenceHX1EGTFTSDVSSYLEEQAAKEFIAWLVRGGG (SEQ ID NO:55), wherein X! is Aib.
In certain embodiments -D- has the sequenceHX1EGTFTSDVSSYLEEQAAKEFIAWLVRGGGGAQPGAQPGAQPGAQPGAQPGAQP GAQPGAQPGAQPGQKP (SEQ ID NO:56), wherein X! is Aib.
In certain embodiments -D- has the sequenceHX1EGTFTSDVSSYLEEQAAKEFIAWLVRGGGGAQPGAQPGAQPGAQPGAQPGAQP GAQPGAQPGAQPGQKP (SEQ ID NO:56), wherein X! is Aib.
In certain embodiments -D- is a drug selected from the group consisting of insulins; amylin and amylin/calcitonin; PYY; GIP; MSH; C5a binders; GDF15; PCSK9 1; immune stimulants; urocortin2; MIC-1; IL-IR antagonists; leptin; gastrin; glucagon; exendin-4; GLP-1; GLP-2; and GIP. 76 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -D- is a drug moiety selected from the group consisting of insulin; insulin analogues; amylin; dual amylin/calcitonin agonists; PYY; GIP; MSH; C5 inhibitors or modulators; GDF15; PCSK9 inhbitors; immune stimulants; urocortin II; MIC-1; IL-IR antagonists; leptin; gastrin; glucagon; oxyntomodulin; neurokinin A; tachykinin/neurokinin receptor 2 (NK2R) agonists; neurokinin receptor (NKR) agonists and GLP-2.
In certain embodiments -D- is an insulin, such as insulin detemir, insulin degludec and insulin. In certain embodiments -D- is amylin and amylin/calcitonin, such as for example cagrilintide. In certain embodiments -D- is PYY, such as NNC0165-1875. In certain embodiments -D- is GIP. In certain embodiments -D- is MSH. In certain embodiments -D- is a C5a binder, such as zilucoplan. In certain embodiments -D- is GDF15, such as NN LA-GDF15. In certain embodiments -D- is PCSK9 i. In certain embodiments -D- is an immune stimulant, such as romurtide or mifamurtide. In certain embodiments -D- is muramyl dipeptide. In certain embodiments -D- is urocortin2. In certain embodiments -D- is MIC-1. In certain embodiments -D- is an IL-IR antagonist. In certain embodiments -D- is leptin. In certain embodiments -D- is gastrin.
In certain embodiments -D- is selected from the list consisting of growth hormones, such as human growth hormone; FGF21; EGF(a); and coagulations factors.
In certain embodiments -D- is a growth hormone, such as a human growth hormone, such as somapacitan. In certain embodiments -D- is FGF21, such as NNC0194 0499. In certain embodiments -D- is EGF(a). In certain embodiments -D- is a coagulation factor.
In certain embodiments -D- is selected from cytotoxic small molecule drugs; chemotherapy small molecule drugs; and immune activating small molecule drugs.
In certain embodiments -D- is a cytotoxic small molecule drug. In certain embodiments -D- is a chemotherapy small molecule drug. In certain embodiments -D- is and immune activating small molecule drug, such as telratolimod.
In certain embodiments -D- is paclitaxel. In certain embodiments -D- is doxorubicin. In certain embodiments -D- is 5-FU. 77 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -D- is a PTH moiety.
In certain embodiments -AB is a fatty acid-based albumin-binding moiety.
A moiety -AB binds to albumin, such as human albumin, under physiological conditions (aqueous buffer pH 7.4, 37°C).
A moiety -D- may be conjugated to one moiety -AB. A moiety -D- may be conjugated to more than one moiety -AB. In certain embodiments the linkage between -D- and a moiety -AB is a stable linkage. In case a moiety -D- comprises two moieties -AB, the linkage between -D- and a first moiety -AB may be reversible and the linkage between -D- and a second moiety -AB may be stable. Alternatively, in case a moiety -D- comprises two moieties -AB, the linkage between -D- and both moieties -AB may be stable.
In certain embodiments -AB is of formula (A):Fo— LA— L6־!־ . ..(A), whereinthe dashed line indicates attachment to -D-;-F° is of formula (a-1) לץ> 1 ^ R0° (a-1), whereinthe dashed line indicates attachment to -LA-;-R° is selected from the group consisting of -CR1Rla Rlb , -COOR1, ׳ ° r«—j—S-OH "Nand H ;-R1, -Rla and -Rlb are selected from the group consisting of -H, methyl, ethyl, propyl and isopropyl;n is an integer ranging from and including 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21 and 22;-La- is absent or is of formula (a-2) 78 WO 2024/184351 PCT/EP2024/055724 whereinP (a-2), the unmarked dashed line indicates attachment to -LB-;the dashed line marked with the asterisk indicates attachment to -F°;HO^O, L , /*/ N / */ N /-Ra - is selected from the group consisting of H and H whereinthe dashed line marked with the asterisk indicates attachment to -F°;the unmarked dashed line indicates attachment to the remainder of -LA-; H O, x H ׳ VN .-Rh-is" ־' ' or /xm is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;-Lb- is absent or is of formula (a-3) ، DC ne /R ׳ (a-3), whereinthe unmarked dashed line indicates attachment to -D-;the dashed line marked with the asterisk indicates attachment to -LA;H OVN/ x U /- Rc - is ׳x or /Xx A ;- Rd - is selected from the group consisting of C1-50 alkyl, C2-50 alkenyl and C2-alkynyl, wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl may be substituted with one or more -R1, which may be the same or different, and which C1-50 alkyl, C2-50 alkenyl or C2-50 alkynyl may be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-,- C(O)N(R2)-, -S(O)2N(R2)-, -S(O)N(R2)-, -S(O)2-, -S(O)-,- N(R2)S(O)2N(R2a )-, -S-, -N(R2)-, -OC(OR2)(R2a )-, -N(R2)C(O)N(R2a )-, and -OC(O)N(R2)-; 79 WO 2024/184351 PCT/EP2024/055724 each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each -T- may independently be substituted with one or more -R1, which may be the same or different;each -R1 is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00R3, -OR3, -C(0)R3, -C(O)N(R3R3a ), -S(O)2N(R3R3a ), -S(O)N (R3R3a ), -S(O)2R3, -S(O)R3, -N(R3)S(O)2N(R3a R3b), -SR3,-N(R3R3a ), -NO2, -0C(0)R3, -N(R3)C(O)R3a , -N(R3)S(O)2R3a , -N(R3)S(O)R3a ,-N(R3)C(O)OR3a , -N(R3)C(O)N(R3a R3b), -OC(O)N(R3R3a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;each -R2, -R2a , -R3, -R3a and -R3b is independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl may be substituted with one or more halogen, which may be the same or different; andO , II / -Re- is selected from the group consisting of -CH2-, x A and H ؟ ؟ ׳ N 'If -Rb - is '''' and -LB- is not absent, then -Rc - is A and if -Rb - is A and -LB- is HVN/not absent, then -Rc - isN A.
In certain embodiments -LA- is of formula (a-2), i.e., is not absent. In certain embodiments -LA- is absent.
HO^O */־N AIn certain embodiments -Ra - is H י wherein the dashed line marked with the asterisk indicates attachment to -F° and the unmarked dashed line indicates attachment to the remainder of-L A-. 80 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -Ra - is H י wherein the dashed line marked with the asterisk indicates attachment to -F° and the unmarked dashed line indicates attachment to the remainder of-L A-.
H O. VN/In certain embodiments -R - is ׳ .In certain embodiments -R - is In certain embodiments m of formula (a-2) is 1. In certain embodiments m of formula (a-2) is 2. In certain embodiments m of formula (a-2) is 3. In certain embodiments m of formula (a-2) is 4. In certain embodiments m of formula (a-2) is 5. In certain embodiments m of formula (a- 2) is 6. In certain embodiments m of formula (a-2) is 7. In certain embodiments m of formula (a-2) is 8. In certain embodiments m of formula (a-2) is 9. In certain embodiments m of formula (a-2) is 10.
In certain embodiments p of formula (a-2) is 1. In certain embodiments p of formula (a-2) is 2.In certain embodiments p of formula (a-2) is 3. In certain embodiments p of formula (a-2) is 4.In certain embodiments p of formula (a-2) is 5. In certain embodiments p of formula (a-2) is 6.In certain embodiments p of formula (a-2) is 7. In certain embodiments p of formula (a-2) is 8.In certain embodiments p of formula (a-2) is 9. In certain embodiments p of formula (a-2) is 10.
In certain embodiments -LB- is of formula (a-3). In certain embodiments -LB- is absent. If -Lb- is absent, the unmarked dashed line in formula (a-2) indicates attachment to -D-.
H OVN/In certain embodiments -Rc - is "' ׳ In certain embodiments -Rc - is A.
JD In certain embodiments -Re- is -CH2-. In certain embodiments -Re- is In certainO embodiments -Re- is H 81 WO 2024/184351 PCT/EP2024/055724 In certain embodiments both -LA- and -LB- are absent. If both -LA- and -LB- are absent, the dashed line in formula (a-1) indicates attachment to -D-.
In certain embodiments -F° is selected from the group consisting of 82 WO 2024/184351 PCT/EP2024/055724 (a 21־), 83 WO 2024/184351 PCT/EP2024/055724 wherein dashed lines indicate attachment to -LA-.
If -La- is absent, the dashed line in formulas (a-4) to (a-39) indicates attachment to -LB-. If both -La- and -LB- are absent, the dashed line in formulas (a-4) to (a-39) indicates attachmentto -D-. 84 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -F° is of formula (a-4). In certain embodiments -F° is of formula (a-5).In certain embodiments -F° is of formula (a-6). In certain embodiments -F° is of formula (a-7).In certain embodiments -F° is of formula (a-8). In certain embodiments -F° is of formula (a-9).In certain embodiments -F° is of formula (a- 10). In certain embodiments -F° is of formula(a-11). In certain embodiments -F° is of formula (a-12). In certain embodiments -F° is of formula (a-13). In certain embodiments -F° is of formula (a-14). In certain embodiments -F° is of formula (a- 15). In certain embodiments -F° is of formula (a- 16). In certain embodiments -F° is of formula (a- 17). In certain embodiments -F° is of formula (a- 18). In certain embodiments -F° is of formula (a- 19). In certain embodiments -F° is of formula (a-20). In certain embodiments -F° is of formula (a-21). In certain embodiments -F° is of formula (a-22). In certain embodiments -F° is of formula (a-23). In certain embodiments -F° is of formula (a-24). In certain embodiments -F° is of formula (a-25). In certain embodiments -F° is of formula (a-26). In certain embodiments -F° is of formula (a-27). In certain embodiments -F° is of formula (a-28). In certain embodiments -F° is of formula (a-29). In certain embodiments -F° is of formula (a-30). In certain embodiments -F° is of formula (a-31). In certain embodiments -F° is of formula (a-32). In certain embodiments -F° is of formula (a-33). In certain embodiments -F° is of formula (a-34). In certain embodiments -F° is of formula (a-35). In certain embodiments -F° is of formula (a-36). In certain embodiments -F° is of formula (a- 37). In certain embodiments -F° is of formula (a-38). In certain embodiments -F° is of formula (a-39).
In certain embodiments -F° is of formula (a-4) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-5) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-6) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-7) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-8) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-9) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a- 10) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-11) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-12) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-13) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-14) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a- 15) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a- 16) and both -LA- and -LB- are absent. In certain 85 WO 2024/184351 PCT/EP2024/055724 embodiments -F° is of formula (a- 17) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a- 18) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a- 19) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-20) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-21) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-22) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-23) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-24) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-25) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-26) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-27) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-28) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-29) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-30) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-31) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-32) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-33) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-34) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-35) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-36) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-37) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-38) and both -LA- and -LB- are absent. In certainembodiments -F° is of formula (a-39) and both -LA- and -LB- are absent.
HO^^O HO^^O HO^/O HO^/O In certain embodiments -LA- is selected from the group consisting of WO 2024/184351 PCT/EP2024/055724 87 WO 2024/184351 PCT/EP2024/055724 Ox /O (a-76), (a-79), H 11O (a-81) and (a-82),wherein a dashed line marked with an asterisk indicates attachment to -F°- and an unmarked dashed line indicates attachment to -LB-. If -LB- is absent an unmarked dashed indicates attachment to -D-.
In certain embodiments -LA- is of formula (a-40). In certain embodiments -LA- is of formula (a-41). In certain embodiments -LA- is of formula (a-42). In certain embodiments -LA- is of formula (a-43). In certain embodiments -LA- is of formula (a-44). In certain embodiments -LA- is of formula (a-45). In certain embodiments -LA- is of formula (a-46). In certain embodiments -LA- is of formula (a-47). In certain embodiments -LA- is of formula (a- 48). In certain embodiments -LA- is of formula (a-49). In certain embodiments -LA- is of formula (a-50). In certain embodiments -LA- is of formula (a-51). In certain embodiments -LA- is of formula (a-52). In certain embodiments -LA- is of formula (a-53). In certain embodiments -LA- is of formula (a-54). In certain embodiments -LA- is of formula (a- 55). In certain embodiments -LA- is of formula (a-56). In certain embodiments -LA- is of formula (a-57). In certain embodiments -LA- is of formula (a-58). In certain embodiments -LA- is of formula (a-59). In certain embodiments -LA- is of formula (a-60). In certain embodiments -LA- is of formula (a-61). In certain embodiments -LA- is of formula (a- 62). In certain embodiments -LA- is of formula (a-63). In certain embodiments -LA- is of formula (a-64). In certain embodiments -LA- is of formula (a-65). In certain 88 WO 2024/184351 PCT/EP2024/055724 embodiments -LA- is of formula (a-66). In certain embodiments -LA- is of formula (a-67). In certain embodiments -LA- is of formula (a-68). In certain embodiments -LA- is of formula (a- 69). In certain embodiments -LA- is of formula (a-70). In certain embodiments -LA- is of formula (a-71). In certain embodiments -LA- is of formula (a-72). In certain embodiments -LA- is of formula (a-73). In certain embodiments -LA- is of formula (a-74). In certain embodiments -LA- is of formula (a-75). In certain embodiments -LA- is of formula (a- 76). In certain embodiments -LA- is of formula (a-77). In certain embodiments -LA- is of formula (a-78). In certain embodiments -LA- is of formula (a-79). In certain embodiments -LA- is of formula (a-80). In certain embodiments -LA- is of formula (a-81). In certain embodiments -LA- is of formula (a-82).
In certain embodiments -LB- is selected from the group consisting of H H . (a-83), ؟ H 2 (a-85), H h Y* 2H H H Y* 2H H H Y * H (a-89), H H Y * H (a-90), H ? ,^ ןס '* L J q(a-84),. O^OHH H Y* 2 n ||(a-86), rTso (a-87), rTso (a-88), Y h ؟ h-----------------------------------------------0 Y h ؟ h 0 0 89 WO 2024/184351 PCT/EP2024/055724 (a-94),whereinthe dashed line marked with the asterisk indicates attachment to -LA-;the unmarked dashed line indicates attachment to -D-; andq is an integer ranging from and including 2 to 50.
If -La- is absent, the dashed line marked with the asterisk in formulas (a-83) to (a-94) indicates attachment to -F°.
In certain embodiments q of formula (a-84) is an integer ranging from and including 3 to 45.In certain embodiments q of formula (a-84) is an integer ranging from and including 4 to 40.In certain embodiments q of formula (a-84) is an integer ranging from and including 5 to 35.In certain embodiments q of formula (a-84) is an integer ranging from and including 6 to 30.In certain embodiments q of formula (a-84) is an integer ranging from and including 7 to 25.In certain embodiments q of formula (a-84) is an integer ranging from and including 10 to 20.In certain embodiments q of formula (a-84) is 23. 90 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -LB- is of formula (a-83). In certain embodiments -LB- is of formula (a-84). In certain embodiments -LB- is of formula (a-84) with q = 23. In certain embodiments -LB- is of formula (a-85). In certain embodiments -LB- is of formula (a-86). In certain embodiments -LB- is of formula (a-87). In certain embodiments -LB- is of formula (a-88). In certain embodiments -LB- is of formula (a-89). In certain embodiments -LB- is of formula (a-90). In certain embodiments -LB- is of formula (a-91). In certain embodiments -LB- is of formula (a-92). In certain embodiments -LB- is of formula (a-93). In certain embodiments -LB- is of formula (a-94).
In certain embodiments -AB is of formula (i) wherein the dashed line indicates attachment to -D-;n is an integer ranging from and including 14 to 22; andthe stereocenter marked with the asterisk is either in S- or R-configuration.
In certain embodiments -AB is of formula (i) and n is 14. In certain embodiments -AB is of formula (i) and n is 15. In certain embodiments -AB is of formula (i) and n is 16. In certain embodiments -AB is of formula (i) and n is 17. In certain embodiments -AB is of formula (i) and n is 18. In certain embodiments -AB is of formula (i) and n is 19. In certain embodiments -AB is of formula (i) and n is 20. In certain embodiments -AB is of formula (i) and n is 21. In certain embodiments -AB is of formula (i) and n is 22.
In certain embodiments -AB is of formula (i) and n is 14 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (i) and n is 15 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (i) and n is 16 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (i) and n is 17 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (i) and n is 18 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (i) and n is 19 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (i) and n is 20 and the stereocenter marked with the HO^^O WO 2024/184351 PCT/EP2024/055724 asterisk is in R-configuration. In certain embodiments -AB is of formula (i) and n is 21 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (i) and n is 22 and the stereocenter marked with the asterisk is in R-configuration.
In certain embodiments -AB is of formula (i) and n is 14 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (i) and n is 15 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (i) and n is 16 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (i) and n is 17 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (i) and n is 18 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (i) and n is 19 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (i) and n is 20 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (i) and n is 21 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (i) and n is 22 and the stereocenter marked with the asterisk is in S-configuration.
In certain embodiments -AB is of formula (i-a): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (i-b): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (i-c): HO^^O WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (i-d): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (i-e): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (i-f): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (ii) wherein the dashed line indicates attachment to -D-; 93 WO 2024/184351 PCT/EP2024/055724 n is an integer ranging from 14 to 22; andthe stereocenter marked with the asterisk is either in S- or R-configuration.
In certain embodiments -AB is of formula (ii) and n is 14. In certain embodiments -AB is of formula (ii) and n is 15. In certain embodiments -AB is of formula (ii) and n is 16. In certain embodiments -AB is of formula (ii) and n is 17. In certain embodiments -AB is of formula (ii) and n is 18. In certain embodiments -AB is of formula (ii) and n is 19. In certain embodiments -AB is of formula (ii) and n is 20. In certain embodiments -AB is of formula (ii) and n is 21. In certain embodiments -AB is of formula (ii) and n is 22.
In certain embodiments -AB is of formula (ii) and n is 14 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (ii) and n is 15 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (ii) and n is 16 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (ii) and n is 17 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (ii) and n is 18 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (ii) and n is 19 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (ii) and n is 20 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (ii) and n is 21 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (ii) and n is 22 and the stereocenter marked with the asterisk is in R-configuration.
In certain embodiments -AB is of formula (ii) and n is 14 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (ii) and n is 15 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (ii) and n is 16 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (ii) and n is 17 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (ii) and n is 18 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (ii) and n is 19 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (ii) and n is 20 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (ii) and n is 21 and the 94 WO 2024/184351 PCT/EP2024/055724 stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (ii) and n is 22 and the stereocenter marked with the asterisk is in S-configuration.
In certain embodiments -AB is of formula (ii-a): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (ii-b): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (ii-c): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (ii-d): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (ii-e): 95 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (ii-f): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (iii) whereinthe dashed line indicates attachment to -D-;t is an integer ranging from and including 14 to 22; andthe stereocenter marked with the asterisk is either in S- or R-configuration.
In certain embodiments -AB is of formula (iii) and t is 14. In certain embodiments -AB is of formula (iii) and t is 15. In certain embodiments -AB is of formula (iii) and t is 16. In certain embodiments -AB is of formula (iii) and t is 17. In certain embodiments -AB is of formula (iii) and t is 18. In certain embodiments -AB is of formula (iii) and t is 19. In certain embodiments -AB is of formula (iii) and t is 20. In certain embodiments -AB is of formula (iii) and t is 21. In certain embodiments -AB is of formula (iii) and t is 22.
In certain embodiments -AB is of formula (iii) and t is 14 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (iii) and t is 15 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is 96 WO 2024/184351 PCT/EP2024/055724 of formula (iii) and t is 16 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (iii) and t is 17 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (iii) and t is 18 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (iii) and t is 19 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (iii) and t is 20 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (iii) and t is 21 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (iii) and t is 22 and the stereocenter marked with the asterisk is in R-configuration.
In certain embodiments -AB is of formula (iii) and t is 14 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (iii) and t is 15 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (iii) and t is 16 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (iii) and t is 17 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (iii) and t is 18 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (iii) and t is 19 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (iii) and t is 20 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (iii) and t is 21 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (iii) and t is 22 and the stereocenter marked with the asterisk is in S-configuration.
In certain embodiments -AB is of formula (iii-a) whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (iii-b) 97 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line indicates attachment to -D-; In certain embodiments -AB is of formula (iii-c) whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (iii-d) whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (iii-e) wherein(iii-e), the dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (iii-f) 98 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line indicates attachment to -D-. whereinthe dashed line indicates attachment to -D-, and u is an integer ranging from and including 14 to 22.
In certain embodiments -AB is of formula (iv) and u is 14. In certain embodiments -AB is of formula (iv) and u is 15. In certain embodiments -AB is of formula (iv) and u is 16. In certain embodiments -AB is of formula (iv) and u is 17. In certain embodiments -AB is of formula (iv) and u is 18. In certain embodiments -AB is of formula (iv) and u is 19. In certain embodiments -AB is of formula (iv) and u is 20. In certain embodiments -AB is of formula (iv) and u is 21. In certain embodiments -AB is of formula (iv) and u is 22.
In certain embodiments -AB is of formula (v) the dashed line indicates attachment to -D-;v is an integer ranging from and including 14 to 22; andthe stereocenter marked with the asterisk is either in S- or R-configuration.
In certain embodiments -AB is of formula (iv) wherein WO 2024/184351 PCT/EP2024/055724 In certain embodiments -AB is of formula (v) and v is 14. In certain embodiments -AB is of formula (v) and v is 15. In certain embodiments -AB is of formula (v) and v is 16. In certain embodiments -AB is of formula (v) and v is 17. In certain embodiments -AB is of formula (v) and v is 18. In certain embodiments -AB is of formula (v) and v is 19. In certain embodiments -AB is of formula (v) and v is 20. In certain embodiments -AB is of formula (v) and v is 21. In certain embodiments -AB is of formula (v) and v is 22.
In certain embodiments -AB is of formula (v) and v is 14 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (v) and v is 15 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (v) and v is 16 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (v) and v is 17 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (v) and v is 18 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (v) and v is 19 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (v) and v is 20 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (v) and v is 21 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (v) and v is 22 and the stereocenter marked with the asterisk is in R-configuration.
In certain embodiments -AB is of formula (v) and v is 14 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (v) and v is 15 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (v) and v is 16 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (v) and v is 17 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (v) and v is 18 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (v) and v is 19 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (v) and v is 20 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (v) and v is 21 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (v) and v is 22 and the stereocenter marked with the asterisk is in S-configuration.
In certain embodiments -AB is of formula (v-a) 100 WO 2024/184351 PCT/EP2024/055724 N H(v-a), whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (v-b) HO. (v-b),whereinthe dashed line indicates attachment to -D-; In certain embodiments -AB is of formula (v-c) whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (v-d) (v-d),whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (vi-e) 101 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (vi-f) whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (vii) wherein the dashed line indicates attachment to -D-;w is an integer ranging from and including 14 to 22; andthe stereocenter marked with the asterisk is either in S- or R-configuration.
In certain embodiments -AB is of formula (vii) and w is 14. In certain embodiments -AB is of formula (vii) and w is 15. In certain embodiments -AB is of formula (vii) and w is 16. In certain embodiments -AB is of formula (vii) and w is 17. In certain embodiments -AB is of formula (vii) and w is 18. In certain embodiments -AB is of formula (vii) and w is 19. In certain embodiments -AB is of formula (vii) and w is 20. In certain embodiments -AB is of formula (vii) and w is 21. In certain embodiments -AB is of formula (vii) and w is 22.
In certain embodiments -AB is of formula (vii) and w is 14 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (vii) and w is and the stereocenter marked with the asterisk is in R-configuration. In certain 102 WO 2024/184351 PCT/EP2024/055724 embodiments -AB is of formula (vii) and w is 16 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (vii) and w is 17 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (vii) and w is 18 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (vii) and w is 19 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (vii) and w is and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (vii) and w is 21 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (vii) and w is 22 and the stereocenter marked with the asterisk is in R-configuration.
In certain embodiments -AB is of formula (vii) and w is 14 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (vii) and w is and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (vii) and w is 16 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (vii) and w is 17 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (vii) and w is 18 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (vii) and w is 19 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (vii) and w is and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (vii) and w is 21 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (vii) and w is 22 and the stereocenter marked with the asterisk is in S-configuration.
In certain embodiments -AB is of formula (vii-a): whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (vii-b): 103 WO 2024/184351 PCT/EP2024/055724 (vii-b),whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (vii-c): (vii-c),whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (vii-d): (vii-d),whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (vii-e): (vii-e),whereinthe dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (vii-f): wherein(vii-f), 104 WO 2024/184351 PCT/EP2024/055724 the dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (viii) wherein the dashed line indicates attachment to -D-;w is an integer ranging from and including 14 to 22; andthe stereocenter marked with the asterisk is either in S- or R-configuration.
In certain embodiments -AB is of formula (viii) and x is 14. In certain embodiments -AB is of formula (viii) and x is 15. In certain embodiments -AB is of formula (viii) and x is 16. In certain embodiments -AB is of formula (viii) and x is 17. In certain embodiments -AB is of formula (viii) and x is 18. In certain embodiments -AB is of formula (viii) and x is 19. In certain embodiments -AB is of formula (viii) and x is 20. In certain embodiments -AB is of formula (viii) and x is 21. In certain embodiments -AB is of formula (viii) and x is 22.
In certain embodiments -AB is of formula (viii) and x is 14 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (viii) and x is and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (viii) and x is 16 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (viii) and x is 17 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (viii) and x is 18 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (viii) and x is 19 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (viii) and x is and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (viii) and x is 21 and the stereocenter marked with the asterisk is in R-configuration. In certain embodiments -AB is of formula (viii) and x is 22 and the stereocenter marked with the asterisk is in R-configuration.
In certain embodiments -AB is of formula (viii) and x is 14 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (viii) and x is 105 WO 2024/184351 PCT/EP2024/055724 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (viii) and x is 16 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (viii) and x is 17 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (viii) and x is 18 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (viii) and x is 19 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (viii) and x is and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (viii) and x is 21 and the stereocenter marked with the asterisk is in S-configuration. In certain embodiments -AB is of formula (viii) and x is 22 and the stereocenter marked with the asterisk is in S-configuration.
In certain embodiments -AB is of formula (viii-a)HO^^O (viii-a),wherein the dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (viii-b)HO^/O _ (viii-b),wherein the dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (viii-c)HO^/O _ (viii-c),wherein the dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (viii-d) 106 WO 2024/184351 PCT/EP2024/055724 wherein the dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (viii-e) wherein the dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (viii-f) wherein the dashed line indicates attachment to -D-.
In certain embodiments -AB is of formula (ix-i) whereinO H X1-isPhH 2CO< (؛ phH 2C0 )or 2O O 0 O■X2is with Ph being phenyl,a is 0, 1,2, 3, 4, 5, 6, 7, 8, 9 or 10;b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;dis 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; 107 WO 2024/184351 PCT/EP2024/055724 mis 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;nis 10, 11, 12, 13 ,14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 ; p is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
In certain embodiments -AB is of formula (ix-i) with a being 1, b being 1, c being 1, d being 1, m being 1, n being 18 and m being 1.
In certain embodiments -AB is of formula (ix-i) and X1- is HO /*and -X2 is>p(0h)2 t' . In certain embodiments -AB is of formula (ix-i) and X1- is PhH 2CO an j _^2 O' P(OCH2Ph) 2 jn certain embodiments -AB is of formula (ix-i) and X1- is PhH2cO 0,P(OH)2and -X2 is A . In certain embodiments -AB is of formula (ix-i) and X1- is HO O^P^is ' (OCH2Ph) 2 !n certain embodiments -AB is of formula (ix-i) and X1- is /*and -X2O P. and -X2 is ' OCH2Ph jn certain embodiments -AB is of formula (ix-i) and X1- is O (ho)2pS O P.and -X2 is x ' OH in certain embodiments -AB is of formula (ix-i) and X1- is and -X2 is ' OCH2Ph jn certain embodiments -AB is of formula (ix-i) and X1- isO(140)2*''and -X2is'' OH in certain embodiments -AB is of formula (ix-i) and X1- is O O o o is O P.O^P^and -X2 is ' (OCH2Ph) 2 jn certain embodiments -AB is of formula (ix-i) andOp . 0P•/ 11'* . >P(OH)2and -X is '' In certain embodiments -AB is of formula (ix-i) and 108 WO 2024/184351 PCT/EP2024/055724 Oand -X2is ׳'' 2 ^ HO ؛ is ؛- Xx * (OCH2Ph) 2 jn certain embodiments -AB is of formula (ix-i) and X1-is O(H0)2 / * an( | -X2 is>P(OH)2 In certain embodiments -AB is a peptidic albumin-binding moiety.
If -D- is a peptide or protein drug moiety, such peptidic moiety -AB may be fused to the N- or C-terminus of -D-, either directly or with a peptidic spacer between -D- and -AB.
In certain embodiments -AB is selected from the group consisting of WWEQDRDWDFDVFGGGTP (SEQ ID NO:34);DICLPRWGCLW (SEQ ID NO:3 5),wherein the cysteines at position 3 and 9 are connected via a disulfide bridge;RLIEDICLPRWGCLWEDD (SEQ ID NO:36),wherein the cysteines at position 7 and 13 are connected via a disulfide bridge;LAEAI In certain embodiments -AB is of SEQ ID NO:34. In certain embodiments -AB is of SEQ ID NO:35. In certain embodiments -AB is of SEQ ID NO:36. In certain embodiments -AB is of SEQ ID NO:37. In certain embodiments -AB is of SEQ ID NO:38. In certain embodiments -AB is of SEQIDNO:39.
In certain embodiments -AB is of formula (A-a): f °— la — l bN- , . ץ ' (A-a), whereinthe dashed line indicates attachment to -D-;-F° and -LA- are used as defined in formula (A), 109 WO 2024/184351 PCT/EP2024/055724 -LB - is a polymeric moiety.
The moiety -LB - is a polymeric moiety, meaning that it comprises at least one polymer moiety. In certain embodiments the one or more polymer moiety has a molecular weight of at least 4Da. In certain embodiments the one or more polymer moiety has a molecular weight of at least I kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 1.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 2 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 2.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 3 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 3.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 4 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 5 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 160 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 120 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 100 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 70 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 60 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 50 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 40 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 450 Da. In certain embodiments the one or more polymer moiety has a molecular weight of about 1 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 1.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 2 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 2.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 3 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 3.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 4 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 4.kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 5.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight 110 WO 2024/184351 PCT/EP2024/055724 of about 6 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 6.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 7 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 7.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 8 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 8.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 9 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 9.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 10 kDa. It is understood that if -LB - comprises one polymer moiety the minimum and maximum molecular weights provided above apply to this one polymer moiety and if -LB - comprises more than one polymer moiety the minimum and maximum molecular weights provided above refer to the minimum and maximum molecular weight of all polymer moieties together.
In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of at least 1.2 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of at least 1.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of at least 2 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of at least 2.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of at least 3 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of at least 3.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of at least 4 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of at least 4.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of at least 5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of no more than 200 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of no more than 1nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of no more than 150 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of no more than 125 nm. In certain embodiments the one or more polymer moiety of -Lb - has a Flory radius of no more than 100 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of no more than 75 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of no more than 50 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of no more than nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of no ill WO 2024/184351 PCT/EP2024/055724 more than 40 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of no more than 35 nm. In certain embodiments the one or more polymer moiety of -Lb - has a Flory radius of no more than 30 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 1.2 nm. In certain embodiments the one or more polymer moiety of -LB -has a Flory radius of about 1.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 2 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 2.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 3 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 3.nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 4 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 4.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 5.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 6 nm. In certain embodiments the one or more polymer moiety of -LB -has a Flory radius of about 6.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 7 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 8.5 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 9 nm. In certain embodiments the one or more polymer moiety of -LB - has a Flory radius of about 10 nm. It is understood that if -LB - comprises one polymer moiety the Flory radius provided above applies to this one polymer moiety and if -LB - comprises more than one polymer moiety the Flory radius provided above refers to the Flory radius of all polymer moieties together.
-LB - comprises one or more polymer moiety, such as polymer moiety selected from the group consisting of poly(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(hydroxyethyl acrylates), poly(hydroxyethyl- oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), 112 WO 2024/184351 PCT/EP2024/055724 poly(lact1c acids), poly(lact1c-co-glycohc acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, alginate, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof.
In certain embodiments -LB - comprises a PEG-based polymer. In certainembodiments -LB - comprises a hyaluronic acid-based polymer. In certainembodiments -LB - comprises a random coil polymer. In certain embodiments -LB - comprises a poly-sarcosine polymer.
In certain embodiments -LB - of formula (A-a) is of formula (a-3 ‘). dc □e /' ' (a-3 ’),whereinthe unmarked dashed line indicates attachment to -D-;the dashed line marked with the asterisk indicates attachment to -LA; ؟ HVN' X/- Rc - is ׳ or ;- Rd - is a polymeric moiety; andOO ,11/- Re- is selected from the group consisting of -CH2-, "' ''x and H ؟ Hh VN' A/If -Rb - of formula (A-a) is "' ׳ then -Rc - of formula (a-3 ’) is and if -Rb - of formula H ؟A/ VN,;(A-a) is ־"' then-R c - of formula (a-3 ’) is "' ׳ .
The moiety -Rd - of formula (a-3 ’) is a polymeric moiety, meaning that it comprises at least one polymer moiety. In certain embodiments the one or more polymer moiety has a molecular weight of at least 450 Da. In certain embodiments the one or more polymer moiety has a 113 WO 2024/184351 PCT/EP2024/055724 molecular weight of at least 1 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 1.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 2 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 2.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 3 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 3.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 4 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of at least 5 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 1kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 120 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 100 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 80 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 70 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 60 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 50 kDa. In certain embodiments the one or more polymer moiety has a maximum molecular weight of 40 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 450 Da. In certain embodiments the one or more polymer moiety has a molecular weight of about 1 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 1.kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 2.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 3 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 3.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 4 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 4.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 5.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 6 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 6.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 7 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 7.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 8 kDa. In certain embodiments the one or 114 WO 2024/184351 PCT/EP2024/055724 more polymer moiety has a molecular weight of about 8.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 9 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 9.5 kDa. In certain embodiments the one or more polymer moiety has a molecular weight of about 10 kDa. It is understood that if -Rd - of formula (a-3 ‘) comprises one polymer moiety the minimum and maximum molecular weights provided above apply to this one polymer moiety and if -Rd - of formula (a-3 ’) comprises more than one polymer moiety the minimum and maximum molecular weights provided above refer to the minimum and maximum molecular weight of all polymer moieties together.
In certain embodiments the one or more polymer moiety of -Rd - of formula (a-3 ’) has a Flory radius of at least 1.2 nm. In certain embodiments the one or more polymer moiety has a Flory radius of at least 1.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of at least 2 nm. In certain embodiments the one or more polymer moiety has a Flory radius of at least 2.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of at least 3 nm. In certain embodiments the one or more polymer moiety has a Flory radius of at least 3.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of at least 4 nm. In certain embodiments the one or more polymer moiety has a Flory radius of at least 4.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of at least 5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 200 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 175 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 150 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 125 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 100 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 75 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 50 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 45 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 40 nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than nm. In certain embodiments the one or more polymer moiety has a Flory radius of no more than 30 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 1.2 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 1.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of 115 WO 2024/184351 PCT/EP2024/055724 about 2 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 2.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 3 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 3.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 4 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 4.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 5.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 6 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 6.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 7 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 8.5 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 9 nm. In certain embodiments the one or more polymer moiety has a Flory radius of about 10 nm. It is understood that if -Rd - of formula (a-3 ‘) comprises one polymer moiety the Flory radius provided above applies to this one polymer moiety and if -Rd - of formula (a-3 ‘) comprises more than one polymer moiety the Flory radius provided above refers to the Flory radius of all polymer moieties together.
-Rd - of formula (a-3 ’) comprises one or more polymer moiety, such as polymer moiety selected from the group consisting of poly(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(hydroxyethyl acrylates), poly(hydroxyethyl- oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), polypropylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), polypinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, alginate, mannans, pectins, 116 WO 2024/184351 PCT/EP2024/055724 rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof.
In certain embodiments -Rd - of formula (a-3 ‘) comprises a PEG-based polymer. In certain embodiments -Rd - of formula (a-3 ‘) comprises a hyaluronic acid-based polymer. In certain embodiments -Rd - of formula (a-3 ’) comprises a random coil polymer. In certain embodiments -Rd - of formula (a-3 ’) comprises a poly-sarcosine polymer.
In certain embodiments the distance between any two moieties -AB of a compound is such that they can bind to two different binding sites on the same albumin molecule or to two different albumin molecules. All or some moieties -AB may bind to different albumin molecules and/or two or more moieties -AB may bind to one albumin molecule. In general, if a compound has x moieties -AB they may bind to up to x albumin molecules. It is understood that not all moieties -AB of a compound may be bound to an albumin molecule at any given time.
Binding to two or more different albumin molecules increases the molecular weight of the compound significantly, which has an advantageous effect on circulation half-life.
In certain embodiments -D- is a protein or peptide drug moiety and -AB is conjugated to a functional group of -D- provided by the N-terminal amine, the C-terminal carboxyl or a side chain of an amino acid residue. In certain embodiments -AB is conjugated to the N-terminal amine functional group of -D-. In certain embodiments -AB is conjugated to the C-terminal carboxyl functional group. In certain embodiments -AB is conjugated to a functional group provided by an amino acid residue of -D-, such as by a lysine, serine, aspartic acid, glutamic acid, arginine, histidine, threonine, glutamine, asparagine, cysteine, proline, tyrosine or tryptophan. In certain embodiments -AB is conjugated to the functional group of the side chain of a lysine of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of a serine of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of an aspartic acid of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of a glutamic acid of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of an arginine of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of a histidine of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of a threonine of -D-. In certain embodiments -AB is conjugated to the functional group of the side 117 WO 2024/184351 PCT/EP2024/055724 chain of a glutamine of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of an asparagine of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of a cysteine of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of a proline of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of a tyrosine of -D-. In certain embodiments -AB is conjugated to the functional group of the side chain of a tryptophan of -D-.
In certain embodiments -D-AB is selected from the group consisting of semaglutide, liraglutide, ecnoglutide, GZR18, GL0034, tirzepatide, cotadutide, BI-456906, pemvidutide, mazdutide, dapiglutide and retatrutide.
In certain embodiments -D-AB is selected from the group consisting of semaglutide, liraglutide, ecnoglutide, GZR18 and GL0034.
In certain embodiments -D-AB is semaglutide. Semaglutide is a compound of formula HX1EGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO:40), whereinX! is a-aminoisobutyric acid (Aib); andthe lysine at position 20 is chemically modified through conjugation to the epsilon-amine group of the lysine side-chain with whereinthe dashed line indicates attachment to the epsilon-amine group of the lysine side chain of the lysine at position 20.
Semaglutide may be prepared using methods known to those skilled in the art, such as those described in WO2006/097537.
In certain embodiments -D-AB is liraglutide. Liraglutide is a compound of formula HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO:41),wherein 118 WO 2024/184351 PCT/EP2024/055724 the lysine at position 20 is chemically modified through conjugation to the epsilon-amine group of the lysine side chain with whereinthe dashed line indicates attachment to the epsilon-amine group of the lysine side chain of the lysine at position 20.
In certain embodiments -D-AB is ecnoglutide. Ecnoglutide is a compound of formula HVEGTFTSDVSSYLEEQAAREFIKWLVRGRG (SEQ ID NO:42), whereinthe lysine at position 24 is chemically modified through conjugation to the epsilon-amine group of the lysine side chain with wherein the dashed line indicates attachment to the epsilon-amine group of the lysine side chain of the lysine at position 24.
In certain embodiments -D-AB is GZR18. GZR18 is a compound of formulaHGEGTFTSDVSSYLEGQAAKEFIAWLVRGRG (SEQ ID NO:43),whereinthe lysine at position 20 is chemically modified through conjugation to the epsilon-amine group of the lysine side-chain with wherein the dashed line indicates attachment to the epsilon amine group of the lysine side chain of the lysine at position 20. 119 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -D-AB is GL0034. GL0034 is also known as utreglutide and is a compound of formulaHXEGTFTSDVSSYLEGQAAKEFIAWLVRGRGL (SEQ ID NO:44), whereinX! is Aib; andthe lysine at position 20 is chemically modified through conjugation to the epsilon-amine group of the lysine side-chain with In certain embodiments -D- or -D-AB is a dual GLP-1 receptor agonist selected from the group consisting of tirzepatide, cotadutide, BI-456906, pemvidutide and mazdutide.
In certain embodiments -D-AB is a dual GLP-1 receptor agonist that activates the GLP-receptor and the GIP receptor. An example for such dual GLP-1 receptor agonist is tirzepatide. In certain embodiments -D-AB is tirzepatide. Tirzepatide is a compound of formulaYXEGTFTSDYSIXLDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO:45), whereinX! is Aib;X2 is Aib;the lysine at position 20 is chemically modified through conjugation to the epsilon-amine group of the lysine side-chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(YGlu)1-CO- (CH2)18-CO2H; andthe C-terminal serine, i.e. the serine at position 39, is amidated as a C-terminal primary amide.
The moiety ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(YGlu)1-CO-(CH2)18-CO2H has the following structure 120 wherein the dashed line indicates attachment to the epsilon amine group of the lysine side chain of the lysine at position 20.
WO 2024/184351 PCT/EP2024/055724 wherein the dashed line indicates attachment to -D-.
In certain embodiments -D-AB is a dual GLP-1 receptor agonist that activates the GLP-receptor and the glucagon receptor selected from the group consisting of cotadutide, BI- 456906, pemvidutide and mazdutide.
In certain embodiments -D-AB is cotadutide. Cotadutide is a compound of formula HSQGTFTSDKSEYLDSERARDFVAWLEAGG (SEQ ID NO:46), whereinthe lysine at position 10 is chemically modified through conjugation to the epsilon- amine group of the lysine side-chain with y-Glu-palmitoyl.
The moiety y-Glu-palmitoyl has the following structure: wherein the dashed line indicates attachment to -D-.
In certain embodiments -D-AB is BI-456906. BI-456906 is also known as survodutide and is a compound of formulaHXQGTFTSDYSKYLDERAAKDFIKWLESA (SEQ ID NO :47), whereinX! is 1-amino-cyclobutanecarboxylic acid (Ac4c);the lysine at position 24 is chemically modified through conjugation to the epsilon-amine group of the lysine side-chain with [17-carboxy-heptadecanoyl]-isoGlu-GSGSGG; and the C-terminal alanine, i.e. the alanine at position 29, is ami dated as a C-terminal primary amide.
The moiety [17-carboxy-heptadecanoyl]-isoGlu-GSGSGG has the following structure: 121 WO 2024/184351 PCT/EP2024/055724 wherein the dashed line indicates attachment to -D-.
In certain embodiments -D-AB is pemvidutide. Pemvidutide is a compound of formulaHXQGTFTSDYSKYLDEKAAKEFIQWLLQT (SEQ ID NO:48), whereinX! is Aib;the glutamic acid at position 16 and the lysine at position 20 are connected via a lactam bridge;the lysine at position 17 is chemically modified through conjugation to the epsilon-amine group of the lysine side-chain with glucuronic acid C-18, which is a moiety of formula whereinthe dashed line indicates attachment to the epsilon-amine group of the lysine at position 17; andthe C-terminal threonine, i.e. the threonine at position 29, is amidated as a C-terminal primary amide In certain embodiments -D-AB is mazdutide. Mazdutide is a compound of formulaHXQGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG (SEQ ID NO:49), whereinX! is Aib,the lysine at position 20 is chemically modified by conjugation of the epsilon-amine group of the lysine side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO- (CH2)18-CO2H; andthe C-terminal glycine, i.e. the glycine at position 34, is amidated. 122 WO 2024/184351 PCT/EP2024/055724 HO wherein the dashed line indicates attachment to -D-.
In certain embodiments -D-AB is a dual GLP-1 receptor agonist that activates the GLP-receptor and the GLP-2 receptor, such as dapiglutide. Dapiglutide is a compound of formulaHXEGSFTSELATILDKQAARDFIAWLIQHKITD (SEQ ID NO:50), whereinX! is Aib; andthe lysine in position 16 is chemically modified by conjugation of the epsilon-amino- group of the lysine side chain with [17-carboxy-heptadecanoyl]-isoGlu.
The moiety [17-carboxy-heptadecanoyl]-isoGlu has the following structure: wherein the dashed line indicates attachment to -D-.
In certain embodiments -D-AB is retatrutide, which is a triple GLP-1 receptor agonist that activates the GLP-1 receptor, the GIP receptor and the GCG receptor. Retatrutide is a compound of formulaYX1QGTFTSDYSIX2LDKKAQX3AFIEYLLEGGPSSGAPPPS (SEQ IDNO:51), whereinX! is Aib;X2 is a-methyl-leucine (aMeL);X3 is Aib;the lysine at position 17 is chemically modified by conjugation of the epsilon-amine group of the lysine side chain with (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(YGlu)-CO- (CH2)18-CO2H; and 123 The moiety ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)18-CO2H has the following structure: WO 2024/184351 PCT/EP2024/055724 the C-terminal serine, i.e. the serine at position 39, is amidated.
Retatrutide can also be described as Y-Aib-QGTFTSDYSI-aMeL-LDKK ((2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)-(YGlu)-CO-(CH 2)18-CO2H) AQ-Aib-AFIEYLLEGGPSSGAPPPS- NH2(SEQIDNO:51).
The moiety (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(yGlu)-CO-(CH2)18-CO2H has the following structure: In certain embodiments -D-AB is noiiglutide, also known as SHR20004.
In certain embodiments -D-AB is ZTOO2.
In certain embodiments -D-AB is selected from the group consisting of semaglutide, liraglutide, ecnoglutide, GZR18, GL0034, tirzepatide, cotadutide, BI-456906, pemvidutide, mazdutide, dapiglutide and retatrutide.
In certain embodiments -D-AB is of formula (b-1) wherein X1- is HO 124 EGTFTSDYS I—N WO 2024/184351 PCT/EP2024/055724 ס 0 ס 0■X2 is with Ph being phenyl.
The moiety -D- of formula (b-1) has the sequence of SEQ ID NO:57YXEGTFTSDYSIXLDKIAQKAFVQWLIAGGPSSGAPPPS,with X! and X2 being Aib.
The compounds of formula (b-1) are disclosed in WO2022159395 and WO2023/044290, the content of which is herewith incorporated by reference in its entirety. 0 0A/ V׳P(OH)2In certain embodiments -D-AB is of formula (b-1) and X1- is HO /*and -X2 is ''' . In certain embodiments D-AB is of formula (b-1) and X1- is PhH 2CO a nd _^2 (OCH2Ph) 2 jn certain embodiments D-AB is of formula (b-1) and X1- isPhH2CO 0 0VP(OH)2 A/and -X2 is ''' . In certain embodiments D-AB is of formula (b-1) and X1- is HO /*O^P^and -X2 is ' (OCH2Ph) 2 jn certain embodiments D-AB is of formula (b-1) and X1- is ? 0A ;Aand -X2 is ' OCH2Ph jn certain embodiments D-AB is of formula (b-1) andOp . °/ph|_| qq^A 'AX1- is ' 2 '2 and -X2 is x ' OH in certain embodiments D-AB is of formula (b-1)O 0, A ;Aand X1- is HO72 / * an( | _x 2 is x ' OCH2Ph jn certain embodiments D-AB is of formula (b-1) O °( A* 'Aand X1- is HO/2 / an( | _x 2 is x ' OH in certain embodiments D-AB is of formula (b-1) and 125 WO 2024/184351 PCT/EP2024/055724 is (b-1) and X1- is 9 ° and -X2 is ' (OCH2Ph) 2 jn certain embodiments D-AB is of formulaOp . 0P•/ 11 ׳ , >P(OH)2and -X is '' In certain embodiments D-AB is ofO o Il II formula (b-1) and X1- is *־*O/2 / * anc j _x 2 is x ' (OCH2Ph) 2 jn certain embodiments D-AB is o 0( P(OH - י > k1nf P ) ,of formula (b-1) and X1- is 2 ' and -X2 is '' In certain embodiments -D-AB is a compound of formulak(YE-(miniPEG)2-YE-COC16H32CO 2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEW LRKKLQDVHK(YE-(miniPEG)2-YE-COC16H32CO 2H)-OH (SEQ ID NO:52), whereink is d-Lys;yE is the 1-isomer of gamma, glutamic acid;miniPEG is COCH,OCHCHOCHCHNH;COC16H32CO2H is C18 diacid;(N-Me)G is sarcosine;K is 1-isomer of lysine; and-OH designates the C-terminal amino acid has a terminal carboxylic acid.
In certain embodiments -D-AB is a compound of formulak(YE-(miniPEG)2-YE-COC16H32CO 2H)(N-Me)GSVSEIQLMHNLGKHLNSMERVEW LRKKLQDVHK(YE-(miniPEG)2-YE-COC16H32CO 2H)-OH (SEQ ID NO:53), whereink is d-Lys;yE is the 1-isomer of gamma, glutamic acid;(miniPEG)2 is COCHOCHCHOCHCH,NH;COC16H32CO2H is C18 diacid;(N-Me)G is sarcosine;K is 1-isomer of lysine; and-OH designates the C-terminal amino acid has a terminal carboxylic acid. 126 WO 2024/184351 PCT/EP2024/055724 If -D- is a peptide or protein drug moiety, -L1- is either conjugated to a functional group of a side chain of an amino acid residue of -D-, to the N-terminal amine functional group or to the C-terminal carboxyl functional group of -D- or to a nitrogen atom in the backbone chain of -D-.
If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of -D- selected from the group consisting of carboxylic acid, primary amine, secondary amine, maleimide, thiol, sulfonic acid, carbonate, carbamate, hydroxyl, aldehyde, ketone, hydrazine, isocyanate, isothiocyanate, phosphoric acid, phosphonic acid, haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, sulfate, disulfide, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, guanidine and aziridine. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of -D- selected from the group consisting of hydroxyl, primary amine, secondary amine and guanidine. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of -D- selected from the group consisting of primary amine and secondary amine. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a primary amine of-D-.
If -D- is a peptide or protein drug moiety, -L1- may be conjugated to a functional group of the side chain of an amino acid residue of -D-, which may be a proteinogenic amino acid residue or a non-proteinogenic amino acid residue.
If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of the side chain of a proteinogenic amino acid residue of -D-. In certain embodiments such amino acid residue is selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid and arginine. In certain embodiments such amino acid residue is selected from the group consisting of lysine, aspartic acid, arginine and serine. In certain embodiments such amino acid residue is selected from the group consisting of lysine, arginine and serine.
If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of a lysine residue of -D-. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of a histidine residue of -D-. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group 127 WO 2024/184351 PCT/EP2024/055724 of a tryptophan residue of -D-. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of a serine residue of -D-. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of a threonine residue of -D-. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of a tyrosine residue of -D-. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of an aspartic acid residue of -D-. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of a glutamic acid residue of -D-. If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of an arginine residue of -D-.
If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to a functional group of the side chain of a non-proteinogenic amino acid residue of -D-.
It is understood that not every peptide or protein drug moiety -D- may comprise all of these amino acid residues.
If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to the N- terminal amine functional group of -D-.
If -D- is a peptide or protein drug moiety, -L1- is in certain embodiments conjugated to the C- terminal functional group of -D-.
The moiety -L1- may be connected to -D- through any type of linkage, provided that it is reversible. In certain embodiments -L1- is connected to -D- through a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide and acylguanidine. In certain embodiments -L1- is connected to -D- through a linkage selected from the group consisting of amide, ester, carbamate and acylguanidin. It is understood that some of these linkages per se are not reversible, but that in the present invention neighboring groups present in -L1- render these linkages reversible.
In certain embodiments -L1- is connected to -D- through an amide linkage. In certain embodiments -L1- is connected to -D- through a carbamate linkage. In certain 128 WO 2024/184351 PCT/EP2024/055724 embodiments -L1- is connected to -D- through an ester linkage. In certain embodiments -L1- is connected to -D- through an acylguanidine linkage.
The moiety -L1- is a reversible prodrug linker from which the drug, i.e., H-D-AB, is released in its free form, i.e. it is a traceless prodrug linker. It is understood that the “H-“ in “H-D-AB” is a hydrogen. Suitable prodrug linkers are known in the art, such as for example the reversible prodrug linker moieties disclosed in WO 2005/099768 A2, WO 2006/136586 A2, WO 2011/089216 Al and WO 2013/024053 Al, which are incorporated by reference herewith.
In certain embodiments -L1- is disclosed in WO 2009/095479 A2. Accordingly, in certain embodiments the moiety -L1- is of formula (II): wherein the dashed line indicates attachment to a nitrogen, hydroxyl or thiol of -D-;- X- is selected from the group consisting of -C(R4R4a )-; -N(R4)-; -O-; -C(R4R4a )- C(R5R5a )-; -C(R5R5a )-C(R4R4a )-; -C(R4R4a )-N(R6)-; -N(R6)-C(R4R4a )-;C(R4R4a )-O-; -O-C(R4R4a )-; and -C(R7R7a )-;X 1 is selected from the group consisting of C; and S(O);- X2- is selected from the group consisting of -C(R8R83)-; and -C(R8R8a )-C(R9R93)-;= X3 is selected from the group consisting of =0; =S; and =N-CN;- R1, -Rla , -R2, -R2a , -R4, -R4a , -R5, -R53, -R6, -R8, -R83, -R9, and -R93 are independently selected from the group consisting of -H; and C1-6 alkyl;- R3, and -R33 are independently selected from the group consisting of -H; and C1-6 alkyl, provided that in case one of -R3, -R33 or both are other than -H they are connected to N to which they are attached through an SP3-hybridized carbon atom;- R7 is selected from the group consisting of -N(R10R10a ); and -NR10-(C=O)-R11;-R7a , -R10, -R10a , and -R11 are independently of each other selected from the group consisting of -H; and C1-6 alkyl;optionally, one or more of the pairs -Rla /-R4a , -R13/-R53, -Rla /-R7a , -R4a /-R5a , and -R8a /-R9a form a chemical bond;optionally, one or more of the pairs -RV-R13, -R2/-R2a , -R4/-R4a , -R5/-R5a , -R8/-R8a , 129 WO 2024/184351 PCT/EP2024/055724 and -R9/-R9a are joined together with the atom to which they are attached to form a C3- cycloalkyl; or 3- to 10-membered heterocyclyl;optionally, one or more of the pairs -R1/-R4, -R1/-R5, -R1/-R6, -R1/-R7, -R4/-R5, -R4/-R6, -R8/-R9, and -R2/-R3 are joined together with the atoms to which they are attached to form a ring A;optionally, R3/R3a 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; C3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; andwherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L2- or a substituent.
In certain embodiments -L1- of formula (II) is substituted with one moiety -L2-.
In certain embodiments -L1- of formula (II) is not further substituted.
It is understood that if -R3/-R3a of formula (II) are joined together with the nitrogen atom to which they are attached to form a 3 - to 10-membered heterocycle, only such 3- to 10-membered heterocycles may be formed in which the atoms directly attached to the nitrogen are SP3- hybridized carbon atoms. In other words, such 3- to 10-membered heterocycle formed by -R3/-R3a together with the nitrogen atom to which they are attached has the following structure: whereinthe dashed line indicates attachment to the rest of -L1-;the ring comprises 3 to 10 atoms comprising at least one nitrogen; andR# and R## represent an sp3-hydridized carbon atom.
It is also understood that the 3- to 10-membered heterocycle may be further substituted. 130 WO 2024/184351 PCT/EP2024/055724 Exemplary embodiments of suitable 3- to 10-membered heterocycles formed by -R3/-R3a of formula (II) together with the nitrogen atom to which they are attached are the following: -؛־ CH R-V N-r- O, / and '-----' whereindashed lines indicate attachment to the rest of the molecule; and-R is selected from the group consisting of -H and C1-6 alkyl.
-L1- of formula (II) may optionally be further substituted. In general, any substituent may be used as far as the cleavage principle is not affected, i.e., the hydrogen marked with the asterisk in formula (II) is not replaced and the nitrogen of the moiety of formula (II) remains part of a primary, secondary or tertiary amine, i.e., -R3 and -R3a are independently of each other -H or are connected to -N< through an sp3-hybridized carbon atom.
In one embodiment -R1 or -Rla of formula (II) is substituted with -L2-. In another embodiment -R2 or -R2a of formula (II) is substituted with -L2-. In another embodiment -Ror -R3a of formula (II) is substituted with -L2-. In another embodiment -R4 of formula (II) is substituted with -L2-. In another embodiment -R5 or -R5a of formula (II) is substituted with -L2-. In another embodiment -R6 of formula (II) is substituted with -L2-. In another embodiment -Ror -R7a of formula (II) is substituted with -L2-. In another embodiment -R8 or -R8a of formula (II) is substituted with -L2-. In another embodiment -R9 or -R9a of formula (II) is substituted with -L2-. In another embodiment -R10 is substituted with -L2-. In another embodiment -R11 is substituted with -L2-. In certain embodiments -R3 of formula (II) is substituted with -L2-.
In certain embodiments -X- of formula (II) is selected from the group consisting of -C(R4R4a )-, -N(R4)- and -C(R7R7a )-. In certain embodiments -X- of formula (II) is -C(R4R4a )-. In certain embodiments -X- of formula (II) is -C(R7R7a )-. 131 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -R7 of formula (II) is -NR10-(C=O)-Rn.
In certain embodiments -R7a of formula (II) is selected from -H, methyl and ethyl. In certain embodiments -R7a of formula (II) is -H.
In certain embodiments -R10 is selected from -H, methyl and ethyl. In certain embodiments -Ris methyl.
In certain embodiments -R11 is selected from -H, methyl and ethyl. In certain embodiments -Ris -H. In certain embodiments -R11 is substituted with -L2-.
In certain embodiments -X- of formula (II) is -N(R4)-.
In certain embodiments -R4 is selected from the group consisting of -H, methyl and ethyl. In certain embodiments -R4 is -H.
In certain embodiments X1 of formula (II) is C.
In certain embodiments =X3 of formula (II) is =0.
In certain embodiments -X2- of formula (II) is -C(R8R8a )-.
In certain embodiments -R8 and -R8a of formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R8 and -R8a of formula (II) is -H. In certain embodiments both -R8 and -R8a of formula (II) are -H.
In certain embodiments -R1 and -Rla of formula (II) are independently selected from the group consisting of -H, methyl and ethyl.
In certain embodiments at least one of -R1 and -Rla of formula (II) is -H. In certain embodiments -R1 and -Rla of formula (II) are -H. 132 WO 2024/184351 PCT/EP2024/055724 In certain embodiments at least one of -R1 and -Rla of formula (II) is methyl. In certain embodiments both -R1 and -Rla of formula (II) are methyl.
In certain embodiments -R2 and -R2a of formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments at least one of -R2 and -R2a of formula (II) is -H. In certain embodiments both -R2 and -R2a of formula (II) are H.
In certain embodiments -R3 and -R3a of formula (II) are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl.
In certain embodiments at least one of -R3 and -R3a of formula (II) is methyl. In certain embodiments -R3 of formula (II) is methyl and -R3a of formula (II) is -H.
In certain embodiments -R3 and -R3a of formula (II) are both -H.
In certain embodiments -D- is connected to -L1- through a nitrogen by forming an amide bond.
In certain embodiments -L1- is of formula (II), wherein X is -C(R7R7a )-; X1 is C; -X2- is -C(R8R8a )-C(R9R9a )-; =X3 is =0; -R1 and -Rla are -H; -R2 and -R2a are -H; -Rand -R3a are methyl; -R7 is -N(R10R10a ); -R7a is -H; -R8, -R8a , -R9 and -R9a are -H; and -R10 is methyl and -R10a is -H.
In certain embodiments -L1- is of formula (Ila) whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L2-.
In certain embodiments -L1- is of formula (lla-a) 133 WO 2024/184351 PCT/EP2024/055724 (IIa-a),whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L2-.
In certain embodiments -L1- is of formula (lla-b) whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L2-.
The moiety of formula (Ila), (IIa-a) and (lla-b) is connected to -D- via an amide bond formed by a nitrogen of an amine functional group and the carbonyl to the left of the dashed line marked with the asterisk.
In certain embodiments -L1- is of formula (II), wherein X is -C(R7R7a )-; X1 is C; -X2- is -C(R8R8a )-C(R9R9a )-; =X3 is =0; -R1 and -Rla are -H; -R2 and -R2a are -H; -Rand -R3a are methyl; -R7 is -NR10-(C=O)-R11; -R7a is -H; -R8, -R8a , -R9 and -R9a are -H; and -Ris methyl and -R11 is -H.
In certain embodiments -L1- is of formula (II), wherein X is -C(R7R7a )-; X1 is C; -X2- is -C(R8R8a )-C(R9R9a )-; =X3 is =0; -R1 and -Rla are -H; -R2 and -R2a are -H; -Rand -R3a are methyl; -R7 is -NR10-(C=O)-R11; -R7a is -H; -R8, -R8a , -R9 and -R9a are -H; and -Ris -H and -R11 is -H.
In certain embodiments -L1- is of formula (llab) 134 WO 2024/184351 PCT/EP2024/055724 N TH I (llab), whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L2-.
In certain embodiments -L1- is of formula (llab-a) (llab-a),whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L2-.
In certain embodiments -L1- is of formula (llab-b) (llab-b),whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L2-.
The moiety of formula (llab), (llab-a) and (llab-b) is connected to -D- via an amide bond formed by a nitrogen of an amine functional group and the carbonyl to the left of the dashed line marked with the asterisk.
In certain embodiments -L1- is disclosed in WO2016/020373A1. Accordingly, in certain embodiments the moiety -L1- is of formula (III): WO 2024/184351 PCT/EP2024/055724 wherein the dashed line indicates attachment to a primary or secondary amine or hydroxyl of -D- through an amide or ester linkage, respectively;- R1, -Rla , -R2, -R2a , -R3 and -R3a are independently of each other selected from the group consisting of -H, -C(R8R8a R8b), -C(=O)R8, -C=N, -C(=NR8)R8a ,- CR8(=CR8a R8b), -OCR8 and -T;- R4, -R5 and -R5a are independently of each other selected from the group consisting of-H, -C(R9R9a R9b) and -T;al and a2 are independently of each other 0 or 1;each -R6, -R6a , -R7, -R7a , -R8, -R8a , -R8b , -R9, -R9a , and -R9b are independently of each other selected from the group consisting of -H, halogen, -CN, -COOR10, -OR10, -C(O)R10, -C(O)N(R10R10a ), -S(O)2N(R10R10a ), -S(O) N(R10R10a ), -S(O)2R10, -S(O)R10, -N(R10)S(O)2N(R10a R10b), -SR10, -N(R10R10a ), -NO2, -OC(O)R10, -N(R10)C(O)R10a , -N(R10)S(O)2R10a , -N(R10)S(O)R10a ,- N(R10)C(O)OR10a , -N(R10)C(O)N(R10a R10b),-OC(O)N(R10R10a ), -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl; wherein -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more -R11, which are the same or different and wherein C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(R12)-, -S(O)2N(R12)-, -S(O)N(R12)-,- S(O)2-, -S(O)-, -N(R12)S(O)2N(R12a )-,-S-,- N(R12)-, -OC(OR12)(R12a )-, -N(R12)C(O)N(R12a )-, and -OC(O)N(R12)-;each -R10, -R10a , and -R10b is independently selected from the group consisting of -H, -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl; wherein -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more -R11, which are the same or different and wherein C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R12)-, -S(O)2N(R12)-, -S(O)N(R12)-, -S(O)2-, 136 WO 2024/184351 PCT/EP2024/055724 -S(O)-, -N(R12)S(O)2N(R12a )-, -S-, -N(R12)-, -OC(OR12)(R12a )-, -N(R12)C(O)N(R12a )-, and -OC(O)N(R12)-;each T is independently of each other 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 -R11, which are the same or different;each -R11 is independently of each other selected from halogen, -CN, oxo (=0), -C00R13, -OR13, -C(0)R13, -C(O)N(R13R13a ), -S(O)2N(R13R13a ),-S(O)N(R13R13a ), -S(O)2R13, -S(O)R13, -N(R13)S(O)2N(R13a R13b), -SR13,-N(R13R13a ), -NO2, -0C(0)R13, -N(R13)C(O)R13a , -N(R13)S(O)2R13a ,-N(R13)S(O)R13a , -N(R13)C(O)OR13a , -N(R13)C(O)N(R13a R13b),-OC(O)N(R13R13a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;each -R12, -R12a , -R13, -R13a , and -R13b is independently selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;optionally, one or more of the pairs -RV-R13, -R2/-R2a , -R3/-R3a , -R6/-R6a , and -R7/-R7a are joined together with the atom to which they are attached to form a C3-10 cycloalkyl or a 3- to 10-membered heterocyclyl;optionally, one or more of the pairs -R1/-R2, -R1/-R3, -R1/-R4, -R1/-R5, -R1/-R6, -r V-r 7, -r 2/-r 3, -r 2/-r 4, -r 2/-r 5, -r 2/-r 6, -r 2/-r 7, -r 3/-r 4, -r 3/-r 5, -r 3/-r 6, -R3/-R7, -R4/-R5, -R4/-R6, -R4/-R7, -R5/-R6, -R5/-R7, and -R6/-R7 are joint 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;wherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted.
The optional further substituents of -L1- of formula (III) are in certain embodiments as described above.
In certain embodiments -L1- of formula (III) is substituted with one moiety -L2-. 137 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -L1- of formula (III) is not further substituted.
In certain embodiments -L1- is as disclosed in EP1536334B1, WO2009/009712A1, WO2008/034122A1, WO2009/143412A2, WO2011/082368A2, and US8618124B2, which are herewith incorporated by reference in their entirety.
In certain embodiments -L1- is as disclosed in US8946405B2 and US8754190B2, which are herewith incorporated by reference in their entirety. Accordingly, in certain embodiments -L1- is of formula (IV): R2 R5 0R—C—|-C=0|----- C—X-C-Y،؛ 15 1 L 1 mH R (IV). whereinthe dashed line indicates attachment to -D- and wherein attachment is through a functional group of -D- selected from the group consisting of -OH, -SH and -NH2;m is 0 or 1;at least one or both of -R1 and -R2 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(O)R3, -S(O)R3, -S(O)2R3, and -SR4,one and only one of -R1 and -R2 is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl;-R3 is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR9 and -N(R9)2;-R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;each -R5 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; 138 WO 2024/184351 PCT/EP2024/055724 - R9 is selected from the group consisting of -H and optionally substituted alkyl;- Y- is absent and -X- is -0- or -S-; or- Y- is -N(Q)CH2- and -X- is -0-;Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;optionally, -R1 and -R2 may be joined to form a 3 to 8-membered ring; and optionally, both -R9 together with the nitrogen to which they are attached form a heterocyclic ring;wherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted.
Only in the context of formula (IV) the terms used have the following meaning: The term “alkyl ” as used herein includes linear, branched or cyclic saturated hydrocarbon groups of 1 to 8 carbons, or in certain embodiments 1 to 6 or 1 to 4 carbon atoms.
The term “alkoxy ” includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar.
The term “alkenyl ” includes non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds.
The term "alkynyl" includes non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds.
The term “aryl ” includes aromatic hydrocarbon groups of 6 to 18 carbons, such as 6 to carbons, including groups such as phenyl, naphthyl, and anthracenyl. The term “heteroaryl ” includes aromatic rings comprising 3 to 15 carbons containing at least one N, O or S atom, such as 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. 139 WO 2024/184351 PCT/EP2024/055724 In some instance, alkenyl, alkynyl, aryl or heteroaryl moieties may be coupled to the remainder of the molecule through an alkylene linkage. Under those circumstances, 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.
The term “halogen ” includes bromo, fluoro, chloro and iodo.
The term “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, 0, or S atom. Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term “heteroaryl ” above.
When a ring system is optionally substituted, 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, -NR2, -OCOR, -NRCOR, -COOR, -CONR2, -SOR, -SO,R, -SONR2, -SO,N R2, 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.
In certain embodiments -L1- of formula (IV) is substituted with one moiety -L2-.
In certain embodiments -L1- of formula (IV) is not further substituted.
In certain embodiments -L1- is as disclosed in WO2013/036857A1, which is herewith incorporated by reference in its entirety. Accordingly, in certain embodiments -L1- is of formula (V): 4O H RII I R—S-C-------II 12 •O R R(V),whereinthe dashed line indicates attachment to -D- through an amine functional group of -D-; 140 WO 2024/184351 PCT/EP2024/055724 - R1 is selected from the group consisting of optionally substituted C1-C6 linear, branched, or cyclic alkyl; optionally substituted aryl; optionally substituted heteroaryl; alkoxy; and -NR52;- R2 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;- R3 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;-R4 is selected from the group consisting of -H; optionally substituted C1-C6 alkyl; optionally substituted aryl; and optionally substituted heteroaryl;each -R5 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 -R5 can be cycloalkyl or cycloheteroalkyl;wherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted.
Only in the context of formula (V) the terms used have the following meaning: “Alkyl ”, “alkenyl ”, and "alkynyl" include linear, branched or cyclic hydrocarbon groups of 1- 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, such as 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, such as 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.
The term “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 141 WO 2024/184351 PCT/EP2024/055724 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; thiocarbamate; thiourea; ketone; sulfone; sulfonamide; aryl including phenyl, naphthyl, and anthracenyl; heteroaryl including 5-member heteroaryls including as pyrrole, imidazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, thiadiazole, triazole, oxadiazole, and tetrazole, 6-member heteroaryls including pyridine, pyrimidine, pyrazine, and fused heteroaryls including benzofuran, benzothiophene, benzoxazole, benzimidazole, indole, benzothiazole, benzisoxazole, and benzisothiazole.
In certain embodiments -L1- of formula (V) is substituted with one moiety -L2-.
In certain embodiments -L1- of formula (V) is not further substituted.
In certain embodiments -L1- is as disclosed in US7585837B2, which is herewith incorporated by reference in its entirety. Accordingly, in certain embodiments -L1- is of formula (VI): (VI), whereinthe dashed line indicates attachment to -D- through an amine functional group of -D;R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, aralkyl, halogen, nitro, -SO3H, -SO2NHR5, amino, ammonium, carboxyl, POzH2, and OPO3H2;R3, R4, and R5 are independently selected from the group consisting of hydrogen, alkyl, and aryl;wherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted. 142 WO 2024/184351 PCT/EP2024/055724 Suitable substituents for formulas (VI) are alkyl (such as C1-6 alkyl), alkenyl (such as C2-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.
Only in the context of formula (VI) the terms used have the following meaning: The terms “alkyl ”, “alkoxy ”, “alkoxyalkyl ”, “aryl ”, "alkaryl" and “aralkyl ” mean alkyl radicals of 1-8, such as 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. The term “halogen ” includes bromo, fluoro, chloro and iodo.
In certain embodiments -L1- of formula (VI) is substituted with one moiety -L2-.
In certain embodiments -L1- of formula (VI) is not further substituted.
A further preferred embodiment for -L1- is disclosed in WO2002/089789A1, which is herewith incorporated by reference in its entirety. Accordingly, a preferred moiety -L1- is of formula (VII): (VII),whereinthe dashed line indicates attachment to -D- through an amine functional group of -D-;Li is a bifunctional linking group,Yi and ¥2 are independently 0, S or NR7;R2, R3, R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy, and C1-6 heteroalkoxy; 143 WO 2024/184351 PCT/EP2024/055724 Ar is a moiety which when included in formula (VII) forms a multi substituted 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;wherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted.
Only in the context of formula (VII) the terms used have the following meaning: The term “alkyl ” shall be understood to include, e.g., straight, branched, substituted Cmalkyls, including alkoxy, C3-8 cycloalkyls or substituted cycloalkyls, etc.
The term “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; substituted 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 moieties such as methoxy; and phenoxy includes moieties such as 3-nitrophenoxy. Halo- shall be understood to include fluoro, chloro, iodo and bromo.
In certain embodiments -L1- of formula (VII) is substituted with one moiety -L2-.
In certain embodiments -L1- of formula (VII) is not further substituted.
In certain embodiments -L1- comprises a substructure of formula (VIII) (VIII), 144 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D- through an amide bond;the unmarked dashed lines indicate attachment to the remainder of -L1-; and wherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted.
In certain embodiments -L1- of formula (VIII) is substituted with one moiety -L2-.
In certain embodiments -L1- of formula (VIII) is not further substituted.
In certain embodiments -L1- comprises a substructure of formula (IX) whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D- through a carbamate bond;the unmarked dashed lines indicate attachment to the remainder of -L1-; and wherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted.
In certain embodiments -L1- of formula (IX) is substituted with one moiety -L2-.
In certain embodiments -L1- of formula (IX) is not further substituted.
In certain embodiments -L1- has a structure as disclosed in WO2020/206358 Al. Accordingly, in certain embodiments the moiety -L1- is of formula (X): 145 WO 2024/184351 PCT/EP2024/055724 *CH2)n ) — ؛ — R1 R4 HC------R2 o؛ 11 IIc --- c ----- o -----c ----- y —■— R4 H (X),wherein the unmarked dashed line indicates attachment to -D-;the dashed line marked with the asterisk indicates attachment to -L2-;n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6;-R1 and -R2 are independently an electron-withdrawing group, alkyl, or -H, and wherein at least one of -R1 or -R2 is an electron-withdrawing group;each -R4 is independently C1-C3 alkyl or the two -R4 are taken together with the carbon atom to which they are attached to form a 3- to 6-membered ring; and-Y- is absent when -D- is a drug moiety connected through an amine, or -Y- is -N(R6)CH2- when -D- is a drug moiety connected through a phenol, alcohol, thiol, thiophenol, imidazole, or non-basic amine; wherein -R6 is optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
In certain embodiments n of formula (X) is an integer selected from 1, 2, 3, 4, 5 and 6. In certain embodiments n of formula (X) is an integer selected from 1, 2 and 3. In certain embodiments n of formula (X) is an integer from 0, 1, 2 and 3. In certain embodiments n of formula (X) is 1. In certain embodiments n of formula (X) is 2. In certain embodiments n of formula (X) is 3.
In certain embodiments the electron-withdrawing group of -R1 and -R2 of formula (X) is selected from the group consisting of -CN; -NO2; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted alkenyl; optionally substituted alkynyl; -COR3, -SOR3, or -SO2R3, wherein -R3 is -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR8 or -NR82, wherein each -R8 is independently -H or optionally substituted alkyl, or both -R8 groups are taken together with the nitrogen to which they are attached to form a heterocyclic ring; or -SR9, wherein -R9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl. 146 WO 2024/184351 PCT/EP2024/055724 In certain embodiments the electron-withdrawing group of -R1 and -R2 of formula (X) is -CN. In certain embodiments the electron-withdrawing group of -R1 and -R2 of formula (X) is -NO2. In certain embodiments the electron-withdrawing group of -R1 and -R2 of formula (X) is optionally substituted aryl comprising 6 to 10 carbons. In certain embodiments the electron- withdrawing group of -R1 and -R2 of formula (X) is optionally substituted phenyl, naphthyl, or anthracenyl. In certain embodiments the electron-withdrawing group of -R1 and -R2 of formula (X) is optionally substituted heteroaryl comprising 3 to 7 carbons and comprising at least one N, O, or S atom. In certain embodiments the electron-withdrawing group of -R1 and -R2 of formula (X) is optionally substituted pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, or indenyl. In certain embodiments the electron-withdrawing group of -R1 and -R2 of formula (X) is optionally substituted alkenyl containing 2 to 20 carbon atoms. In certain embodiments the electron-withdrawing group of -Rand -R2 of formula (X) is optionally substituted alkynyl comprising 2 to 20 carbon atoms. In certain embodiments the electron-withdrawing group of -R1 and -R2 of formula (X) is -COR3, -SOR3, or -SO2R3, wherein -R3 is -H, optionally substituted alkyl comprising 1 to carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -OR8 or -NR82, wherein each -Ris independently -H or optionally substituted alkyl comprising 1 to 20 carbon atoms, or both -Rgroups are taken together with the nitrogen to which they are attached to form a heterocyclic ring. In certain embodiments the electron-withdrawing group of -R1 and -R2 of formula (X) is -SR9, wherein -R9 is optionally substituted alkyl comprising 1 to 20 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl.
In certain embodiments at least one of -R1 or -R2 of formula (X) is -CN, -SOR3 or -SO2R3. In certain embodiments at least one of -R1 and -R2 of formula (X) is -CN or -SO2R3. In certain embodiments at least one of -R1 and -R2 of formula (X) is -CN or -SO2R3, wherein -R3 is optionally substituted alkyl, optionally substituted aryl, or -NR82. In certain embodiments at least one of -R1 and -R2 of formula (X) is -CN, -SO2N(CH3)2, -SO.CH3, phenyl substituted with -SO2, phenyl substituted with -SO2 and -Cl, -SO2N(CH2CH2)2O, -S02CH(CH3)2, -SO2N(CH3)(CH2CH3), or -SO2N(CH2CH2OCH3)2. 147 WO 2024/184351 PCT/EP2024/055724 In certain embodiments each -R4 of formula (X) is independently C1-C3 alkyl. In certain embodiments both -R4 are methyl.
In certain embodiments -Y- of formula (X) is absent. In certain embodiments -Y- of formula (X) is -N(R6)CH2-.
In certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is -CN, -R2 is -H, and -Ris -CH3. In certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is -SO2N(CH3)2, -Ris -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is SO2CH3, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is -SO2N(CH2CH2)2CHCH3, -R2 is -H, and -R4 is -CH3 In certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is phenyl substituted with -SO2, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is phenyl substituted with -SO2 and -Cl, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is -SO2N(CH2CH2)2O, -R2 is -H, and -R4 is -CH3 in certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is -SO2CH(CH3)2, -R2 is -H, and -Ris -CH3. In certain embodiments -L1- is of formula (X), wherein n is 1, -Ris -SO2N(CH3)(CH2CH3), -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is -SO2N(CH2CH2OCH3)2, -R2 is -H, and -R4 is -CH3 in certain embodiments -L1- is of formula (X), wherein n is 1, -R1 is phenyl substituted with-SOand -CH3, -R2 is -H, and -R4 is -CH3 In certain embodiments -L1- is of formula (X), wherein n is 2, -R1 is -CN, -R2 is -H, and -Ris -CH3. In certain embodiments -L1- is of formula (X), wherein n is 2, -R1 is -SO2N(CH3)2, -Ris -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 2, -R1 is SO2CH3, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 2, -R1 is -SO2N(CH2CH2)2CHCH3, -R2 is -H, and -R4 is -CH3 In certain embodiments -L1- is of formula (X), wherein n is 2, -R1 is phenyl substituted with -SO2, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 2, -R1 is phenyl substituted with -SO2 and -Cl, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 2, -R1 is -SO2N(CH2CH2)2O, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 2, -R1 is -SO2CH(CH3)2, -R2 is -H, and -Ris -CH3. In certain embodiments -L1- is of formula (X), wherein n is 2, -Ris -SO2N(CH3)(CH2CH3), -R2 is -H, and -R4 is -CHs. In certain embodiments -L1- is of formula 148 WO 2024/184351 PCT/EP2024/055724 (X), wherein n is 2, -R1 is -SO2N(CH2CH2OCH3)2, -R2 is -H, and -R4 is -CH. In certain embodiments -L1- is of formula (X), wherein n is 2, -R1 is phenyl substituted with -SOand -CH3, -R2 is -H, and -R4 is -CH3 In certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is -CN, -R2 is -H, and -Ris -CH3. In certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is -SO2N(CH3)2, -Ris -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is SO2CH3, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is -SO2N(CH2CH2)2CHCH3, -R2 is -H, and -R4 is -CH3 In certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is phenyl substituted with -SO2, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is phenyl substituted with -SO2 and -Cl, -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is -SO2N(CH2CH2)2O, -R2 is -H, and -R4 is -CH3 in certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is -SO2CH(CH3)2, -R2 is -H, and -Ris -CH3. In certain embodiments -L1- is of formula (X), wherein n is 3, -Ris -SO2N(CH3)(CH2CH3), -R2 is -H, and -R4 is -CH3. In certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is -SO2N(CH2CH2OCH3)2, -R2 is -H, and -R4 is -CH3 in certain embodiments -L1- is of formula (X), wherein n is 3, -R1 is phenyl substituted with -SOand -CH3, -R2 is -H, and -R4 is -CH3 Only in the context of formula (X) the terms used have the following meaning: The term "alkyl" refers to linear, branched, or cyclic saturated hydrocarbon groups of 1 to 20, to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In certain embodiments an alkyl is linear or branched. Examples of linear or branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, and n-decyl. In certain embodiments an alkyl is cyclic. Examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, and cyclohexyl.
The term "alkoxy" refers to alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, and cyclobutoxy.
The term "alkenyl" refers to non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. 149 WO 2024/184351 PCT/EP2024/055724 The term "alkynyl" refers to non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds and 2 to 20, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms.
The term "aryl" refers to aromatic hydrocarbon groups of 6 to 18 carbons, preferably 6 to carbons, including groups such as phenyl, naphthyl, and anthracenyl. The term "heteroaryl" refers to aromatic rings comprising 3 to 15 carbons comprising at least one N, O or S atom, preferably 3 to 7 carbons comprising at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, and indenyl.
In certain embodiments alkenyl, alkynyl, aryl or heteroaryl moieties may be coupled to the remainder of the molecule through an alkyl linkage. Under those circumstances, 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.
The term "halogen" or "halo" refers to bromo, fluoro, chloro and iodo.
The term "heterocyclic ring" or "heterocyclyl" refers to a 3- to 15-membered aromatic or non- aromatic ring comprising at least one N, O, or S atom. Examples include piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term "heteroaryl" above. In certain embodiments a heterocyclic ring or heterocyclyl is non-aromatic. In certain embodiments a heterocyclic ring or heterocyclyl is aromatic.
The term "optionally substituted" refers to a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents which may be the same or different. Examples of substituents include alkyl, alkenyl, alkynyl, halogen, -CN, -ORaa , -SRaa , -NRaa Rbb , -NO2, -C=NH(0Raa ), -C(O)Raa , -OC(O)Raa , -C(O)ORaa , -C(O)NRaa Rbb , -OC(O)NRaa Rbb , -NRaa C(O)Rbb , -NRaa C(O)ORbb , -S(O)Raa , -S(O)2Raa , -NRaa S(O)Rbb , -C(O)NRaa S(O)Rbb , -NRaa S(O)2Rbb , -C(O)NRaa S(O)2Rbb , -S(O)NRaa Rbb , -S(O)2NRaa Rbb , -P(O)(ORaa )(ORbb ), heterocyclyl, heteroaryl, or aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl are each independently optionally substituted 150 WO 2024/184351 PCT/EP2024/055724 by -Rcc , wherein -Raa and -Rbb are each independently -H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, or aryl, or -Raa and -Rbb are taken together with the nitrogen atom to which they attach to form a heterocyclyl, which is optionally substituted by alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, or -CN, and wherein: each -Rcc is independently alkyl, alkenyl, alkynyl, halogen, heterocyclyl, heteroaryl, aryl, -CN, or -NO2.
In certain embodiments -L1- has a structure as disclosed in formula 1 of WO2021/242756 Al. Accordingly, in certain embodiments the moiety -L1- is of formula (Xlla): ° R4 R8 (Xlla), whereinthe unmarked dashed line indicates attachment to -D-;the dashed line marked with the asterisk indicates attachment to -L2-;- R2, -R4 and -R8 are independently selected from the group consisting of -H or C1-4 alkyl;- R3 is C1-4 alkyl or -R3 and -R4 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring;- R5 is -NH2;with the proviso that when -R4 and -R3 together with the atoms to which they are attached from a 5- or 6-membered heterocyclic ring -R2 is not -H; and wherein the -L1- of formula (Xlla) is optionally substituted.
In certain embodiments both -R4 and -R8 of formula (Xlla) are -H.
In certain embodiments -R3 is methyl. In certain embodiments -R3 is -H.
In certain embodiments -R2 is -H.
In certain embodiments -L1- is of formula (Xlla-i) (Xlla-i),the unmarked dashed line indicates attachment to -D-; and 151 WO 2024/184351 PCT/EP2024/055724 the dashed line marked with the asterisk indicates attachment to -L2-.
In certain embodiments -L1- is of formula (Xlla-ii) O (Xlla-ii), the unmarked dashed line indicates attachment to -D-; andthe dashed line marked with the asterisk indicates attachment to -L2-.
In certain embodiments -L1- is of formula (Xlla-iii) O (Xlla-iii),the unmarked dashed line indicates attachment to -D-; andthe dashed line marked with the asterisk indicates attachment to -L2-.
In certain embodiments -L1- has a structure as disclosed in formula II of WO2022/096636 Al.Accordingly, in certain embodiments the moiety -L1- is of formula (XIIb):*I O (XIIb), whereinthe unmarked dashed line indicates attachment to -D-; andthe dashed line marked with the asterisk indicates attachment to -L2-.
In certain embodiments -L2- is absent.
In certain embodiments -L2- is a spacer moiety, in particular selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-,- N(Ryl )C(0)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C250 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are 152 WO 2024/184351 PCT/EP2024/055724 optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-50 alkenyl, and C2-alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;each -Ry2 is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00Ry5, -ORy5, -C(0)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), -S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -NO2, -0C(0)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)ORy5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; andeach -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -L2- is selected from -T-, -C(O)O-, -0-, -C(O)-, -C(0)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(0)2N(Ryla )-, -S-, -N(Ry1)-, -0C(0Ryl )(Ryla )-, -N(Ryl )C(0)N(Ryla )-, -0C(0)N(Ryl )-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-20 alkyl, C2-alkenyl, and C2-20 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(0)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, 153 WO 2024/184351 PCT/EP2024/055724 - S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of -H, -T, Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein -T, Cmo alkyl, C2-10 alkenyl, and C2-alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein Cmo alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;- Ry2 is selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), -S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5, -N(Ry5Ry5a ), -NO2, -OC(O)Ry5, -N(Ry5) C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)ORy5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and Cm alkyl; wherein Cm alkyl is optionally substituted with one or more halogen, which are the same or different; andeach -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other 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.
In certain embodiments -L2- is selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(0)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -8(0)2-, -8(0)-,- N(Ryl )S(0)2N(Ryla )-, -S-, -N(Ry1)-, -0C(0Ryl )(Ryla )-, -N(Ryl )C(0)N(Ryla )-, -0C(0)N(Ryl )-, Cmo alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, Cmo alkyl, C2-50 alkenyl, and C2-alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein Cmo alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(0)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -8(0)2-, -8(0)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -0C(0)N(Ry3)-; 154 WO 2024/184351 PCT/EP2024/055724 -Ryl and -Ryla are independently selected from the group consisting of -H, -T, Cmo alkyl, C2-alkenyl, and C2-10 alkynyl;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; each -Ry2 is independently selected from the group consisting of halogen, and C1-6 alkyl; and each -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently of each other selected from the group consisting of -H, and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
In certain embodiments -L2- is a C1-20 alkyl chain, which is optionally interrupted by one or more groups independently selected from -O-, -S-, -T- and -C(O)N(Ry1)-; and which C1-20 alkyl chain is optionally substituted with one or more groups independently selected from -OH, -T and -C(O)N(Ry6Ry6a ); wherein -Ryl , -Ry6, -Ry6a are independently selected from the group consisting of H and Cm alkyl and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30-membered heteropoly cyclyl.
In certain embodiments -L2- has a molecular weight in the range of from 14 g/mol to 750 g/mol.
In certain embodiments -L2- comprises a moiety selected from 155 WO 2024/184351 PCT/EP2024/055724 wherein-R and -Ra 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, 2,3- dimethylbutyl and 3,3-dimethylpropyl.
In certain embodiments -L2- has a chain length of 1 to 20 atoms. In certain embodiments -L2- has a chain length of 2 to 10 atoms.
In certain embodiments -L2- has a chain length of at least 35 atoms. In certainembodiments -L2- has a chain length of at least 50 atoms. In certain embodiments -L2- has a 156 WO 2024/184351 PCT/EP2024/055724 chain length of at least 75 atoms. In certain embodiments -L2- has a chain length of at least 1atoms. In certain embodiments -L2- has a chain length of at least 150 atoms. In certain embodiments -L2- has a chain length of at least 200 atoms. In certain embodiments -L2- has a chain length of at least 250 atoms. In certain embodiments -L2- has a chain length of at least 300 atoms. In certain embodiments -L2- has a chain length of at most 3000 atoms. In certain embodiments -L2- has a chain length of at most 2500 atoms. In certain embodiments -L2- has a chain length of at most 2000 atoms. In certain embodiments -L2- has a chain length of at most 1500 atoms. In certain embodiments -L2- has a chain length ranging from 35 to 3000 atoms. In certain embodiments -L2- has a chain length ranging from 50 to 2500 atoms. In certain embodiments -L2- has a chain length ranging from 75 to 2000 atoms. In certain embodiments -L2- has a chain length ranging from 100 to 1500 atoms. In certain embodiments -L2- has a chain length ranging from 125 to 1000 atoms.
In certain embodiments -L2- is of formula (XI) whereinthe unmarked dashed line indicates attachment to -L1-;the dashed line marked with the asterisk indicates attachment to the at least one polymeric moiety;h is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13.14, 15 and 16.
In certain embodiments -L2- is of formula (XI) and h is 1. In certain embodiments -L2- is of formula (XI) and h is 2. In certain embodiments -L2- is of formula (XI) and h is 3. In certain embodiments -L2- is of formula (XI) and h is 4. In certain embodiments -L2- is of formula (XI) and h is 5. In certain embodiments -L2- is of formula (XI) and h is 6. In certain embodiments -L2- is of formula (XI) and h is 7. In certain embodiments -L2- is of formula (XI) and h is 8. In certain embodiments -L2- is of formula (XI) and h is 9. In certain embodiments -L2- is of formula (XI) and h is 10. In certain embodiments -L2- is of formula (XI) and h is 11. In certain embodiments -L2- is of formula (XI) and h is 12. In certain embodiments -L2- is of formula (XI) and h is 13. In certain embodiments -L2- is of formula (XI) and h is 14. In certain embodiments -L2- is of formula (XI) and h is 15. 157 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -L2- has a molecular weight of at least 450 Da. In certain embodiments -L2- has a molecular weight of at least 1 kDa. In certain embodiments -L2- has a molecular weight of at least 1.5 kDa. In certain embodiments -L2- has a molecular weight of at least 2 kDa. In certain embodiments -L2- has a molecular weight of at least 2.5 kDa. In certain embodiments -L2- has a molecular weight of at least 3 kDa. In certain embodiments -L2- has a molecular weight of at least 3.5 kDa. In certain embodiments -L2- has a molecular weight of at least 4 kDa. In certain embodiments -L2- has a molecular weight of at least 5 kDa. In certainembodiments-L2-has a maximum molecular weight of 160 kDa. In certainembodiments-L2-has a maximum molecular weight of 120 kDa. In certainembodiments-L2-has a maximum molecular weight of 100 kDa. In certainembodiments-L2-has a maximum molecular weight of 80 kDa. In certainembodiments-L2-has a maximum molecular weight of 70 kDa. In certainembodiments-L2-has a maximum molecular weight of 60 kDa. In certainembodiments-L2-has a maximum molecular weight of 50 kDa. In certainembodiments-L2-has a maximum molecular weight of 40 kDa. In certainembodiments -L2- has a molecular weight of about 450 Da. In certain embodiments -L2- has a molecular weight of about 1 kDa. In certain embodiments -L2- has a molecular weight of about 1.5 kDa. In certain embodiments -L2- has a molecular weight of about 2 kDa. In certain embodiments -L2- has a molecular weight of about 2.5 kDa. In certain embodiments -L2- has a molecular weight of about 3 kDa. In certain embodiments -L2- has a molecular weight of about 3.5 kDa. In certain embodiments -L2- has a molecular weight of about 4 kDa. In certain embodiments -L2- has a molecular weight of about 4.5 kDa. In certain embodiments -L2- has a molecular weight of about 5 kDa. In certain embodiments -L2- has a molecular weight of about 5.5 kDa. In certain embodiments -L2- has a molecular weight of about 6 kDa. In certain embodiments -L2- has a molecular weight of about 6.5 kDa. In certain embodiments -L2- has a molecular weight of about 7 kDa. In certain embodiments -L2- has a molecular weight of about 7.5 kDa. In certain embodiments -L2- has a molecular weight of about 8 kDa. In certain embodiments -L2- has a molecular weight of about 8.5 kDa. In certain embodiments -L2- has a molecular weight of about 9 kDa. In certain embodiments -L2- has a molecular weight of about 9.5 kDa. In certain embodiments -L2- has a molecular weight of about 10 kDa.
In certain embodiments -L2- comprises a polymeric moiety, meaning that it comprises at least one polymer moiety. It is understood that if -L2- comprises one polymer moiety the minimum and maximum molecular weights provided above apply to this one polymer moiety and 158 WO 2024/184351 PCT/EP2024/055724 if -L2- comprises more than one polymer moiety the minimum and maximum molecular weights provided above refer to the minimum and maximum molecular weight of all polymer moieties together.
In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of at least 1.2 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of at least 1.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of at least 2 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of at least 2.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of at least 3 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of at least 3.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of at least 4 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of at least 4.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of at least 5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 200 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 1nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 150 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 125 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 100 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 75 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 50 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 40 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 35 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of no more than 30 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 1.2 nm. In certain embodiments the one or more polymer moiety of -L2-has a Flory radius of about 1.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 2 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 2.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 3 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 3.nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 159 WO 2024/184351 PCT/EP2024/055724 4 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 4.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 5.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 6 nm. In certain embodiments the one or more polymer moiety of -L2-has a Flory radius of about 6.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 7 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 8.5 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 9 nm. In certain embodiments the one or more polymer moiety of -L2- has a Flory radius of about 10 nm. It is understood that if -L2- comprises one polymer moiety the Flory radius provided above applies to this one polymer moiety and if -L2- comprises more than one polymer moiety the Flory radius provided above refers to the Flory radius of all polymer moieties together.
-L2- comprises one or more polymer moiety, such as polymer moiety selected from the group consisting of poly(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(hydroxyethyl acrylates), poly(hydroxyethyl- oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), polypropylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), polypinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, alginate, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof. 160 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -L2- comprises a PEG-based polymer. In certainembodiments -L2- comprises a hyaluronic acid-based polymer. In certainembodiments -L2- comprises a random coil polymer. In certain embodiments -L2- comprises a poly-sarcosine polymer.
In certain embodiments the albumin-binding moieties of a compound disclosed herein bind to one albumin, such as via different binding domains. Suitably, the albumin-binding moieties of a compound disclosed herein bind to at least two albumins, such as to two albumins.
In certain embodiments -L1-L2- is selected from the group consisting whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to the at least one polymeric moiety. 161 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -L1-L2- is of formula (Xia). In certain embodiments -L1-L2- is of formula (Xlb). In certain embodiments -L1-L2- is of formula (XIc). In certain embodiments -L1-L2- is of formula (Xld). In certain embodiments -L'-L2- is of formula (Xie).In certain embodiments -L1-L2- is of formula (XIf).
In certain embodiments -L1-L2- is selected from the group consisting whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to the at least one polymeric moiety.
In certain embodiments -L1-L2- is of formula (Xia ’). In certain embodiments -L1-L2- is of formula (Xlb ’). In certain embodiments -L1-L2- is of formula (XIc ’). In certain 162 WO 2024/184351 PCT/EP2024/055724 embodiments -L1-L2- is of formula (XId ‘). In certain embodiments -L1-L2- is of formula (Xie’).In certain embodiments -L1-L2- is of formula (Xlf).
In certain embodiments -L1-L2- is selected from the group consisting whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to the at least one polymeric moiety.
In certain embodiments -L1-L2- is of formula (Xia ”). In certain embodiments -L1-L2- is of formula (Xlb ”). In certain embodiments -L1-L2- is of formula (XIc ”). In certain embodiments -L1-L2- is of formula (Xld ”). In certain embodiments -L1-L2- is of formula (Xie”). In certain embodiments -L1-L2- is of formula (Xlf). 163 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -L1-L2- is selected from the group consisting whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to the at least one polymeric moiety.
In certain embodiments -L1-L2- is of formula (XIg). In certain embodiments -L1-L2- is of formula (Xlh). In certain embodiments -L1-L2- is of formula (Xli). In certain embodiments -L1-L2- is of formula (Xlj). In certain embodiments -L'-L2- is of formula (Xlk). In certain embodiments -L1-L2- is of formula (XII).
In certain embodiments -L1-L2- is selected from the group consisting 164 WO 2024/184351 PCT/EP2024/055724 O whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to the at least one polymeric moiety.
In certain embodiments -L1-L2- is of formula (XIg‘). In certain embodiments -L1-L2- is offormula (XIh ‘). In certain embodiments -L1-L2- is of formula (XIi‘). In certain embodiments -L1-L2- is of formula (Xlj ’). In certain embodiments -L1-L2- is of formula (XIk‘). In certain embodiments -L1-L2- is of formula (XII’).
In certain embodiments -L1-L2- is selected from the group consisting 165 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to the at least one polymeric moiety.
In certain embodiments -L1-L2- is of formula (XIg”). In certain embodiments -L1-L2- is of formula (Xlh ”). In certain embodiments -L1-L2- is of formula (Xli ”). In certain embodiments -L1-L2- is of formula (Xlj ”). In certain embodiments -L1-L2- is of formula (Xlk ”). In certain embodiments -L1-L2- is of formula (XII”). 166 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -L1- is a multi-release linker, i.e., a linker from which more than one drug is released. An exemplary class of such multi-release linker is described in the following sections.
In certain embodiments -L1 - is of formula (2a) Tr- wherein- Tr is a cleavable triggering moiety;- Y3- is independently selected from the group consisting of -O-, -S- and -N(R6)-;z is selected from the group consisting of 2 and 3;y is selected from the group consisting of 0, 1, 2, 3, 4 and 5;- Ar- is a ring selected from the group consisting of monocyclic or bicyclic aryl and heteroaryl, provided that -Ar- is connected to -Y3- and -R1 via carbon atoms; wherein said monocyclic or bicyclic aryl and heteroaryl are optionally substituted with -R°, which are the same or different;each -R° is independently selected from the group consisting of -C(O)OH, -halogen, -NO2, -CN, Ci-30 alkyl, C2-30 alkenyl and C2-30 alkynyl; wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally substituted with one or more -R4, which are the same or different; and wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R5)-, -S(O)2N(R5)-, -S(O)N(R5)-, -S(O)2-, -S(O)-, -N(R5)S(O)2N(R5a )-, -S-, -N(R5)-, -OC(OR5)(R5a )-, -N(R5)C(O)N(R5a )- and -OC(O)N(R5)-;each -R1 is independently selected from the group consisting of whereinan unmarked dashed line indicates attachment to -Ar-; 167 WO 2024/184351 PCT/EP2024/055724 a dashed lined marked with an asterisk indicates attachment to -D-;the total number of moieties -D- in the compound ranges from 2 to 6;each -Y1- is independently selected from the group consisting of -0- and -S-;each =¥2 is independently selected from the group consisting of =0 and =S; - ¥4- is R , wherein the dashed line marked with the asterisk indicates attachment to -Ar- and the unmarked dashed lines indicate attachment to -Y1-;each -R2 is independently selected from the group consisting of -H, -C(O)OH, -halogen, -NO2, -CN, C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl; wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally substituted with one or more -R4, which are the same or different; and wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R5)-, -S(O)2N(R5)-, -S(O)N(R5)-, -S(O)2-, -S(O)-, -N(R5)S(O)2N(R5a )-, -S-, -N(R5)-, -OC(OR5)(R5a )-, -N(R5)C(O)N(R5a )- and -OC(O)N(R5)-;each -R3a , -R3b , -R3c , -R3d are independently selected from the group consisting of -H, -C(O)OH, -F, -NO2, -CN, C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl; wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally substituted with one or more -R4, which are the same or different; and wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R5)-, -S(O)2N(R5)-, -S(O)N(R5)-, -S(O)2-, -S(O)-, -N(R5)S(O)2N(R5a )-, -S-, -N(R5)-, -OC(OR5)(R5a )-, -N(R5)C(O)N(R5a )- and -OC(O)N(R5)-;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 -R4, which are the same or different;- R4 is selected from the group consisting of -NO2, -OCH3, -CN, -N(R5)(R5a ), -OH, -C(O)OH and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; 168 WO 2024/184351 PCT/EP2024/055724 - R5 and -R5a are independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;each -R6 is independently selected from the group consisting of -H and C1-6 alkyl;and wherein -L1 - is substituted with one moiety -L2-.
In certain embodiments all -R1 of formula (2a) are of formula (a).
In certain embodiments all -R1 of formula (2a) are of formula (b).
In certain embodiments z of formula (2a) is 2. In certain embodiments z of formula (2a) is 3.In certain embodiments z of formula (2a) is 2 and both -R1 are of formula (a). In certainembodiments z of formula (2a) is 2 and both -R1 are of formula (b). In certain embodiments z is of formula (2a) is 2 and one -R1 is of formula (a) and one -R1 is of formula (b).
In certain embodiments z of formula (2a) is 3 and all -R1 are of formula (a). In certain embodiments z of formula (2a) is 3 and all -R1 are of formula (b). In certain embodiments z of formula (2a) is 3 and one -R1 is of formula (a) and two -R1 are of formula (b). In certain embodiments z of formula (2a) is 3 and two -R1 are of formula (a) and one -R1 is of formula (b).
In certain embodiments y of formula (2a) is 0. In certain embodiments y of formula (2a) is 1. In certain embodiments y of formula (2a) is 2. In certain embodiments y of formula (2a) is 3. In certain embodiments y of formula (2a) is 4. In certain embodiments y of formula (2a) is 5.
In certain embodiments z of formula (2a) is 2, both -R1 of formula (2a) are of formula (a) and y of formula (2a) is 0. In certain embodiments z of formula (2a) is 3, all -R1 of formula (2a) are of formula (a) and y of formula (2a) is 0. In certain embodiments z of formula (2a) is 3, two - R1 are of formula (a), one -R1 of formula (2a) is of formula (b) and y of formula (2a) is 0.
In certain embodiments -Y1- of formula (2a) is -O-. In certain embodiments -Y1- of formula (2a) is -S-. 169 WO 2024/184351 PCT/EP2024/055724 In certain embodiments =¥2 of formula (2a) is =0. In certain embodiments =¥2 of formula (2a) is =S.
In certain embodiments -¥3- of formula (2a) is -0-. In certain embodiments -¥3- of formula (2a) is -S-. In certain embodiments -¥3- of formula (2a) is -N(R6)-, wherein -R6 is as described elsewhere within the section covering the exemplary multi-release linker.
In certain embodiments -Tr of formula (2a) is selected from the group consisting of a peptidyl moiety; whereinthe dashed line marked with an asterisk indicates attachment to -Y3-;- Nu is a nucleophile;- Y§- is selected from the group consisting of -0-, -C(R10)(R10a )-, -N(R6)- and -S-;=Yo is selected from the group consisting of =0, =S and =N(R5 );- E- and -R are independently selected from the group consisting of C1-6 alkyl, C2-alkenyl, C2-6alkynyl and -Q-; wherein C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl are optionally substituted with one or more -R11, which are the same or different; and wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -Q-, -C(O)O-, -0-, -C(O)-, -C(0)N(R12)-, -S(O)2N(R12)-, -S(O)N(R12)-, -S(O)2-, -S(O)-, -N(R12)S(O)2N(R12a )-, -S-, -N(R12)-, -OC(OR12)R12a -, -N(R12)C(O)N(R12a )- and -0C(0)N(R12)-; 170 WO 2024/184351 PCT/EP2024/055724 - Mod is selected from the group consisting of CFzPhSO2-, ClPhSO2-, PhS02-, MePhSO2-, MeOPhSO2-, 2,4,6-Me3PhSO2-, MeSO2-, O(CH2CH2)2N-SO2-, CN- and Et2NSO2-;- R6 is selected from the group consisting of -H and C1-6 alkyl;- R5, -R6 , -R7, -R8, -R9, -R10, -R10a are independently selected from the group consisting of-H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl and -Q; wherein C1-20 alkyl, C2-20 alkenyl and C2-20 alkynyl are optionally substituted with one or more -R11, which are the same or different; and wherein C1-20 alkyl, C2-20 alkenyl and C2-20 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -Q-, -C(O)O-, -0-, -C(O)-, -C(O)N(R12)-, -S(O)2N(R12)-, -S(O)N(R12)-, -S(O)2-, -S(O)-, -N(R12)S(O)2N(R12a )-, -S-, -N(R12)-, -OC(OR12)R12a -, -N(R12)C(O)N(R12a )- and -OC(O)N(R12)-;each Q 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 Q is independently optionally substituted with one or more -R11, which are the same or different; and- R11 is selected from the group consisting of C1-6 alkyl and -N3, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and -R12 and -R12a are independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
- Nu of formula (2aa) is a nucleophile that may be selected from the group consisting of primary, secondary, or tertiary amine and amide. In certain embodiments -Nu of formula (2aa) is selected from the group consisting of secondary and tertiary amine. In certain embodiments -Nu of formula (2aa) is a primary amine. In certain embodiments -Nu of formula (2aa) is a secondary amine. In certain embodiments -Nu of formula (2aa) is a tertiary amine. In certain embodiments -Nu of formula (2aa) is an amide.
In certain embodiments -Y§- of formula (2aa) is selected from the group consisting of -O-, -C(R10)(R10a )- and-N(R 6)-, wherein -R10, -R10a and -R6 . In certain embodiments -Y§- of formula (2aa) is -O-. 171 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -Y§- of formula (2aa) is -C(R10)(R10a )-, wherein -R10, -R10a are independently selected from the group consisting of -H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl and -Q; wherein C1-20 alkyl, C2-20 alkenyl and C2-20 alkynyl are optionally substituted with one or more -R11, which are the same or different; and wherein C1-20 alkyl, C2-20 alkenyl and C2-alkynyl are optionally interrupted by one or more groups selected from the group consisting of -Q-, -C(O)O-,-O-, -C(O)-, -C(O)N(R12)-, -S(O)2N(R12)-, -S(O)N(R12)-,-S(O)2-, -S(O)-, -N(R12)S(O)2N(R12a )-, -S-, -N(R12)-, -OC(OR12)R12a -, -N(R12)C(O)N(R12a )- and -OC(O)N(R12)-;each Q 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 Q is independently optionally substituted with one or more -R11, which are the same or different; and- R11 is selected from the group consisting of C1-6 alkyl and -N3, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and- R12 and -R12a are independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different In certain embodiments -Y§- of formula (2aa) is -N(R6)-, wherein -R6 is selected from the group consisting of -H and C1-6 alkyl.
In certain embodiments =Yo of formula (2aa) is selected from the group consisting of =0 and =S. In certain embodiments =Yo of formula (2aa) is =0. In certain embodiments =Yo of formula (2aa) is =S.
In certain embodiments =Yo of formula (2aa) is =N(R5), wherein -R5 is selected from the group consisting of -H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl and -Q; wherein C1-20 alkyl, C2- alkenyl and C2-20 alkynyl are optionally substituted with one or more -R11, which are the same or different; and wherein C1-20 alkyl, C2-20 alkenyl and C2-20 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -Q-, -C(O)O-,-O-, -C(O)-, -C(0)N(R12)-, -S(O)2N(R12)-, -S(O)N(R12)-, -S(O)2-, -S(O)-, -N(R12)S(O)2N(R12a )-, -S-, -N(R12)-, -OC(OR12)R12a -, -N(R12)C(O)N(R12a )- and -0C(0)N(R12)-;each Q 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 172 WO 2024/184351 PCT/EP2024/055724 heterobicyclyl, wherein each Q is independently optionally substituted with one or more -R11, which are the same or different; and- R11 is selected from the group consisting of C1-6 alkyl and -N3, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and- R12 and -R12a are independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different In certain embodiments -E- of formula (2aa) is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -E- of formula (2aa) is C1-6 alkyl. In certain embodiments -E- of formula (2aa) is C2-6 alkenyl. In certain embodiments -E- of formula (2aa) is C2-6 alkynyl. In certain embodiments -E- of formula (2aa) is -Q-, which in certain embodiments 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. In certain embodiments Q is phenyl. In certain embodiments Q is naphthyl. In certain embodiments Q is indenyl. In certain embodiments Q is indanyl. In certain embodiments Q is tetralinyl. In certain embodiments Q is C3-10 cycloalkyl. In certain embodiments Q is 3- to 10-membered heterocyclyl. In certain embodiments Q is 8- to 11-membered heterobicyclyl. In certain embodiments Q is substituted with one or more -R11. In certain embodiments Q is not substituted with -R11.
In certain embodiments -R5 of formula (2aa) is selected from the group consisting of -H, C1-alkyl, C2-6 alkenyl and C2-6 alkynyl. In certain embodiments -R5 of formula (2aa) is selected from the group consisting of -H and C1-6 alkyl. In certain embodiments -R5 of formula (2aa) is -H. In certain embodiments -R5 of formula (2aa) is C1-6 alkyl.
In certain embodiments -R6 , -R7, -R8, -R9, -R10, -R10a as used in the various embodiments for Tr are independently selected from the group consisting of -H, Cmo alkyl, C2-10 alkenyl, C2-alkynyl and -Q, wherein -Q is as defined elsewhere within the section covering the exemplary multi-release linker.
In certain embodiments -R7 and -R9 as used in the various embodiments for Tr are independently selected from the group consisting of -H and C1-6 alkyl. In certain embodiments 173 WO 2024/184351 PCT/EP2024/055724 both -R7 and -R9 are -H. In certain embodiments -R7 is -H. In certain embodiments -R7 is C1-alkyl. In certain embodiments -R9 is -H. In certain embodiments -R9 is C1-6 alkyl.
In certain embodiments -R10 and -R10a of formula (2aa) are independently selected from the group consisting of -H and C1-6 alkyl. In certain embodiments both -R10 and -R10a of formula (2aa) are -H. In certain embodiments -R10 of formula (2aa) is -H. In certain embodiments -Rof formula (2aa) is C1-6 alkyl. In certain embodiments -R10a of formula (2aa) is -H. In certain embodiments -R10a of formula (2aa) is C1-6 alkyl.
In certain embodiments -Tr of formula (2a) is of formula (2aa) YouNu—E—Ys A(2aa), whereinthe dashed line marked with an asterisk indicates attachment to -Y3-; and- Nu, -E-, -Y§- and =Y0 are as defined elsewhere within the section covering the exemplary multi-release linker herein.
It is understood that in this instance the release of the drug is not triggered by an enzyme, and that the drug is released in its unmodified, pharmacologically active form in the absence of an enzyme.
In certain embodiments -Tr of formula (2a) isO wherein and the dashed line marked with an asterisk indicates attachment to- Y3-; and- R6 is as defined elsewhere within the section covering the exemplary multi-release linker herein. 174 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -R6 is, wherein the dashed line marked with theasterisk indicates attachment to the carbon atom substituted by the oxygen atom.
In certain embodiments -R6 is of formula (a'): wherein -Y4 - 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 -R18 which are the same or different;-R16 and -R17 are independently selected from the group consisting of -H,C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl; wherein C1-10 alkyl, C2-10 alkenyl and C2-alkynyl are optionally substituted with one or more -R18 which are the same or different; and wherein C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -A'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R19)-, -S(O)2N(R19), -S(O)N(R19)-, -S(O)2-, -S(O)-, -N(R19)S(O)2N(R19a )-, -S-, -N(R19)-, -OC(OR19)R19a -, -N(R19)C(O)N(R19a )-, -OC(O)N(R19)- and-N(R19)C(NH2)N(R19a )-;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 -R18 which are the same or different;wherein -R18, -R19 and -R19a are independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; andwherein the dashed line marked with an asterisk indicates attachment to the rest of -Tr.
In certain embodiments -Y4 - is selected from the group consisting of C3-10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl. In certain embodiments -Y4 - is C3-10 cycloalkyl. In certain embodiments -Y4 - is 3- to 10-membered heterocyclyl. In certain embodiments -Y4 - is 8- to 11-membered heterobicyclyl. In certain embodiments -Y4 - 175 WO 2024/184351 PCT/EP2024/055724 is substituted with one or more -R18 which are the same or different. In certain embodiments -Y4 - is not substituted with -R18.
In certain embodiments -R16 and -R17 are selected from the group consisting of Cmo alkyl, C2-10 alkenyl and C2-10 alkynyl. In certain embodiments -R16 is Cmo alkyl. In certain embodiments -R16 is C2-10 alkenyl. In certain embodiments -R16 is C2-10 alkynyl. In certain embodiments -R17 is Cmo alkyl. In certain embodiments -R17 is C2-10 alkenyl. In certain embodiments -R17 is C2-10 alkynyl.
In certain embodiments 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. In certain embodiments A' is phenyl. In certain embodiments A' is naphthyl. In certain embodiments A' is indenyl. In certain embodiments A' is indanyl. In certain embodiments A' is tetralinyl. In certain embodiments A' is C3-10 cycloalkyl. In certain embodiments A' is 3- to 10-membered heterocyclyl. In certain embodiments A' is 8- to 11-membered heterobicyclyl. In certain embodiments A' is substituted with one or more -R18, which are the same or different. In certain embodiments A' is not substituted with -R18.
In certain embodiments -R18, -R19 and -R19a are selected from the group consisting of -H and C1-6 alkyl. In certain embodiments -R18 is -H. In certain embodiments -R18 is C1-6 alkyl. In certain embodiments -R19 is -H. In certain embodiments -R19 is C1-6 alkyl. In certain embodiments -R19a is -H. In certain embodiments -R19a is C1-6 alkyl.
In certain embodiments -R6 is of formula (b ): (b ),wherein -Y5 - is selected from the group consisting of -Q'-, Cmo alkyl, C2-10 alkenyl andC2-10 alkynyl; wherein Cmo alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally substituted with one or more -R23, which are the same or different; and wherein Cmo alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -Q'-, -C(O)O-, -0-, -C(O)-, -C(O)N(R24)-, -S(O)2N(R24)-, -S(O)N(R24)-, -S(O)2-, -S(O)-, -N(R24)S(O)2N(R24a )-, -S-, -N(R24)-, 176 WO 2024/184351 PCT/EP2024/055724 -OC(OR24)R24a -,-N(R24)C(O)N(R24a )-, -OC(O)N(R24)- and -N(R24)C(NH2)N(R24a )-;- R20, -R21, -R21a and -R22 are independently selected from the group consisting of -H, C1- alkyl, C2-10 alkenyl and C2-10 alkynyl; wherein Cmo alkyl, C2-10 alkenyl and C2-alkynyl are optionally substituted with one or more -R23 which are the same or different; and wherein Cmo alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -Q'-, -C(O)O-, -O-, -C(O)-, -C(O)N(R24)-, -S(O)2N(R24)-, -S(O)N(R24)-, -S(O)2-, -S(O)-, -N(R24)S(O)2N(R24a )-, -S-, -N(R24)-, -OC(OR24)R24a -, -N(R24)C(O)N(R24a )-, -OC(O)N(R24)- and-N(R24)C(NH2)N(R24a )-;each Q' 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 Q' is independently optionally substituted with one or more -R23, which are the same or different;wherein -R23, -R24 and -R24a are independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;optionally, the pair -R21/-R21a is joined together with the atoms to which is attached to form a C3-10 cycloalkyl, 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclyl; andwherein the dashed line marked with an asterisk indicates attachment to the rest of -Tr.
In certain embodiments -Y5 - is selected from the group consisting of -Q'-, Cmo alkyl, C2-alkenyl and C2-10 alkynyl. In certain embodiments -Y5 - is -Q'-. In certain embodiments -Y5 - is Cmo alkyl. In certain embodiments -Y5 - is C2-10 alkenyl. In certain embodiments -Y5 - is C2-10 alkynyl.
In certain embodiments Q' 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. In certain embodiments Q' is phenyl. In certain embodiments Q' is naphthyl. In certain embodiments Q' is indenyl. In certain embodiments Q' is indanyl. In certain embodiments Q' is C3-10 cycloalkyl. In certain embodiments Q' is 3- to 10-membered heterocyclyl. In certain embodiments Q' is 8- to 11-membered heterobicyclyl. In certain 177 WO 2024/184351 PCT/EP2024/055724 embodiments Q' is substituted with one or more -R23 which are the same or different. In certain embodiments Q' is not substituted with -R23.
In certain embodiments -R20, -R21, -R21a and -R22 are selected from the group consisting of -H, Cmo alkyl, C2-10 alkenyl and C2-10 alkynyl. In certain embodiments -R20 is -H. In certain embodiments -R20 is Cmo alkyl. In certain embodiments -R20 is C2-10 alkenyl. In certain embodiments -R20 is C2-10 alkynyl. In certain embodiments -R21 is -H. In certain embodiments -R21 is Cmo alkyl. In certain embodiments -R21 is C2-10 alkenyl. In certain embodiments -R21 is C2-10 alkynyl. In certain embodiments -R21a is -H. In certain embodiments -R21a is Cmo alkyl. In certain embodiments -R21a is C2-10 alkenyl. In certain embodiments -R21a is C2-10 alkynyl. In certain embodiments -R22 is -H. In certain embodiments -R22 is Cmo alkyl. In certain embodiments -R22 is C2-10 alkenyl. In certain embodiments -R22 is C2-10 alkynyl.
In certain embodiments -R23, -R24 and -R24a are selected from the group consisting of -H and C1-6 alkyl. In certain embodiments -R23 is -H. In certain embodiments -R23 is C1-6 alkyl. In certain embodiments -R24 is -H. In certain embodiments -R24 is C1-6 alkyl. In certain embodiments -R24a is -H. In certain embodiments -R24a is C1-6 alkyl.
In certain embodiments the pair -R21/-R21a is joined together with the atoms to which is attached to form a C3-10 cycloalkyl.
In certain embodiments -R6 is of formula (c) wherein- R25, -R26, -R26a and -R27 are independently selected from the group consisting of -H, C1- alkyl, C2-10 alkenyl and C2-10 alkynyl; wherein Cmo alkyl, C2-10 alkenyl and C2-alkynyl are optionally substituted with one or more -R28 which are the same or different; and wherein Cmo alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -Q*-, -C(O)O-, -O-, -C(O)-, -C(O)N(R29)-, -S(O)2N(R29)-, -S(O)N(R29)-, -S(O)2-, -S(O)-, -N(R29)S(O)2N(R29a )-, -S-, 178 WO 2024/184351 PCT/EP2024/055724 - N(R29)-, -OC(OR29)R29a -, -N(R29)C(O)N(R29a )-, -OC(O)N(R29)- and-N(R29)C(NH2)N(R29a )-;each Q* 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 Q* is independently optionally substituted with one or more -R28, which are the same or different;wherein -R28, -R29 and -R29a are independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;optionally, the pair -R26/-R26a is joined together with the atoms to which is attached to form a C3-10 cycloalkyl, 3- to 10-membered heterocyclyl or an 8- to 11-membered heterobicyclyl; andwherein the dashed line marked with an asterisk indicates attachment to the rest of -Tr.
In certain embodiments -R25, -R26, -R26a and -R27 are selected from the group consisting of -H, Cmo alkyl, C2-10 alkenyl and C2-10 alkynyl. In certain embodiments -R25 is -H. In certain embodiments -R25 is Cmo alkyl. In certain embodiments -R25 is C2-10 alkenyl. In certain embodiments -R25 is C2-10 alkynyl. In certain embodiments -R26 is -H. In certain embodiments -R26 is Cmo alkyl. In certain embodiments -R26 is C2-10 alkenyl. In certain embodiments -R26 is C2-10 alkynyl. In certain embodiments -R26a is -H. In certain embodiments -R26a is Cmo alkyl. In certain embodiments -R26a is C2-10 alkenyl. In certain embodiments -R26a is C2-10 alkynyl. In certain embodiments -R27 is -H. In certain embodiments -R27 is Cmo alkyl. In certain embodiments -R27 is C2-10 alkenyl. In certain embodiments -R27 is C2-10 alkynyl.
In certain embodiments Q* 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. In certain embodiments Q* is phenyl. In certain embodiments Q* is naphthyl. In certain embodiments Q* is indenyl. In certain embodiments Q* is indanyl. In certain embodiments Q* is tetralinyl. In certain embodiments Q* is C3-10 cycloalkyl. In certain embodiments Q* is 3- to 10-membered heterocyclyl. In certain embodiments Q* is 8- to 11-membered heterobicyclyl. In certain embodiments Q* is substituted with one or more - R28, which are the same or different. In certain embodiments Q* is not substituted with -R28. 179 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -R28, -R29 and -R29a are selected from the group consisting of -H and C1-6 alkyl. In certain embodiments -R28 is -H. In certain embodiments -R28 is C1-6 alkyl. In certain embodiments -R29 is -H. In certain embodiments -R29 is C1-6 alkyl. In certain embodiments -R29a is -H. In certain embodiments -R29a is C1-6 alkyl.
In certain embodiments the pair -R26/-R26a is joined together with the atoms to which is attached to form a C3-10 cycloalkyl. In certain embodiments the pair -R26/-R26a is joined together with the atoms to which is attached to form a cyclobutyl.
In certain embodiments -Tr isO 7 11 !* — ؛ — r 7o-pOR7 , wherein the dashed line marked with an asterisk indicates attachment to -Y3- and -R7 is defined as elsewhere within the section covering the exemplary multi-release linker herein. In this instance the release of the drug may be triggered by an enzyme, such as phosphatase.
In certain embodiments -Tr is 1* — ؛ ־ R8S, wherein the dashed line marked with an asterisk indicates attachment to -Y - which is -S- and -R8 is as defined elsewhere within the section covering the exemplary multi-release linker herein.
In certain embodiments -Tr isO11 !*؛ r 9o-sO י wherein the dashed line marked with an asterisk indicates attachment to -Y3- and -R9 is as defined elsewhere within the section covering the exemplary multi-release linker herein. In this instance the release of the drug may be triggered by an enzyme, such as sulfatase.
In certain embodiments -Tr is 180 WO 2024/184351 PCT/EP2024/055724 OH HO.
HO' OH , wherein the dashed line marked with an asterisk indicates attachment to -Y3- In this instance the release of the drug may be triggered by an enzyme, such as a- galactosidase.
In certain embodiments -Tr is OH , wherein the dashed line marked with an asterisk indicates attachment to -Y3- in this instance the release of the drug may be triggered by an enzyme, such as P־ glucuronidase.
In certain embodiments -Tr isCOOH A ךכ ؛OH , wherein the dashed line marked with an asterisk indicates attachmentto -Y3-. In this instance the release of the drug may be triggered by an enzyme, such as P־ glucuronidase.
In certain embodiments -Tr is a peptidyl moiety. It is understood that if -Tr is a peptidyl moiety, then the release of the -D- may be triggered by an enzyme, such as protease. In certain embodiments the protease is selected from the group consisting of cathepsin B and cathepsin K. In certain embodiments the protease is cathepsin B. In certain embodiments the protease is cathepsin K.
In certain embodiments -Tr is a peptidyl moiety, such as a dipeptidyl, tripeptidyl, tetrapeptidyl, pentapeptidyl or hexapeptidyl moiety. In certain embodiments -Tr is a dipeptidyl moiety. In certain embodiments -Tr is a tripeptidyl moiety. In certain embodiments -Tr is a tetrapeptidyl COOH WO 2024/184351 PCT/EP2024/055724 moiety. In certain embodiments -Tr is a pentapeptidyl moiety. In certain embodiments -Tr is a hexapeptidyl moiety.
In certain embodiments -Tr is a peptidyl moiety selected from the group consisting of: wherein the dashed line marked with an asterisk indicates attachment to -Y3-.
In certain embodiments -Tr is In certain embodiments -Tr is nh 2 In certain embodiments -Tr is O 182 WO 2024/184351 PCT/EP2024/055724 In certain embodiments -Y3- is -N(R6)- and -Tr has the structure of -L1- as disclosed in WO 2011/012722 Al, which is herewith incorporated by reference. Accordingly, In certain embodiments -Tr is of formula (a012): h* o (a 012),wherein the dashed line indicates attachment -Y3-;- X1- is -C(R1Rla )- or a cyclic fragment selected from C3-7 cycloalkyl, 4 to 7 membered heterocyclyl, phenyl, naphthyl, indenyl, indanyl, tetralinyl, or 9 to 11 membered heterobicyclyl,wherein in case -X1- is a cyclic fragment, said cyclic fragment is incorporated into the moiety of formula (a012) via two adjacent ring atoms and the ring atom of -X1-, which is adjacent to the carbon atom of the amide bond, is also a carbon atom;- X2- is a chemical bond or selected from -C(R3R3a )-, -N(R3)-, -O-, -C(R3R3a )- C(R4R4a )-, -C(R3R3a )-N(R4)-, -N(R3)-C(R4R4a )-, -C(R3R3a )-O-, or -O-C(R3R3a )-, wherein in case -X1- is a cyclic fragment, -X2- is a chemical bond, -C(R3R3a )-, -N(R3)- or -O-;optionally, in case -X1- is a cyclic fragment and -X2- is -C(R3R3a )-, the order of the -X1- fragment and the -X2- fragment within the moiety of formula (a012) may be changed and the cyclic fragment is incorporated into the moiety of formula (a012) via two adjacent ring atoms;- R1, -R3 and -R4 are independently selected from the group consisting of -H, Cm alkyl and -N(R5R5a );- Rla , -R2, -R3a , -R4a and -R5a are independently selected from the group consisting of -H, and Ci-4 alkyl;- R5 is -C(O)R6;- R6 is Cm alkyl; andoptionally, one of the pairs -Rla /-R4a , -R3a /-R4a or -Rla /-R3a form a chemical bond.
In certain embodiments -Tr and -Y3- form together a functional group selected from the group consisting of 183 WO 2024/184351 PCT/EP2024/055724 ° I* , I*؛- — N=N ־= N ؛ zNU and 1 , wherein the dashed line marked with the asterisk indicatesattachment to -Ar-.
In certain embodiments -Tr is Mod^H Q , wherein -Mod and -R are as defined elsewhere within the section covering the exemplary multi-release linker herein.
Suitably, -Mod is MeSO2-. 184 WO 2024/184351 PCT/EP2024/055724 indicates attachment to -Y3- as defined elsewhere within the section covering the exemplarymulti-release linker herein.
In certain embodiments -L1 - is of formula (Hal): whereineach -R1 is independently selected from the group consisting of whereinan unmarked dashed line indicates attachment to -Ar-;a dashed line marked with an asterisk indicates attachment to -D-;the total number of moieties -D- within the compound is ranging from 2 to 6;z is selected from the group consisting of 2 and 3;each -Y1- is -O-;each =Y2 is =0;-Nu and -E are used as defined in formula (2aa), and-Ar-, -Y4-, -R3a and -R3b are used as defined in formula (2a); andwherein -L1 - is substituted with one moiety -L2-.
In certain embodiments all -R1 of formula (Hal) are of formula (a).
In certain embodiments all -R1 of formula (Hal) areof formula (b).
In certain embodiments -L1 - is of formula (Ila2): 185 WO 2024/184351 PCT/EP2024/055724 ס wherein(Ha2), each -R1 is independently selected from the group consisting of wherein 5 the unmarked dashed line indicates attachment to -Ar-;a dashed line marked with an asterisk indicates attachment to -D-;z is selected from the group consisting of 2 and 3;the total number of moieties -D- within the compound ranges from 2 to 6;-Nu is a secondary or tertiary amine functional group;each -Y1- is -O-;each =¥2 is =0;-Ar-, -Y4-, -R3a and -R3b are used as defined in formula (2a); and wherein -L1 - is substituted with one moiety -L2-.
In certain embodiments all -R1 of formula (Ila2) are of formula (a).
In certain embodiments all -R1 of formula (Ila2) are of formula (b).
In certain embodiments-L 1 - is selected from the group consisting of 186 WO 2024/184351 PCT/EP2024/055724 whereina dashed line marked with an asterisk indicates attachment to -D-;-R and -Mod are used as described for formula (2ai); and- Tr is selected from the group consisting of 187 WO 2024/184351 PCT/EP2024/055724 wherein the dashed line indicates attachment to the oxygen atom.
In certain embodiments -L1 - is of formula (2b)O (2b),whereinthe dashed lines marked with the asterisk indicate attachment to -D-; and- L1 - is substituted with -L2-.
In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to semaglutide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to lixisenatide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to PEG-loxenatide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to liraglutide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to ecnoglutide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to GZR18. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to GL0018. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to tirzepatide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to cotadutide. In certain embodiments the moiety -L1 - is of formula (2b) 188 WO 2024/184351 PCT/EP2024/055724 and the dashed lines marked with the asterisk indicate attachment to BI-456906. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to pemvidutide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to mazdutide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to dapiglutide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to retatrutide. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:52. In certain embodiments the moiety -L1 - is of formula (2b) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:53.
In certain embodiments -L1 - is of formula (2b-i) (2b-1),whereinthe dashed lines marked with the asterisk indicate attachment to -D-; andthe unmarked dashed line indicates attachment to -L2-.
In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to semaglutide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to lixisenatide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to PEG-loxenatide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to liraglutide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to ecnoglutide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to GZR18. In certain embodiments the moiety -L1 - is of formula (2b-i) and the 189 WO 2024/184351 PCT/EP2024/055724 dashed lines marked with the asterisk indicate attachment to GE0018. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to tirzepatide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to cotadutide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to B1-456906. In certain embodiments the moiety -L1 - is of formula (2b- i) and the dashed lines marked with the asterisk indicate attachment to pemvidutide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to mazdutide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to dapiglutide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to retatrutide. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:52. In certain embodiments the moiety -L1 - is of formula (2b-i) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:53.
In certain embodiments -L2-Ll - is of formula (2b-ii) (2b-ii), whereinthe dashed lines marked with the asterisk indicate attachment to -D-; andthe unmarked dashed line indicates attachment to the at least one polymeric moiety, to formula (I-ai), to formula (I-aii) or to formula (I-aiii).
In certain embodiments the unmarked dashed line in formula (2b-ii) indicates attachment to the at least one polymeric moiety. In certain embodiments the unmarked dashed line in formula (2b-ii) indicates attachment to formula (I-ai). In certain embodiments the unmarked dashed line in formula (2b-ii) indicates attachment to formula (I-aii). In certain embodiments the unmarked dashed line in formula (2b-ii) indicates attachment to formula (I-aiii). 190 WO 2024/184351 PCT/EP2024/055724 In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to semaglutide, in particular attachment to the N-terminal amine functional group of semaglutide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to lixisenatide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to PEG-loxenatide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to liraglutide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to ecnoglutide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to GZR18. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to GL0018. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to tirzepatide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to cotadutide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to BI-456906. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to pemvidutide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to mazdutide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to dapiglutide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to retatrutide. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:52. In certain embodiments the moiety -L^L1 - is of formula (2b-ii) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:53.
In certain embodiments -L1 - is of formula (2b ’) 191 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed lines marked with the asterisk indicate attachment to -D-; and- L1 - is substituted with -L2-.
In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to semaglutide, in particular attachment to the N-terminal amine functional group of semaglutide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to lixisenatide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to PEG-loxenatide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to liraglutide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to ecnoglutide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to GZR18. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to GL0018. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to tirzepatide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to cotadutide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to BI-456906. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to pemvidutide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to mazdutide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to dapiglutide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to retatrutide. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk 192 WO 2024/184351 PCT/EP2024/055724 indicate attachment to the compound of SEQ ID NO:52. In certain embodiments the moiety -L1 - is of formula (2b ’) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:53.
In certain embodiments -L1 - is of formula (2b ’-i) (2b ’-i), whereinthe dashed lines marked with the asterisk indicate attachment to -D-; and the unmarked dashed line indicates attachment to -L2-.
In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to semaglutide, in particular attachment to the N-terminal amine functional group of semaglutide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to lixisenatide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to PEG-loxenatide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to liraglutide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to ecnoglutide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to GZR18. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to GE0018. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to tirzepatide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to cotadutide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to BI-456906. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to 193 WO 2024/184351 PCT/EP2024/055724 pemvidutide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to mazdutide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to dapiglutide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to retatrutide. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:52. In certain embodiments the moiety -L1 - is of formula (2b ’-i) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:53.
In certain embodiments -L2-Ll - is of formula (2b ’-ii) (2b’-ii),whereinthe dashed lines marked with the asterisk indicate attachment to -D-; andthe unmarked dashed line indicates attachment to the at least one polymeric moiety, to formula (I-ai), to formula (I-aii) or to formula (I-aiii).
In certain embodiments the unmarked dashed line in formula (2b ’-ii) indicates attachment to the at least one polymeric moiety. In certain embodiments the unmarked dashed line in formula (2b ’-ii) indicates attachment to formula (I-ai). In certain embodiments the unmarked dashed line in formula (2b ’-ii) indicates attachment to formula (I-aii). In certain embodiments the unmarked dashed line in formula (2b ’-ii) indicates attachment to formula (I-aiii).
In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to semaglutide, in particular attachment to the N-terminal amine functional group of semaglutide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to lixisenatide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed 194 WO 2024/184351 PCT/EP2024/055724 lines marked with the asterisk indicate attachment to PEG-loxenatide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to liraglutide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to ecnoglutide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to GZR18. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to GL0018. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to tirzepatide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to cotadutide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to BI-456906. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to pemvidutide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to mazdutide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to dapiglutide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to retatrutide. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:52. In certain embodiments the moiety -L^L1 - is of formula (2b ’-ii) and the dashed lines marked with the asterisk indicate attachment to the compound of SEQ ID NO:53.
In certain embodiments the compound is of formula (2c) 195 WO 2024/184351 PCT/EP2024/055724 whereinnl, n2, n3 and n4 are independently an integer ranging from about 11 to about 115; dashed lines indicate attachment to a moiety the unmarked dashed line indicates attachment to an unmarked dashed line of formula (2c); andthe dashed line marked with the asterisk indicates attachment to the N-terminalamine functional group of semaglutide.
In certain embodiments the compound is of formula (2c ”) 196 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line indicates attachment to the N-terminal amine functional group of semaglutide; andnl, n2, n3 and n4 are independently an integer ranging from about 11 to about 115.
In certain embodiments the compound is of formula (2c ’) 197 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line indicates attachment to the N-terminal amine functional group of semaglutide; andnl, n2, n3 and n4 are independently an integer ranging from about 11 to about 115.
In certain embodiments nl, n2, n3 and n4 of formula (2c), (2c ’) and (2c ”) are about 22. Incertain embodiments nl, n2, n3 and n4 of formula (2c), (2c ’) and (2c ”) are about 23. In certain 10embodiments embodiments embodiments embodiments embodiments embodiments nl, n2, n3 and nl, n2, n3 and nl, n2, n3 and nl, n2, n3 and nl, n2, n3 and nl, n2, n3 and n4 of formulan4 of formulan4 of formulan4 of formulan4 of formulan4 of formula (2c), (2c ’) and(2c), (2c ’) and(2c), (2c ’) and(2c), (2c ’) and(2c), (2c ’) and(2c), (2c ’) and (2c ”) are about(2c ”) are about(2c ”) are about(2c ”) are about(2c ”) are about(2c ”) are about 28. In certain34. In certain45. In certain56. In certain68. In certain80. In certain 198 WO 2024/184351 PCT/EP2024/055724 embodiments nl, n2, n3 and n4 of formula (2c), (2c ’) and (2c ”) are about 90. In certain embodiments nl, n2, n3 and n4 of formula (2c), (2c ’) and (2c ”) are about 100. In certain embodiments nl, n2, n3 and n4 of formula (2c), (2c ’) and (2c ”) are about 115.
In certain embodiments nl, n2, n3 and n4 of formula (2c), (2c ’) and (2c ”) are selected such that the total molecular weight of the moiety ranges from 7 to 13 kDa, such as from 8 to 12, from 9 to 11 kDa or is about 10 kDa. In certain embodiments nl, n2, n3 and n4 of formula (2c), (2c ’) and (2c ”) are selected such that the total molecular weight of this moiety ranges from 4 to 6 kDa or is about 5 kDa.
In certain embodiments the compound is of formula (2d) 199 WO 2024/184351 PCT/EP2024/055724 whereinnl, n2, n3 and n4 are independently an integer ranging from about 11 to about 115; dashed lines indicate attachment to a moiety N whereinthe unmarked dashed line indicates attachment to an unmarked dashed line offormula (2d); andthe dashed line marked with the asterisk indicates attachment to the N-terminalamine functional group of semaglutide. 200 WO 2024/184351 PCT/EP2024/055724 In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 22. In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 23. In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 34. In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 45. In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 56. In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 68. In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 80. In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 90. In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 100. In certain embodiments nl, n2, n3 and n4 of formula (2d) are about 115.
In certain embodiments nl, n2, n3 and n4 of formula (2d) are selected such that the total molecular weight of the moiety 0ranges from 7 to 13 kDa, such as from 8 to 12, from 9 to 11 kDa or is about 10 kDa.
In certain embodiments the compound is of formula (26) 201 WO 2024/184351 PCT/EP2024/055724 whereinnl, n2, n3 and n4 are independently an integer ranging from about 11 to about 115; dashed lines indicate attachment to a moiety whereinthe unmarked dashed line indicates attachment to an unmarked dashed line of formula (2e); andthe dashed line marked with the asterisk indicates attachment to the N-terminalamine functional group of semaglutide. 202 WO 2024/184351 PCT/EP2024/055724 In certain embodiments nl, n2, n3 and n4 of formula (26) are about 22. In certain embodiments nl, n2, n3 and n4 of formula (26) are about 23. In certain embodiments nl, n2, n3 and n4 of formula (26) are about 34. In certain embodiments nl, n2, n3 and n4 of formula (26) are about 45. In certain embodiments nl, n2, n3 and n4 of formula (26) are about 56. In certain embodiments nl, n2, n3 and n4 of formula (26) are about 68. In certain embodiments nl, n2, n3 and n4 of formula (26) are about 80. In certain embodiments nl, n2, n3 and n4 of formula (26) are about 90. In certain embodiments nl, n2, n3 and n4 of formula (26) are about 100. In certain embodiments nl, n2, n3 and n4 of formula (26) are about 115.
In certain embodiments nl, n2, n3 and n4 of formula (26) are selected such that the total molecular weight of the moiety ranges from 7 to 13 kDa, such as from 8 to 12, from 9 to 11 kDa or is about 10 kDa. In certain embodiments the total molecular weight of this moiety is about 5 kDa.
In certain embodiments the compound is of formula (2f) 203 WO 2024/184351 PCT/EP2024/055724 whereinnl, n2, n3 and n4 are independently an integer ranging from about 11 to about 115; dashed lines indicate attachment to a moiety whereinthe unmarked dashed line indicates attachment to an unmarked dashed line of formula (2f); andthe dashed line marked with the asterisk indicates attachment to the N-terminalamine functional group of semaglutide. 204 WO 2024/184351 PCT/EP2024/055724 In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 22. In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 23. In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 34. In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 45. In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 56. In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 68. In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 80. In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 90. In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 100. In certain embodiments nl, n2, n3 and n4 of formula (2f) are about 115.
In certain embodiments nl, n2, n3 and n4 of formula (2f) are selected such that the total molecular weight of the moiety ranges from 7 to 13 kDa, such as from 8 to 12, from 9 to 11 kDa or is about 10 kDa. In certain embodiments the total molecular weight of this moiety is about 5 kDa.
In certain embodiments the compound is of formula (2g) 205 WO 2024/184351 PCT/EP2024/055724 whereinn is independently an integer ranging from about 22 to about 230;dashed lines indicate attachment to a moiety wherein the unmarked dashed line indicates attachment to an unmarked dashed line of formula (2g); andthe dashed line marked with the asterisk indicates attachment to the N-terminal aminefunctional group of semaglutide.
In certain embodiments the compound is of formula (2g’) 206 WO 2024/184351 PCT/EP2024/055724 n is independently an integer ranging from about 22 to about 230;dashed lines indicate attachment to a moiety the unmarked dashed line indicates attachment to an unmarked dashed line of formula (2g’); andthe dashed line marked with the asterisk indicates attachment to the N-terminal aminefunctional group of semaglutide.
In certain embodiments n of formula (2g) and (2g’) is about 44. In certain embodiments n of formula (2g) and (2g’) is about 46. In certain embodiments n of formula (2c) is about 68. Incertain embodiments n of formula (2g) and (2g’) is about 90. In certain embodiments n of formula (2g) and (2g’) is about 112. In certain embodiments n of formula (2g) and (2g’) is about 90. In certain embodiments n of formula (2g) and (2g’) is about 113. In certain embodiments n of formula (2g) and (2g’) is about 136. In certain embodiments n of formula (2g) and (2g’) is about 160. In certain embodiments n of formula (2g) and (2g’) is about 180. 207 WO 2024/184351 PCT/EP2024/055724 In certain embodiments n of formula (2g) and (2g’) is about 200. In certain embodiments n of formula (2g) and (2g’) is about 230.
In certain embodiments n of formula (2g) is selected such that the total molecular weight of the moiety ranges from 3 to 7 kDa, such as from 4 to 6, from 4.5 to 5.5 kDa or is about 5 kDa.
In certain embodiments the compound is of formula (2h) whereinthe dashed line marked with the asterisk indicates attachment to the dashed line of a moiety of formula (2i) I#1 H (2i),whereinthe dashed line marked with the # indicates attachment to the N-terminal amine functional group of semaglutide;and wherein the unmarked dashed line of formula (2h) indicates attachment to the unmarked dashed line of formula (2j) (2j), 208 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line marked with the # indicates attachment to the N-terminal amine functional group of semaglutide.
In certain embodiments the compound is of formula (2h ’) ° (2h ’);wherein the dashed line marked with the asterisk indicates attachment to the dashed line marked with the asterisk of a moiety of formula (2i) I#1 1 H (2i), whereinthe dashed line marked with the # indicates attachment to the N-terminal amine functional group of semaglutide;wherein the unmarked dashed line of formula (2h ’) indicates attachment to the unmarked dashed line of formula (2j) wherein(2j), the dashed line markedwith the # indicates attachment to the N-terminal aminefunctional group of semaglutide;and wherein n is an integer ranging from about 22 to about 230.
In certain embodiments the compound is of formula (2h ”) 209 WO 2024/184351 PCT/EP2024/055724 whereina dashed line indicates attachment to the N-terminal amine functional group of semaglutide.
In certain embodiments n of formula (2h ’) is about 44. In certain embodiments n of formula (2h ’) is about 46. In certain embodiments n of formula (2h ’) is about 68. In certain embodiments n of formula (2h ’) is about 90. In certain embodiments n of formula (2h ’) is about 112. In certain embodiments n of formula (2h ’) is about 113. In certain embodiments n of formula (2h ’) is about 136. In certain embodiments n of formula (2h ’) is about 160. In certain embodiments n of formula (2h ’) is about 180. In certain embodiments n of formula (2h ’) is about 200. In certain embodiments n of formula (2h ’) is about 230.
In certain embodiments the half-life of the drug released from the compound is it at least 1.5- fold higher than the corresponding free drug ’s half-life. In certain embodiments the half-life of the drug released from the compound is it at least 2.5-fold higher than the corresponding free drug ’s half-life. In certain embodiments the half-life of the drug released from the compound is it at least 5-fold higher than the corresponding free drug ’s half-life. In certain embodiments the half-life of the drug released from the compound is it at least 7.5-fold higher than the corresponding free drug ’s half-life. In certain embodiments the half-life of the drug released from the compound is it at least 10-fold higher than the corresponding free drug ’s half-life.
In certain embodiments the release half-life of the compound is at least the circulation half-life of the corresponding free drug. In certain embodiments the release half-life of the compound is at least 2-fold higher than the circulation half-life of the corresponding free drug. In certain embodiments the release half-life of the compound is at least 3-fold higher than the circulation half-life of the corresponding free drug.
In certain embodiments the distance between two moieties -AB is such that they are capable of binding to a binding domain of two different albumins or to two different binding domains of 210 WO 2024/184351 PCT/EP2024/055724 the same albumin. In certain embodiments the distance between two moieties -AB is such that they are capable of binding to a binding domain of two different albumins. In certain embodiments the distance between two moieties -AB is such that they are capable of binding to two different binding domains of the same albumin.
In another aspect the present invention relates to a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt thereof and at least one excipient.
In another aspect the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention for use as a medicament, optionally in combination with one or more additional therapeutically active compounds.
The present invention also relates to a compound or its pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention for use as a medicament.
The present invention also relates to a compound or its pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention for use in the manufacture of a medicament.
Such medicament may be used in the treatment or prevention of a disease that can be treated or prevented with H-D-AB.
Another aspect of the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said compound of the present invention for use in a method of treating or preventing a disease that can be treated or prevented with H-D-AB or its pharmaceutically acceptable salt thereof, optionally in combination with one or more additional therapeutically active compounds.
In another aspect the present invention relates to a method of treating a patient having a disease that can be treated or prevented with H-D-AB, wherein the method comprises the step of administering a pharmaceutically acceptable amount of a compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention to a patient in 211 WO 2024/184351 PCT/EP2024/055724 need thereof, optionally in combination with one or more additional therapeutically active compounds.
Administration of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention may be via external application, injection or infusion, including intraarticular, periarticular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcuticular, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion; direct delivery to the brain via implanted device allowing delivery of the invention or the like to brain tissue or brain fluids (e.g., Ommaya Reservoir), direct intracerebroventricular injection or infusion, injection or infusion into brain or brain associated regions, injection into the subchoroidal space, retro-orbital injection and ocular instillation. In certain embodiments the medicament is for subcutaneous injection, which may be done with a pen injector or via a syringe.
A compound, in which -D-AB is a GLP-1 receptor agonist, or its pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such compound may be used in the treatment or prevention of a disease selected from the group consisting of (i) all forms of diabetes, (ii) obesity, (iii) non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), (iv) cardiovascular disease, (v) neurodegenerative disorders, (vi) chronic kidney disease (CKD), (vii) diabetic kidney disease (DKD), (viii) peripheral arterial disease (PAD), and/or (ix) heart failure (HF).
Exemplary cardiovascular diseases may be selected from the group consisting of syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia, an early cardiac or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertensive emergency, cardiomyopathy, heart insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass and/or stent reocclusion, intermittent claudication (atheroschlerosis oblitterens), diastolic dysfunction, and/or systolic dysfunction; and reduction of blood pressure, such as reduction of systolic blood pressure. 212 WO 2024/184351 PCT/EP2024/055724 A compound, in which -D-AB is a GLP-1 receptor agonist, or its pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention may be also used in the treatment or prevention of dyslipidemia and/or diseases where one or more of the following clinical outcomes are the treatment goal: lowering total serum lipids; increasing HDL; lowering small, dense LDL; lowering VLDL; lowering triglycerides; lowering cholesterol; lowering plasma levels of lipoprotein a (Lp(a)) in a human; inhibiting generation of apolipoprotein A (apo(A)).
Exemplary neurodegenerative disorders may be selected from the group consisting of Alzheimer's disease and Parkinson's disease.
Exemplary forms of HF may be selected from the group consisting of heart failure with reduced ejection fraction (HFrEF), heart failure with mid-range ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF).
In certain embodiments the compound or pharmaceutically acceptable salt thereof of the present invention is used for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
A compound, in which -D-AB is a GLP-1 receptor agonist, or its pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention may be also used in the treatment of obesity and/or eating disorders, where one or more of the following clinical outcomes are the treatment goal: decreasing food intake, increasing energy expenditure, reducing body weight, suppressing appetite, inducing satiety.
A compound, in which -D-AB is a GLP-1 receptor agonist, or its pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention may also be combined with one or more additional drugs, such as drugs selected from cardiovascular agents, antidiabetic agents, and/or anti-obesity agents. Examples of these pharmacologically active substances are: inotropes, beta adrenergic receptor blockers, HMG-C0A reductase inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, calcium channel blockers, endothelin antagonists, renin inhibitors, diuretics, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors, CETP inhibitor, relaxin, PCSKinhibitors, BNP and NEP inhibitors, GLP-1 analogues, insulin, sulphonylureas, biguanides, 213 WO 2024/184351 PCT/EP2024/055724 meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV inhibitors, SGLTinhibitors. The treatment with the compound or pharmaceutically its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention may also be combined with heart surgery.
A compound, in which -D-AB is a GLP-1 receptor agonist, or its pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention may also be administered in combination with a growth hormone, such as a human growth hormone. Such human growth hormone may be in the form of an unmodified drug, such as the human growth hormone of SEQ ID NO:58, or as a conjugate or complex comprising human growth hormone. Suitably, the compound, in which -D-AB is a GLP-1 receptor agonist, is administered to a patient in a co-treatment with lonapegsomatropin, which has the following structure: whereinD is a human growth hormone polypeptide of SEQ ID NO:58 connected to the rest of the molecule through an amine functional group provided by a lysine side chain; and each pl, p2, p3, p4 is independently an integer ranging from 210 to 240.
SEQ ID NO:58 has the following sequence:FPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSFLQNPQTSLCFSESIP TPSNREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGASDSNVYDLLKDL EEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHNDDALLKNYGLLYCFRKDMDKV ETFLRIVQCRSVEGSCGF 214 WO 2024/184351 PCT/EP2024/055724 In such co-treatment the compound, in which -D-AB is a GLP-1 receptor agonist, may be administered prior to, at the same time or after administration of the unmodified human growth hormone, the conjugate or complex comprising human growth hormone.
A compound, in which -D-AB is a PTH, such as the compound of SEQ ID NO:52 or SEQ ID NO:53, or its pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention may be used in the treatment or prevention of a disease selected from the group consisting of of hypoparathyroidism, hyperphosphatemia, osteoporosis, fracture repair, osteomalacia, osteomalacia and osteoporosis in patients with hypophosphatasia, steroid- induced osteoporosis, male osteoporosis, arthritis, osteoarthritis, osteogenesis imperfecta, fibrous dysplasia, rheumatoid arthritis, Paget ’s disease, humoral hypercalcemia associated with malignancy, osteopenia, periodontal disease, bone fracture, alopecia, chemotherapy-induced alopecia, thrombocytopenia, chronic periodontitis, osteonecrosis of jaw and poorly healing fractures due to ALPL gene mutations.
In certain embodiments, said disease is hypoparathyroidism.
In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), PD-1 (programmed cell death protein 1), PD-El (programmed death-ligand l), PD- E2 (programmed death-ligand 2), KIR (killer-cell immunoglobulin-like receptor), B7-H3, B7-H4, BTLA (B- and T-lymphocyte attenuator), LAG3 (lymphocyte-activation gene 3), TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), VISTA (V-domain Ig suppressor of T cell activation), ILT2/LILRB1 (Ig-like transcript 2/leukocyte Ig-like receptor 1), ILT3/LILRB4 (Ig-like transcript 3/leukocyte Ig-like receptor 4), ILT4/LILRB2 (Ig-like transcript 4/leukocyte Ig-like receptor 2), TIGIT (T cell immunoreceptor with Ig and ITIM domains), NKG2A, PVRIG or combinations thereof.
In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting CTLA-4, PD-1, PD-LI or combinations thereof. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting CTLA-4 with immune checkpoint inhibitors such as ipilimumab, tremelimumab, MK-1308, FPT155, PRS010, BMS-986249, BPI-002, CBT509, JS007, 215 WO 2024/184351 PCT/EP2024/055724 ONC392, TE1254, IBI310, BR02001, CGO161, KN044, PBI5D3H5, BCD145, ADU1604, AGEN1884, AGEN1181, CS1002 or CP675206. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting PD-1 with immune checkpoint inhibitors such as pembrolizumab, nivolumab, pidilizumab, AMP-224, BMS-936559, cemiplimab or PDR001. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting PD-El with immune checkpoint inhibitors such as MDX-1105, MEDI4736, atezolizumab, avelumab, BMS-936559 or durvalumab. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting PD-E2. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting KIR with immune checkpoint inhibitors such as lirilumab (IPH2102) or IPH2101. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting B7-H3 with immune checkpoint inhibitors such as MGA271. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting B7-H4 with immune checkpoint inhibitors such as FPA150. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting BTLA. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting LAG3 with immune checkpoint inhibitors such as IMP321 (eftilagimod alpha), relatlimab, MK-4280, AVA017, BI754111, ENUM006, GSK2831781, INCAGN2385, LAG3Ig, LAG525, REGN3767, Sym016, Sym022, TSRO33, TSRO75 or XmAb22841. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting TIM-3 with immune checkpoint inhibitors such as LY3321367, MBG453 or TSR- 022. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting VISTA with immune checkpoint inhibitors such as JNJ-61610588. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting ILT2/LILRB1. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting ILT3/LILRB4. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting ILT3/LILRB2 with immune checkpoint inhibitors such as MK-4830. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting TIGIT with immune checkpoint inhibitors such as MK-7684, PTZ-201, RG6058 or COM902. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting 216 WO 2024/184351 PCT/EP2024/055724 NKG2A with immune checkpoint inhibitors such as IPH-2201. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting PVRIG with immune checkpoint inhibitors such as COM701. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment targeting both PD-1 and CTLA-4. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment with nivolumab. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment with ipilimumab. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment with pembrolizumab. In certain embodiments, said disease is hypoparathyroidism induced by immune checkpoint inhibitor treatment with a combination of nivolumab and ipilimumab.
In certain embodiments, said disease is rheumatoid arthritis induced by immune checkpoint inhibitor treatment. In certain embodiments, said disease is rheumatoid arthritis induced by immune checkpoint inhibitor treatment targeting PD-1 or PD-L1. In certain embodiments, said disease is rheumatoid arthritis induced by immune checkpoint inhibitor treatment targeting PD- 1. In certain embodiments, said disease is rheumatoid arthritis induced by immune checkpoint inhibitor treatment targeting PD-L1. In certain embodiments, said disease is rheumatoid arthritis induced by immune checkpoint inhibitor treatment with nivolumab. In certain embodiments, said disease is rheumatoid arthritis induced by immune checkpoint inhibitor treatment with pembrolizumab. In certain embodiments, said disease is rheumatoid arthritis induced by immune checkpoint inhibitor treatment with a combination of nivolumab and ipilimumab. In certain embodiments, said disease is rheumatoid arthritis which recursed after immune checkpoint inhibitor treatment.
A compound or its pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention may be administered, such as via subcutaneous administration, once a week, every two weeks, every three weeks or once a month.
In certain embodiments the compound or its pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention may be administered once a week, every two weeks, every three weeks or once a month.
The invention is further described by the following non-limiting items. 217 WO 2024/184351 PCT/EP2024/055724 1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises at least one polymeric moiety, to which at least two moieties of formula (I) are conjugated and/or to which at least one moiety of formula (F) is conjugated, wherein formula (I) and (F) are ( D-AB (I ־ l 1 ־ l 2 ؛־ - (p)j whereineach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety; andeach a is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.2. The compound or a pharmaceutically acceptable salt thereof of item 1, wherein the compound comprises at least one polymeric moiety, to which at least two moieties of formula (I) are conjugated, wherein formula (I) is -I-l 2-L1-d-ab (i) whereineach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety; andeach -AB is independently an albumin-binding moiety.3. The compound or a pharmaceutically acceptable salt thereof of item 1, wherein the compound comprises at least one polymeric moiety, to which at least one moiety of formula (F) is conjugated, wherein formula (F) is -:-l ^-l 'Id-ab ], (r )j wherein 218 WO 2024/184351 PCT/EP2024/055724 each -L2- is independently a spacer moiety or is absent;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety; andeach a is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.4. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 3, wherein the at least one polymeric moiety of the compound is a linear polymeric moiety -P-.5. The compound or a pharmaceutically acceptable salt thereof of item 4, wherein a moiety of formula (I) or (T) is conjugated to each of the two ends of such linear moiety -P-.6. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 5, wherein the compound is of formula (1-a) or (I-a ‘) I-aab־d-l 1-l 2-p—l 2-l 1-d-ab ab-d-l 1’-l 2-p—l 2—l 1؛d-ab |-a L Ja(I-a ’), whereineach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety;-P- is a polymeric moiety; andeach a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.7. The compound or a pharmaceutically acceptable salt thereof of item 6, wherein the compound is formula (I-a).8. The compound or a pharmaceutically acceptable salt thereof of item 6, wherein the compound is of formula (I-a ’). 219 WO 2024/184351 PCT/EP2024/055724 9. The compound or a pharmaceutically acceptable salt thereof of item 6 or 8, wherein both a are 2.10. The compound or a pharmaceutically acceptable salt thereof of item 6 or 8, wherein both a are 3.11. The compound or a pharmaceutically acceptable salt thereof of item 6 or 8, wherein both a are 4.12. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to 11, wherein -P- comprises one or more polymer selected from the group consisting of poly(2-methacryloyl-oxyethyl phosphoyl cholines), poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkoxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(hydroxybutyrate), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates),poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethylene phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(2- hydroxyethyl methacrylates), poly(N-(2-hydroxypropyl)methacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), polypropylene glycols), poly(siloxanes), polyprethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), celluloses, carboxymethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof.13. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to 12, wherein -P- is a PEG-based or hyaluronic acid-based moiety.14. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to 13, wherein -P- is a PEG-based polymer.15. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to 14, wherein -P- is of formula (I-ai) 220 WO 2024/184351 PCT/EP2024/055724 whereindashed lines indicate attachment to -L2-;n is an integer such that the molecular weight of the PEG moiety ranges from about about 20 kDa;- X1- and -X2- are independently of each other selected from the group consisting of-T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-,- N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;- Ryl and -Ryla are independently of each other selected from the group consisting of-H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of-T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-,- N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30- membered heteropolycyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;each -Ry2 is independently selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), -S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5,- N(Ry5Ry5a ), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)ORy5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), 221 WO 2024/184351 PCT/EP2024/055724 and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; andeach -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.16. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 1 kDa;17. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 2 kDa.18. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 3 kDa.19. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 4 kDa.20. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 5 kDa.21. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 6 kDa.22. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 7 kDa.23. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 8 kDa.24. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 9 kDa.25. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 10 kDa.26. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 15 kDa.27. The compound or a pharmaceutically acceptable salt thereof of item 15, wherein n is an integer such that the molecular weight of the PEG moiety is about 20 kDa.28. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to14, wherein -P- is of formula (I-ai) wherein 222 WO 2024/184351 PCT/EP2024/055724 dashed lines indicate attachment to -L2-;n is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22;- X1- and -X2- are independently of each other selected from the group consisting of-T-, -C(O)O-, -0-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ryl )S(O)2N(Ryla )-, -S-, -N(Ry1)-, -OC(ORyl )(Ryla )-,- N(Ryl )C(O)N(Ryla )-, -OC(O)N(Ry1)-, C1-50 alkyl, C250 alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-, -S(O)2N(Ry3)-, -S(O)N(Ry3)-, -S(O)2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a )-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a )-, -N(Ry3)C(O)N(Ry3a )-, and -OC(O)N(Ry3)-;-Ryl and -Ryla are independently of each other selected from the group consisting of-H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of-T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a )-, -S-,- N(Ry4)-, -OC(ORy4)(Ry4a )-, -N(Ry4)C(O)N(Ry4a )-, and -OC(O)N(Ry4)-;each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30- membered heteropolycyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different;each -Ry2 is independently selected from the group consisting of halogen, -CN, oxo (=0), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a ), -S(O)2N(Ry5Ry5a ), -S(O)N(Ry5Ry5a ), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5a Ry5b ), -SRy5,- N(Ry5Ry5a ), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a , -N(Ry5)S(O)2Ry5a , -N(Ry5)S(O)Ry5a , -N(Ry5)C(O)ORy5a , -N(Ry5)C(O)N(Ry5a Ry5b ), -OC(O)N(Ry5Ry5a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and 223 WO 2024/184351 PCT/EP2024/055724 each -Ry3, -Ry3a , -Ry4, -Ry4a , -Ry5, -Ry5a and -Ry5b is independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.29. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to 14, wherein -P- is of formula (I-ai-i) wherein dashed lines indicate attachment to -L2-;each -XA- is independently selected from the group consisting of 224 WO 2024/184351 PCT/EP2024/055724 225 WO 2024/184351 PCT/EP2024/055724 0 0e >o /^o'< lox(x-45), (x-46), (x-47), (x-48), (x-51), (x-50), .04aOR04aR°^N• (x-56),N N 04O-RO-R04< ؛, P ؛ >(x-60), '° ° ' 63), 04b ״ 04a ״ 04 ״RXR XR x o s p o s p o s p 0^P"0^P"0^P"0< 66), R04 R04 O OO O 04 ״ ״O R .04 A°4b(x-58), (x-61), (x-64),04aK K OOOO< ‘ /R04c^ O ^ ؟ O ׳04״b/ ,R O-^ .r 04c R04B،(x-69), ,°4 (x-73),O'BV R°4a 104bR (x 59־), =>'R04 O<(x-62), 04a ״ 04 ״RR x O O 0o x "O< 04a ״ 04 ״RXR xOOOO0-p- R04b (x-67), (x-70), (x-74), -P'O> o-r 04c(x-65), R°t ,04B.
R04 0 00•Bv _04c 04״aR XR 0x p px 0'p 'p >؟ Ox04b/R04c R04xOOOO r^04C ׳ , R04b2(x-68), (x-71), (x-75), R04 o oBv ,°4 Bv0' (x-72), (x-76), 226 WO 2024/184351 PCT/EP2024/055724 0 0< ‘s‘ >"O O O>N/S"N<104 104aR R(x-91), 227 WO 2024/184351 PCT/EP2024/055724 (x-107), 228 WO 2024/184351 PCT/EP2024/055724 229 WO 2024/184351 PCT/EP2024/055724 230 WO 2024/184351 PCT/EP2024/055724 whereina dashed line indicates attachment to -L2- or the remainder of the moiety of formula (I-ai-i);each -R04, -R04a , -R04b and -R04c is independently selected from the group consisting of halogen, -H, -CN, -T°, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T°, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -R06, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T0-, -C(O)O-, -O-, -C(O)-, -C(O)N(R07)-, -S(O)2N(R07)-, -S(O)N(R07)-, -S(O)2-, -S(O)-, -N(R07)S(O)2N(R07a )-, -S-,-N(R07)-, -OC(OR07)(R07a )-, -N(R07)C(O)N(R07a )-, and -OC(O)N(R07)-;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 -R06, which are the same or different; andeach -R06, -R07 and -R07a is independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;each b is independently an integer selected from the group consisting of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;each c is independently an integer selected from the group consisting of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; andn is an integer such that the molecular weight of the PEG moiety ranges from about kDa to about 20 kDa.30. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to 14, wherein -P- is of formula (I-ai-i) whereindashed lines indicate attachment to -L2-;each -XA- is independently used as defined in item 30;each b and each c are independently used as defined in item 30; 231 WO 2024/184351 PCT/EP2024/055724 n is selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22.31. The compound or a pharmaceutically acceptable salt thereof of item 29 or 30, wherein both moieties -XA- are identical.32. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 to 31, wherein -XA- is selected from the group consisting of formula (x-1), (x-2), (x-3), (x-5), (x-12), (x-13), (x-14), (x-15), (x-16), (x-17) and (x-18).33. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 to 32, wherein both -XA- are of formula (x-1).34. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 to33, wherein both -XA- are of formula (x-1 ‘) 0 (x-1 ‘),wherein the dashed line marked with the asterisk indicates attachment to -L2- and the unmarked dashed line indicates attachment to the remainder of -P-.35. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to14, wherein -P- is of formula (I-aii) whereindashed lines indicate attachment to -L2-;each b is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;each c is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; andn is an integer such that the molecular weight of the PEG moiety ranges from about about 20 kDa36. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 1 kDa; 232 WO 2024/184351 PCT/EP2024/055724 37. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 2 kDa.38. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 3 kDa.39. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 4 kDa.40. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 5 kDa.41. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 6 kDa.42. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 7 kDa.43. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 8 kDa.44. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 9 kDa.45. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 10 kDa.46. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 15 kDa.47. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 or to 35, wherein n is an integer such that the molecular weight of the PEG moiety is about 20 kDa. 233 WO 2024/184351 PCT/EP2024/055724 48. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 to 47, wherein b is 1.49. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 to 47, wherein b is 2.50. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 to 47, wherein b is 3.51. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 to 47, wherein b is 4.52. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 to 47, wherein b is 5.53. The compound or a pharmaceutically acceptable salt thereof of any one of items 29 to52, wherein c is 1.54. The compound or a pharmaceutically acceptable salt thereof of any one of items 21 to 52, wherein c is 2.55. The compound or a pharmaceutically acceptable salt thereof of any one of items 21 to 52, wherein c is 3.56. The compound or a pharmaceutically acceptable salt thereof of any one of items 21 to 52, wherein c is 4.57. The compound or a pharmaceutically acceptable salt thereof of any one of items 21 to 52, wherein c is 5.58. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to 14, wherein -P- is of formula (I-aii ‘) (I-aii ’),whereindashed lines indicate attachment to -L2-; andn is an integer such that the molecular weight of the PEG moiety ranges from about about 20 kDa.59. The compound or a pharmaceutically acceptable salt thereof of any one of items 6 to14, wherein -P- is selected from the group consisting of 234 WO 2024/184351 PCT/EP2024/055724 (I-aii ’-viii), (I-aii ’-ix),OA; (I-aii ’-x), 235 WO 2024/184351 PCT/EP2024/055724 wherein dashed lines indicate attachment to -L2-;-R04 is used as defined in item 29; andn is an integer such that the molecular weight of the PEG moiety ranges from about about 20 kDa.60. The compound or a pharmaceutically acceptable salt thereof of any one of item 58 or 59, wherein n is an integer such that the molecular weight of the PEG moiety ranges from 1 to 15 kDa.61. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 60, wherein n is an integer such that the molecular weight of the PEG moiety ranges from 1 to 10 kDa.62. The compound or a pharmaceutically acceptable salt thereof of item 58 or 59, wherein n is an integer ranging and including about 22 to about 450.63. The compound or a pharmaceutically acceptable salt thereof of any one of items 58, or 62, wherein n is about 22. 236 WO 2024/184351 PCT/EP2024/055724 64. The compound or a pharmaceutically acceptable salt thereof of any one of items 58, 59or 62, wherein n is about 23.65. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 61, wherein n is about 45.66. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 61, wherein n is about 57.67. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 61, wherein n is about 68.68. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 6!wherein n is about 90.69. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 61, wherein n is about 113.70. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 61, wherein n is about 170.71. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 61, wherein n is about 230.72. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 61, wherein n is about 340.73. The compound or a pharmaceutically acceptable salt thereof of any one of items 58 to 61, wherein n is about 450.74. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 4, wherein the compound of the present invention comprises a plurality of linearly connected units selected from the group consisting of whereinan unmarked dashed line indicates a point of attachment to an adjacent unit at a dashed line marked with # or to a hydrogen,a dashed line marked with # indicates a point of attachment to an adjacent unit at an unmarked dashed line or to a hydroxyl; 237 WO 2024/184351 PCT/EP2024/055724 a dashed line marked with the asterisk indicates attachment to -L2-;the total number of units Z2 in -P- is at least 2;the total number of units Z1 and Z2 is at least 5;-Ra 1 and -Ra 2 are each independently selected from the group consisting of hydrogen; Cm alkyl; an alkali metal ion, an ammonium ion, an alkaline earth metal ion, or other suitable counterion;-X3- is used as defined for -X1- and -X2- of formula (I-ai) in item 11.75. The compound or a pharmaceutically acceptable salt thereof of item 74, wherein -X3- is of formula (1-b) whereinthe unmarked dashed line indicates attachment to the carbonyl of Z2;the dashed line marked with the asterisk indicates attachment to -L2-;dl is independently an integer selected from the group consisting of 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;d2 is independently an integer selected from the group consisting of 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.76. The compound or a pharmaceutically acceptable salt thereof of item 74 or 75, wherein -X3- is of formula (I-b ’)O o whereinthe unmarked dashed line indicates attachment to the carbonyl of Z2; and the dashed line marked with the asterisk indicates attachment to -L2-.77. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 3, wherein the at least one polymeric moiety of the compound of the present invention is a multi-arm polymeric moiety.78. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to or 77, wherein the compound comprises at least one branching point B, to which at least 238 WO 2024/184351 PCT/EP2024/055724 two moieties of formula (Ib) and/or at least one moiety of formula (Ib ’) are conjugated, wherein formula (Ib) and (Ib ’) are ך-A-L2-L,-D-AB (Ib) -|-A-l 2-l 14d-Ab |1 Ja (Ib ),whereinthe dashed line indicates attachment to a branching point B;-A- is a polymeric moietyeach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety; andeach a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.79. The compound or a pharmaceutically acceptable salt thereof of any one of items 1, 2, 4, 77 or 78, wherein the compound comprises at least one branching point B, to which at least two moieties of formula (Ib) are conjugated, wherein formula (Ib) is I-a-^-l ’-d-ab (Ib) whereinthe dashed line indicates attachment to a branching point B;-A- is a polymeric moietyeach -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety; andeach -AB is independently an albumin-binding moiety..80. The compound or a pharmaceutically acceptable salt thereof of any one of items 1, 3, 4, 77 or 78, wherein the compound comprises at least one branching point B, to which at least one moiety of formula (Ib ’) is conjugated, wherein formula (Ib ’) is -|-a-l 2-l 14d-ab | /t , ״l Ja (Ib ’), 239 WO 2024/184351 PCT/EP2024/055724 wherein the dashed line indicates attachment to a branching point B;-A- is a polymeric moietyeach -L2- is independently a spacer moiety or is absent;each -L1 - is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety; andeach a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.81. The compound or a pharmaceutically acceptable salt thereof of any one of items 78 to80, wherein -A- comprises a PEG-based polymer.82. The compound or a pharmaceutically acceptable salt thereof of any one of items 78 to81, wherein -A- is of formula (I-ba) z (I-ba),whereinthe unmarked dashed line indicates attachment to the branching point B;the dashed line marked with the asterisk indicates attachment to -L2-;-X8- is defined as -X1- and -X2- in formula (I-ai); andz is an integer selected such that the molecular weight of -A- ranges from about 0.kDa to about 10 kDa.83. The compound or a pharmaceutically acceptable salt thereof of any one of items 78 to82, wherein -A- is of formula (1-bb) or (I-bb ‘) whereinthe unmarked dashed line indicates attachment to the branching point B;the dashed line marked with the asterisk indicates attachment to -L2-; 240 WO 2024/184351 PCT/EP2024/055724 z is an integer selected such that the molecular weight of -A- ranges from about 0.kDa to about 10 kDa;zl is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16; andz2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16.84. The compound or a pharmaceutically acceptable salt thereof of item 83, wherein -A- is of formula (1-bb).85. The compound or a pharmaceutically acceptable salt thereof of item 83, wherein -A- is of formula (I-bb ‘).86. The compound or a pharmaceutically acceptable salt thereof of any one of items 78 to 82, wherein -A- is of formula (i-bc) or (I-bc ‘) o (I-bc) L Jz L JZ1 H z2 (I-bc ’), whereinthe unmarked dashed line indicates attachment to the branching point B;the dashed line marked with the asterisk indicates attachment to -L2-;z is an integer selected such that the molecular weight of -A- ranges from about 0.kDa to about 10 kDa;zl is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16; andz2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 16.87. The compound or a pharmaceutically acceptable salt thereof of item 85, wherein -A- is of formula (I-bc).88. The compound or a pharmaceutically acceptable salt thereof of item 85, wherein -A- is of formula (I-bc ’).89. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 88, wherein z is an integer ranging from and including about 11 to about 230. 241 WO 2024/184351 PCT/EP2024/055724 90. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to89, wherein z is an integer ranging from and including about 11 to about 225.91. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to90, wherein z is about 11.92. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to90, wherein z is about 12.93. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to90, wherein z is about 22.94. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to90, wherein z is about 23.95. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to90, wherein z is about 34.96. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to90, wherein z is about 45.97. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 57.98. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to90, wherein z is about 68.99. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 79.100. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 90.101. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 102.102. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 113.103. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 135.104. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 160.105. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 180.106. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to90, wherein z is about 205. 242 WO 2024/184351 PCT/EP2024/055724 115, wherein z2 is 6. 107. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 230.108. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 90, wherein z is about 270.109. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 108, wherein zl is 1.110. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 108, wherein zl is 2.111. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 108, wherein zl is 3.112. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 108, wherein zl is 4.113. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 108, wherein zl is 5.114. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 108, wherein zl is 6.115. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 115, wherein z2 is 1.116. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 115, wherein z2 is 2.117. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 115, wherein z2 is 3.118. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 115, wherein z2 is 4.119. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 115, wherein z2 is 5.120. The compound or a pharmaceutically acceptable salt thereof of any one of items 82 to 121. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to or 77 to 121, wherein the compound comprises one branching point B selected from the group consisting of 243 WO 2024/184351 PCT/EP2024/055724 . X6(I-bl), (I-b3),wherein dashed lines indicate attachment to -A- of formula (lb);-R1 is used as defined for the term “substituent ”; and-X4-, -X5-, -X6- and -X7- are independently used as defined for -X1- and -X2- of formula (I-ai).122. The compound or a pharmaceutically accepted salt thereof of item 121, wherein B is of formula (I-bl).123. The compound or a pharmaceutically accepted salt thereof of item 121, wherein B is of formula (I-b2).124. The compound or a pharmaceutically accepted salt thereof of item 121, wherein B is of formula (I-b3).125. The compound or a pharmaceutically accepted salt thereof of item 122 or 123, wherein -X4-, -X5- and -X6- are identical.126. The compound or a pharmaceutically accepted salt thereof of any one of items 122, 1or 125, wherein -X4-, -X5- and -X6- are selected from the group consisting of-CH2-, -CH2CH2- and -CH CH CH-127. The compound or a pharmaceutically accepted salt thereof of any one of items 122, 123, 125 or 126, wherein -X4-, -X5- and -X6- are -CH2-.128. The compound or a pharmaceutically accepted salt thereof of item 124, wherein -X4-, -X5-, -X6- and -X7- are identical.129. The compound or a pharmaceutically accepted salt thereof of item 124 or 128, wherein -X4-, -X5-, -X6- and -X7- are selected from the group consisting of-CH2-, -CH2CH2- and -CH CH CH-130. The compound or a pharmaceutically accepted salt thereof of any one of items 124, 1or 129, wherein -X4-, -X5-, -X6- and -X7- are -CH2-,131. The compound or a pharmaceutically acceptable salt thereof of any one of items 1, 2, to 7, 10 to 33 or 35 to 59, wherein the compound is of formula (I-b4)X4-A—L2-L1-D-ABAB—D-L1-L2-A-X7-|—X5-A-L2-L1-D-ABx6-a—l2-l1-d-ab (1-b4), 244 WO 2024/184351 PCT/EP2024/055724 wherein-X4-, -X5-, -X6- and -X7- are independently used as defined for -X1- and -X2- of formula (I-ai) in item 15;each -A- is a polymeric moiety;each -L2- is independently a spacer moiety or is absent;each -L1- is independently a linker moiety that is covalently and reversibly conjugated to -D-;each -D- is independently a drug moiety;each -AB is independently an albumin-binding moiety.132. The compound or a pharmaceutically acceptable salt thereof of item 131, wherein themoiety is of formula (I-b5) -؛- A ־ X4־؛- A-X7-kx 5-A -؛-— ؛ X6 A b5),wherein 245 WO 2024/184351 PCT/EP2024/055724 dashed lines indicate attachment to -L2-; andnl, n2, n3 and n4 are independently an inter ranging from and including about 10 to about 450.133. The compound or a pharmaceutically acceptable salt thereof of item 131, wherein themoiety-؛- A ־ X4־؛- A-X7-kx 5-A -؛-— ؛ X6 A is of formula (I-b6) (I־b6),whereindashed lines indicate attachment to -L2-; andnl, n2, n3 and n4 are independently an inter ranging from and including about 10 to about 230.134. The compound or a pharmaceutically acceptable salt thereof of item 132 or 133, wherein nl, n2, n3 and n4 are an integer ranging from and including about 11 to about225. 246 WO 2024/184351 PCT/EP2024/055724 135. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to 134, wherein nl, n2, n3 and n4 are about 11.136. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 12.137. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 22.138. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 23.139. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 28.140. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to 134, wherein nl, n2, n3 and n4 are about 29.141. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 45.142. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 56.143. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 68.144. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 80.145. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 90.146. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 100.147. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 115.148. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 135.149. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 160.150. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 180.151. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to134, wherein nl, n2, n3 and n4 are about 200. 247 WO 2024/184351 PCT/EP2024/055724 152. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to 134, wherein nl, n2, n3 and n4 are about 225.153. The compound or a pharmaceutically acceptable salt thereof of any one of items 132 to 134, wherein nl, n2, n3 and n4 are about 230.154. The compound or a pharmaceutically acceptable salt thereof of any one of items 1, 2, to 7, 12 to 79 or 81 to 153, wherein -L1- is of formula (II): wherein the dashed line indicates attachment to a nitrogen, hydroxyl or thiol of -D-; -X- is selected from the group consisting of -C(R4R4a )-; -N(R4)-; -O-; -C(R4R4a )- C(R5R5a )-; -C(R5R5a )-C(R4R4a )-; -C(R4R4a )-N(R6)-; -N(R6)-C(R4R4a )-;C(R4R4a )-O-; -O-C(R4R4a )-; and -C(R7R7a )-;X1 is selected from the group consisting of C; and S(O);- X2- is selected from the group consisting of -C(R8R83)-; and -C(R8R8a )-C(R9R93)-;=X3 is selected from the group consisting of =0; =S; and =N-CN;- R1, -Rla , -R2, -R2a , -R4, -R4a , -R5, -R53, -R6, -R8, -R83, -R9, and -R9a are independently selected from the group consisting of -H; and C1-6 alkyl;- R3 and -R33 are independently selected from the group consisting of -H; and C1-alkyl, provided that in case one of -R3, -R33 or both are other than -H they are connected to N to which they are attached through an SP3-hybridized carbon atom; -R7 is selected from the group consisting of -N(R10R10a ); and -NR10-(C=O)-R11;- R7a , -R10, -R10a , and -R11 are independently of each other selected from the group consisting of -H; and C1-6 alkyl;optionally, one or more of the pairs -Rla /-R4a , -R13/-R53, -Rla /-R7a , -R4a /-R5a , and -R8a /-R9a form a chemical bond;optionally, one or more of the pairs -RV-R13, -R2/-R2a , -R4/-R4a , -R5/-R5a , -R8/-R8a , and -R9/-R9a are joined together with the atom to which they are attached to form a C3-10 cycloalkyl; or 3- to 10-membered heterocyclyl;optionally, one or more of the pairs -R1/-R4, -R1/-R5, -R1/-R6, -R1/-R78, -R4/-R5, -R4/-R6, -R8/-R9, and -R2/-R3 are joined together with the atoms to which they are attached to form a ring A; 248 WO 2024/184351 PCT/EP2024/055724 optionally, R3/R3a 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; C3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; andwherein -L1- is substituted with at least one -L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L2- or a substituent.155. The compound or a pharmaceutically acceptable salt thereof of item 154, wherein -Rand -R3a are both -H.156. The compound or a pharmaceutically acceptable salt thereof of item 154, wherein -Rand -R3a are both methyl.157. The compound or a pharmaceutically acceptable salt thereof of item 154, wherein -Ris methyl and -R3a is -H.158. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 157, wherein -X2- is -C(R8R8a )-.159. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 157, wherein -X2- is -C(R8R8a )-C(R9R9a )-.160. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 159, wherein -R8 and -R8a are both -H.161. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 160, wherein -R9 and -R9a are both -H.162. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 161, wherein -R2 and -R2a are both -H.163. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 162, wherein X1 is C.164. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 163, wherein =X3 is =0.165. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 164, wherein -R1 and -Rla are both -H.166. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 164, wherein -R1 and -Rla are both methyl.167. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 164, wherein -R1 is -H and -Rla is methyl. 249 WO 2024/184351 PCT/EP2024/055724 168. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 167, wherein -X- is -C(R4R4a )-.169. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to167, wherein -X- is -C(R4R4a )-C(R5R5a )-.170. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to167, wherein -X- is -C(R7R7a )-.171. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 170, wherein -R7 is -N(R10R10a ).172. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 170, wherein both -R10 and -R10a are -H.173. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 170, wherein both -R10 and -R10a are methyl.174. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 170, wherein -R10 is -H and -R10a is methyl.175. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 170, wherein -R7 is -NR10-(C=O)-Rn176. The compound or a pharmaceutically acceptable salt thereof of item 175, wherein -Ris -H.177. The compound or a pharmaceutically acceptable salt thereof of any one of items 154 to 172, wherein -R11 is methyl.178. The compound or a pharmaceutically acceptable salt thereof of any one of items 175 to177, wherein -R10 is -H.179. The compound or a pharmaceutically acceptable salt thereof of any one of items 175 to 177, wherein -R10 is methyl.180. The compound or a pharmaceutically acceptable salt thereof of item 154, wherein X is -C(R7R7a )-; X1 is C; -X2- is -C(R8R8a )-C(R9R9a )-; =X3 is =0; -R1 and -Rla are -H; -Rand -R2a are -H; -R3 and -R3a are methyl; -R7 is -N(R10R10a ); -R7a is -H; -R8, -R8a , -Rand -R9a are -H; and -R10 is methyl and -R10a is -H.181. The compound or a pharmaceutically acceptable salt thereof of item 154 or 180, wherein -L1- is of formula (Ila) 250 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; andthe unmarked dashed line indicates attachment to -L2-.182. The compound or a pharmaceutically acceptable salt thereof of item 154, wherein -L1- is of formula (II), wherein X is -C(R7R7a )-; X1 is C; -X2- is -C(R8R8a )- C(R9R9a )-; =X3 is =0; -R1 and -Rla are -H; -R2 and -R2a are -H; -R3 and -R3a are methyl; -R7 is -NR10-(C=O)-R11; -R7a is -H; -R8, -R8a , -R9 and -R9a are -H; and -R10 is methyl and -R11 is -H.183. The compound or a pharmaceutically acceptable salt thereof of item 154 or 182, wherein -L1- is of formula (llab) O (llab), whereinthe dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; andthe unmarked dashed line indicates attachment to -L2-.184. The compound or a pharmaceutically acceptable salt thereof of any one of items 1, 3, to 6, 8 to 78, 80 to 183, wherein -L1’- is of formula (2a) wherein- Tr is a cleavable triggering moiety;- Y3- is independently selected from the group consisting of -O-, -S- and -N(R6)-;z is selected from the group consisting of 2 and 3;y is selected from the group consisting of 0, 1, 2, 3, 4 and 5;- Ar- is a ring selected from the group consisting of monocyclic or bicyclic aryl and heteroaryl, provided that -Ar- is connected to -Y3- and -R1 via carbon atoms; wherein said monocyclic or bicyclic aryl and heteroaryl are optionally substituted with -R°, which are the same or different; 251 WO 2024/184351 PCT/EP2024/055724 each -R° is independently selected from the group consisting of -C(O)OH, -halogen, -NO2, -CN, Ci-30 alkyl, C2-30 alkenyl and C2-30 alkynyl; wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally substituted with one or more -R4, which are the same or different; and wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R5)-, -S(O)2N(R5)-, -S(O)N(R5)-, -S(O)2-, -S(O)-, -N(R5)S(O)2N(R5a )-, -S-, -N(R5)-, -OC(OR5)(R5a )-, -N(R5)C(O)N(R5a )- and -OC(O)N(R5)-;each -R1 is independently selected from the group consisting of whereinan unmarked dashed line indicates attachment to -Ar-;a dashed lined marked with an asterisk indicates attachment to -D-;the total number of moieties -D- in the compound ranges from 2 to 6;each -Y1- is independently selected from the group consisting of -0- and -S-;each =¥2 is independently selected from the group consisting of =0 and =S; - ¥4- is R , wherein the dashed line marked with the asterisk indicates attachment to -Ar- and the unmarked dashed lines indicate attachment to -Y1-;each -R2 is independently selected from the group consisting of -H, -C(O)OH, -halogen, -NO2, -CN, Ci-30 alkyl, C2-30 alkenyl andC2-30 alkynyl; wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally substituted with one or more -R4, which are the same or different; and wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, -C(O)-, -C(O)N(R5)-, -S(O)2N(R5)-, -S(O)N(R5)-, -S(O)2-, -S(O)-, -N(R5)S(O)2N(R5a )-, -S-, -N(R5)-, -OC(OR5)(R5a )-, -N(R5)C(O)N(R5a )- and -OC(O)N(R5)-; 252 WO 2024/184351 PCT/EP2024/055724 each -R3a , -R3b , -R3c , -R3d are independently selected from the group consisting of -H, -C(O)OH, -F, -NO2, -CN, Ci-30 alkyl, C2-30 alkenyl and C2-30 alkynyl; wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally substituted with one or more -R4, which are the same or different; and wherein C1-30 alkyl, C2-30 alkenyl and C2-30 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R5)-, -S(O)2N(R5)-, -S(O)N(R5)-, -S(O)2-, -S(O)-, -N(R5)S(O)2N(R5a )-, -S-, -N(R5)-, -OC(OR5)(R5a )-, -N(R5)C(O)N(R5a )- and -OC(O)N(R5)-;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 -R4, which are the same or different;- R4 is selected from the group consisting of -NO2, -OCH3, -CN, -N(R5)(R5a ), -OH, -C(O)OH and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;- R5 and -R5a are independently selected from the group consisting of -H and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;each -R6 is independently selected from the group consisting of -H and C1-6 alkyl;and wherein -L1 - is substituted with one moiety -L2-.185. The compound or a pharmaceutically acceptable salt thereof of item 184, wherein -L1 - is of formula (2b) (2b),whereinthe dashed lines marked with the asterisk indicate attachment to -D-; and -L1 - is substituted with -L2-. 253 WO 2024/184351 PCT/EP2024/055724 186. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to185, wherein -L2- is of formula (XI) whereinthe unmarked dashed line indicates attachment to -L1-;the dashed line marked with the asterisk indicates attachment to the at least one polymeric moiety;h is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, 15 and 16.187. The compound or a pharmaceutically acceptable salt thereof of item 185, wherein h is3.188. The compound or a pharmaceutically acceptable salt thereof of item 185, wherein h is4.189. The compound or a pharmaceutically acceptable salt thereof of item 185, wherein h is5.190. The compound or a pharmaceutically acceptable salt thereof of item 185, wherein h is6.191. The compound or a pharmaceutically acceptable salt thereof of item 185, wherein h is 7.192. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to191, wherein -AB is of formula (A): Fo— LA— Lb-:־ . ..(A),whereinthe dashed line indicates attachment to -D-;-F° is of formula (a-1) לץ> 1 ^ R0° (a-1),whereinthe dashed line indicates attachment to -LA-;-R° is selected from the group consisting of -CR1Rla Rlb , -COOR1, 254 WO 2024/184351 PCT/EP2024/055724 1 11 / w—!—S־OH XNII '' Nxand H ;-R1, -Rla and -Rlb are selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl;n is an integer ranging from and including 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22;-La- is absent or is of formula (a-2) whereinP (a-2), the unmarked dashed line indicates attachment to -LB-;the dashed line marked with the asterisk indicates attachment to -F°;HO^O, L , /*/ N / */ N /-Ra - is selected from the group consisting of H and H whereinthe dashed line marked with the asterisk indicates attachment to -F°;the unmarked dashed line indicates attachment to the remainder of -LA-; H Q-Rb - is״N/ A,׳' ' x or -A A;m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; -Lb- is absent or is of formula (a-3)، DC De /R ׳ (a-3), whereinthe unmarked dashed line indicates attachment to -D-;the dashed line marked with the asterisk indicates attachment to -LA;HVN/-Rc - is ׳x or-Rd - is selected from the group consisting of C1-50 alkyl, C2-50 alkenyl or C2-50 alkynyl, wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl may be substituted with one or more -R1, which may be the same or different, and which C1-50 alkyl, C2-50 alkenyl 255 WO 2024/184351 PCT/EP2024/055724 or C2-50 alkynyl may be interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -0-, ־C(O)-,- C(O)N(R2)-, -S(O)2N(R2)-, -S(O)N(R2)-, -S(O)2-, -S(O)-,- N(R2)S(O)2N(R2a )-, -S-, -N(R2)-, -OC(OR2)(R2a )-, -N(R2)C(O)N(R2a )-,and -OC(O)N(R2)-;each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30- membered heteropolycyclyl; wherein each -T- may independently be substituted with one or more -R1, which may be the same or different;each -R1 is independently selected from the group consisting of halogen, -CN, oxo (=0), -C00R3, -OR3, -C(O)R3, -C(O)N(R3R3a ), -S(O)2N(R3R3a ), -S(O)N(R3Ra ), -S(O)2R3, -S(O)R3, -N(R3)S(O)2N(R3a R3b), -SR3,-N(R3R3a ), -NO2,- OC(O)R3, -N(R3)C(O)R3a , -N(R3)S(O)2R3a , -N(R3)S(O)R3a ,- N(R3)C(O)OR3a , -N(R3)C(O)N(R3a R3b), -OC(O)N(R3R3a ), and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;each -R2, -R2a , -R3, -R3a and -R3b is independently selected from the group consisting of -H, and C1-6 alkyl, wherein C1-6 alkyl may be substituted with one or more halogen, which may be the same or different; andO , II / - Re- is selected from the group consisting of -CH2-, x '" and H193. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-4).194. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-5).195. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-6).196. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-7).197. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-8). 256 WO 2024/184351 PCT/EP2024/055724 198. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-9).199. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a- 10).200. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-11).201. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a- 12).202. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a- 13).203. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a- 14).204. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a- 15).205. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a- 16).206. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a- 17).207. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a- 18).208. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a- 19).209. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-20).210. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-21).211. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-22).212. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-23).213. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-24).214. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-25). 257 WO 2024/184351 PCT/EP2024/055724 215. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-26).216. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-27).217. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-28).218. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-29).219. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-30).220. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-31).221. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-32).222. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-33).223. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-34).224. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-35).225. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-36).226. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-37).227. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-38).228. The compound or a pharmaceutically acceptable salt thereof of item 192, wherein -F° is of formula (a-39).229. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to228, wherein -LA- is absent.230. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to229, wherein -LB- is absent.231. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-40). 258 WO 2024/184351 PCT/EP2024/055724 232. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-41).233. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-42).234. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-43).235. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-44).236. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-45).237. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-46).238. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-47).239. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-48).240. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-49).241. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-50).242. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-51).243. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-52).244. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-53).245. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-54).246. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-55).247. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-56).248. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-57). 259 WO 2024/184351 PCT/EP2024/055724 249. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-58).250. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-59).251. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-60).252. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-61).253. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-62).254. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-63).255. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-64).256. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-65).257. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-66).258. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-67).259. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-68).260. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-69).261. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-70).262. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-71).263. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-72).264. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-73).265. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-74). 260 WO 2024/184351 PCT/EP2024/055724 266. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-75).267. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-76).268. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-77).269. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-78).270. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-79).271. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-80).272. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-81).273. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-82).274. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 228 or 230, wherein -LA- is of formula (a-82).275. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-83).276. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-84).277. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-85).278. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-86).279. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-87).280. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-88).281. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-89).282. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-90). 261 WO 2024/184351 PCT/EP2024/055724 283. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-91).284. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-92).285. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-93).286. The compound or a pharmaceutically acceptable salt thereof of any one of items 192 to 229 or 231 to 274, wherein -LB- is of formula (a-94).287. The compound or a pharmaceutically acceptable salt thereof of item 276, wherein q is an integer ranging from and including 3 to 45.288. The compound or a pharmaceutically acceptable salt thereof of item 276 or 287, wherein q is an integer ranging from and including 4 to 40.289. The compound or a pharmaceutically acceptable salt thereof of any one of items 276, 287 or 288, wherein q is an integer ranging from and including 5 to 35.290. The compound or a pharmaceutically acceptable salt thereof of any one of items 276 or 287 to 289, wherein q is an integer ranging from and including 6 to 30.291. The compound or a pharmaceuti cally acceptable salt thereof of any one of items 276 or 287 to 290, wherein q is an integer ranging from and including 7 to 25.292. The compound or a pharmaceutically acceptable salt thereof of any one of items 276 or 287 to 291, wherein q is an integer ranging from and including 10 to 20.293. The compound or a pharmaceutically acceptable salt thereof of any one of item s 276 or 287 to 292, wherein q is 23.294. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 293, wherein -D- is a drug moiety selected from the group consisting of small molecule drug moieties, medium size molecule drug moieties, oligonucleotide drug moieties, peptide nucleic acid drug moieties, peptide drug moieties and protein drug moieties.295. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294, wherein -D- is a small molecule drug moiety.296. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294, wherein -D- is a medium size drug moiety.297. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294, wherein -D- is an oligonucleotide drug moiety.298. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294, wherein -D- is a peptide nucleic drug moiety. 262 WO 2024/184351 PCT/EP2024/055724 299. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294, wherein -D- is a peptide drug moiety.300. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294, wherein -D- is a protein drug moiety.301. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294, wherein -D- or -D-AB is a GLP-1 receptor agonist moiety.302. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO: 1.303. The compound or a pharmaceutically acceptable salt thereof of any item 301,wherein -D- is SEQ ID NO:2.304. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:3.305. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:4.306. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:5.307. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:6.308. The compound or a pharmaceutically acceptable salt thereof of any item 301,wherein -D- is SEQ ID NO:7.309. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:8.310. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:9.311. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO: 10.312. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO: 11.313. The compound or a pharmaceutically acceptable salt thereof of any item 301,wherein -D- is SEQ ID NO: 12.314. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO: 13.315. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO: 14. 263 WO 2024/184351 PCT/EP2024/055724 316. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO: 15.317. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO: 16.318. The compound or a pharmaceutically acceptable salt thereof of any item 301,wherein -D- is SEQ ID NO: 17.319. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO: 18.320. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO: 19.321. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:20.322. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:21.323. The compound or a pharmaceutically acceptable salt thereof of any item 301,wherein -D- is SEQ ID NO:22.324. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:23.325. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:24.326. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:25.327. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:26.328. The compound or a pharmaceutically acceptable salt thereof of any item 301,wherein -D- is SEQ ID NO:27.329. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:28.330. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:29.331. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:30.332. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:31. 264 WO 2024/184351 PCT/EP2024/055724 333. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:32.334. The compound or a pharmaceutically acceptable salt thereof of any item 301, wherein -D- is SEQ ID NO:33.335. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294 or 301, wherein -D- or -D-AB is a mono agonist of the GLP-1 receptor.336. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294 or 301, wherein -D- or -D-AB is a dual GLP-1 receptor.337. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 294 or 301, wherein -D- or -D-AB is a triple GLP-1 receptor.338. The compound or a pharmaceutically acceptable salt thereof of item 336, wherein the dual agonist is a GLP-1 receptor agonist and an agonist of a further receptor selected from the group consisting of the GIP receptor, the GCG receptor, an amylin receptor, a PYY receptor and the GLP-2 receptor.339. The compound or a pharmaceutically acceptable salt thereof of item 338, wherein the further receptor is the GIP receptor.340. The compound or a pharmaceutically acceptable salt thereof of item 338, wherein the further receptor is GCG receptor.341. The compound or a pharmaceutically acceptable salt thereof of item 338, wherein the further receptor is an amylin receptor.342. The compound or a pharmaceutically acceptable salt thereof of item 338, wherein the further receptor is a PYY receptor.343. The compound or a pharmaceutically acceptable salt thereof of item 338, wherein the further receptor is the GLP-2 receptor.344. The compound or a pharmaceutically acceptable salt thereof of item 337, wherein the triple agonist is a GLP-1 receptor agonist and an agonist of two further receptors selected from the group consisting of the GIP receptor, the GCG receptor, an amylin receptor, a PYY receptor and the GLP-2 receptor.345. The compound or a pharmaceutically acceptable salt thereof of item 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, the GIP receptor and the GCG receptor.346. The compound or a pharmaceutically acceptable salt thereof of item 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, the GIP receptor and an amylin receptor. 265 WO 2024/184351 PCT/EP2024/055724 347. The compound or a pharmaceutically acceptable salt thereof of 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, the GIP receptor and a PYY receptor.348. The compound or a pharmaceutically acceptable salt thereof of 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, the GIP receptor and the GLP-receptor.349. The compound or a pharmaceutically acceptable salt thereof of 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, the GCG receptor and an amylin receptor.350. The compound or a pharmaceutically acceptable salt thereof of 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, the GCG receptor and a PYY receptor.351. The compound or a pharmaceutically acceptable salt thereof of 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, the GCG receptor and the GLP-receptor.352. The compound or a pharmaceutically acceptable salt thereof of 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, an amylin receptor and a PYY receptor.353. The compound or a pharmaceutically acceptable salt thereof of 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, an amylin receptor and the GLP-receptor.354. The compound or a pharmaceutically acceptable salt thereof of 337 or 344, wherein the triple agonist is an agonist of the GLP-1 receptor, a PYY receptor and the GLP-receptor.355. The compound or a pharmaceutically acceptable salt thereof of item 301, 303 or 335, wherein -D-AB is semaglutide.356. The compound or a pharmaceutically acceptable salt thereof of item 301, 313 or 335, wherein -D-AB is liraglutide.357. The compound or a pharmaceutically acceptable salt thereof of item 301, 315 or 335, wherein -D-AB is ecnoglutide.358. The compound or a pharmaceutically acceptable salt thereof of item 301, 317 or 335, wherein -D-AB is GZR18.359. The compound or a pharmaceutically acceptable salt thereof of item 301, 319 or 335, wherein -D-AB is GL0034. 266 WO 2024/184351 PCT/EP2024/055724 360. The compound or a pharmaceutically acceptable salt thereof of item 301, 321 or 336, wherein -D-AB is tirzepatide.361. The compound or a pharmaceutically acceptable salt thereof of item 301, 323 or 336, wherein -D-AB is cotadutide.362. The compound or a pharmaceutically acceptable salt thereof of item 301, 325 or 336,wherein -D-AB is BI-456906.363. The compound or a pharmaceutically acceptable salt thereof of item 301, 327 or 336, wherein -D-AB is pemvidutide.364. The compound or a pharmaceutically acceptable salt thereof of item 301, 329 or 336, wherein -D-AB is mazdutide.365. The compound or a pharmaceutically acceptable salt thereof of item 301, 331 or 336, wherein -D-AB is dapiglutide.366. The compound or a pharmaceutically acceptable salt thereof of item 301, 333 or 337, wherein -D-AB is retatrutide.367. A compound or a pharmaceutically acceptable salt thereof of formula (2c ’ ’) 267 WO 2024/184351 PCT/EP2024/055724 whereinthe dashed line indicates attachment to the N-terminal amine functional group of semaglutide; andnl, n2, n3 and n4 are independently an integer ranging from about 11 to about 115.368. A compound or a pharmaceutically acceptable salt thereof of formula (2c ’). 268 WO 2024/184351 PCT/EP2024/055724 (2c،),whereina dashed line indicates attachment to the N-terminal amine functional group ofsemaglutide; andnl, n2, n3 and n4 independently range from about 11 to about 115.369. A compound or a pharmaceutically acceptable salt thereof of formula (2d) 269 WO 2024/184351 PCT/EP2024/055724 (2d), wherein nl, n2, n3 and n4 independently range from about 11 to about 115;dashed lines indicate attachment to a moiety whereinthe unmarked dashed line indicates attachment to an unmarked dashed line of formula (2d); andthe dashed line marked with the asterisk indicates attachment to the N-terminalamine functional group of semaglutide.370. A compound or a pharmaceutically acceptable salt thereof of formula (2c ’) 270 WO 2024/184351 PCT/EP2024/055724 whereina dashed line indicates attachment to the N-terminal amine functional group of semaglutide; andnl, n2, n3 and n4 independently range from about 11 to about 115.371. A compound or a pharmaceutically acceptable salt thereof of formula (26) 271 WO 2024/184351 PCT/EP2024/055724 (2e), wherein 5nl, n2, n3 and n4 independently range from about 11 to about 115; dashed lines indicate attachment to a moiety wherein the unmarked dashed line indicates attachment to an unmarked dashed line of formula (2e); andthe dashed line marked with the asterisk indicates attachment to the N-terminalamine functional group of semaglutide.372. A compound or a pharmaceutically acceptable salt thereof of formula (2f) 272 WO 2024/184351 PCT/EP2024/055724 (2f), wherein nl, n2, n3 and n4 independently range from about 11 to about 115;dashed lines indicate attachment to a moiety whereinthe unmarked dashed line indicates attachment to an unmarked dashed line of formula (2f); andthe dashed line marked with the asterisk indicates attachment to the N-terminalamine functional group of semaglutide. 273 WO 2024/184351 PCT/EP2024/055724 373. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 22.374. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 23.375. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 28.376. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 45.377. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 56.378. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 68.379. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 80.380. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 90.381. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 100.382. The compound or a pharmaceutically acceptable salt thereof of any one of items 367 to372, wherein nl, n2, n3 and n4 are about 115.383. A compound or a pharmaceutically acceptable salt thereof of formula (2h) whereinthe dashed line marked with the asterisk indicates attachment to the dashed line of a moiety of formula (2i) I#1 1 H (2i), wherein 274 WO 2024/184351 PCT/EP2024/055724 the dashed line marked with the # indicates attachment to the N-terminal amine functional group of semaglutide;and wherein the unmarked dashed line of formula (2h) indicates attachment to the unmarked dashed line of formula (2j) whereinthe dashed line marked with the # indicates attachment to the N-terminal amine functional group of semaglutide.384. A compound or a pharmaceutically acceptable salt thereof of formula (2g) whereinn is an integer ranging from about 22 to about 230; dashed lines indicate attachment to a moiety 15wherein 275 WO 2024/184351 PCT/EP2024/055724 the unmarked dashed line indicates attachment to an unmarked dashed line of formula (2g); andthe dashed line marked with the asterisk indicates attachment to the N-terminalamine functional group of semaglutide. 385. A compound or a pharmaceutically acceptable salt thereof of formula (2h ’) ° (2h ’);whereinthe dashed line marked with the asterisk indicates attachment to the dashed linemarked with the asterisk of a moiety of formula (2i) I#1 H (2i),whereinthe dashed line marked with the # indicates attachment to the N-terminal amine functional group of semaglutide;and wherein the unmarked dashed line of formula (2h ’) indicates attachment to the unmarked dashed line of formula (2j) whereinthe dashed line marked with the # indicates attachment to the N-terminal amine functional group of semaglutide;and wherein n is an integer ranging from about 22 to about 230.386. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 44. 276 WO 2024/184351 PCT/EP2024/055724 387. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 46.388. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 68.389. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 90.390. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 112.391. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 113.392. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 136.393. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 160.394. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 180.395. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 200.396. The compound or a pharmaceutically acceptable salt thereof of item 384 or 385, wherein n is about 230.397. The compound or a pharmaceutically acceptable salt thereof of any one of item 1 to 396, wherein the half-life of the drug released from the compound is it at least 1.5-fold higher than the corresponding free drug ’s half-life.398. The compound or a pharmaceutically acceptable salt thereof of any one of item 1 to 397, wherein the half-life of the drug released from the compound is it at least 2.5-fold higher than the corresponding free drug ’s half-life.399. The compound or a pharmaceutically acceptable salt thereof of any one of item 1 to 398, wherein the half-life of the drug released from the compound is it at least 5-fold higher than the corresponding free drug ’s half-life.400. The compound or a pharmaceutically acceptable salt thereof of any one of item 1 to 399, wherein the half-life of the drug released from the compound is it at least 7.5-fold higher than the corresponding free drug ’s half-life. 277 WO 2024/184351 PCT/EP2024/055724 401. The compound or a pharmaceutically acceptable salt thereof of any one of item 1 to 400, wherein the half-life of the drug released from the compound is it at least 10-fold higher than the corresponding free drug ’s half-life.402. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 401, wherein the release half-life of the compound is at least the circulation half-life of the corresponding free drug.403. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 402, wherein the release half-life of the compound is at least 2-fold higher than circulation half-life of the corresponding free drug.404. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 403, wherein the release half-life of the compound is at least 3-fold higher than circulation half-life of the corresponding free drug.405. A pharmaceutical composition comprising at least one compound or a pharmaceuticallyacceptable salt thereof of any one of items 1 to 404.406. A pharmaceutical composition comprising at least one compound or a pharmaceuticallyacceptable salt thereof of any one of items 301 to 396.407. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 405 or the pharmaceutical composition of item 374 for use as a medicament.408. The compound or a pharmaceutically acceptable salt thereof of any one of items 301 to 396 or the pharmaceutical composition of item 406 for use as a medicament for the treatment of a disease that can be treated with a GLP-1 receptor agonist.409. The compound or a pharmaceutically acceptable salt thereof of any one of items 1 to 404 or the pharmaceutical composition of item 405 for use in the treatment of a disease.410. The compound or a pharmaceutically acceptable salt thereof of any one of items 301 to 396 or the pharmaceutical composition of item for use in the treatment of a disease that can be treated with a GLP-1 receptor agonist.411. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of item 408 or 410, wherein the disease that can be treated with a GLP-1 receptor agonist is selected from the group consisting of (i) all forms of diabetes, (ii) obesity, (iii) non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), (iv) cardiovascular disease, (v) neurodegenerative disorders, (vi) chronic kidney disease (CKD), (vii) diabetic kidney disease (DKD), (viii) peripheral arterial disease (PAD), and/or (ix) heart failure (HF). 278 WO 2024/184351 PCT/EP2024/055724 412. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition use of item 411, wherein the cardiovascular disease is selected from the group consisting of syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, cerebral ischemia, an early cardiac or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertensive emergency, cardiomyopathy, heart insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass and/or stent reocclusion, intermittent claudication (atheroschlerosis oblitterens), diastolic dysfunction, and/or systolic dysfunction; and reduction of blood pressure, such as reduction of systolic blood pressure.413. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of item 408 or 410, wherein the disease that can be treated with a GLP-1 receptor agonist is selected from the list consisting of dyslipidemia and/or diseases where one or more of the following clinical outcomes are the treatment goal: lowering total serum lipids; increasing HDL; lowering small, dense LDL; lowering VLDL; lowering triglycerides; lowering cholesterol; lowering plasma levels of lipoprotein a (Lp(a)) in a human; inhibiting generation of apolipoprotein A (apo(A)).414. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of item 411, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease and Parkinson's disease.415. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of item 411, wherein the heart failure is selected from the group consisting of heart failure with reduced ejection fraction (HFrEF), heart failure with mid-range ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF).416. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of item 411, wherein the disease that can be treated with a GLP-receptor agonist is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).417. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of item 408 or 410, wherein the disease that can be treated with a GLP-1 receptor agonist is obesity and/or eating disorders, where one or more of the 279 WO 2024/184351 PCT/EP2024/055724 following clinical outcomes are the treatment goal: decreasing food intake, increasing energy expenditure, reducing body weight, suppressing appetite, inducing satiety.418. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of any one of items 407 to 417, wherein the treatment is a co- treatment with one or more additional drugs.419. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of 408 or 410 to 417, wherein the treatment is a co-treatment with one or more additional drugs.420. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of item 419, wherein the one or more additional drugs is selected from the group consisting of inotropes, beta adrenergic receptor blockers, HMG-CoA reductase inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, calcium channel blockers, endothelin antagonists, renin inhibitors, diuretics, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors, CETP inhibitor, relaxin, PCSK9 inhibitors, BNP and NEP inhibitors, GLP-1 analogues, insulin, sulphonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV inhibitors, SGLT2 inhibitors.421. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of any one of items 408, 410 to 417, 419 or 420, wherein the treatment is combined with heart surgery.
Materials and methods Chemicals All materials were obtained from commercial vendors except where stated otherwise. Semaglutide was purchased as the free acid from AdipoGen AG (Fullinsdorf, Switzerland). Tirzepatide hydrochloride was purchased from MedChemExpress (New Jersey, USA) Pentaerythritol tetra{[3-3(3-maleimido-l-oxopropyl)amino]propyl} polyoxyethylene (alternative name: 4-arm lOkDa-PEG tetramaleimide) was purchased fromNOF Corporation. Bis-Mal-Lysine-PEG4-TFP ester, Amine-PEG-amine, MW 5,000 and Mal-PEG-Mal, MW 5,000 were purchased from Broadpharm, San Diego, CA. mal-dPEG(3)-mal was purchased from Iris Biotech GmbH, Marktredwitz, Germany. 4-arm PEG-Mal, 5 kDa was purchased from Creative PEGWorks. 280 WO 2024/184351 PCT/EP2024/055724 The number of ethylene glycol units “n” in a PEG reagent varies from batch to batch due to the polydispersity of polymeric moieties. All values for “n” are thus calculated based on the nominal molecular weight of a PEG reagent as provided by the manufacturer.
Reactions Generally, reactions were stirred at room temperature and monitored by LCMS.
RP-HPLC purification Preparative RP-HPLC purifications were performed with a Waters 600 controller with a 24Dual Absorbance Detector, an Agilent 1260 Infinity II preparative system, or a Knauer Azura Preparative gradient system. A Waters XBridge BEH300 Prep C18 10 pm, 150 x 30 mm column or XSelect CSH Prep C18 10 pm 150 x 30 mm column were used as stationary phase. Products were detected at 215 nm, 254 nm or 280 nm. Linear gradients of solvent system A (water containing 0.1% TFA v/v) and solvent system B (acetonitrile containing 0.1% TFA v/v) were used. HPLC fractions containing product were pooled and lyophilized if not stated otherwise.
UPLC-MS analysis Analytical ultra-performance LC (UPLC)-MS was performed on a Waters Acquity system or an Agilent 1290 Infinity II equipped with a Waters BEH300 C18 column (2.1 x 50 mm, 1.pm particle size or 2.1 x 100 mm, 1.7 pm particle size) or with a XSelect CSH Cl 8 (2.1 x mm, 2.5 pm particle size); solvent A: water containing 0.04% TFA (v/v), solvent B: acetonitrile containing 0.05% TFA (v/v) coupled to a Waters Micromass ZQ, Waters SQ Detector 2 or to an Agilent Single Quad MS system.
Example 1 N 1 HN، kTmobCompound 1was prepared following the procedure described in WO2020064847 (exampleH).MS: m/z, 283.15 = [M+H]+, (calculated [M+H]+ = 283.20). 281 WO 2024/184351 PCT/EP2024/055724 Example 2 Compound 2was prepared as the TFA salt from 1according to the procedure described in WO2020064847 (example 11).MS: m/z, 881.36 = [M+H]+, (calculated [M+H]+ = 881.42).
Example 3 3 Conjugated via His1 Na Semaglutide (5 mg, 1.0 eq., 1.22 umol) was dissolved in a mixture of 100 mM pH 8 borate buffer (0.5 mL) and acetonitrile (0.5 mL). To this was added 2(7.3 mg, 6.0 eq., 7.29 umol) dissolved in acetonitrile (73 uL). After stirring at it for 21 h, the reaction was quenched by addition of 10% aq. TFA (20 pL) and purified directly by preparative RP-HPLC to give 3as the TFA salt.Yield: 1.6 mg (25%, TFA salt)MS: m/z 1627.74 = [M+3H]3+, (calculated [M+3H]3+= 1627.17).
Example 4 282 WO 2024/184351 PCT/EP2024/055724 4 Conjugated via His1 Na The protected conjugate 3(1.6 mg, 1.0 eq., 0.30 umol) was treated with 80 pL of HFIP/TES/water/DTT (39/1/5/2.5) then 20 pL of TFA. The mixture was shaken at it for 55 min before addition of 1 mL of ice-cold diethyl ether. The mixture was vortexed, centrifuged, and the supernatant removed. The resulting precipitate was washed twice more with 1 mL of ice- cold diethyl ether. The crude conjugate was then purified via preparative RP-HPLC to give 4 as the TFA salt.Yield:MS:1.1 mg (75%, TFA salt)m/z 1486.94 = [M+3H]3+, (calculated [M+3H]3+ = 1486.45). 283 WO 2024/184351 PCT/EP2024/055724 : R = Conjugated via His1 Na To a solution of 4-arm lOkDa-PEGtetramaleimide (0.38 mg, 1.0 eq., 0.037 umol) in 250 mM pH 7.4 phosphate buffer (38 pL) was added conjugate 4(0.37 mg, 2.0 eq, 0.075 umol) in 250 mM pH 7.4 phosphate buffer (50 pL), acetonitrile (50 pL), and water (25 pL). After shaking at rt for 20 mins at rt, conjugate 4(0.37 mg, 2.0 eq, 0.075 pmol) in 250 mM pH 7.phosphate buffer (50 pL), acetonitrile (50 pL), and water (25 pL) were added to the reaction mixture. After a further 20 mins shaking at rt, conjugate 4(0.19 mg, 1.0 eq, 0.037 pmol) in 250 mM pH 7.4 phosphate buffer (25 pL), acetonitrile (25 pL), and water (13 pL) were added to the reaction mixture. After a further 95 mins, the reaction was quenched by addition of TFA (5 pL) and the mixture was purified by preparative RP-HPLC to give 5as a TFA salt.Yield: 0.6 mg (54%, TFA salt) Example 6 Preparation of [Lys(Boc)16]tirzepatide Tirzepatide hydrochloride (2.0 mg, 1.0 eq., 0.41 pmol) was dissolved in water (19 pL), 1 M aq. NaHCO3 solution (5.5 pL) and DMF (56 pL). To this was added N-(tert- butoxycarbonyloxy)succinimide (0.09 mg, 1.0 eq., 0.41 pmol) in DMF (1.8 pL). The solution was shaken in an Eppendorf tube at rt for 160 min before quenching with 400 pL 1:acetonitrile/water (+0.1% TFA), TFA (1 pL) and water (200 pL). The crude product was then purified by preparative RP-HPLC to give 6 as a white solid.Yield: 1.2 mg (58%, TFA salt)MS: m/z 1638.91= [M+3H]3+, (calculated for [M+3H]3+= 1638.53). 284 WO 2024/184351 PCT/EP2024/055724 Example7 7 Conjugated via Tyr1 Na Conjugate 7 is prepared from 6 as per example 3 and 4.
Conjugated via Tyr1 NaCompound 8 is prepared from 7 and 4-arm lOkDa-PEGtetramaleimide as per example 5. 285 WO 2024/184351 PCT/EP2024/055724 Example 9 Maleimide functionalized hyaluronic acid Maleimide functionalized hyaluronic acid 9 is prepared from hyaluronic acid (8 kDa) as described in WO2018175788 (example 2B). A degree of functionalization is achieved that gives between 2 and 6 maleimide groups per molecule. 286 WO 2024/184351 PCT/EP2024/055724 Maleimide functionalized hyaluronic acid 9is conjugated to compound 4as per example 5, except that the resulting conjugate 10is purified by centrifugal filtration using a membrane with a 5 kDa molecular weight cut-off.
Example 11 Compound 11:Compound 11is prepared as described in US3689540 (example 1).
Compound 12:Compound 12is prepared by coupling compound 11with 6-azidohexan-l-amine using HATU and DIPEA in DMF Compound 13: Compound 13is prepared from 12and 1,1-dimethyl ethyl N-methyl-N-[3- (methylamino)propyl]carbamate using a protocol similar to that described in AngewandteChemie International Edition 2005, 44 (5), 716-720.
Compound 14:Compound 14is prepared from 13using a protocol similar to that described in Angewandte Chemie International Edition 2005, 44 (5), 716-720. 287 WO 2024/184351 PCT/EP2024/055724 Example 12 Conjugated via Tyr1 Na To [Lys(Boc)16]tirzepatide 6(2.25 eq.) in pH 7.0 phosphate buffer is added compound 14inDMF. After stirring for l h, the mixture is diluted with water and lyophilized. The crude mixture is treated with HFIP/TES/water/DTT (39/1/5/2.5) then TFA. The conjugate is isolated by precipitation with ice-cold ether and is then purified by preparative RP-HPLC to give 15.
Example 13 16n = ca. 227 17n = ca. 227 Conjugated via Tyr1 Na 288 WO 2024/184351 PCT/EP2024/055724 To the commercially available bis-functional 10 kDa PEG 16is added 15in 1:1 buffer/DMF. After stirring at it for 2 h, the crude material is purified directly by preparative RP-HPLC to give 17.
Example 14 Bis-Mal-Lysine-PEG4-TFP ester (20.8 mg, 2.5 eq, 24.7 umol) was dissolved in 1 mL acetonitrile / water (3:1 v/v). Amine-PEG-amine, MW 5,000 (50.0 mg, 1 eq, 9.88 umol) dissolved in 1 mL acetonitrile / water (3:1 v/v) was added, followed by DIPEA (2.55 mg, 3.44 pL, 2 Eq, 19.8 umol). The clear solution was stirred at rt. After 30 min the reaction wasquenched with 3 pl TEA and the product purified by preparative RP-HPLC to give 18ascolorless solid.Yield: 35 mg (55%) Example 15 289 WO 2024/184351 PCT/EP2024/055724 An excess of 4in acetonitrile / water was added to 1 eq of the respective PEG maleimide portion-wise. The pH of the reaction was adjusted by addition of pH 7.0 or 7.4 sodium phosphate buffer. The reaction solution was shaken at it and monitored by LC/MS. Upon completion the reaction was acidified with TFA. The product was purified by preparative RP- HPLC.
Synthesis of 19:1.0 eq mal-dPEG(3)-mal (0.6 mg),2.2 eq 4(11.0 mg), pH 7.4: yield: 8.80 mg (75%, 8x TFA salt),MS: m/z 1349.31 = [M+7H]7+, (calculated [M+7H]7+ = 1349.12) Synthesis of 20:1 eq Mal-PEG-Mal, MW 5,000 (11.7 mg),2.0 eq 4(21.4 mg), pH 7.0: yield: 18.4 mg (56%, 8x TFA salt) Synthesis of 21:1 eq 18(2.90 mg), 4.5 eq 4(10.0 mg), pH 7.4: yield: 7.1 mg (60%, 16x TFA salt) Example 16: PK study in Sprague Dawley rats The objective of the study was to determine the pharmacokinetic (PK) characteristics of 5 when administered once by the intravenous (IV) or the subcutaneous (SC) route to the adult male Sprague Dawley rat. A semaglutide IV and SC group was included as comparator. 290 WO 2024/184351 PCT/EP2024/055724 The Study design is shown in Table 1. Blood samples were processed to plasma and provided for PK analysis of semaglutide released from 5.
Table 1: Design of Study(Dose is in mg semaglutide equivalents/kg)Group Test item n Dose (mg/kg)Administration RouteBlood sampling timepoints (hours post dose)Semaglutide 3 0.030 IV Predose, 0.25, 0.5, 1, 2, 4, 6, 24, 48Semaglutide 3 0.030 SC Predose, 1, 3, 4, 6, 8, 12, 24, 48 5 3 0.222 IV 0.25, 3, 8, 24, 36, 48, 72, 168, 264 5 3 0.222 SC 3, 6, 10, 24, 36, 48, 72, 168, 264 Example 17: PK study in Sprague Dawley rats The objective of the study was to determine the PK characteristics of 19and 20when administered once by the IV or the SC route to the adult male Sprague Dawley rat. A semaglutide SC group was included as comparator and a vehicle SC group was included as control.
The Study design is shown in Table 2. Blood samples were processed to plasma and provided for PK analysis of released semaglutide (except from group F).
(Dose is in mg semaglutide equivalents/kg)Table 2: Design of Study Group Test item n Dose (mg/kg)Administration RouteBlood sampling timepoints (hours post dose) bA 20 3 0.45 IV 0.25, 3, 8, 24, 36, 48, 72, 120, 168 and 264B 19 3 0.45 IV 0.25, 3, 8, 24, 36, 48, 72, 120, 168 and 264C 20 3 0.45 SC 3, 6, 10, 24, 36, 48, 72,96, 168 and 264D 19 3 0.45 SC 3, 6, 10, 24, 36, 48, 72,96, 168 and 264E Semaglutide 3 0.030 SC 1, 2, 4, 6, 8, 12, 24, and 58 291 WO 2024/184351 PCT/EP2024/055724 F Vehicle control3 0 SC 3, 6, 10, 24, 36, 48, 72,96, 168 and 264 Example 18: PK analysis of semaglutide released from compounds 5,19, 20 compared to semaglutide and PK analysis of semaglutide released from 22 and 24 in Sprague Dawley rats The PK of semaglutide and semaglutide released from 5,19,20, 22or 24was determined after IV or SCadministration of semaglutide and of 5,19, 20, 22or 24to rats according to the study described in example 16, example 17 and example 29.
Blood samples were collected from all animals according to Table 1, Table 2 and Table 8. Plasma samples were analyzed for semaglutide.
Semaglutide and semaglutide released from 5, 19, 20, 22and 24was quantified in Sprague Dawley rat KzEDTA plasma via LC-MS/MS after plasma protein precipitation. Samples containing semaglutide were pipetted into the wells of a 96-well plate, followed by the addition of internal standard (d8-semaglutide). Plasma protein precipitation was carried out using a mixture of acetonitrile and water (85/15, v/v). The precipitate was centrifuged at 4 °C and a fraction of the supernatant was transferred to a new 96-well plate, evaporated to dryness under a stream of heated nitrogen and reconstituted in water containing 0.2 % formic acid.
Chromatography was performed on a Waters Acquity UPLC Peptide BEH C18 analytical column (1.7 pm particle size; pore size 300 A; column dimensions 50 x 2.1 mm). Water (UPLC grade) containing 0.1 % formic acid (v/v) was used as mobile phase A and acetonitrile (UPLC grade) with 0.1 % formic acid as mobile phase B. Multiple reaction monitoring (MRM) was performed for semaglutide and the internal standard and quantification was based on peak area and linear regression with 1/x 2 weighting.
A summary of the individual and mean PK parameters for semaglutide and semaglutide released from 5,19, 20, 22and 24in rat plasma are shown below in Table 3, Table 4 and Table 5.
Table 3: Summary of the Mean PK Parameters of semaglutide and semaglutide released from 5in rat plasma in study described in example 16. 292 WO 2024/184351 PCT/EP2024/055724 Dose groupTest Item ROA Dose level (pg/kg) Cmax (ng/mL) atmax (h)btlast(h)b AUClast (h*ng/mL) atl/2(h)asemaglutide IV 30 570c 0.25 48 5,400c 10csemaglutide SC 30 130±26 6 48 3,000±620 11±1.3 5 IV 222 34±1.3 24 168 2,500±660 43±2 5 SC 222 24±3 24 72 l,100±120 30±0.93mean value±SD; 1,median value; c n = 2 Table 4: Summary of the mean PK parameters of semaglutide and semaglutide released from 19or 20in rat plasma in example 17.Dose groupTest Item ROADose level(pg/kg)Cmax (ng/mL) atmax (h)btlast(h)bAUClast (h*ng/mt) atl/2(h)aA 20 IV 450 56±7.1 24 120 3,400±250 28±2.2B 19 IV 450 37±0.9 8 72 l,800±60 23±2.1 C 20 SC 450 50±l 24 96 2,500±460 27±2.6D 19 SC 450 40±5.2 24 96 l,700±320 20±1.9E semaglutide SC 30 110±21 8 58 3,100±560 12±0.2 3mean value±SD; 1,median valueNote: group F served as vehicle control and was not dosed with an active compound 24in rat plasma in study described in example 29.Table 5: Summary of the Mean PK Parameters of semaglutide and semaglutide released from 22and Dose groupTest Item ROA Dose level (pg/kg) Cmax (ng/mL) atmax (h)btlast(h)b AUClast (h*ng/mE) atl/2(h)a 22 IV 450 58±3.0 24 120 3,800±170 29±1.0 24 IV 450 35±1.8 8 72 l,300±190 18±0.963mean value±SD; *,median value Example 19: PK study in cynomolgus monkey The objective of the study was to determine the PK characteristics of 5 when administered once by the IV or SC route to the cynomolgus monkey.
The Study design is shown in Table 6. Blood samples were processed to plasma and provided for PK analysis of semaglutide released from 5.
Table 6: Design of StudyDose is in mg semaglutide equivalents/kg 293 WO 2024/184351 PCT/EP2024/055724 Group No.Test itemNo. ofAnimalsDose (mg/kg)AdministrationRouteBlood sampling time points (hours post dose)Males Females 1 5 1 1 0.15 IV Predose, 0.25, 2, 6, 12, 24, 48, 72, 96, 120, 144, 168, 216, 264, 288 and 336 2 5 1 1 0.15 SC Predose, 3, 6, 10, 16, 24, 36, 48, 72, 96, 120, 144, 168, 216, 264, 288 and 336 Example 20: PK analysis of semaglutide released from 5 in cynomolgus monkeys The PK of semaglutide released from 5was determined after IV or SCadministration of 5to monkeys in the study described in example 19.
Semaglutide released from 5was quantified in cynomolgus monkey KzEDTA plasma via LC-MS/MSafter plasma protein precipitation. Samples containing semaglutide were pipetted into the wells of a 96-well plate, followed by the addition of internal standard (d8- semaglutide) solution containing 4 % formic acid. Plasma protein precipitation was carried out using a mixture of acetonitrile and water (85/15, v/v). The precipitate was centrifuged at 4 °C and a fraction of the supernatant was transferred to a new 96-well plate, evaporated to dryness under a stream of heated nitrogen and reconstituted in water containing 0.2 % formic acid.
Chromatography was performed on a Waters Acquity UPLC Peptide BEH C18 analytical column (1.7 pm particle size; pore size 300 A; column dimensions 50 x 2.1 mm). Water (UPLC grade) containing 0.1 % formic acid (v/v) was used as mobile phase A and acetonitrile (UPLC grade) with 0.1 % formic acid as mobile phase B. Multiple reaction monitoring (MRM) was performed for semaglutide and the internal standard and quantification was based on peak area and linear regression with 1/x 2 weighting.
A summary of the individual and mean PK parameters for semaglutide released from 5 in monkey plasma are shown below in Table 7. 294 WO 2024/184351 PCT/EP2024/055724 No sex-specific differences between the male and female animal within each group could be observed. Cmax and area under the curve (AUC) were slighter lower for the SC group than for the IV group, but the half-life was comparable in both groups.
Table 7: Summary of the individual and mean PK parameters of semaglutide released from 5 in monkey Plasma in study described in example 19.
Dose groupTest ItemROADose level (fg/kg)AnimalCmax(ng/mL)tmax(h)tlast (h)AUClast (h*ng/mL)tl/2(h)IV150 m 84 72 336 19,000 123f 92 72 336 20,000 123mean 88 20,000 123median 72 336SC150 m 68 120 336 16,000 144f 71 72 336 16,000 130mean 69 16,000 137median 96 336 Example 21 295 WO 2024/184351 PCT/EP2024/055724 / Conjugated via His1 Na To a solution of 4-arm 5kDa-PEG tetramaleimide (5.0 mg, 1.0 eq., 0.98 umol) in acetonitrile (150 pL) was added conjugate 4(4.8 mg, 1.0 eq, 0.98 umol) in 1:1 acetonitrile/water (200 p.L) followed by 250 mM pH 7.4 phosphate buffer (200 uL). After shaking at it for 20 min,conjugate 4(9.6 mg, 2.0 eq, 1.96 mmol) in 1:1 acetonitrile/water (400 pL) was added. After a further 15 min shaking at rt, conjugate 4(7.2 mg, 1.5 eq, 1.47 mmol) in 1:1 acetonitrile/water (300 pL) was added followed by additional 1:1 acetonitrile/water (3 mL). After a further min, the reaction was quenched by addition of 10 % TFA in water (50 pL) and the mixturewas purified by preparative RP-HPLC to give 22as a TFA salt Yield: 10.2 mg (42 %) Example 22 < R x °؟ר . Cy° hn/^~n ן n-A N° V /-- /-׳ ° * ° AANH J HNAhn O؟ ° f °/ SA!R ^-4 23 -n 24: R = Compound 23: s־Ri/ 0HN. A / RN-A/—x 0^NH J HNAHNaor^0/ 0 Vo Xx/ '^N'' ^^^semaglutide Conjugated via His1 Na 296 WO 2024/184351 PCT/EP2024/055724 2,2-bis(aminomethyl)propane-l,3-diamine tetrahydrochloride (10.0 mg, 1.0 eq, 36.0 umol) was dissolved in acetonitrile (2.0 mL), DIPEA (23.2 mg, 31.3 pL, 5.0 eq, 180 umol) and water (0.4 mL). 3-(Maleimido)propionic acid N-hydroxysuccinimide ester (47.9 mg, 5.0 eq, 180 umol) was added, followed by DIPEA (23.2 mg, 31.3 pL, 5.0 eq, 180 pmol). After stirring at rt for 25 min, the reaction was quenched by addition of TFA (20 pL), and the mixture was purified by preparative RP-HPLC to give 23. Yield: 23.8 mg (90 %)MS: m/z, 737.48 = [M+H]+, (calculated [M+H]+ = 737.25).
Compound 24: To a solution of conjugate 4(30.0 mg, 4.5 eq, 6.11 pmol) in 1:1 acetonitrile/water (2.0 mL) was added a solution of compound 23(1.00 mg, 1 eq, 1.36 pmol) in acetonitrile (0.1 mL), followed by 250 mM pH 7.4 phosphate buffer (0.5 mL). After stirring at rt for 45 min, the reaction was quenched by addition of TFA (5 pL). The mixture was diluted with 1:acetonitrile/water (1 mL) and 250 mM pH 7.4 phosphate buffer (0.5 mL) and purified by preparative RP-HPLC to give 24as a TFA salt.Yield: 16.6 mg (60 %)MS: m/z, 1857.80 = [M+10H]ll)+ , (calculated [M+10H]ll)+ = 1857.52).
Example 23 Boc .NH/NBoc 25HN.Tmob 26HN.TmobA solution of the respective amine (1.5 eq, see below) in acetic acid was added to a solution of 2,4,6-trimethoxybenzaldehyde (1.0 eq) in acetic acid. The reaction solution was stirred at rt and monitored by LCMS. After complete imine formation an excess of sodium borohydride was added portion wise. The reaction solution was stirred at rt and monitored by LCMS. After the reaction was complete it was quenched by addition of 1 N HC1. The mixture was stirred for min and then added into water. The aqueous phase was washed with dichloromethane. The pH of the aqueous phase was adjusted to 14 using 12.5 N NaOH and extracted with dichloromethane. The organic phase was dried over sodium sulfate, evaporated and dried under high vacuum. 297 WO 2024/184351 PCT/EP2024/055724 Synthesis of 25:1.0 eq tert-butyl N-(3-ammopropyl)-N-methylcarbamate (1.41 g), 1.2 eq sodium borohydride (229 mg), yield: 2.14 g (100 %, 86 % purity), m/z 369.42 = [M+H]+, (calculated [M+H]+ = 369.47).
Synthesis of 261.0 eq N-Boc-l,3-diaminopropane (1.31 g), 15. eq sodium borohydride (286 mg), yield: 2.16 g (100 %, 82 % purity), m/z 355.40 = [M+H]+, (calculated [M+H]+ = 355.45).
Example 24 Compound 27was prepared according to example 2using compound 25instead of 1 MS: m/z, = 967.95 [M+H]+, (calculated [M+H]+ = 968.19).Compound 28was prepared according to example 2using 26instead of 1 MS: m/z, = 953.90 [M+H]+, (calculated [M+H]+ = 954.16).
Example 25 ^NH semaglutide semaglutide 0 0O^N O 29 Conjugated via His1 Na 30 Conjugated via His1 Na Compound 29was prepared as TFA salt according to examples 3and 4starting from compound 27instead of 2. MS:m/z, = 1481.92 [M+3H]3+, (calculated [M+3H]3+ = 1482.03).
WO 2024/184351 PCT/EP2024/055724 Compound 30was prepared as TFA salt according to examples 3and 4starting from compound 28instead of 3. MS: m/z, = 1477.97 [M+3H]3+, (calculated [M+3H]3+ = 1477.36). 31: R = Conjugated via His1 Na 32: R = Conjugated via His1 Na 299 WO 2024/184351 PCT/EP2024/055724 A solution of 4-arm 10 kDa-PEGtetramal eimide (1.0 eq) in acetonitrile was added to a solution of the respective conjugate (4.5 eq, 29or 30)in 1:1 acetonitrile/water. 250 mM pH 7.phosphate buffer was added and the reaction solution was stirred at it and monitored by LCMS. Upon completion the reaction was acidified by addition of TFA and purified by preparative RP-HPLC.Synthesis of 31:4.5 eq 29(2.0 mg), yield: 1.0 mg (35 %, TFA salt)Synthesis of 32:4.5 eq 30(2.6 mg), yield: 3.9 mg (57 %, TFA salt) Example 27: Alternative synthesis of compound 7 tirzepatide 7 Conjugated via Tyr1 Na [Lys(B0c)16]tirzepatide 6(1.2 mg, 1.0 eq, 0.24 umol) was dissolved in a mixture of 120 pL acetonitrile and 120 pL 60 mM pH 8 phosphate buffer. To this was added a solution of 2 (1.43 mg, 6.0 eq, 1.43 pmol) in acetonitrile (14.3 pL). After stirring at rt for 2 d the solution was diluted with 1:1 acetonitrile/water + 0.1 % TFA (250 pL) and quenched with TFA (1 pL). The crude mixture was purified by preparative RP-HPLC to give of the protected conjugate as TFA salt.Yield: 0.5 mg (36 %),MS: m/z 1421.07 = [M+4H]4+, (calculated [M+4H]4+ = 1420.91).The protected conjugate (0.5 mg, 1.0 eq, 0.086 pmol) was dissolved in HFIP/TES/water/DTT (39/1/5/2.5) (80 pL) and TFA (20 pL) was added. After stirring for 65 min the product was precipitated by addition of 1 mL ice-cold diethyl ether. The precipitate was washed with ice- cold diethyl ether and purified by preparative RP-HPLC to give 7 as the TFA salt.Yield: 0.2 mg (43 %),MS: m/z 1720.15 = [M+3H]3+, (calculated [M+3H]4+ = 1720.00).
Example 28: Alternative synthesis of compound 8 300 WO 2024/184351 PCT/EP2024/055724 Conjugated via Tyr1 NaA solution of 7 (0.2 mg, 4.5 eq, 0.037 umol) in 1:1 acetonitrile/water (225 uL) was prepared.100 pL of the solution of 7 (2.0 eq) were added to a solution of 4-arm 10 kDa-PEGtetramaleimide (91 pg, 1.0 eq, 8.3 nmol) in 1:1 acetonitrile/water (9.1 pL), followed by 250 mM pH 7.4 phosphate buffer (10 pL). After shaking at rt for 15 min, 100 pL of the solution of 7 (2.0 eq) were added. After a further 15 min shaking at rt, 25 pL of the solution of 7 (0.eq) were added. After a further 50 min, the reaction was quenched by addition of TFA (1 pL), and the mixture was purified by preparative RP-HPLC to give 8as a TFA salt. Example 29: PK study in Sprague Dawley rats 301 WO 2024/184351 PCT/EP2024/055724 The objective of the study was to determine the PK characteristics of 22and 24when administered once by the IV route to the adult male Sprague Dawley rat.The Study design is shown in Table 8. Blood samples were processed to plasma and provided for PK analysis of released semaglutide.
Table 8: Design of Study(Dose is in mg semaglutide equivalents/kg)Group Test item n Dose (mg/kg)Blood sampling timepoints (hours post dose)0.45 0.25, 3, 8, 24, 36, 48, 60, 72,120 and 1680.45 0.25, 3, 8, 24, 36, 48, 60, 72,120 and 168 Abbreviations: aq.AUCAqueousarea under the curveBoc tert-butyloxycarbonylDIPEA diisopropylethylamineDMF dimethylformamidedPEG discrete PEGDTT dithiothreitoleqequivalentHATU O-(7-Azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium- hexafluorphosphatHFIP 1,1,1,3,3,3 -hexafluor oi sopropanolHPLC high performance liquid chromatographyIV intravenousLCMS liquid chromatography mass spectrometrymal maleimideMS mass spectrometryPEG polyethylene glycolPK phaemacokineticsROA Route of administration 302 WO 2024/184351 PCT/EP2024/055724 RP reversed phaseit room temperaturesat. saturatedSC subcutaneousSD standard deviationTBS ZerLbutyl(dimethyl)silylTES triethylsilaneTFA trifluoroacetic acidTFP tetrafluorophenylTmob 2,4,6-TrimethoxybenzylTit tritylUPLC ultra performance liquid chromatographyUPLC-MS ultra performance liquid chromatography coupled to mass spectrometry 303

Claims (35)

Ascendis Pharma A/S CPX74790PCIL 3 Claims
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises at least one polymeric moiety, to which at least two moieties of formula (I) are conjugated and/or to which at least one moiety of formula (I’) is conjugated, wherein formula (I) and (I’) are (I) (I‘), wherein each -L- is independently a spacer moiety or is absent; each -L- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -L1’- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -D- is independently a drug moiety; each -AB is independently an albumin-binding moiety; and each a is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
2. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the at least one polymeric moiety of the compounds of the present invention is a linear polymeric moiety -P-. 3. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 2, wherein the compound is of formula (I-a) or (I-a’) (I-a) (I-a’), wherein each -L- is independently a spacer moiety or is absent; each -L- is independently a linker moiety that is covalently and reversibly conjugated to -D-; Ascendis Pharma A/S CPX74790PCIL
3 each -L1’- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -D- is independently a drug moiety; each -AB is independently an albumin-binding moiety; -P- is a polymeric moiety; and each a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
4. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the at least one polymeric moiety of the compound of the present invention is a multi-arm polymeric moiety.
5. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 4, wherein the compound comprises at least one branching point B, to which at least two moieties of formula (Ib) and/or at least one moiety of formula (Ib’) are conjugated, wherein formula (Ib) and (Ib’) are (Ib) (Ib’), wherein the dashed line indicates attachment to a branching point B; -A- is a polymeric moiety each -L- is independently a spacer moiety or is absent; each -L- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -L1’- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -D- is independently a drug moiety; each -AB is independently an albumin-binding moiety; and each a is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16.
6. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1, or 5, wherein the compound is of formula (I-b4) Ascendis Pharma A/S CPX74790PCIL 3 (I-b4), wherein -X-, -X-, -X- are independently of each other selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry1)-, -S(O)2N(Ry1)-, -S(O)N(Ry1)-, -S(O)2-, -S(O)-, -N(Ry1)S(O) 2N(Ry1a)-, -S-, -N(Ry1)-, -OC(ORy1)(Ry1a)-, -N(Ry1)C(O)N(Ry1a)-, -OC(O)N(Ry1)-, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C 1-50 alkyl, C 2-alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-, -S(O) 2N(Ry3)-, -S(O)N(Ry3)-, -S(O) 2-, -S(O)-, -N(Ry3)S(O) 2N(Ry3a)-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a)-, -N(Ry3)C(O)N(Ry3a)-, and -OC(O)N(Ry3)-; -Ry1 and -Ry1a are independently of each other selected from the group consisting of -H, -T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T, C 1-50 alkyl, C 2-alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O)2N(Ry4)-, -S(O)N(Ry4)-, -S(O)2-, -S(O)-, -N(Ry4)S(O)2N(Ry4a)-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a)-, -N(Ry4)C(O)N(Ry4a)-, and -OC(O)N(Ry4)-; each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different; each -Ry2 is independently selected from the group consisting of halogen, -CN, oxo (=O), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a), -S(O)2N(Ry5Ry5a), -S(O)N(Ry5Ry5a), -S(O) 2Ry5, -S(O)Ry5, -N(Ry5)S(O) 2N(Ry5aRy5b), -SRy5, -N(Ry5Ry5a), -NO 2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a, -N(Ry5)S(O) 2Ry5a, -N(Ry5)S(O)Ry5a, -N(Ry5)C(O)ORy5a, -N(Ry5)C(O)N(Ry5aRy5b), -OC(O)N(Ry5Ry5a), and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and Ascendis Pharma A/S CPX74790PCIL 3 each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5a and -Ry5b is independently selected from the group consisting of -H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; each -A- is a polymeric moiety; each -L- is independently a spacer moiety or is absent; each -L- is independently a linker moiety that is covalently and reversibly conjugated to -D-; each -D- is independently a drug moiety; and each -AB is independently an albumin-binding moiety.
7. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 6, wherein -L- is of formula (II): (II) , wherein the dashed line indicates attachment to a nitrogen, hydroxyl or thiol of -D-; -X- is selected from the group consisting of -C(RR4a)-; -N(R)-; -O-; -C(RR4a)-C(RR5a)-; -C(RR5a)-C(RR4a)-; -C(RR4a)-N(R)-; -N(R)-C(RR4a)-; C(RR4a)-O-; -O-C(RR4a)-; and -C(RR7a)-; X is selected from the group consisting of C; and S(O); -X- is selected from the group consisting of -C(RR8a)-; and -C(RR8a)-C(RR9a)-; =X is selected from the group consisting of =O; =S; and =N-CN; -R, -R1a, -R, -R2a, -R, -R4a, -R, -R5a, -R, -R, -R8a, -R, and -R9a are independently selected from the group consisting of -H; and C 1-6 alkyl; -R, and -R3a are independently selected from the group consisting of -H; and C1-alkyl, provided that in case one of -R, -R3a or both are other than -H they are connected to N to which they are attached through an SP-hybridized carbon atom; -R is selected from the group consisting of -N(RR10a); and -NR-(C=O)-R; -R7a, -R, -R10a, and -R are independently of each other selected from the group consisting of -H; and C1-6 alkyl; optionally, one or more of the pairs -R1a/-R4a, -R1a/-R5a, -R1a/-R7a, -R4a/-R5a, and -R8a/-R9a form a chemical bond; Ascendis Pharma A/S CPX74790PCIL 3 optionally, one or more of the pairs -R/-R1a, -R/-R2a, -R/-R4a, -R/-R5a, -R/-R8a, and -R/-R9a are joined together with the atom to which they are attached to form a C3-10 cycloalkyl; or 3- to 10-membered heterocyclyl; optionally, one or more of the pairs -R/-R, -R/-R, -R/-R, -R/-R7a, -R/-R, -R/-R, -R/-R, and -R/-R are joined together with the atoms to which they are attached to form a ring A; optionally, R/R3a 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 wherein -L- is substituted with at least one -L- and wherein -L- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L- or a substituent.
8. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein -L- is of formula (IIa) (IIa), wherein the dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L-.
9. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein -L- is of formula (IIab) (IIab), wherein Ascendis Pharma A/S CPX74790PCIL 3 the dashed line marked with the asterisk indicates attachment to a nitrogen of -D-; and the unmarked dashed line indicates attachment to -L-.
10. The compound of any one of claims 1 to 9, wherein -L- is a spacer moiety selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry1)-, -S(O) 2N(Ry1)-, -S(O)N(Ry1)-, -S(O) 2-, -S(O)-, -N(Ry1)S(O) 2N(Ry1a)-, -S-, -N(Ry1)-, -OC(ORy1)(Ry1a)-, -N(Ry1)C(O)N(Ry1a)-, -OC(O)N(Ry1)-, C 1-50 alkyl, C 2-alkenyl, and C2-50 alkynyl; wherein -T-, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry3)-, -S(O) 2N(Ry3)-, -S(O)N(Ry3)-, -S(O) 2-, -S(O)-, -N(Ry3)S(O)2N(Ry3a)-, -S-, -N(Ry3)-, -OC(ORy3)(Ry3a)-, -N(Ry3)C(O)N(Ry3a)-, and -OC(O)N(Ry3)-; -Ry1 and -Ry1a are independently of each other selected from the group consisting of -H, -T, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1-50 alkyl, C2-alkenyl, and C2-50 alkynyl are optionally substituted with one or more -Ry2, which are the same or different, and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(Ry4)-, -S(O) 2N(Ry4)-, -S(O)N(Ry4)-, -S(O) 2-, -S(O)-, -N(Ry4)S(O) 2N(Ry4a)-, -S-, -N(Ry4)-, -OC(ORy4)(Ry4a)-, -N(Ry4)C(O)N(Ry4a)-, and -OC(O)N(Ry4)-; each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8-to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each T is independently optionally substituted with one or more -Ry2, which are the same or different; each -Ry2 is independently selected from the group consisting of halogen, -CN, oxo (=O), -COORy5, -ORy5, -C(O)Ry5, -C(O)N(Ry5Ry5a), -S(O) 2N(Ry5Ry5a), -S(O)N(Ry5Ry5a), -S(O)2Ry5, -S(O)Ry5, -N(Ry5)S(O)2N(Ry5aRy5b), -SRy5, -N(Ry5Ry5a), -NO2, -OC(O)Ry5, -N(Ry5)C(O)Ry5a, -N(Ry5)S(O)2Ry5a, -N(Ry5)S(O)Ry5a, -N(Ry5)C(O)ORy5a,-N(Ry5)C(O)N(Ry5aRy5b), -OC(O)N(Ry5Ry5a), Ascendis Pharma A/S CPX74790PCIL 3 and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and each -Ry3, -Ry3a, -Ry4, -Ry4a, -Ry5, -Ry5a and -Ry5b is independently selected from the group consisting of -H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
11. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 10, wherein L- is of formula (XI) (XI), wherein the unmarked dashed line indicates attachment to -L-; the dashed line marked with the asterisk indicates attachment to the at least one polymeric moiety; h is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, 15 and 16.
12. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 11, wherein -D-AB is a GLP-1 receptor agonist moiety.
13. The compound or a pharmaceutically acceptable salt thereof of claim 12, wherein the GLP-1 receptor agonist moiety is selected from the group consisting of semaglutide, liraglutide, ecnoglutide, GZR18, GL0034, tirzepatide, cotadutide, BI-456906, pemvidutide, mazdutide, dapiglutide and retatrutide.
14. The compound or a pharmaceutically acceptable salt thereof of claim 12 or 13, wherein -D-AB is semaglutide.
15. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 or to 14, wherein the compound is of formula (2c’’) Ascendis Pharma A/S CPX74790PCIL 3 (2c’’), wherein the dashed line indicates attachment to the N-terminal amine functional group of semaglutide; and n1, n2, n3 and n4 are independently an integer ranging from about 11 to about 115.
16. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 or to 15, wherein the compound is of formula (2c’) Ascendis Pharma A/S CPX74790PCIL 3 (2c‘), wherein the dashed line indicates attachment to the N-terminal amine functional group of semaglutide; and n1, n2, n3 and n4 are independently an integer ranging from about 11 to about 115.
17. The compound or a pharmaceutically acceptable salt thereof of claim 15 or 16, wherein n1, n2, n3 and n4 are independently an integer of about 28.
18. The compound or a pharmaceutically acceptable salt thereof of claim 15 or 16, wherein n1, n2, n3 and n4 are independently an integer of about 56.
19. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1, or 7 to 14, wherein the compound is of formula (2g’) Ascendis Pharma A/S CPX74790PCIL 3 (2g’), wherein n is independently an integer ranging from about 22 to about 230; dashed lines indicate attachment to a moiety wherein the unmarked dashed line indicates attachment to an unmarked dashed line of formula (2g’); and the dashed line marked with the asterisk indicates attachment to the N-terminal amine functional group of semaglutide.
20. A pharmaceutical composition comprising one or more of the compounds or a pharmaceutically acceptable salt thereof of any one of claims 1 to 19 and one or more excipients.
21. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to or the pharmaceutical composition of claim 20 for the manufacture of a medicament. Ascendis Pharma A/S CPX74790PCIL 3
22. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to or the pharmaceutical composition of claim 20 for use in a treatment of a disease that can be treated with -D-AB.
23. The compound or a pharmaceutically acceptable salt thereof of any one of claims 12 to or a pharmaceutical composition comprising one or more compounds of any one of claims 12 to 19 for use in the treatment of a disease selected from the group consisting of (i) all forms of diabetes, (ii) obesity, (iii) non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), (iv) cardiovascular disease, (v) neurodegenerative disorders, (vi) chronic kidney disease (CKD), (vii) diabetic kidney disease (DKD), (viii) peripheral arterial disease (PAD), and/or (ix) heart failure (HF).
24. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of claim 23, wherein the disease is diabetes.
25. The compound or a pharmaceutically acceptable salt thereof of any one of claims 12 to or a pharmaceutical composition comprising one or more compounds of any one of claims 12 to 19 for use in the treatment or prevention of dyslipidemia and/or diseases where one or more of the following clinical outcomes are the treatment goal: lowering total serum lipids; increasing HDL; lowering small, dense LDL; lowering VLDL; lowering triglycerides; lowering cholesterol; lowering plasma levels of lipoprotein a (Lp(a)) in a human; inhibiting generation of apolipoprotein A (apo(A)).
26. The compound or a pharmaceutically acceptable salt thereof of any one of claims 12 to or a pharmaceutical composition comprising one or more compounds of any one of claims 12 to 19 for use in the treatment of obesity and/or eating disorders, where one or more of the following clinical outcomes are the treatment goal: decreasing food intake, increasing energy expenditure, reducing body weight, suppressing appetite, inducing satiety.
27. The compound or a pharmaceutically acceptable salt thereof of any one of claims 12 to or a pharmaceutical composition comprising one or more compounds of any one of claims 12 to 19 for use in the treatment of a disease selected from the group consisting of syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, Ascendis Pharma A/S CPX74790PCIL 3 reperfusion injury, stroke, cerebral ischemia, an early cardiac or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertensive emergency, cardiomyopathy, heart insufficiency, exercise intolerance, acute and/or chronic heart failure, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass and/or stent reocclusion, intermittent claudication (atheroschlerosis oblitterens), diastolic dysfunction, and/or systolic dysfunction; and reduction of blood pressure, such as reduction of systolic blood pressure.
28. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of any one of claims 23 to 27, wherein the treatment is in combination with one or more additional therapeutically active compounds.
29. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 28, wherein the one or more additional therapeutically active compounds are selected from the group consisting of cardiovascular agents, antidiabetic agents, and anti-obesity agents.
30. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 28 or 29, wherein the one or more therapeutically active compounds are selected from the group consisting of inotropes, beta adrenergic receptor blockers, HMG-CoA reductase inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, calcium channel blockers, endothelin antagonists, renin inhibitors, diuretics, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors, CETP inhibitor, relaxin, PCSKinhibitors, BNP and NEP inhibitors, GLP-1 analogues, insulin, sulphonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, DPP-IV inhibitors and SGLT2 inhibitors.
31. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of any one of claims 28 to 30, wherein the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition are administered in combination with a growth hormone. Ascendis Pharma A/S CPX74790PCIL 3
32. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of claim 31, wherein the growth hormone is lonapegsomatropin.
33. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of any one of claims 22 to 32, wherein administration is via external application, injection or infusion, including intraarticular, periarticular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcuticular, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion; direct delivery to the brain via implanted device allowing delivery of the invention or the like to brain tissue or brain fluids (e.g., Ommaya Reservoir), direct intracerebroventricular injection or infusion, injection or infusion into brain or brain associated regions, injection into the subchoroidal space, retro-orbital injection and ocular instillation.
34. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of any one of claims 22 to 33, wherein administration is via subcutaneous injection.
35. The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for use of any one of claims 22 to 34, wherein administration is once per month.
IL323019A 2023-03-06 2024-03-05 Compounds of drugs with an albumin binding moiety IL323019A (en)

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